Classification of Gallbladder Polyps [10,11]

http://www.e-yujm.org eISSN 2384-0293 Vol. 38, No. 1 January 2021 Yeungnam University Journal of Medicine Vol. 38, No. 1 January 2021 pages 1-82

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Vol. 38 · No. 1 · January 2021

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Published on January 31, 2021

Editor-in-chief Joon Hyuk Choi Yeungnam University College of Medicine, Korea

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Editorial board Kiwon Ban City University of Hong Kong, Hong Kong Min Cheol Chang Yeungnam University College of Medicine, Korea Du-Hyong Cho Yeungnam University College of Medicine, Korea Kyu Hyang Cho Yeungnam University College of Medicine, Korea Kwang Hae Choi Yeungnam University College of Medicine, Korea Jinmyoung Dan CHA University College of Medicine, Korea Kyung-Oh Doh Yeungnam University College of Medicine, Korea Jong Ryul Eun Hanyang University College of Medicine, Korea Mi Jin Gu Yeungnam University College of Medicine, Korea Geu-Ru Hong Yonsei University College of Medicine, Korea Ming-Yen Hsiao National Taiwan University College of Medicine, Taiwan Insoo Kang Yale University School of Medicine, USA Noriyuki Kanzaki Kobe University Graduate School of Medicine, Japan Jae Woon Kim Yeungnam University College of Medicine, Korea Ung Kim Yeungnam University College of Medicine, Korea Shaw Hua Anthony Kueh Auckland City Hospital, New Zealand Dong Shik Lee Yeungnam University College of Medicine, Korea Jae-Lyun Lee Ulsan University College of Medicine, Korea Keun Mi Lee Yeungnam University College of Medicine, Korea Yong Su Lim Gachon University College of Medicine, Korea Chul Hyun Park Yeungnam University College of Medicine, Korea Hosun Park Yeungnam University College of Medicine, Korea Jeong Hyun Park Kangwon National University College of Medicine, Korea So-Young Park Yeungnam University College of Medicine, Korea Joon Sakong Yeungnam University College of Medicine, Korea In Hwan Song Yeungnam University College of Medicine, Korea Hoon-Ki Sung University of Toronto, Canada Kyu Chang Won Yeungnam University College of Medicine, Korea Wan-Hee Yoo Chonbuk National University College of Medicine, Korea

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Vol. 38 · No. 1 · January 2021

Review articles

1 Gallbladder polyps: evolving approach to the diagnosis and management Kook Hyun Kim

10 Classification of endometriosis Soo-Young Lee, Yu-Jin Koo, Dae-Hyung Lee

19 Updates on the treatment of adhesive capsulitis with hydraulic distension Jang Hyuk Cho

27 Pathophysiology and protective approaches of gut injury in critical illness Chang Yeon Jung, Jung Min Bae

Original articles

34 Association between gestational age at delivery and lymphocyte-monocyte ratio in the routine second trimester complete blood cell count Hyun-Hwa Cha, Jong Mi Kim, Hyun Mi Kim, Mi Ju Kim, Gun Oh Chong, Won Joon Seong

39 Pelvic floor muscle exercise with biofeedback helps regain urinary continence after robot-assisted radical prostatectomy Yeong Uk Kim, Dong Gyu Lee, Young Hwii Ko

47 Evaluation of craniofacial morphology in short-statured children: growth hormone deficiency versus idiopathic short stature Ki Bong Kim, Eun-Kyong Kim, Kyung Mi Jang, Min Seon Kim, Eun Young Park

53 Effect of in vitro testicular spermatozoa culture on pregnancy outcomes: an experience at a single university hospital Jisun Lee, Jung Hyeon Yoo, Jae Hun Lee, Hyun Soo Ahn, Kyung Joo Hwang, Miran Kim

Case reports

60 Cushing syndrome in pregnancy, diagnosed after delivery Han Byul Kim, Mi Kyung Kim, El Kim, Keun Soo Ahn, Hye Soon Kim, Nam Kyung Kim

65 Development of donepezil-induced hypokalemia following treatment of cognitive impairment Dongryul Kim, Hye Eun Yoon, Hoon Suk Park, Seok Joon Shin, Bum Soon Choi, Byung Soo Kim, Tae Hyun Ban

Vol. 38 · No. 1 · January 2021

70 Co-existence of relapsing polychondritis and Crohn disease treated successfully with infliximab Hye-In Jung, Hyun Jung Kim, Ji-Min Kim, Ju Yup Lee, Kyung Sik Park, Kwang Bum Cho, Yoo Jin Lee

74 Transpedal lymphatic embolization for lymphorrhea at the graft harvest site after coronary artery bypass grafting Jung Guen Cha, Sang Yub Lee, Jihoon Hong, Hun Kyu Ryeom, Gab Chul Kim, Young Woo Do

78 Pancreatic metastasis from malignant phyllodes tumor of the breast Seung Eun Lee, Young Kyung Bae, Joon Hyuk Choi

Gallbladder polyps: evolving approach to the diagnosis and management Kook Hyun Kim Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea

Received: March 28, 2020 Revised: April 26, 2020 Gallbladder (GB) polyp is a mucosal projection into the GB lumen. With increasing health aware- Accepted: April 29, 2020 ness, GB polyps are frequently found using ultrasonography during health screening. The prevalence of GB polyps ranges between 1.3% and 9.5%. Most patients are asymptomatic and have Corresponding author: benign characteristics. Of the nonneoplastic polyps, cholesterol polyps are most common, ac- Kook Hyun Kim counting for 60%–70% of lesions. However, a few polyps have malignant potential. Currently, Division of Gastroenterology and the guidelines recommend laparoscopic cholecystectomy for polyps larger than 1 cm in diameter Hepatology, Department of Internal due to their malignant potential. The treatment algorithm can be influenced by the size, shape, Medicine, Yeungnam University College of Medicine, 170 and numbers of polyps, old age (>50 years), the presence of primary sclerosing cholangitis, and Hyeonchung-ro, Nam-gu, Daegu gallstones. This review summarizes the commonly recognized concepts on GB polyps from diag- 42415, Korea nosis to an algorithm of treatment. Tel: +82-53-620-3576 Fax: +82-53-654-8386 Keywords: Cholecystectomy; Diagnostic imaging; Gallbladder diseases; Gallbladder neoplasms; E-mail: [email protected] Polyps

Introduction Imaging modalities for the diagnosis of gallbladder polyps Gallbladder (GB) polyps are defined as mucosal projection of the GB wall into the lumen [1]. Recently, with the easy availability of ul- GB polyps are generally detected using US, followed infrequently trasonography (US) and the increasing awareness of physical check- by abdominal computed tomography (CT), magnetic resonance up, the detection of GB polypoid lesion is steadily on the rise [2]. imaging (MRI), and positron emission tomography (PET) [9]. Most GB polyps are incidentally found and asymptomatic. Although US is noninvasive, safe, easily accessible, and less costly; therefore, benign lesions are overwhelming, some can be transformed into ma- it is the primary choice in the diagnosis of GB polyps. The sono- lignant. Polyps more than 1 cm in size and adenomatous polyps are graphic features of GB polyps are hyperechoic lesions protruding of clinical importance due to the risk of cancerous change. The prev- into the GB lumen, absence of post-acoustic shadow, and lack of alence of GB polyps ranges from 1.3% to 9.5%, with geographical positional change of lesions (Fig. 1). Under the supine with/or differences [3-6]. A Korean data demonstrated that the prevalence of decubitus position, the lesion should be scanned for better visual- GB polyps in Korea ranges from 2.2% to 9.9%, which is similar to ization of polyps. Sometimes, the body habitus can affect the im- other studies [7,8]. The guidelines for the diagnosis and treatment of age quality. It is crucial to identify the size, number, and shape of GB polyps have remained unchanged for a while. In this review, the polyps, GB wall thickening, and presence of gallstones. During diagnosis, classification, natural history, and algorithm for the man- US examination, however, gallstones smaller than 5 mm cannot agement of GB polyps will be described. be distinguished between polyps and stones in real practice

EUS can enhance the diagnostic power with sensitivity and specificity of 90.3% and 96.6%, respectively [19]. Other imaging modalities including CT, fluorine-18-labeled fluorodeoxyglucose (18F-FDG) PET-CT, and MRI are occasion- ally collaborative to enhance the diagnostic power in cases of suspicious GB malignancy or cancer staging [20,21]. CT scans are considered as first-line modality for symptomatic patients. Al- though CT has lower sensitivity for the detection of small polyps, it is valuable for the preoperative evaluation of GB malignancy [22,23]. The role of PET scan is not fully defined yet. 18F-FDG PET-CT is usually used for staging of known or suspected GB cancer, but it is not tumor specific. Benign inflammatory GB lesions can also show false-positive on PET image [24]. The diagnostic power and limitations of MRI are similar to those of CT Fig. 1. Ultrasonography shows a polypod lesion (arrow) in the [25]. In particular, MRI is highly useful in the evaluation of tumor gallbladder. It measured 9.9 mm in maximal diameter and was not mobile regardless of the positional change. Pathologically, it infiltration because of its high sensitivity of detection and evalua- was confirmed as adenoma. tion of the primary lesion [26].

Classification of gallbladder polyps [10,11]. Sometimes, the presence of biliary sludge, or small stones (< 5 mm), can be mistaken as GB polyps [12,13]. Polypoid GB lesions are mainly categorized as benign and malig- With the increasing use of endoscopic ultrasonography (EUS) nant. Specifically, benign lesions are divided into neoplastic and in the gastrointestinal field, it is opted for detailed GB structures nonneoplastic (Tables 1, 2) [1,27-29]. Most benign lesions are re- and augmenting the diagnostic accuracy of GB polyps. EUS is garded as nonneoplastic. Cholesterol polyps, inflammatory pol- favorable, in particular, in patients who are obese or harbor bow- yps, and adenomyomas belong to nonneoplastic lesions; however, el gas, because the probe is proximally positioned and scanning adenoma is classified as a neoplastic lesion. Abdominal US alone is performed from the duodenum. The sensitivity and specifici- cannot determine whether it is a neoplastic or nonneoplastic pol- ty of EUS for carcinoma diagnosis were 91.7% and 87.7%, re- yp. Therefore, once GB polyps are incidentally identified using spectively [14]. A Japanese group has proposed that an EUS US, surgical treatment is frequently being considered if the size is scoring system based on polyp size, internal echo, and hypere- larger than 1 cm. choic spotting may be a useful parameter for differentiating between neoplastic and nonneoplastic polyps, with high sensitivity 1. Nonneoplastic polyps (77.8%) and specificity (82.7%) [15]. Additionally, EUS can be Nonneoplastic polyps have been identified based on the radiolog- an alternative in cases of diagnostic difficulty of GB polyps by ic image, surgery, and pathologic findings (Table 1). The most abdominal US. However, the differential diagnosis between ade- common histologic types of nonneoplastic polyps are cholesterol nomatous polyps and cholesterol polyps based on EUS or US is polyps (60%–90%), followed by adenomyomas (25%–40%), and still challenging because morphology and echo patterns are inflammatory polyps (10%) [9]. However, in the study of Taskin alike. Recently, contrast-enhanced harmonic EUS (CEH-EUS) et al. [29], fibromyoglandular polyps are the most common type was introduced to differentiate between GB adenomas and cho- (48%) of nonneoplastic GB polyps. lesterol polyps [16]. Following injection of contrast agents of microbubbles into the vessel, CEH-EUS can detect signals scat- 1) Cholesterol polyps tering from microbubbles because harmonic components de- Cholesterol polyps are most common nonneoplastic polyp, ac- rived from microbubbles are integer multiples of the fundamen- counting for 60%–90% of lesions [12,30]. They are formed as a tal frequency and higher than those from tissue [17]. Sensitivity sequence of phagocytosis of cholesterol ester, triglyceride, and es- and specificity of CEH-EUS for the differential diagnosis of GB terified sterols by macrophage located in the lamina propria, cov- adenomas from cholesterol polyps were 75.0% and 66.6%, re- ering the columnar epithelium with foamy histiocytes. It is under- spectively [18]. In addition, an irregular vessel pattern by CEH- stood that their gradual accumulation develops as a result of cho-

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Table 1. Nonneoplastic gallbladder polyps Number Nonneoplastic polyp Mean size (mm) Radiologic finding Pathologic finding (single/multiple, %) Frequency (%) Cholesterol polyp < 10 US: hyperechoic polyp, typically Grossly, yellow appearance, microscopi- Single (36.4) 60−90 round shape with “ball on the cally, distinctive cauliflower configu- Multiple (63.6) wall” sign ration and cholesterol-laden macrophages Inflammatory polyp < 10 US: variable echogenicity Pseudopapillary fronds with reactive mu- Usually multiple 10 (iso-, hypo-, or hyper-) cosal changes, inflammation, and increased vascularity Adenomyoma NA US: wall thickening with Trabeculated appearance cystic dilation Usually single 25−40 ‘‘comet tail’’ of glandular spaces (Rokitansky-Aschoff MRI: ‘‘pearl necklace” sign of sinuses) and smooth muscle hypertro- by fluid containing diverticula phy Fibromyoglandular polyp 4.3 (2−13) NA Broad-based polyps Single (56) 48 Lobular units of small glands Multiple (44) Fibroblastic and/or muscular stroma Hamartoma NA NA NA NA Very rare US, ultrasonography; MRI, magnetic resonance imaging; NA, not available.

Table 2. Neoplastic gallbladder polyps Number Neoplastic polyp Mean size (mm) Radiologic finding Pathologic finding (single/multiple, %) Frequency (%) Benign tumor Epithelial tumor Adenoma 7 (5−20) US: isoechoic sessile or Sessile or pedunculated benign Mainly single 4−8.9 pedunculated glandular structures ICPN with low- and high-grade > 20 NA A distinct polypoid mass, in- Single (82) 0.5−0.8 intraepithelial neoplasia traluminal papillary growth, Multiple (18) with low- and high-grade dysplasia Mesenchymal tumor Leiomyoma/lipoma NA NA NA NA NA Malignant tumor Epithelial tumor Adenocarcinoma > 10 US: a wide polyp base, Mainly papillary form; densely Mainly single 0.6−1.7 thickening of wall cellular papillary fronds pro- (80% of gallbladder (> 3 mm), a polypoid truding into the lumen, with malignancy) mass projecting intra- infiltrative growth luminally ICPN with associated invasive > 20 Intraluminal growth; mainly Single (78) 0.5−0.8 carcinoma papillary growth pattern and Multiple (22) stromal invasion Mesenchymal tumor Leiomyosarcoma NA NA NA NA < 0.1 (1%−2% of gallbladder malignancy) US, ultrasonography; ICPN, intracholecystic papillary neoplasm; NA, not available. lesterol metabolism disruption [11,31]. These polyps are more um with underlying thick, cholesterol-laden, or widened edema- prevalent in middle-aged women, with sizes less than 10 mm [31]. tous cores (Fig. 2) [29]. In cholesterolosis, the mucosa acquires a At US, cholesterol polyps appear as small and round lesions that velvety pattern with yellow-green-colored papillary structures are attached to the wall, characterized as “ball on the wall” sign with a diameter of less than 1 mm. [23]. Cholesterol polyps have a distinctive cauliflower configuration, which is commonly lined by single-layered normal epitheli- https://doi.org/10.12701/yujm.2020.00213 3 Kim KH. Gallbladder polyp

A B

Fig. 2. Cholesterol polyp in a 55-year-old woman. (A) Grossly, the gallbladder shows multiple yellowish polyps in the lumen. (B) Microscopically, cholesterol polyps are characterized by cauliflower architecture. Numerous cholesterol-laden macrophages are present (hematoxylin and eosin stain, x100).

A B

Fig. 3. Adenomatous gallbladder polyp in a 69-year-old man. (A) Ultrasonography shows a sessile polyp (arrow) with a wide base that was immobile and lacks an acoustic shadow. The polyp measured 16.8 mm in maximal diameter. (B) Microscopically, the adenoma is composed of closely packed, pyloric-type glands lined by mucin-containing cuboidal cells (hematoxylin and eosin stain, x100).

2) Adenomyomas 3) Inflammatory polyps It is known that these lesions are formed during cholecystitis Inflammatory polyps reportedly constitute 10% of benign polyps, events as a result of mucosal hyperplasia or thickening of the mus- measuring less than 10 mm in diameter [21]. They occur as a sec- cular tissue [11]. Mucosal hyperplasia can lead to adenomyoma ondary change following chronic inflammation and gallstone for- with the formation and branching of Rokitansky-Aschoff sinuses mation. Gradual and long-lasting precipitation of cholesterol results in the muscular layer of the GB. These are commonly classified in subsequent mucosal irritation of the GB. It is presumed that the into three types based on the morphology: fundal (localized), inflammatory process involving lymphocytes and plasma cells is at- segmental (annular), and diffuse (generalized) types. A typical tributed to chronic inflammation, finally ensuing granulation and fi- sonographic finding is the presence of reverberation or “comet brous tissue formation [20]. Consequently, pathology shows pseu- tail” artifact posterior to the lesion [22]. Particularly, the segmen- dopapillary fronds with reactive mucosal changes, inflammation, tal type mimics the hourglass configuration due to the concentric and increased vascularity [23]. Little is known about the imaging circumferential thickening of the GB wall [20]. At MRI, the Roki- features of these polyps. At US, it presents a variety of echoic pat- tansky-Aschoff sinuses create a “pearl necklace” sign of multiple terns, including iso-, hypo-, and hyper-echogenicity [33]. round spaces on T2-weighted images, which has 92% specificity for adenomyomatosis [25,32].

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2. Neoplastic polyps been a valuable modality for the differential diagnosis of GB ma- The most important neoplastic polyps are adenoma and adeno- lignancy [43,44]. Koh et al. [44] reported that the sensitivity of carcinoma. However, there have been case reports of mesenchy- 18F-FDG PET was 75% for the diagnosis of GB carcinoma. mal tumors, such as leiomyosarcoma, leiomyomas, and lipomas [9,21,34]. Natural course of gallbladder polyps

1) Adenoma To date, the natural history and pathogenesis of GB polypoid le- GB adenomas occur in 4%–8.9% of all GB polyps (Table 2) sions are still scarce. A meta-analysis about a 7-year follow-up of [21,30,34,35]. The adenoma can be sessile, pedunculated, or pol- GB polyps revealed a size progression in 7.6%, no interval changes ypoid and usually measures from 5 to 20 mm. At US, the adeno- in 45.1%, shrinkage in 7%, and complete disappearance of polyps matous polyp is characterized by an isoechoic appearance and in 7.6% [45]. An 11-year follow-up conducted by Heitz et al. [46] usually solitary (Fig. 3) [23,25]. Its malignant potential remains demonstrated an increase in 35.7%, no change of polyps in 14.3%, controversial. Unlike the colon, in which the adenoma-carcinoma and a decrease in size in 50%. Park et al. [42] reported that 75% of pathway is the well-established mechanism of carcinogenesis, the polyps were unchanged, 15% increased, and 10% decreased in dysplasia-carcinoma sequence is believed to play a major role in size during a median 60-month follow-up. Colecchia et al. [47] GB carcinogenesis [36-39]. Its plausible explanation is that chron- reported that polyps were 91% unchanged, 5.7% increased, and ic inflammation can lead to dysplasia, which ultimately develops 3.8% decreased in size during a 5-year follow-up. However, no into cancer. Most adenomas are incidentally found, similar to oth- clinical data are available on the duration of follow-up of small er polyps. Unfortunately, there is no reliable imaging modality to polyps (< 1 cm). Some studies have described that 94% of polyps differentiate GB adenoma from adenocarcinoma yet. with diameter less than 1 cm were benign [10,48]. Colecchia et al. [47] showed that there were no symptoms and/or morphological 2) Intracholecystic papillary neoplasms changes of small-sized polyps during the 5-year follow-up. Intracholecystic papillary neoplasms (ICPNs) are very rare, occurring in 0.5%–0.8% of all cholecystectomies [40,41]. Little is known Management of gallbladder polyps about their clinicopathological trait and natural history due to the lack of standardized terminology among pathologists or published As the presence of a polyp larger than 10 mm in diameter is ac- data. ICPNs are mass-forming neoplasms (≥1 cm), which are the cepted as having malignancy potential, cholecystectomy is cur- GB counterparts of the pancreatic intraductal papillary mucinous rently the treatment of choice [12,49-51]. However, there is still neoplasms and the biliary ductal intraductal papillary neoplasms no agreement on the management of GB polyps less than 10 mm [40]. Grossly, ICPNs are featured by single or multifocal large pe- in diameter. Recently, the European Society of Gastrointestinal dunculated or sessile exophytic cauliflower-like configuration or and Abdominal Radiology proposed a treatment algorithm for polypoid projections [40]. Microscopic image shows a variety of GB polyps [49]. A small polyp rarely causes any symptoms in the cytological atypia, architectural atypia with papillary and tubular clinical setting. Nevertheless, laparoscopic resection is recom- patterns [41]. The frequency of high-grade dysplasia and associated mended if there is no definite cause for upper abdominal pain and invasive carcinoma was significantly higher in those with papillary the patient is eligible for cholecystectomy (Fig. 4) [11,49]. There growth pattern than in tubular ones. are other predictive risk factors for the physician to consider for appropriate management. The risk factors of GB malignancy are 3) Adenocarcinoma old age (>50 years), history of primary sclerosing cholangitis It is the most common malignant GB polyp and is more frequent- (PSC), and the presence of gallstones and sessile polyp [49]. For ly found in women and elderly patients [23]. Histopathologically, those with nonneoplastic and polypoid lesions smaller than 10 the most common histologic types of GB cancers are adenocarci- mm, a “wait and see” policy and regular follow-up are warranted noma. Based on the architecture and cytological morphology, it [11]. Among patients with small polyps, cholecystectomy is rec- can be classified into three types: well, moderately, and poorly dif- ommended if they have the aforementioned risk factors [49]. ferentiated [11]. Of the several subtypes, the papillary form is the Likewise, cholecystectomy is advised in cases of rapid polyp most common and presents densely cellular papillary fronds, growth. which project into the GB lumen [9]. On US, it usually has a solitary polyp larger than 10 mm with a wide base [42]. PET-CT has https://doi.org/10.12701/yujm.2020.00213 5 Kim KH. Gallbladder polyp

Gallbladder polyps

Size

Size ≥10 mm Size <10 mm Yes Cholecystectomy Any symptom?

Size <6 mm: Any risk factors? follow upa) every year Yes - Age >50 years No - PSC Regular follow upa) - Sessile polyps - Size <6 mm: every year - Gallstone - Size 6-9 mm: every 0.5-1 year Size: 6-9 mm

No Yes Fit for and accept surgery?

Fig. 4. Algorithm for the management of gallbladder polyps. PSC, primary sclerosing cholangitis. a)During follow up, cholecystectomy is advised if the polyp size increases, however, follow up is unnecessary if the polyp disappears.

1. Age crease the risk of malignancy by a factor of 7.70 (95% confidence The risk of malignant change of a GB polyp increases with age. interval [CI], 2.48–23.95). Likewise, a systemic review by Bhatt et Several studies have different cutoff values for malignancy risk. al. [53] revealed that the sessile shape in a GB polyp was identi- Kwon et al. [52] reported that age over 60 years (p= 0.021; odds fied as an independent risk factor of malignancy by a factor of 7.32 ratio [OR], 8.16) is a risk factor for malignant polyps. However, (95% CI, 4.18–12.82). the age 50 is usually indicated as a risk factor threshold for cholecystectomy. A systemic review indicated that if the patient is older 4. Gallstones than 50 years of age, the odds of malignancy increase by 11.83 A few studies have proposed that gallstones may be a risk factor [12,53,54]. Bhatt et al. [53] suggested that when the polyp was for malignancy in GB polyps [56]. However, the risk of malignan- smaller than 10 mm and age was over 50, the probability of malig- cy of polyps when combined with gallstones is relatively low and nancy was 20.7%, in which resection has been recommended. evidence is weak. Although Aldouri et al. [56] suggested that the presence of gallstones was an independent risk factor, Park et al. 2. Numbers [42] did not reveal any connection between concurrent gallstones The relationship of malignant potential between single and multi- and malignancy. ple polyps has not been established yet. Several studies did not prove any association between a solitary polyp and high risk of 5. Primary sclerosing cholangitis malignancy. Meanwhile, in a systematic review by Bhatt et al. [53], PSC is a well-established risk factor for a GB polyp malignancy, re- a solitary polyp alone increased the odds of malignancy by a factor quiring cholecystectomy regardless of the polyp size [57]. Said et al. of 2.05. Furthermore, a solitary polyp in a patient over 50 years [58] revealed that GB polyps were found in 6% (18/286) of pa- old escalated the probability of malignancy by 24.25%. tients, GB malignancy in 56% (10/18), and dysplasia in 9% [58]. An inflammation-dysplasia-carcinoma sequence might be the plau- 3. Sessile polyps sible elucidation, which was similar to that of cholangiocarcinoma A sessile morphology is more predominant in malignant polyps. in PSC and colorectal cancer in ulcerative colitis [58-60]. GB cancer usually arises in situ from a flat, dysplastic epithelium, which explains the malignant potential of the sessile shape [52,55]. Kwon et al. [52] demonstrated that sessile polyps in-

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Conclusion population. Yonsei Med J 2016;57:1370–5. 9. Mellnick VM, Menias CO, Sandrasegaran K, Hara AK, Kielar Of the imaging modalities, US played a pivotal role in diagnosing AZ, Brunt EM, et al. Polypoid lesions of the gallbladder: disease GB polyps. A diameter greater than 10 mm is undoubtedly the spectrum with pathologic correlation. Radiographics 2015; most important risk factor of malignancy, requiring cholecystec- 35:387-99. tomy. It is currently warranted to take the “wait and see” policy at 10. Chattopadhyay D, Lochan R, Balupuri S, Gopinath BR, Wynne a regular interval, rather than resection, for incidental polyps of KS. Outcome of gall bladder polypoidal lesions detected by 6–9 mm in size. Other risk factors, including any symptoms, con- transabdominal ultrasound scanning: a nine year experience. current gallstones, age > 50 years, sessile polyps, and PSC, should World J Gastroenterol 2005;11:2171–3. be considered in determining the treatment plan. 11. Dilek ON, Karasu S, Dilek FH. Diagnosis and treatment of gallbladder polyps: current perspectives. Euroasian J Hepatogastro- Acknowledgments enterol 2019;9:40–8. 12. Lee KF, Wong J, Li JC, Lai PB. Polypoid lesions of the gallblad- Conflicts of interest der. Am J Surg 2004;188:186–90. No potential conflict of interest relevant to this article was report- 13. Zielinski MD, Atwell TD, Davis PW, Kendrick ML, Que FG. ed. Comparison of surgically resected polypoid lesions of the gallbladder to their pre-operative ultrasound characteristics. J Gas- ORCID trointest Surg 2009;13:19–25. Kook Hyun Kim, https://orcid.org/0000-0001-7786-7882 14. Azuma T, Yoshikawa T, Araida T, Takasaki K. Differential diagnosis of polypoid lesions of the gallbladder by endoscopic ultra- References sonography. Am J Surg 2001;181:65–70. 15. Sadamoto Y, Oda S, Tanaka M, Harada N, Kubo H, Eguchi T, et 1. Christensen AH, Ishak KG. Benign tumors and pseudotumors al. A useful approach to the differential diagnosis of small polyp- of the gallbladder: report of 180 cases. Arch Pathol 1970; oid lesions of the gallbladder, utilizing an endoscopic ultrasound 90:423–32. scoring system. Endoscopy 2002;34:959–65. 2. Moriguchi H, Tazawa J, Hayashi Y, Takenawa H, Nakayama E, 16. Kitano M, Kudo M, Yamao K, Takagi T, Sakamoto H, Komaki Marumo F, et al. Natural history of polypoid lesions in the gall T, et al. Characterization of small solid tumors in the pancreas: bladder. Gut 1996;39:860–2. the value of contrast-enhanced harmonic endoscopic ultraso- 3. Lin WR, Lin DY, Tai DI, Hsieh SY, Lin CY, Sheen IS, et al. Prev- nography. Am J Gastroenterol 2012;107:303–10. alence of and risk factors for gallbladder polyps detected by ul- 17. Kitano M, Sakamoto H, Matsui U, Ito Y, Maekawa K, von trasonography among healthy Chinese: analysis of 34 669 cases. Schrenck T, et al. A novel perfusion imaging technique of the J Gastroenterol Hepatol 2008;23:965–9. pancreas: contrast-enhanced harmonic EUS (with video). Gas- 4. Jørgensen T, Jensen KH. Polyps in the gallbladder: a prevalence trointest Endosc 2008;67:141–50. study. Scand J Gastroenterol 1990;25:281–6. 18. Park CH, Chung MJ, Oh TG, Park JY, Bang S, Park SW, et al. 5. Segawa K, Arisawa T, Niwa Y, Suzuki T, Tsukamoto Y, Goto H, Differential diagnosis between gallbladder adenomas and cho- et al. Prevalence of gallbladder polyps among apparently healthy lesterol polyps on contrast-enhanced harmonic endoscopic ul- Japanese: ultrasonographic study. Am J Gastroenterol 1992; trasonography. Surg Endosc 2013;27:1414–21. 87:630–3. 19. Choi JH, Seo DW, Choi JH, Park DH, Lee SS, Lee SK, et al. 6. Chen CY, Lu CL, Chang FY, Lee SD. Risk factors for gallblad- Utility of contrast-enhanced harmonic EUS in the diagnosis of der polyps in the Chinese population. Am J Gastroenterol malignant gallbladder polyps (with videos). Gastrointest En- 1997;92:2066–8. dosc 2013;78:484–93. 7. Kim SY, Lee HS, Lee YS, Chung KW, Jang BK, Chung WJ, et al. 20. Golse N, Lewin M, Rode A, Sebagh M, Mabrut JY. Gallbladder Prevalence and risk factors of gallbladder polyp in adults living adenomyomatosis: diagnosis and management. J Visc Surg in Daegu and Gyeongbuk provinces. Korean J Gastroenterol 2017;154:345–53. 2006;48:344–50. 21. Gallahan WC, Conway JD. Diagnosis and management of gall- 8. Choi YS, Do JH, Seo SW, Lee SE, Oh HC, Min YJ, et al. Preva- bladder polyps. Gastroenterol Clin North Am 2010;39:359– lence and risk factors of gallbladder polypoid lesions in a healthy 67. https://doi.org/10.12701/yujm.2020.00213 7 Kim KH. Gallbladder polyp

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https://doi.org/10.12701/yujm.2020.00213 9 Review article eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):10-18 https://doi.org/10.12701/yujm.2020.00444 Classification of endometriosis Soo-Young Lee1, Yu-Jin Koo2, Dae-Hyung Lee2 1Department of Obstetrics and Gynecology, Yeungnam University Hospital, Daegu, Korea 2Department of Obstetrics and Gynecology, Yeungnam University College of Medicine, Daegu, Korea

Received: June 9, 2020 Revised: July 9, 2020 Endometriosis is a chronic disease associated with pelvic pain and infertility. Several classification Accepted: July 16, 2020 systems for the severity of endometriosis have been proposed. Of these, the revised American So- ciety for Reproductive Medicine classification is the most well-known. The ENZIAN classification Corresponding author: was developed to classify deep infiltrating endometriosis and focused on the retroperitoneal Yu-Jin Koo structures. The endometriosis fertility index was developed to predict the fertility outcomes in Department of Obstetrics and patients who underwent surgery for endometriosis. Finally, the American Association of Gyneco- Gynecology, Yeungnam University logical Laparoscopists classification is currently being developed, for which 30 endometriosis ex- College of Medicine, 170 perts are analyzing and researching data by assigning scores to categories considered important; Hyeonchung-ro, Nam-gu, Daegu however, it has not yet been fully validated and published. Currently, none of the classification 42415, Korea systems are considered the gold standard. In this article, we review the classification systems, Tel: +82-53-620-3433 identify their pros and cons, and discuss what improvements need to be made to each system in Fax: +82-53-654-0676 E-mail: [email protected] the future.

Keywords: American Society for Reproductive Medicine classification; Classification; Endometrio- sis; ENZIAN classification

Introduction among physicians but also to standardize the optimal treatment strategy. Sampson [5] first classified endometriosis by describing Endometriosis is a chronic inflammatory disease that can cause pel- ovarian hemorrhagic cysts and their associated adhesion formation vic pain and infertility. It usually affects 2% to 10% of women of rein 1921. He classified ovarian hematomas into four subgroups: fol- productive age [1]. In 2010, the prevalence of endometriosis in licular, corpus luteal, stromal, and endometrial. However, no opti- women aged 15 to 49 years was about 1.7 billion worldwide [2]. mal classification system currently exists, and the usefulness of the According to a survey conducted by Statistics Korea, the number of current classification systems is controversial. The clinical manifes- patients who visited the hospital for endometriosis was about tations of endometriosis are diverse, and the relationship between 100,000 in 2016 and 120,000 in 2018, and is gradually increasing symptom and disease severities is ambiguous. So far, many efforts [3]. With the rising trend of endometriosis, medical expenses are have been made to better classify endometriosis. The ideal classifi- also likely to increase. The annual economic burden of endometrio- cation system should be able to explain the extent of disease, predict sis, including direct health care costs and indirect productivity loss, pain and fertility, provide accurate information to patients, and re- was estimated to be 22 billion US dollar (USD) in 2002 and 69.4 flect the anatomical features. This article reviews the four standard billion USD in 2009 in the United States of America [4]. classification systems, namely, the revised American Society for Re- The lack of a gold standard staging system is a concerning issue in productive Medicine (rASRM) classification, ENZIAN classifica- the treatment of endometriosis. A reproducible and well-organized tion, endometriosis fertility index (EFI), and American Association classification system is necessary not only to clarify communication of Gynecological Laparoscopists (AAGL) classification.

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American Society for Reproductive pareunia. In addition, according to Guzick et al. [12], there was a Medicine classification slight decrease in the pregnancy rate in stage IV endometriosis, but no significant difference in pregnancy rates between different The American Fertility Society (AFS) proposed a unique ap- stages was found. Fourth, rASRM classification does not consider proach, the AFS score, in 1979 [6]. The stage of endometriosis the presence of deeply infiltrating endometriosis (DIE) in differ- was derived from a cumulative score. The weighted value system ent sites such as the uterosacral ligaments, bladder, vagina, and was scored and summed according to the size of the endometriot- bowel. Therefore, in order to supplement DIE in retroperitoneal ic lesions in the ovaries, peritoneum, and fallopian tubes, and the structures, the ENZIAN classification was developed. severity of adhesion at each of the aforementioned sites. The staging system was divided into four stages: I (1 to 5 points, mild), II ENZIAN classification (6 to 15 points, moderate), III (16 to 30 points, severe), and IV (31 to 54 points, extensive). However, some critics have indicated The ENZIAN classification was introduced in Austria in 2005 a problem with this classification system. Hasson [7], for example, [13]. The ENZIAN score, like the rASRM classification, is deter- pointed out the lack of a relationship between the disease stage mined by the extent of endometriosis during surgery. When the and the clinical symptoms of pain and infertility. Therefore, this ENZIAN classification was first developed, its purpose was not to system was revised in 1985 (Fig. 1). They defined the stage classi- compete with the rASRM classification, but to supplement it with fication as minimal, mild, moderate, and severe, and each score respect to the description of DIE. However, according to Haas et al. was reclassified as 1 to 5, 6 to 15, 16 to 40, and more than 40. Tub- [14], there was unintended partial overlapping with the rASRM al endometriosis was omitted from the revised classification, and score. Fifty-eight of 160 patients with solitary superficial peritoneal the lesions of endometriosis were classified as superficial and deep disease in the pouch of Douglas cavity, uterosacral ligament, or a lesions. The size of deep ovarian endometriosis > 3 cm scored 20 combination of the two, were classified according to ENZIAN, al- points, and dense ovarian adhesion and dense tubal blockage though they did not fulfill the criteria of DIE and had previously were adjusted upward to 16 points. In addition, a single finding of been classified according to the rASRM classification. Therefore, complete cul-de-sac obliteration scored 40 points and was classi- two revisions of the ENZIAN classification system were carried out fied as severe disease. In 1996, this scoring system was renamed as in 2010 and 2011 to correct the overlap between rASRM and EN- the revised American Society for Reproductive Medicine (rAS- ZIAN systems and to make it easier to use (Fig. 2) [15,16]. The re- RM) classification [8]. vised ENZIAN classification was simplified by dividing retroperi- One of the advantages of the rASRM classification is that it has toneal structures into three compartments. The posterior part of been accepted globally and has been widely used in recent years. the uterus was divided into compartment A consisting of the rec- In addition, it is easy to use and helpful for physicians to explain tovaginal septum and vagina, compartment B consisting of the the degree of endometriosis in simple terms to patients. However, uterosacral ligament and pelvic walls, and compartment C con- there are several disadvantages. First, there is a difference between sisting of the sigmoid colon and rectum. The severity of the lesion histologically diagnosed endometriosis and visually diagnosed is set to invasiveness < 1 cm for grade 1, invasiveness 1 to 3 cm for stage. Fernando et al. [9] compared the pathologic findings of the grade 2, and invasiveness > 3 cm for grade 3. The prefix “E” indi- surgically removed endometriosis and visually diagnosed the rAS- cates the presence of a tumor of endometriosis. The number that RM stage. The rASRM stages I to IV were concordant in 49.7%, follows the prefix indicates the size of the lesion, and after the 80.3%, 78.1%, and 78.9% of the patients, respectively, indicating number, the lowercase English letter indicates the affected com- that women with rASRM stage I disease are more likely to be mis- partment. Two lowercase English letters mean bilateral disease. diagnosed as having endometriosis on visual inspection. Second, The invasion of endometriosis to other organs in the pelvic cavity the reproducibility of the rASRM score is poor. Hornstein et al. and to distant organs is expressed as follows: “FA” is defined as ad- [10] reported that comparison of interobserver and intraobserver enomyosis, “FB” as involvement of the bladder, “FU” as intrinsic scores resulted in a change in endometriosis stage in 52% and 38% ureter involvement, “FO” as involvement of other locations, and of the patients, respectively. Third, severities of pain and infertility “FI” as intestinal involvement. This revision is helpful for physi- are not correlated with rASRM stage. In a study of 244 patients, cians to better understand and readily use the ENZIAN classifica- Vercellini et al. [11] reported that endometriosis stage was not tion. consistently related to pain symptoms, and that only the presence One of the advantages of the ENZIAN classification is that it of vaginal lesions was frequently associated with severe deep dys- provides detailed descriptions of the retroperitoneal structures. https://doi.org/10.12701/yujm.2020.00444 11 Lee SY et al. Endometriosis classification

Fig. 1. The revised American Society for Reproductive Medicine classification of endometriosis. This system is the well-known classification of endometriosis. Reproduced from American Society for Reproductive Medicine [8] with permission of Elsevier.

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Fig. 2. The ENZIAN staging system for women with deep endometriosis. This system was developed as a supplement to the revised American Society for Reproductive Medicine score, in order to provide detailed descriptions of the retroperitoneal structure. Adapted from 7th Conference of the Stiftung Endometriose Forschung [16] (https://www.endometriose-sef.de/aktivitaeten/klassifikation-enzian/).

https://doi.org/10.12701/yujm.2020.00444 13 Lee SY et al. Endometriosis classification

The compartment can be divided into three sections and the se- fimbria, and ovary is required. The functional score indicates verity of each compartment as well as that of the distant lesions, whether the embryo is well implanted into the uterus, whether such as diaphragmatic and ureteral invasions, can be described. the uterus can provide an early environment for the embryo, or Second, the ENZIAN classification can be determined by imag- whether the fallopian tubes can pick up the ovum well. The least ing modalities and used for surgical planning. A study has report- function score is calculated by evaluating the function of the ova- ed that magnetic resonance imaging (MRI) predicts the extent of ry, fallopian tube, and fimbria for each side, and adding the lowest disease before surgery using ENZIAN score and enables preoper- score on the left and the lowest score on the right. Functional ative surgical planning. Di Paola et al. [17] conducted a retrospec- scores are determined by the surgeon and range from 0 to 4 points tive study (n= 115) comparing histopathological ENZIAN scores as follows; absent or nonfunctional as 0, severe dysfunction as 1, with ENZIAN scores detected by preoperative MRI. The accura- moderate dysfunction as 2, mild dysfunction as 3, and normal as cy of the ENZIAN scores detected by preoperative MRI was 95% 4. Not only the least functional score, but also other surgical fac- with a low false-negative rate of 4% [17]. Third, disease localiza- tors such as rASRM total score and endometriosis lesion score of tion and extent, as described by the revised ENZIAN score, are rASRM are included. Finally, The EFI score is calculated by sum- associated and correlated with the presence and severity of differ- ming the historical and surgical scores, and ranges from 0 to 10 ent symptoms [18]. Another researcher has also reported that the points, with 10 indicating the best prognosis and 0 the worst ENZIAN classification seems to have a relationship with pain, al- prognosis. though general consensus is weak [19]. The EFI system has a clear advantage on predicting pregnancy However, there are several drawbacks. First, the ENZIAN clas- outcome. The EFI score reflects the pregnancy rate better than sification has a poor level of international acceptance. It is current- the rASRM classification does. According to Zeng et al. [21], the ly not widely used but mainly used in German-speaking countries. pregnancy rate was 53.6%, 36.0%, 51.7%, and 41.7% in rASRM Second, patients may not readily understand the ENZIAN classi- stages I, II, III, and IV, respectively, with no statistically significant fication because of the complexity of the stage and insufficient difference (p= 0.246). However, the pregnancy rate according to knowledge of the pelvic anatomy. If there is a 2-cm unilateral infil- the EFI score was observed to be statistically significant at 8.3% in tration of endometriosis, the ENZIAN classification expresses it the group with an EFI score of 0 to 3, 41.2% for a score of 4 to 7, as ‘E2b’. This terminology does not accurately convey the severity and 60.9% for a score of 8 to 10 (p< 0.001) [21]. Similarly, the of the disease to the patient. Third, the ENZIAN score will be in- EFI score is a more reliable system to predict IVF outcomes in en- accurate if the surgical dissection of the deep invasive lesions is in- dometriosis patients than the rASRM classification. Wang et al. completely performed, or if image study alone is performed with- [22] reported that the IVF outcomes were higher in patients with out surgery. Fourth, even if the ENZIAN classification is predict- an EFI score of 6 or higher than in those with a score of 5 or less. ed by imaging modalities, there is insufficient research regarding However, the EFI system has the following disadvantages. First, the usefulness of the classification determined by imaging. Fur- the EFI score does not correlate with pain. Second, as the least ther study is needed to clarify whether the preoperative ENZIAN function score is judged subjectively, the total score can vary by score can be used for evaluating the surgical feasibility or com- surgeon. To date, there is no study on the assessments of interob- plete resectability. server reliability and intraobserver reproducibility in the EFI system. Third, the EFI score is more complicated to use than the Endometriosis fertility index rASRM classification and ENZIAN score, since it requires the calculation and addition of the scores of various categories. The purpose of the development of the EFI system is to predict the pregnancy rate in patients with surgically documented endo- American Association of Gynecological metriosis who have not attempted to become pregnant with in vi- Laparoscopists classification tro fertilization (IVF). In 2010, Adamson and Pasta [20] proposed an EFI system based on the data from 579 infertile patients In 2007, the AAGL initiated a project to develop a new classifica- with surgically diagnosed endometriosis (Fig. 3). After EFI was tion of endometriosis [23]. Thirty endometriosis experts were re- developed, the data of an additional 222 patients were collected quested to assign scores ranging from 0 to 10 points on the basis for correlation of actual outcomes. The EFI system reflects histor- of the importance of each involvement site on the outcomes of ical factors such as age, duration of infertility, and previous preg- pain, infertility, and surgical difficulty. This system contained all nancies. For pregnancy, proper functioning of the fallopian tube, the basic information thought to be important in quantifying the

14 https://doi.org/10.12701/yujm.2020.00444 Yeungnam Univ J Med 2021;38(1):10-18

Fig. 3. Endometriosis fertility index (EFI) system. This score predicts the fertility outcome for women who attempt non-in vitro fertilization conception following surgically documented endometriosis. Reproduced from Adamson and Pasta [20] with permission of Elsevier.

https://doi.org/10.12701/yujm.2020.00444 15 Lee SY et al. Endometriosis classification extent of disease in a patient. In addition, surgical difficulties were better reflect the relationship between pain and endometriosis se- categorized into four levels: level 1, excision or desiccation of su- verity. perficial implants and simple thin avascular adhesions; level 2, In 2011, Abrao and Miller [27] published an article entitled ‘Six stripping of ovarian endometriomas; appendectomy; deep endo- good reasons for a NEW Endometriosis Classification’. They pro- metriosis not involving the vagina, bladder (not requiring su- posed that an ideal classification must meet the following condi- tures), bowel, or ureter; dense adhesions not involving the bowel tions: (1) clearly describe the sites and extent of disease —perito- and/or the ureter; level 3, dense adhesions involving the bowel neal, ovarian, and deep endometriosis, including the bowel, ureter, and/or ureter; bladder surgery requiring sutures; ureterolysis; and bladder; (2) provide a close correlation with the symptoms bowel surgery without resection (shaving); level 4, bowel resec- of endometriosis: pain (dysmenorrhea, dyspareunia, dysuria, and tion with end-to-end anastomosis; ureteral reimplantation or dyschezia) and infertility; and (3) reflect the surgical difficulty en- anastomosis [24]. For validation of the score system, visual ana- countered relative to the disease location. This is facilitated by the logue scale scores and infertility history were collected from the inclusion of increasing radical procedures such as ureterolysis and patients before surgery. In 2012, the AAGL Special Interest Group bowel resection; (4) be user-friendly with tools conducive to sup- reported that the preliminary results presented at the AAGL Las porting a surgeon’s busy practice by enabling completion of docu- Vegas meeting were encouraging, and that the AAGL classifica- mentation immediately upon procedure conclusion; (5) be vali- tion for endometriosis was verified to be related to pain, infertility, dated for both pain and infertility. With proper validation, this and surgical difficulty. However, the AAGL classification is yet to new system can be most useful for therapeutic and prognostic be fully validated and published, although over 10 years have considerations; (6) create a comprehensive universal language passed since the classification was first proposed. Further investi- that is meaningful for clinical practitioners and researchers alike, gation and discussion regarding the AAGL classification are re- thus providing the foundation of collegial collaboration, which ul- quired. timately will advance our understanding of the disease. More recently, the European Society of Human Reproduction Concerns for the current four classification and Embryology (ESHRE) published recommendations for the systems and a need for a novel system in surgical treatment of DIE [28]. A working group of the European endometriosis Society for Gynaecological Endoscopy, ESHRE and World Endo- metriosis Society (WES) collaborated to make recommendations In addition to the four classifications described in this article, oth- for surgical treatment of DIE. They stated the importance of clas- er proposals exist. In the mid-1980s, subtle or non-pigmented le- sifying DIE, but also emphasized the limitations of the existing sions were recognized to contain endometrial glands and stroma system, specifically with regard to the scoring of the severity of [25]. Although the significance of subtle lesions is unclear, these disease. The working group recommended documenting the fol- may correspond to the initial phase where endometriosis begins. lowing information: the location of DIE lesions; uterosacral liga- However, it seems difficult to classify these subtle lesions into spe- ments, including whether ureters are infiltrated; rectovaginal sep- cific and subdivided systems with the aforementioned classifica- tum, including involvement of vaginal wall/mucosa; bowel, in- tions. Finally, Koninckx et al. [26] suggested that endometriosis cluding involvement of the muscularis layer; bladder, including in- should be classified into subtle, typical, cystic, deep, adenomyotic, volvement of muscularis and ureteral ostia; other sides in the pel- and peritoneal pocket lesions in 2011. However, this classification vis; extrapelvic locations; involvement of the ovaries; the sizes of has not been generally accepted and validated. the lesions; the number of lesions; and the degree of involvement Each classification reviewed in the present study has its own of adjacent organs and structures. pros and cons. The biggest challenge of the current classification To date, there is no gold standard for the classification of endo- systems seems to be their poor correlation with symptoms. Symp- metriosis. Only expert consensus regarding the current classifica- toms and intensity vary depending on the affected compartment, tion systems exists. The WES released a consensus statement on depth of invasion, and extent of disease; in particular, pain related the classification of endometriosis in 2017. International experts to endometriosis can be expressed in various phenotypes such as from 29 organizations systematically evaluated the classification dysmenorrhea, dyspareunia, chronic pelvic pain, and dysuria. The of endometriosis and reached this consensus [19]. The WES sug- currently existing classification systems have limited research on gested that the following recommendations should be considered the relationship between pain and severity of endometriosis. Ac- in critical situations. All women undergoing surgery must com- cordingly, a novel classification system should be developed to plete rASRM classification to obtain the maximum information

16 https://doi.org/10.12701/yujm.2020.00444 Yeungnam Univ J Med 2021;38(1):10-18 until better classification is available, and women with DIE must women with endometriosis. Hum Reprod 2014;29:400–12. additionally complete ENZIAN classification. EFI must be addi- 2. Adamson GD, Kennedy S, Hummelshoj L. Creating solutions tionally completed in women who need to consider fertility in fu- in endometriosis: global collaboration through the World En- ture [19]. dometriosis Research Foundation. J Endometr 2010;2:3–6. 3. Statistics Korea. Outpatient benefits by frequency of disease (to- Conclusion tal) 2018 [Internet]. Daejeon: Statistics Korea; 2019 [cited 2020 May 8]. http://kosis.kr/statHtml/statHtml.do? orgId=350&t- To date, no single classification system adequately classifies endo- blId=DT_35001_A084112&vw_cd=MT_ZTITLE&list_ metriosis. The rASRM classification is the most widely used and id=350_35001_6&seqNo=&lang_mode=ko&language=kor is useful for physicians to explain the severity of endometriosis in &obj_var_id=&itm_id=&conn_path=MT_ZTITLE. simple terms to the patients. The ENZIAN classification de- 4. Soliman AM, Surrey ES, Bonafede M, Nelson JK, Vora JB, scribes DIE involving retroperitoneal structures in detail. In addi- Agarwal SK. Health care utilization and costs associated with tion, ENZIAN classification can probably be determined using endometriosis among women with medicaid insurance. J imaging modalities and be used for surgical planning. However, Manag Care Spec Pharm 2019;25:566–72. external validation of the value of ENZIAN in further studies is 5. Sampson JA. Perforating hemorrhagic (chocolate) cysts of the needed. EFI score predicts the fertility outcome for women who ovary: their importance and especially their relation to pelvic attempt non-IVF conception following surgically documented adenomas of endometrial type (“adenomyoma” of the uterus, endometriosis. Likewise, the EFI score appears to be a reliable rectovaginal septum, sigmoid, etc.). Arch Surg 1921;3:245– system to predict IVF outcomes in endometriosis patients. There 323. is still much to learn and much to do with respect to the classifica- 6. The American Fertility Society. Classification of endometriosis. tion of this complex and challenging disease. An optimal classifi- Fertil Steril 1979;32:633–4. cation should be established to accurately reflect symptom and 7. Hasson HM. Classification for endometriosis. Fertil Steril disease extents as well as to determine treatment strategies. Fur- 1981;35:368–9. thermore, it would be more ideal if the disease stage and clinical 8. Revised American Society for Reproductive Medicine classifi- prognosis are accurately predictable using a new classification sys- cation of endometriosis: 1996. Fertil Steril 1997;67:817–21. tem without surgical approach. 9. Fernando S, Soh PQ, Cooper M, Evans S, Reid G, Tsaltas J, et al. Reliability of visual diagnosis of endometriosis. J Minim Inva- Acknowledgments sive Gynecol 2013;20:783–9. 10. Hornstein MD, Gleason RE, Orav J, Haas ST, Friedman AJ, Conflicts of interest Rein MS, et al. The reproducibility of the revised American Fer- No potential conflict of interest relevant to this article was report- tility Society classification of endometriosis. Fertil Steril ed. 1993;59:1015–21. 11. Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F, Cro- Author contributions signani PG. Endometriosis and pelvic pain: relation to disease Conceptualization and Supervision: YJK, DHL; Formal analysis: stage and localization. Fertil Steril 1996;65:299–304. all authors; Project administration: DHL; Writing-original draft: 12. Guzick DS, Bross DS, Rock JA. Assessing the efficacy of The SYL; Writing-review & editing: YJK. American Fertility Society’s classification of endometriosis: application of a dose-response methodology. Fertil Steril ORCID 1982;38:171–6. Soo-Young Lee, https://orcid.org/0000-0001-8672-0751 13. Tuttlies F, Keckstein J, Ulrich U, Possover M, Schweppe KW, Yu-Jin Koo, https://orcid.org/0000-0002-5114-8000 Wustlich M, et al. ENZIAN-score, a classification of deep infil- Dae-Hyung Lee, https://orcid.org/0000-0002-0219-0317 trating endometriosis. Zentralbl Gynakol 2005;127:275–81. 14. Haas D, Chvatal R, Habelsberger A, Wurm P, Schimetta W, Op- References pelt P. Comparison of revised American Fertility Society and ENZIAN staging: a critical evaluation of classifications of endo- 1. Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, metriosis on the basis of our patient population. Fertil Steril D’Hooghe T, De Bie B, et al. ESHRE guideline: management of 2011;95:1574–8. https://doi.org/10.12701/yujm.2020.00444 17 Lee SY et al. Endometriosis classification

15. Stiftung Endometriose Forschung. 6th Conference of the ue of the revised American Fertility Society classification and Stiftung Endometriose Forschung (Foundation for Endometri- the endometriosis fertility index. Gynecol Obstet Invest 2014; osis Research); 2010 Feb 19–21; Weissensee, Austria. Weis- 77:180–5. sensee: Stiftung Endometriose Forschung; 2010. 22. Wang W, Li R, Fang T, Huang L, Ouyang N, Wang L, et al. En- 16. Stiftung Endometriose Forschung. The revised Enzian classifi- dometriosis fertility index score maybe more accurate for pre- cation. Consensus meeting, 7th Conference of the Stiftung En- dicting the outcomes of in vitro fertilisation than r-AFS classifi- dometriose Forschung (Foundation for Endometriosis Re- cation in women with endometriosis. Reprod Biol Endocrinol search); 2011 Feb 25–27; Weissensee, Austria. Weissensee: 2013;11:112. Stiftung Endometriose Forschung; 2011. 23. Endometriosis Classification Committee; Ad hoc committee of 17. Di Paola V, Manfredi R, Castelli F, Negrelli R, Mehrabi S, Pozzi the AAGL. AAGL endometriosis tabulation system. California Mucelli R. Detection and localization of deep endometriosis by (CA): Cypress; 2007. means of MRI and correlation with the ENZIAN score. Eur J 24. Chapron C, Abrao MS, Miller CE. Endometriosis classifications Radiol 2015;84:568–74. need to be revisited: a new one is arriving. NewsScope 2012; 18. Montanari E, Dauser B, Keckstein J, Kirchner E, Nemeth Z, 26(4):9–10. Hudelist G. Association between disease extent and pain symp- 25. Jansen RP, Russell P. Nonpigmented endometriosis: clinical, toms in patients with deep infiltrating endometriosis. Reprod laparoscopic, and pathologic definition. Am J Obstet Gynecol Biomed Online 2019;39:845–51. 1986;155:1154–9. 19. Johnson NP, Hummelshoj L, Adamson GD, Keckstein J, Taylor 26. Koninckx PR, Ussia A, Adamyan L, Wattiez A. An endometrio- HS, Abrao MS, et al. World Endometriosis Society consensus sis classification, designed to be validated. Gynecol Surg 2011; on the classification of endometriosis. Hum Reprod 2017;32: 8:1–6. 315–24. 27. Abrao MS, Miller CE. An endometriosis classification, designed 20. Adamson GD, Pasta DJ. Endometriosis fertility index: the new, to be validated. NewsScope 2012;25(4):6. validated endometriosis staging system. Fertil Steril 2010; 28. Working group of ESGE, ESHRE, and WES; Keckstein J, Beck- 94:1609–15. er CM, Canis M, Feki A, Grimbizis GF, et al. Recommenda- 21. Zeng C, Xu JN, Zhou Y, Zhou YF, Zhu SN, Xue Q. Reproduc- tions for the surgical treatment of endometriosis. Part 2: deep tive performance after surgery for endometriosis: predictive val- endometriosis. Hum Reprod Open 2020;2020:hoaa002.

18 https://doi.org/10.12701/yujm.2020.00444 Review article eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):19-26 https://doi.org/10.12701/yujm.2020.00535 Updates on the treatment of adhesive capsulitis with hydraulic distension Jang Hyuk Cho Department of Rehabilitation Medicine, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea

Received: June 30, 2020 Revised: August 8, 2020 Adhesive capsulitis of the shoulder joint is a common disease characterized by pain at the inser- Accepted: August 10, 2020 tional area of the deltoid muscle and decreased range of motion. The pathophysiological process involves fibrous inflammation of the capsule and intraarticular adhesion of synovial folds leading Corresponding authors: to capsular thickening and contracture. Regarding the multidirectional limitation of motion, a Jang Hyuk Cho limitation in external rotation is especially prominent, which is related to not only global fibrosis Department of Rehabilitation but also to a localized tightness of the anterior capsule. Ultrasound and magnetic resonance im- Medicine, Keimyung University aging studies can be applied to rule out other structural lesions in the diagnosis of adhesive cap- Dongsan Medical Center, Keimyung sulitis. Hydraulic distension of the shoulder joint capsule provides pain relief and an immediate University School of Medicine, 1095 improvement in range of motion by directly expanding the capsule along with the infusion of Dalgubeol-daero, Dalseo-gu, Daegu 42601, Korea steroids. However, the optimal technique for hydraulic distension is still a matter of controversy, Tel: +82-53-258-7912 with regards to the infusion volume and rupture of the capsule. By monitoring the real-time Fax: +82-53-258-7130 pressure-volume profile during hydraulic distension, the largest possible fluid volume can be in- E-mail: [email protected] fused without rupturing the capsule. The improvement in clinical outcomes is shown to be greater in capsule-preserved hydraulic distension than in capsule-ruptured distension. Moreover, repeated distension is possible, which provides additional clinical improvement. Capsule-preserved hydraulic distension with maximal volume is suggested to be an efficacious treatment option for persistent adhesive capsulitis.

Keywords: Inflammation; Joint capsule; Pain; Shoulder joint

Introduction range of motion (ROM) are generally considered before surgical treatment [4]. However, these managements require persistent Adhesive capsulitis is a disease that presents with pain due to in- and active treatment, and it can take a long time to show improve- flammation of the joint capsule, which progresses to fibrosis and ments [5]. Hydraulic distension, which is a more aggressive treat- hypertrophy, and gradually causes joint contracture of the shoulder ment, is an interventional procedure in which a sufficient amount [1,2]. Clinical findings are the most important for diagnosis, and of fluid is injected into the stiff shoulder capsule. Hydraulic disten- plain radiography should be normal [3]. Recently, ultrasound and sion is used clinically for adhesive capsulitis to reduce inflamma- magnetic resonance imaging (MRI) have also been commonly tion of the joint capsule and directly relieve contracture, alleviate used for accurate diagnosis. For treatment based on the pathogene- pain, and improve ROM [6]. Although there have been many resis, it is important to reduce inflammation and improve flexibility ports on the clinical effects of hydraulic distension, there is still no of the joint capsule. Conservative treatments—including medica- standardized distension method [7]. In this review, we aim to dis- tion, physical therapy, and exercise—to alleviate pain and restore cuss the clinical presentation of adhesive capsulitis, the principles

Copyright © 2021 Yeungnam University College of Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. https://doi.org/10.12701/yujm.2020.00535 19 Cho JH. Hydraulic distension of adhesive capsulitis and trends of hydraulic distension as a therapeutic intervention. produces good outcomes even when only performed on the anterior part of the joint capsule [22]. The clinical presentation of adhesive The course of the disease can be divided into four stages de- capsulitis pending on pain, duration of illness, arthroscopic findings, and pathologic appearance [18-20]. Stage 1 is the preadhesion and in- Adhesive capsulitis is characterized by shoulder pain and gradually flammation stage, pertaining to the first 3 months, in which severe decreasing shoulder ROM [1]. In 1896, Duplay defined periarthri- pain is mostly experienced at night at the attachment of the deltoid tis as reduced ROM due capsular fibrosis; in 1934, Codman de- muscle, but the shoulder ROM is preserved. Arthroscopy shows fined frozen shoulder as slowly progressing shoulder pain and re- synovial inflammation and there are pathological findings of hy- duced ROM without abnormal radiographic findings; and in pervascular synovitis. Stage 2 is the freezing stage, occurring at 1945, Neviaser defined adhesive capsulitis caused pathologically around 3 to 9 months, in which there is severe pain and progres- by inflammation and fibrosis [2]. Various other names have also sion of reduced ROM. Arthroscopy shows proliferative synovitis been used, including pericapsulitis and painful stiff shoulder [1,8]. and adhesions, and there are pathological appearances of hyper- Adhesive capsulitis affects 2% to 10% of the population, is more vascular synovitis, fibrous proliferation, and scarring. Stage 3 is the prevalent in women, and the age of onset is usually around 40 to 69 frozen stage, at 9 to 15 months, in which pain gradually decreases years (average, 55 years) [9]. The nondominant side is more com- and is experienced at the ends of the ROM, but there is a severe monly affected; however, 20% to 30% of patients are bilaterally af- decrease in ROM. In arthroscopy, hypervascularity is no longer fected and recurrence in the same shoulder is known to be relative- observed, but there is hypertrophy of the joint capsule and loss of ly rare [10-12]. Adhesive capsulitis occurs more frequently in pa- the axillary fold. Pathological findings include burned-out synovi- tients with endocrine diseases, such as diabetes mellitus or thyroid tis and dense hypercellular scarring. Stage 4 is the thawing stage, disease, or autoimmune disease; in particular, diabetes mellitus pa- pertaining to 15 to 24 months, in which there is almost no pain tients show an increased prevalence of up to 20% [13,14]. It has and joint ROM gradually improves. Arthroscopy shows capsular been rarely reported to be associated with hyperlipidemia [15,16]. scarring and mature adhesions. There have been no reports of the Predisposing factors include long-term immobility after trauma or pathological appearance at this stage (Table 1) [18-20]. However, surgery, calcific tendinitis, rotator cuff tear, and glenohumeral or staging of adhesive capsulitis is difficult to implement, because it acromioclavicular arthritis [17]. does not always fit well with the clinical symptoms. According to a In order to diagnose adhesive capsulitis, plain radiography find- recent study, 27.7% of patients with chronic adhesive capsulitis ings should be normal, though there may be accompanying osteo- persisting for more than 2 years are not satisfied with the state of penia. Plain radiography is useful for differentiation from other dis- their shoulders [5]. In addition, it may be difficult to perform the eases causing acute pain and reduced ROM [3]. The MRI and ul- arthroscopic and pathological examinations only required to deter- trasound to differentiate accompanying diseases, such as calcific mine the disease stage. Therefore, adhesive capsulitis can be con- tendinitis, rotator cuff tear, or bursitis, is not directly required but sidered a chronic disease that requires active treatment from the can help with diagnosis. Generally, clinical diagnosis through phys- initial stages. ical examination is the most important. Pathological findings include reactive fibrosis and contracture of Treatment approaches to adhesive the joint capsule due to synovial inflammation, capsular and syno- capsulitis vial adhesions, and dense capsular hypertrophy; these findings are most severe in the axillary recess and may progress as far as the at- Adhesive capsulitis presents with pain due to inflammation of the tachment to the anatomical neck of the humerus [10,18-21]. Ac- joint capsule, progressing to fibrosis and hypertrophy, and gradual- cording to recent research, joint capsules with reduced ROM are ly causing joint contracture. Therefore, the aims of treatment are to accompanied by not only global fibroplasia but also localized con- relieve pain by reducing inflammation and restoring joint ROM. tracture of rotator cuff interval and the coracohumeral ligament General conservative treatments consist of physical therapy, exer- [22]. This may be related to the clinical characteristic wherein ex- cise, nonsteroidal anti-inflammatory drugs, and intraarticular ste- ternal rotation shows the most severe decrease in ROM. The roid injections. Interventional procedures include hydraulic disten- coracohumeral ligament is a target structure of stretching exercises sion and manipulation under anesthesia. Surgical procedures in- and is an important pathological structure in adhesive capsulitis clude arthroscopic capsular release and open capsulotomy. Be- [23]. In addition, this could be the basis for why surgical treatment cause the inflammatory reaction causes fibrosis of the synovium,

20 https://doi.org/10.12701/yujm.2020.00535 Yeungnam Univ J Med 2021;38(1):19-26

Table 1. Stages of adhesive capsulitis [18-20] Stage Variable 1 (Preadhesive) 2 (Freezing) 3 (Frozen) 4 (Thawing) Duration (mo) 0–3 3–9 9–15 15–24 Symptoms and signs Painful shoulder movement Painful shoulder movement Reduced pain with shoulder Progressive improvement of Minimal restriction in motion Progressive loss of joint movement joint motion Pain referred to deltoid insertion motion Severely restricted joint motion Pain minimal Stiffness Stiffness Arthroscopic appearance Fibrinous synovial inflammatory Diffuse, thickened and prolif- Loss of axillary fold Fully mature adhesions reaction erative synovitis Diminished capsular volume Capsular scar No adhesions or capsular Adhesion formation in the No hypervascularity contracture axillary fold extending to the humeral head Minimal synovitis with maturation Pathologic findings Hypervascular, hypertrophic Hypervascular, hypertrophic Hypercellular, dense and collage- Not reported synovitis synovitis nous tissue with a thin synovial Normal capsular tissue Fibroplasia and perivascular membrane similar to other fi- scar formation brosing conditions Extensive fibroplasia “Burned out” synovitis Scar formation

anti-inflammatory treatment is essential to improve symptoms and cause injuries such as fractures near the humeral neck and rotator prevent fibrosis; therefore, intraarticular steroid injections, which cuff tears and may have a risk involved in the use of general anes- have a strong anti-inflammatory action, are effective [4]. thesia [26,27]. Surgical release is usually performed at the anterior Clinically, decisions regarding treatment can be aided by divid- part of the capsule, were local contracture is observed pathological- ing the course of the disease into stage 1, in which there is severe ly [22]. Arthroscopic capsule release can be attempted in patients pain due to inflammation but ROM is preserved; stage 2, in which with diabetes when manipulation under anesthesia has failed, but there is progression of inflammation and joint capsule fibrosis lead- the cases when it is required are limited [27-29]. Open capsuloto- ing to pain and reduced ROM; and stage 3, in which inflammation my can rarely be attempted when capsular release fails [30,31]. recedes and fibrosis peaks, leading to improved pain and worsening ROM. Stage 1 patients show considerable improvement with Current trends in hydraulic distension conservative treatment, including intraarticular steroid injections. In stage 2 patients, the disease often cannot be managed with con- 1. Therapeutic mechanisms of hydraulic distension servative treatment alone, and interventional procedures also need Hydraulic distension, which was first reported in 1965 by Andren to be considered [24]. In other words, in the stage where inflam- and Lundberg [32], is a procedure in which fluid is injected into mation is the main problem, inflammation needs to be treated. In the intraarticular space of the shoulder to expand the stiff joint cap- the stage when joint contracture caused by fibrosis is the main sule and eliminate adhesions that are limiting ROM. The injection problem, treatment to stretch and improve flexibility in the thick- of a large volume of fluid raises the intraarticular pressure, and at ened and contracted joint capsule is more appropriate. In patients peak pressure, the joint capsule ruptures, eliminating adhesions who do not show a sufficient response to conservative treatment and scar tissue, which is known to improve ROM [6,9,32-34]. Ac- and require interventional procedures, hydraulic distension is used, cording to current evidence, hydraulic distension has a superior ef- which requires injecting a sufficient volume of fluid consisting of a fect in the treatment of adhesive capsulitis compared to other gen- mixture of local anesthetic and normal saline into the intraarticular eral conservative treatments. Hydraulic distension with steroids space [6]. During the common treatment for adhesive capsulitis plus physical therapy was superior to physical therapy alone in the based on the current knowledge, hydraulic distension is performed functional improvement of adhesive capsulitis [35]. while injecting intraarticular steroids, and rehabilitation including In a study comparing a group of patients that received only hy- exercise is performed to restore shoulder ROM [7]. Manipulation draulic distension, a group that received only intraarticular steroid under anesthesia has been reported to be an effective intervention injection, and a group that received hydraulic distension and in- to improve pain and joint ROM [25]. However, the procedure can traarticular steroids simultaneously, the improvement in joint https://doi.org/10.12701/yujm.2020.00535 21 Cho JH. Hydraulic distension of adhesive capsulitis

ROM was greatest in the group that received both hydraulic dis- ing hydraulic distension [44-49]. tension and steroids [36]. Thus, hydraulic distension alongside intraarticular steroids allowed not only the dose of analgesics to be 2. Capsule-preserving hydraulic distension reduced but also a significant improvement in ROM compared to Capsule-preserving hydraulic distension is performed per the pro- steroid injection alone. This demonstrates that, when performing tocol described below [45-47]. The skin is properly disinfected, hydraulic distension, injecting steroids with the fluids is far more with the subject in a seated position. A disposable pressure sensor effective [6]. Incorporating hydraulic distension with steroids and a 3.5-inch 22-gauge needle connected to the hydraulic disten- could improve the effectiveness of intraarticular steroid injection in sion device are placed in the posterior shoulder capsule under ul- the treatment of the adhesive capsulitis [37]. trasound guidance. The hydraulic distension device is used to in- The reported adverse effects of hydraulic distension are after- ject 49 mL of 0.5% lidocaine solution and 40 mg of triamcinolone pains, loss of sensation and motor control in the affected arm, (50 mL total) into the intraarticular space at a constant rate of 5 flushing, nausea, dizziness, and syncope [38,39]. These were rated mL/minute. While injecting the solution, the intraarticular pres- as mild and brief, with complete spontaneous resolution [38]. An- sure is monitored in real-time. In order to ensure preservation of other important point is that the clinicians need to be concerned the joint capsule, ultrasound is used to check that the injection with an adverse effect like glenohumeral joint infection [40]. solution is expanding the joint capsule and remaining in the in- In order to obtain a distension effect, a high pressure needs to traarticular space without leakage (Fig. 1) [46,48]. be created by injecting fluid into the stiff joint capsule. Previous Some previous studies have reported that capsule-rupturing hy- studies have used very diverse fluid volumes, from 2 to 150 mL, draulic distension is better than capsule-preserving hydraulic dis- and demonstrated different effects of the procedure according to tension; however, only a small volume of fluid (2–10 mL) was ac- capsule rupture or preservation [9]. In freezing stage patients, hy- tually injected into the intraarticular space [36]. When hydraulic draulic distension causing capsule rupture without the use of ste- distension is performed while monitoring the intraarticular pres- roids was reported to increase joint ROM, providing evidence sure, the mean capsule-preserving volume was reported to be that capsule-ruptured hydraulic distension can produce favorable 25.1± 6.9 mL [49]. The joint capsule ruptures after a mean inject- effects despite thus use of no steroids [33]. Meanwhile, one re- ed volume; therefore, the previous studies might not properly recent study reported that capsule-ruptured hydraulic distension flect the effects of capsule-preserving hydraulic distension. with steroids should be considered as the first treatment for ad- In capsule-preserving hydraulic distension, the maximum vol- hesive capsulitis [7]. However, capsule rupture after hydraulic ume fluid is injected at a constant rate without causing capsule rup- distension occurs most frequently in the subscapular fossa and ture, and the intraarticular pressure is measured in real-time to pre- sometimes in the subacromial-subdeltoid bursa and the long serve the fluid in the capsule for a long time. Monitoring reveals a head of biceps tendon sheath, rather than in the anterior capsule pressure-volume curve with three phases: phase I (initial filling) and rotator cuff interval; these sites are where adhesive capsulitis shows a flat curve, phase II (elastic deformation) shows a steep lin- originates and are responsible for the reduced ROM [41,42]. ear increase in pressure, and phase III (plastic deformation) shows These capsule-rupturing regions do not show increased intraar- a shallow curve [44]. This is similar to the three phases of the ticular stiffness and do not contain rotator cuff attachments. In stress-strain curve of soft tissue in response to extension [49]. addition, the joint capsule in these regions is weak and thin, with When the fluid is injected, there is a flat curve of pressure in phase I a thickness of less than 1 mm [9,34,41,42]. During capsule-rup- until the pressure rapidly rises in phase II and the slope of the steep turing hydraulic distension, the intraarticular steroids leak into curve increases, and then, after a sufficient volume has been inject- the surrounding soft tissues, which can cause adverse effects such ed, the curve becomes shallow in phase III; immediately after this, as atrophy of adipose tissue, weakening of tendons and liga- a sudden loss of pressure is observed, indicating capsule rupture ments, and changes in skin pigmentation [43]. (Fig. 2) [45,49]. For this reason, in order to obtain the maximum Hydraulic distension is not yet standardized and continually de- distension effect, fluid injection should be stopped at the start veloping. Previously, hydraulic distension was mostly performed phase III, which occurs immediately before capsule rupture. using arthrography; ultrasound-guided hydraulic distension has ‘Pre-rupture signs’ were verified to be when phase III of the pres- become more common in recent years as ultrasound devices have sure-volume curve is observed, or the intraarticular pressure ex- advanced. Capsule-preserving hydraulic distension, in which the ceeds 500 mmHg [46,47]. The mean capsule-preserving volume intraarticular pressure is measured during fluid injection to prevent of hydraulic distension in adhesive capsulitis patients was reported capsule rupture in real-time, is more effective than capsule-ruptur- to be 25.1±6.9 mL therefore, the smallest volume for effective

22 https://doi.org/10.12701/yujm.2020.00535 Yeungnam Univ J Med 2021;38(1):19-26

Fluid in

Spinal needle

Pressure sensor Syringe pump

DAQ

Signal out

A B

Fig. 1. Experimental setup for capsule-preserved hydraulic distension (A) with real-time pressure monitoring (B). While the patient is comfortably seated upright on a stool, a 3.5-inch 22-gauge spinal needle is inserted 1 cm lateral to the ultrasound transducer and advanced into the posterior intraarticular space under ultrasound guidance. The pressure sensor is connected to manometric tubes via a 3-way stopcock so that the pressure in the tubes can be measured by the sensor while fluid is infused via the syringe pump. The signal from the sensor is digitalized by a data-acquisition device (DAQ).

750 ing system is used to measure the intraarticular pressure, predict P 700 2 the time of capsule rupture, and stop fluid injection immediately

600 before rupture. A sufficient volume of fluid needs to be injected and maintained in capsule for as long as possible without rupture 500 in order to produce a large treatment effect. Moreover, the intraar- 400 ticular steroids can be retained within the intraarticular space for a P1 300 long time without leakage, resulting in better inflammation control

Pressure (mmHg) [46,49]. 200 The effects of stretching are observed when a prolonged con- 100 stant tension, which is enough to induce plastic elongation of the

-20 shortening tissue, is applied [50]. In the case of adhesive capsulitis, 11:08:34 11:10:00 11:13:20 11:16:40 Time (sec) continuous stretching of the contracted connective tissue is possible when a large volume of fluid is injected into the intraarticular Fig. 2. Typical pressure-volume curve obtained during intraarticular space and it maintain expansion of the adhered capsule without hydraulic distension. The slope of the phase II (from P1 to P2) is considered the capsular stiffness phase. P1, pressure at the causing rupture [47]. Conversely, if fluid is injected until the cap- starting point of phase II; P2, pressure at the ending point of sule ruptures, although it is possible to deliver the greatest load, this phase II. effect may disappear immediately after rupture. Following rupture, the intraarticular pressure drops rapidly as the injected solution capsule-preserving hydraulic distension is suggested to be approxi- leaks outside of the capsule. It then becomes difficult to stretch and mately 18 mL [49]. In the case of real-time pressure monitoring of expand the adhered capsule, and the treatment effect may de- intraarticular hydraulic distension is not available, hydraulic disten- crease. When clinical improvements in pain and joint ROM were sion using a total fluid volume of 18 mL under ultrasound guid- evaluated, compared to capsule rupture, injecting the maximum ance to ensure preservation of the joint capsule may be effective. volume while preserving the joint capsule resulted in superior ef- It is important to stop fluid injection immediately before capsule fects [46]. rupture. To this end, a real-time pressure-volume profile monitor- Hydraulic distension with steroids can be repeated in the case of https://doi.org/10.12701/yujm.2020.00535 23 Cho JH. Hydraulic distension of adhesive capsulitis failure or unsatisfactory results from a single hydraulic distension, dure is better at controlling inflammation and shows a superior and repeated procedures are more effective for pain alleviation treatment effect compared to capsule-rupturing hydraulic disten- than a single procedure [51]. When the hydraulic pressure causes sion. Furthermore, considering the mean maximal capsule-pre- capsule rupture during repeated distension, the intraarticular fluid serving volume of hydraulic distension (25.1± 6.9 mL), the small- leaked through the previously rupture area, and the clinical effect est volume for effective capsule-preserving hydraulic distension is was diminished. Furthermore, capsule-preserving hydraulic disten- indicated to be approximately 18 mL. Therefore, hydraulic distension with steroids showed a greater improvement after repeated sion using a total fluid volume of 18 mL with steroid under ultra- procedures [47]. In order to investigate the effects of repeated hy- sound guidance to ensure preservation of the joint capsule may be draulic distension in adhesive capsulitis patients, a study per- available. In conclusion, capsule-preserving hydraulic distension is formed three capsule-preserving distension procedures at 1-month a safe treatment method that can be used repeatedly. As a result, we intervals [47,51]. Following the second repeated procedure, there believe that it will also be helpful for treating adhesive capsulitis pa- were significant improvements in the outcomes of not only biome- tients who respond poorly to treatment or show recurrence. chanical factors, such as reduced capsule stiffness and increased ca- pacity, but also clinical outcomes, with increased ROM and re- Acknowledgments duced pain. Since biomechanical changes in the contracted joint capsule were accompanied by improvements in the clinical indices Conflicts of interest of ROM and pain, repeated capsule-preserving hydraulic disten- No potential conflict of interest relevant to this article was report- sion can be considered a very useful treatment method for adhe- ed. sive capsulitis [47,51]. In adhesive capsulitis secondary to previous surgery or trauma, Funding there may be stiffness due to outer adhesion of the rotator cuff. This research was supported by the Translational Research Pro- This also may be due to postoperative scarring or soft tissue injury. gram for Care Robots funded by the Ministry of Health & Welfare, In particular, secondary adhesive capsulitis after fracture is less ef- Republic of Korea (grant number: HK20C0007). fective in hydraulic distension; it may be accompanied by a combination of capsule contractures and extraarticular adhesions [52]. Additional information Thus, further studies are needed to verify whether implementing The author would like to thank Keewon Kim, MD and Sun G. repeated capsule-preserving hydraulic distension could produce Chung, MD, Professors at Seoul National University, for their per- better outcomes than conventional treatment methods, even for mission to use and publish their figures. adhesive capsulitis patients with a poor prognosis or recurrent pain. ORCID Jang Hyuk Cho, https://orcid.org/0000-0001-7916-8428 Conclusion References Treatments for adhesive capsulitis are available to reduce inflammation and improve flexibility of the joint capsule. Of these, hy- 1. Baslund B, Thomsen BS, Jensen EM. Frozen shoulder: current draulic distension is an effective interventional procedure. Cap- concepts. Scand J Rheumatol 1990;19:321–5. sule-rupturing hydraulic distension is the method of rupturing the 2. Lewis J. 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26 https://doi.org/10.12701/yujm.2020.00535 Review article eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):27-33 https://doi.org/10.12701/yujm.2020.00703 Pathophysiology and protective approaches of gut injury in critical illness Chang Yeon Jung1, Jung Min Bae2 1Department of Surgery, Yeungnam University Hospital, Daegu, Korea 2Department of Surgery, Yeungnam University College of Medicine, Daegu, Korea

Received: August 10, 2020 Revised: August 25, 2020 The gut is a complex organ that has played an important role in digestion, absorption, endocrine Accepted: August 31, 2020 functions, and immunity. The gut mucosal barriers consist of the immunologic barrier and nonimmunologic barrier. During critical illnesses, the gut is susceptible to injury due to the induction Corresponding author: of intestinal hyperpermeability. Gut hyperpermeability and barrier dysfunction may lead to sys- Jung Min Bae temic inflammatory response syndrome. Additionally, gut microbiota are altered during critical Department of Surgery, Yeungnam illnesses. The etiology of such microbiome alterations in critical illnesses is multifactorial. The in- University College of Medicine, 170 teraction or systemic host defense modulation between distant organs and the gut microbiome Hyeonchung-ro, Nam-gu, Daegu is increasingly studied in disease research. No treatment modality exists to significantly enhance 42415, Korea the gut epithelial integrity, permeability, or mucus layer in critically ill patients. However, multiple Tel: +82-53-620-3580 Fax: +82-53-624-1213 helpful approaches including clinical and preclinical strategies exist. Enteral nutrition is associat- E-mail: [email protected] ed with an increased mucosal barrier in animal and human studies. The trophic effects of enteral nutrition might help to maintain the intestinal physiology, prevent atrophy of gut villi, reduce intestinal permeability, and protect against ischemia-reperfusion injury. The microbiome approach such as the use of probiotics, fecal microbial transplantation, and selective decontamination of the digestive tract has been suggested. However, its evidence does not have a high quality. To promote rapid hypertrophy of the small bowel, various factors have been reported, including the epidermal growth factor, membrane permeant inhibitor of myosin light chain kinase, mucus surrogate, pharmacologic vagus nerve agonist, immune-enhancing diet, and glucagon-like peptide-2 as preclinical strategies. However, the evidence remains unclear.

Keywords: Critical illness; Enteral nutrition; Intestines; Microbiota

Introduction against pathogens and is important for the management of host homeostasis. Additionally, it is the central coordinator of mucosal The gut is a complex organ that carries out important functions in- immunity [2]. The lamina propria serves as a protective layer cluding digestion, absorption, endocrine regulation, and immuni- against microorganisms and is rich in immune cells. The gut is a ty. Microscopically, the gut wall consists of the serosa, muscularis continuously renewing organ with the majority of cells turning propria, submucosa, and mucosa. The mucosa consists of the epi- over within 1 week [3]. Several intestinal cells including absorptive thelium, lamina propria, crypt of Lieberkühn, and so on. The gut is enterocytes, mucus-producing goblet cells, hormone-producing covered by an epithelial layer with a surface area of 30 m2. The size enteroendocrine cells, and tuft cells are differentiated from intesti- of the surface area is similar in size to half a badminton court [1]. nal stem cells residing near the base of crypt of Lieberkühn [4,5]. The epithelium plays a critical role as the first line of protection As a result of constant microorganism exposure, the gut has sig-

Copyright © 2021 Yeungnam University College of Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. https://doi.org/10.12701/yujm.2020.00703 27 Jung CY and Bae JM. Gut injury and protecting the gut in critical illness nificant immune function. Initially, several lymphoid cells in the [17]. The gut has been hypothesized to be the “motor” of critical lamina propria and Peyer’s patch can detect pathogenic antigens. illness [18,19]. This theory is based on the fact that critical illness From these lymphoid cells, afferent lymphatics are drained from induces intestinal hyperpermeability, leading to bacterial transloca- the mesenteric lymph nodes. Secretory immunoglobulins (Ig) in- tion and subsequent systemic infection. Gut damage causes gastro- cluding secretory IgA and immune cells can subsequently inhibit intestinal (GI) symptoms. The GI symptoms caused by gut dam- the pathogenicity of the antigen. Notably, secretory IgA inhibits age occur in approximately 62% of the patients in ICUs [17]. the adherence of bacteria to the epithelium and prevents their col- In the 1970s, a gut mucosal damage grading system in the shock onization and multiplication. In addition, secretory IgA neutralizes state was proposed [20]. Recently, a GI dysfunction grading sys- bacterial toxins and viral activity and blocks the absorption of anti- tem for critically ill patients was developed by the Working Group gens from the gut [6]. These complex immune responses, cellular on Abdominal Problem (WGAP) of the European Society of In- reactions, and immune cascades in the gut are called mucosal bar- tensive Care Medicine (ESICM) [21]. Acute GI injury (AGI) riers [6]. grade I refers to the development of new GI symptoms, such as These mucosal barriers consist of immunologic and nonimmu- vomiting, gastric residual volume, diarrhea, GI bleeding, paralysis nologic barriers. The immunologic barrier consists of secretory of the lower GI tract, or abnormal bowel sounds related to a IgA and IgM lymphocytes. The nonimmunologic barrier consists known cause and perceived as transient (risk of developing GI dys- of digestive enzymes, mucus, peristalsis, and gut flora [6]. In ani- function or failure). AGI grade II refers to a lack of improvement in mal studies, sepsis can induce a decrease in the crypt proliferation these symptoms and no change in the general condition. This and a diminution of the villus length [7,8]. grade is an indication for intervention (for example, prokinetics, Mucus plays an important role in the mucosal defense by pre- postpyloric feeding) to restore the GI function. AGI grade III re- venting the traversal of bacteria, digestive enzymes, and water-solu- fers to the persistence of GI symptoms or worsening of multiple ble toxic molecules into the mucosal surface [9]. In critical illness- organ dysfunction syndrome and lack of improvement in enteral es, the role of the mucus is compromised. Consequently, the dam- feeding. This means that interventions cannot restore the GI func- age to the mucus layer results in epithelial cell dysfunction. Gut tion. Lastly, AGI grade IV refers to the presence of acute life-threat- ischemia/reperfusion leads to the loss of hydrophobicity of the ening GI problems [21] (Table 1). Studies regarding these grading mucus layer and altered intestinal permeability [9]. systems have shown that critically ill patients with GI dysfunction Under normal circumstances, approximately 40 trillion microor- have higher mortality rates than patients without AGI [22]. ganisms reside within the gut. Gut microbiota can degrade dietary During critical illness, excessive or inadequate adaptive respons- plant polysaccharides and proteins, to a small degree, by fermenta- es evoked by intensive stress can have negative effects on the gut tion. The main end products of the fermentation are short-chain motility, mucosal blood flow, and mucosal permeability [19,23- fatty acids (SCFAs) such as butyrate, acetate, and propionate. The 26]. Gut hyperpermeability and barrier dysfunction may lead to a SCFAs play an essential role in the maintenance of colonic integri- systemic inflammatory response syndrome, a clinical state that is ty and metabolism. It has been shown that butyrate serves as the also called “gut-derived sepsis” [27]. Sepsis induces a decrease in main energy source for colonocytes [10,11]. Several mechanisms the crypt proliferation [7]. Critical illness induces gut mucosal hy- regarding the maintenance of gut stability and homeostasis by mi- perpermeability as early as 1 hour after the onset of sepsis and lasts crobiota have been proposed [12]. at least 48 hours [3]. Preclinical studies have shown that the microbiome is essential In addition, catecholamines administered to treat shock may for the protection against enteric and systemic pathogens through lead to decreased microvascular perfusion in the gut [28]. This in- diverse mechanisms [13]. First, commensal microbiota can direct- duces an increase of apoptosis and decrease of proliferation of ly outcompete with intestinal pathogen or kill potential invaders by small bowel mucosal cells, leading to the thinning of gut mucosa producing defensins and signaling molecules [14]. Second, micro- [29]. The resulting gut damage is exacerbated in the presence of biota are potent inducers of the immune system [15]. chronic comorbidities such as cancer and chronic alcohol abuse [30,31]. Such injuries result in the impairment of the gut barrier Pathophysiology of gut injury and dysregulation of intestinal microbiota [32,33]. Therefore, small-intestinal mucosal integrity may be damaged in critically ill During critical illnesses, it is commonly observed that the gut is patients, leading to an increased intestinal permeability and intoler- susceptible to injury [16]. In the intensive care unit (ICU), ap- ance to enteral nutrition [34]. proximately 50% of the patients experience enterocyte damage Additionally, the gut microbiota is altered during conditions of

28 https://doi.org/10.12701/yujm.2020.00703 Yeungnam Univ J Med 2021;38(1):27-33

Table 1. Definition, example, and management of acute gastrointestinal (GI) injury Grade Definition Example Management I The function of the GI tract is partially impaired, Postoperative nausea and/or vomiting during Start or increase enteral feeding expressed as GI symptoms related to a known the first days after abdominal surgery, Re-evaluate daily cause, and perceived as transient postoperative absence of bowel sounds, diminished bowel motility in the early phase of shock II The GI tract is not able to perform digestion and Gastroparesis with high gastric residuals or Start therapy according to the symptom absorption adequately to satisfy the nutrient reflux, paralysis of the lower GI tract, diarrhea, (e.g., prokinetics) and fluid requirements of the body. There are IAH grade I (IAP 12–15 mmHg), visible blood Measure IAP no changes in general condition of the patient in gastric content or stool. Feeding intolerance related to GI problems is present if intake of at least 20 kcal/kg BW Start minimal enteral feeding per day (84 kJ/kg BW per day) via enteral Consider postpyloric feeding route cannot be achieved within 72 hr of feeding attempt III Loss of GI function and restoration of GI Despite treatment, feeding intolerance is Search for undiagnosed abdominal pathology function is not achieved despite interventions, persisting: high gastric residuals, persisting GI Continue therapy according to the symptom and the general condition is not improving paralysis, occurrence or worsening of bowel (e.g., prokinetics) dilatation, progression of IAH to grade II (IAP 15–20 mmHg), low APP (< 60 mmHg) Treat IAH Feeding intolerance is present and possibly Try (challenge) minimal feeding and start associated with persistence or worsening of parenteral nutrition multiple organ dysfunction syndrome IV Acute GI injury has progressed to become Bowel ischemia with necrosis, GI bleeding lead- Requiring laparotomy or other emergency directly and immediately life threatening, with ing to hemorrhagic shock, Ogilvie’s syndrome, interventions (e.g., colonoscopy for colonic worsening of multiple organ dysfunction abdominal compartment syndrome requiring decompression) syndrome and shock decompression Based on Reintam Blaser et al. [21]. IAH, intraabdominal hypertension; IAP, intraabdominal pressure; BW, body weight; kJ, kilojoules; APP, abdominal perfusion pressure. critical illness. Within hours of the onset of a critical illness, the 1. Gut-lung axis normal microbiota can convert to a disease-promoting pathobi- Evidence regarding the gut-lung axis emerged 20 years ago from ome [35]. The diversity of a microbiome is significantly impaired rat model studies of trauma and hemorrhagic shock [41]. It was during critical illness [3]. The etiology of such microbiome alter- demonstrated that during trauma and hemorrhagic shock, gut-de- ation in critical illness is multifactorial. These factors include an rived compounds translocated through the mesenteric lymph, isolated host milieu, ancestral or newly expressed genes, numerous causing distal lung injury [42]. medical drugs, nutrients, and nutrition support routes [3]. In injured gut microbiota, diet is the key to shaping the ecosystem of 2. Gut-brain axis the gut microbiome, which is important for host metabolism [36]. Recent research has shown that an extensive crosstalk between the In critically ill patients, the microbiota can be severely altered to be- gut microbiome and the brain through neuropeptides or endo- come unstable [37]. crine processes, immune system signaling, and nerve signaling. Critical illness leads to multiple changes to the microbiome, in- The gut microbiome has been suggested to play a role in the cogni- cluding the loss of diversity and overgrowth of pathogenic bacteria tive function and behavior [43,44]. [38]. Distortion of the composition and diversity of the gut microbiome is defined as “dysbiosis.” Recently, it has been hypothesized 3. Gut-kidney axis that gut microbiome injury can cause distant organ injury. Micro- Recent murine studies have shown that therapy with SCFAs in- biota-derived components such as pathogen-associated molecular cluding acetate, propionate, and butyrate has protective effects in patterns and metabolites derived from the gut can reach the circu- an ischemia/reperfusion model of acute kidney injury [45]. How- latory system and interact at a systemic level to influence the im- ever, another study showed that the renal resident macrophages in mune homeostasis [39,40]. the normal gut microbiome were sensitive to renal ischemia/ Such interactions or systemic host defense modulations be- reperfusion injury, resulting in initiation of inflammation and sub- tween a distant organ and the gut microbiome is increasingly stud- sequent nephropathy after renal injury. ied in disease research. Subsequently, the theory of gut-organ axes In contrast, the renal resident macrophages in a depleted gut mi- (gut-lung axis, gut-brain axis, gut-kidney axis, and gut-liver axis) crobiome are less sensitive to renal ischemia/reperfusion injury, re- has been developed [40]. sulting in an increased protection against renal ischemia/reperfu- https://doi.org/10.12701/yujm.2020.00703 29 Jung CY and Bae JM. Gut injury and protecting the gut in critical illness sion injury [46]. According to surviving sepsis guidelines, enteral nutrition is recommended as soon as possible [58]. However, the tool for identi- 4. Gut-liver axis fying patients who are likely to benefit from enteral nutrition The liver may also be injured when the gut is injured. The liver is among those who are critically ill with AGI and nutrition support exposed to bacterial components and their metabolites via portal protocol for decreasing enteral nutrition-related complications flow from the gut [47]. Therefore, the maintenance of gut mucosal show poor performances [53]. integrity during critical illness is very important. The microbiome approach such as the use of probiotics, fecal microbial transplantation (FMT), and selective decontamination Protection of gut and several approaches to of the digestive tract has been suggested [3]. However, its evidence enhancing gut integrity and permeability is not of high quality. Theoretically, the microbiome treatment will increase the number of “health-promoting” bacteria and decrease No treatment modality exists to significantly enhance the gut epi- that of the “disease-promoting” bacteria. A microbiome treatment thelial integrity, permeability, or mucus layer in critically ill pa- involves administering probiotics. Although significant evidence is tients. However, multiple helpful approaches including clinical and not yet obtained, meta-analyses have demonstrated that ventila- preclinical strategies exist. In animal studies, enteral nutrition can tor-associated pneumonia improves following the administration increase the blood flow in the gut during a “postprandial hyper- of probiotics [59]. FMT involves the administration of an entire emic response.” This may preserve the gut integrity and prevent microbiome from a healthy donor and is considered for Clostridi- gut-derived complications [48,49]. um difficile infections. Critically ill patients frequently receive anti- Enteral feed is associated with an increased mucosal mass and biotics, and their microbiome is expected to alter due to antibiotic villus height in animal and human studies [50,51]. The trophic ef- therapy. Therefore, FMT may be considered during critical illness- fects of enteral nutrition may help to maintain the intestinal physi- es [3]. However, the current evidence about microbiota-related ology, prevent atrophy of gut villi, reduce intestinal permeability, therapies in critical illness remains unclear and limited to preclini- protect against ischemia-reperfusion injury by stimulating intesti- cal settings [40]. nal perfusion, and preserve the gut immunity by affecting gut-asso- To promote rapid hypertrophy of the small bowel, several com- ciated lymphoid tissue [52]. However, the initiation of enteral nu- pounds have been reported, including epidermal growth factor, trition should be started carefully considering enteral nutrition-de- membrane permeant inhibitor of myosin light chain kinase, mucus rived complication, gut function, and contractility (e.g., ESICM surrogate, pharmacologic vagus nerve agonist, immune-enhancing WGAP recommendations) [53]. diet, and glucagon-like peptide-2 as preclinical strategies [60-64]. Several researchers have proposed that delayed trophic feeding However, the evidence remains unclear. Immune-enhancing nutri- (after 72 hours from intensive stress) is the optimal choice for criti- ents (e.g., glutamine, alanine) can stimulate the enteric blood flow, cally ill patients with AGI, although this lacks evidence. As a pro- maintain the mucosal barrier function by preserving tight-junction tective strategy, trophic feeding may reduce the gut burden, help to integrity, and induce the production and release of mucosal Ig and maintain the intestinal physiology, prevent mucosal atrophy, and critical endogenous growth factors [6] (Table 2). maintain the gut integrity in critically ill patients [54]. However, frequently providing enteral nutrition might have several complica- Conclusion tions, including vomiting, diarrhea, GI bleeding, aspiration pneumonia, refeeding syndrome, and gut ischemia [55,56]. In critically In critical illness, the gut is susceptible to injury due to multifactori- ill patients, enteral nutrition-related complications have been fre- al causes. No treatment modality exists to significantly enhance the quently observed [57]. gut barrier. Although current evidence is not of high quality, the

Table 2. Various materials to improve gut barrier and immunity Material Effect Epidermal growth factor [60] Improve gut apoptosis, proliferation, and permeability Glucagon-like peptide-2 [61] Promote sufficient gut hypertrophy Membrane permeant inhibitor of myosin light chain kinase [62] Improve intestinal permeability Mucus surrogate [63] Prevent trauma/hemorrhagic shock-induced gut injury Pharmacologic vagus nerve agonist [64] Attenuate toxic mesenteric lymph-induced lung injury

30 https://doi.org/10.12701/yujm.2020.00703 Yeungnam Univ J Med 2021;38(1):27-33 enteral feed is associated with an increased gut barrier. Therefore Amiot DM 2nd, Karl IE, et al. Sepsis from Pseudomonas aeru- microbiome treatment has been suggested. Additionally, in our re- ginosa pneumonia decreases intestinal proliferation and induc- view of the various studies, we concisely compiled the most up-to- es gut epithelial cell cycle arrest. Crit Care Med 2003;31:1630– date knowledge, on gut injury mechanisms and protection of the 7. gut during critical illness. Further investigations should be per- 8. Meng M, Klingensmith NJ, Liang Z, Lyons JD, Fay KT, Chen formed with respect to the treatment of gut damage during critical CW, et al. Regulators of intestinal epithelial migration in sepsis. illness. Shock 2019;51:88–96. 9. Qin X, Caputo FJ, Xu DZ, Deitch EA. Hydrophobicity of mu- Acknowledgments cosal surface and its relationship to gut barrier function. Shock 2008;29:372–6. Conflicts of interest 10. Cook SI, Sellin JH. Review article: short chain fatty acids in No potential conflicts of interest relevant to this article were report- health and disease. Aliment Pharmacol Ther 1998;12:499–507. ed. 11. Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Author contributions Gut Microbes 2016;7:189–200. Conceptualization: CYJ, JMB; Investigation and Resources: CYJ; 12. Dickson RP. The microbiome and critical illness. Lancet Respir Writing-original draft: CYJ, JMB; Writing-review & editing: JMB. Med 2016;4:59–72. 13. Haak BW, Levi M, Wiersinga WJ. Microbiota-targeted therapies Previous presentations on the intensive care unit. Curr Opin Crit Care 2017;23:167– The summary of this review was presented in the Acute and Criti- 74. cal Care Conference 2020 and the 40th Annual Meeting of Korean 14. Klingensmith NJ, Coopersmith CM. The gut as the motor of Society of Critical Care Medicine. multiple organ dysfunction in critical illness. Crit Care Clin 2016;32:203–12. ORCID 15. Pamer EG. Resurrecting the intestinal microbiota to combat an- Chang Yeon Jung, https://orcid.org/0000-0002-4681-0936 tibiotic-resistant pathogens. Science 2016;352:535–8. Jung Min Bae, https://orcid.org/0000-0003-0923-763X 16. Reintam A, Parm P, Kitus R, Kern H, Starkopf J. Gastrointesti- nal symptoms in intensive care patients. Acta Anaesthesiol References Scand 2009;53:318–24. 17. Piton G, Belon F, Cypriani B, Regnard J, Puyraveau M, Manzon 1. Helander HF, Fändriks L. Surface area of the digestive tract: re- C, et al. Enterocyte damage in critically ill patients is associated visited. Scand J Gastroenterol 2014;49:681–9. with shock condition and 28-day mortality. Crit Care Med 2. Allaire JM, Crowley SM, Law HT, Chang SY, Ko HJ, Vallance 2013;41:2169–76. BA. The intestinal epithelium: central coordinator of mucosal 18. Clark JA, Coopersmith CM. Intestinal crosstalk: a new para- immunity. Trends Immunol 2018;39:677–96. digm for understanding the gut as the “motor” of critical illness. 3. Otani S, Coopersmith CM. Gut integrity in critical illness. J In- Shock 2007;28:384–93. tensive Care 2019;7:17. 19. Meng M, Klingensmith NJ, Coopersmith CM. New insights 4. Knoop KA, Newberry RD. Goblet cells: multifaceted players in into the gut as the driver of critical illness and organ failure. Curr immunity at mucosal surfaces. Mucosal Immunol 2018;11: Opin Crit Care 2017;23:143–8. 1551–7. 20. Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. Intestinal 5. Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardal- mucosal lesion in low-flow states. I. A morphological, hemody- hon V, et al. Intestinal epithelial tuft cells initiate type 2 mucosal namic, and metabolic reappraisal. Arch Surg 1970;101:478–83. immunity to helminth parasites. Nature 2016;529:226–30. 21. Reintam Blaser A, Malbrain ML, Starkopf J, Fruhwald S, Jakob 6. Townsend CM, Sabiston DC, Beauchamp RD, Evers BM, Mat- SM, de Waele J, et al. Gastrointestinal function in intensive care tox KL. Sabiston textbook of surgery: the biological basis of patients: terminology, definitions and management. Recom- modern surgical practice. 20th ed. Philadelphia (PA): Elsevier; mendations of the ESICM Working Group on Abdominal 2017. Problems. Intensive Care Med 2012;38:384–94. 7. Coopersmith CM, Stromberg PE, Davis CG, Dunne WM, 22. Li H, Zhang D, Wang Y, Zhao S. Association between acute gas- https://doi.org/10.12701/yujm.2020.00703 31 Jung CY and Bae JM. Gut injury and protecting the gut in critical illness

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https://doi.org/10.12701/yujm.2020.00703 33 Original article eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):34-38 https://doi.org/10.12701/yujm.2020.00234

Association between gestational age at delivery and lymphocyte-monocyte ratio in the routine second trimester complete blood cell count Hyun-Hwa Cha, Jong Mi Kim, Hyun Mi Kim, Mi Ju Kim, Gun Oh Chong, Won Joon Seong Department of Obstetrics and Gynecology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea

Received: March 31, 2020 Revised: May 26, 2020 Background: We aimed to determine whether routine second trimester complete blood cell (CBC) Accepted: May 29, 2020 count parameters, including neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), and platelet-lymphocyte ratio (PLR), could predict obstetric outcomes. Corresponding author: Methods: We included singleton pregnancies for which the 50-g oral glucose tolerance test and Won Joon Seong CBC were routinely performed between 24 and 28 weeks of gestation in our outpatient clinic Department of Obstetrics and from January 2015 to December 2017. The subjects were divided into three groups according to Gynecology, Kyungpook National their pregnancy outcomes as follows: group 1, spontaneous preterm births, including preterm la- University Hospital, School of bor and preterm premature rupture of membranes; group 2, indicated preterm birth due to ma- Medicine, Kyungpook National ternal, fetal, or placental causes (hypertensive disorder, fetal growth restriction, or placental University, 807 Hoguk-ro, Buk-gu, Daegu 41404, Korea abruption); and group 3, term deliveries, regardless of the indication of delivery. We compared Tel: +82-53-200-2686 the CBC parameters using a bivariate correlation test. Fax: +82-53-200-2086 Results: The study included 356 pregnancies. Twenty-eight subjects were in group 1, 20 in group E mail: [email protected] 2, and 308 in group 3. There were no significant differences between the three groups in neutrophil, monocyte, lymphocyte, and platelet counts. Although there was no significant difference in NLR, LMR, and PLR between the three groups, LMR showed a negative correlation with gestational age at delivery (r =−0.126, p =0.016). Conclusion: We found that a higher LMR in the second trimester was associated with decreased gestational age at delivery. CBC parameters in the second trimester of pregnancy could be used to predict adverse obstetric outcomes.

Keywords: Blood cell count; Lymphocyte-monocyte ratio; Neutrophil-lymphocyte ratio; Preterm

Introduction (LMR), and platelet-lymphocyte ratio (PLR) have been used for the detection of malignant diseases [1,2] or the prediction of Preterm birth is a major cause of long-term morbidity and mortal- prognosis in various diseases [3-5]. Meanwhile, in pregnant wom- ity in infants. Therefore, there have been many studies about the en, CBC for verifying hematocrit or hemoglobin is usually etiology and pathophysiology of preterm birth and methods for checked between 24–28 weeks during gestational diabetes melli- its early prediction and prevention. tus (GDM) screening. Although CBC is not a good screening tool Complete blood cell (CBC) count parameters including neu- for pregnancy-associated diseases, it can provide valuable physio- trophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio logical information regarding pregnant women [6]. Labor is also

34 https://doi.org/10.12701/yujm.2020.00234 Yeungnam Univ J Med 2021;38(1):34-38 an inflammatory response; therefore, CBC parameters could be nificant when the p-value was below 0.05. used to predict preterm birth [7]. Recently, several studies have reported the association between CBC parameters and adverse Results obstetric outcomes such as GDM, hypertensive disorder, and preterm birth [8-12]. However, they were retrospective [8], During the study period, 50-g OGTT and CBC were performed case-control studies [10], or included cases after threatened on 577 singleton pregnant women in our outpatient clinic. Among preterm labor had developed [12]. This study aimed to determine them, 221 did not deliver their babies at our institution. Conse- whether routine second trimester CBC parameters during GDM quently, we were able to include 356 singleton pregnancies. For- screening could predict obstetric outcomes in pregnancy. ty-eight (13.5%) women delivered their babies before 370/7 weeks of gestation, with 28 (7.9%) being in group 1 and 20 (5.6%) in Materials and methods group 2. The maternal and neonatal outcomes are shown in Table 1. This prospective observational study was conducted at the There were no significant differences in maternal characteristics Kyungpook National University Hospital, Daegu, Korea, between except for maternal weight at delivery and the rate of cesarean sec- January 2015 and December 2017 and approved by the Institu- tion. However, neonatal characteristics, including gestational age at tional Review Board of the Kyungpook National University Chil- delivery, birth weight, and Apgar score, differed between the three gok Hospital (IRB No: 2019-12-009). groups. The comparison of CBC parameters between the three We included singleton pregnancies for which the 50-g oral glu- groups is shown in Table 2. No significant differences were found cose tolerance test (OGTT) and CBC count with differential in neutrophil, monocyte, lymphocyte, and platelet counts. More- count were routinely performed in the outpatient clinic between over, there was no significant difference in other CBC parameters 24 and 28 weeks of gestation. Pregnant women were divided into including NLR, LMR, and PLR between the three groups. How- three groups according to the pregnancy outcomes as follows: ever, we observed a negative correlation between LMR and gesta- group 1 included preterm births due to preterm labor, preterm tional age at delivery (r=−0.126, p=0.016) (Fig. 1). premature rupture of membranes (PPROM), or incompetent internal os of the cervix (IIOC). Preterm births were defined as Discussion births between 200/7 and 370/7 weeks of gestation. Preterm labor was defined as regular uterine contractions with a cervical change In this study, we compared the CBC parameters that were pro- occurring at least three times every 10 minutes before 370/7 weeks spectively obtained from routine GDM screening between 24 and of gestation. PPROM was defined as membrane rupture occur- 28 weeks of gestation according to the obstetric outcomes. Al- ring spontaneously without labor before 370/7 weeks of gestation. though there was no significant difference in CBC parameters ac- IIOC was defined as painless cervical dilatation in the second tri- cording to the obstetric outcomes defined as spontaneous mester. Group 2 included preterm births due to maternal, fetal, or preterm birth, indicated preterm birth, or term delivery, we found placental causes (hypertensive disorders including gestational hy- that LMR was negatively correlated with gestational age at deliv- pertension and preeclampsia (PE), fetal growth restriction which ery. Clinically, there seemed to be a positive correlation between was defined as the estimated fetal weight being suspected in the NLR and gestational age at delivery (p=0.074). These results bottom 10 percentile at the corresponding gestational age, or pla- suggested that an increased lymphocyte count in the second tri- cental abruption). Group 3 included term deliveries regardless of mester could be associated with a lower gestational age at delivery. the indication of delivery. The exclusion criteria were as follows: Recently, several inflammatory markers including CBC param- multifetal gestation, gravidas who had diseases that could influ- eters have been identified as predictive factors in various diseases ence maternal CBC count levels, including malignant diseases, [13,14]. Since labor is also an inflammatory response, the role of rheumatoid disorders, chronic hypertension, renal diseases, pre- inflammatory markers, such as C-reactive protein or CBC param- gestational diabetes mellitus, or hematologic diseases. We com- eters, has been assessed in term and preterm labor [7,12,15]. The pared CBC parameters between the three groups and evaluated analysis of inflammatory markers in addition to CBC parameters the association of gestational age at delivery with CBC parameters could be more informative; however, we aimed to obtain informa- using a bivariate correlation test. Statistical analyses were per- tion about obstetric outcomes from routine CBC sampling with- formed using the IBM SPSS version 19.0 (IBM Corp., Armonk, out an additional laboratory test. NY, USA) software. The results were considered statistically sig- Notably, there have been studies regarding the detection of ac- https://doi.org/10.12701/yujm.2020.00234 35 Cha HH et al. Complete blood cell parameters and obstetric outcomes

Table 1. Comparison of maternal and neonatal characteristics in three groups Variable Group 1 (n= 28) Group 2 (n= 20) Group 3 (n= 308) p-value Age (yr) 32.1±4.2 34.1±4.6 33.1±4.8 0.328a) GAL (wk) 25.2±1.6 25.6±1.4 25.0±1.4 0.200a) GAD (wk) 33.7±2.8 34.2±3.5 38.5±1.1 < 0.001a) Nulliparity 16 (57.1) 8 (40.0) 180 (58.4) 0.271b) Pre-pregnancy weight (kg) 54.6±2.1 58.5±3.1 56.6±0.6 0.498a) Maternal weight at delivery (kg) 63.0±1.9 70.3±3.0 68.9±0.6 0.023a) Cesarean section 15 (53.6) 20 (100) 178 (57.8) 0.001b) Male sex 20 (71.4) 14 (70.0) 160 (51.9) 0.050b) Birth weight (kg) 2.23±0.60 2.01±0.86 3.15±0.39 < 0.001a) AS< 4 at 1 min 2 (7.1) 5 (25.0) 4 (1.3) < 0.001b) AS< 7 at 5 min 2 (7.1) 2 (10.0) 3 (1.0) 0.002b) Values are presented as mean±standard deviation or number (%). GAL, gestational age at laboratory test; GAD, gestational age at delivery; AS, Apgar score. p-values are derived from a)analysis of variance test and b)Pearson chi-square test; the type 1 error was set to 0.05.

Table 2. Comparison of complete blood cell count parameters in three groups Parameter Group 1 (n= 28) Group 2 (n= 20) Group 3 (n= 308) p-valuea) WBC (× 103/mm3) 9.17±2.10 9.47±1.55 9.52±2.12 0.697 PLT (× 103/mm3) 237.75±51.48 210.50±53.66 237.74±58.53 0.124 Neutrophil (× 103/mm3) 6.85±1.75 7.31±1.64 7.30±2.10 0.493 Lymphocyte (× 103/mm3) 1,71±0.44 1.58±0.43 1.70±0.70 0.707 Monocyte (× 103/mm3) 0.41±0.15 0.40±0.13 0.44±0.46 0.854 NLR 4.17±1.22 5.12±2.28 4.59±1.66 0.150 LMR 4.45±1.52 4.55±2.50 4.42±2.40 0.968 PLR 140±38 155±54 149±49 0.533 Values are presented as mean±standard deviation. WBC, white blood cell count; PLT, platelet count; NLR, neutrophil-lymphocyte ratio; LMR, lymphocyte-monocyte ratio; PLR, platelet-lymphocyte ratio. a)p-value are derived from analysis of variance test; the type 1 error was set to 0.05.

20 40 400

15 30 300

10 20 200 PLR NLR LMR

5 10 100

0 0 0 A 25 30 35 40 45 B 25 30 35 40 45 C 25 30 35 40 45 GAD (wk) GAD (wk) GAD (wk)

Fig. 1. Correlations of gestational age at delivery with complete blood cell count parameters. (A) Neutrophil-to-lymphocyte ratio (NLR) does not show a statistically significant correlation with GAD (r=0.095, p=0.074). (B) Lymphocyte-to-monocyte ratio (LMR) shows a negative correlation with GAD (r=−0.126, p=0.016). (C) Platelet-to-lymphocyte ratio (PLR) does not show a statistically significant correlation with gestational age at delivery (r=0.063, p=0.216). GAD, gestational age at delivery.

36 https://doi.org/10.12701/yujm.2020.00234 Yeungnam Univ J Med 2021;38(1):34-38 tual preterm birth in women with threatened preterm labor using diabetes and diabetes mellitus. Previous studies have suggested CBC parameters [12,16]. Daglar et al. [12] reported that LMR the efficacy of CBC parameters as a prognostic factor in women was significantly increased in pregnant women with threatened with PE [10,11]. Gogoi et al. [10] showed that NLR, PLR, red preterm labor who delivered prematurely than in similar women cell distribution width, and mean platelet volume were higher in whose pregnancies continued to term. They also showed a nega- women with PE in a case-control study. Oylumlu et al. [11] sug- tive correlation between gestational age at delivery and LMR in gested that NLR could be used as a marker for risk stratification in preterm births. Additionally, Gezer et al. [16] reported that a high PE patients. We performed subgroup analysis that included indi- NLR value at the time of admission was an independent risk fac- cated preterm birth and term deliveries (group 2 vs. group 3, data tor for preterm birth in women with threatened preterm labor be- not shown), but there was no significant difference between the tween 34 and 37 weeks of gestation. We assumed that there had two groups. Unlike our study, studies by Gogoi et al. [10] and been an increase in neutrophil or lymphocyte counts in the group Oylumlu et al. [11] were retrospective or case-control studies that with true labor. However, these two studies evaluated the role of included patients diagnosed as having GDM or PE. Moreover, CBC parameters in women with threatened preterm labor. Unlike group 3 in our study group included pregnancies complicated these two studies, we prospectively collected maternal CBC pa- with PE beyond 37 weeks of gestation. rameters during routine 50-g OGTT and enrolled our patients This study has several limitations that need to be taken into before they had developed threatened preterm labor. consideration while interpreting the results. Although we ob- The differential count of CBC is known to change during nor- served a negative correlation between LMR and gestational age at mal pregnancy [6,17]. Li et al. [6] established a reference interval delivery, we could not clarify the mechanism underlying this phe- for CBC parameters during normal pregnancy in Chinese women nomenon. Moreover, our study sample was relatively small, and showing a decrease in lymphocyte count contrary to the changes we did not consider the obstetric complications in pregnancies in white blood cell count due to the increase in neutrophil count. beyond 37 complete weeks of gestation. However, we think that They suggested the increased neutrophil count was in response to the most important prognostic factor is the gestational age at de- the physiologic stress of pregnancy or impaired neutrophil apop- livery. Additionally, we evaluated CBC parameters before the on- tosis [6,17]. However, they did not comment about the changes set of obstetric complications unlike previous studies. Further in lymphocyte count that decreased during the first and second studies to evaluate CBC parameters considering the changes of trimesters of pregnancy and increased in the third trimester. those parameters between the second and third trimesters would Moreover, they recorded a definitive increase in monocytes provide predictive information about perinatal morbidity related during pregnancy [17]. The absence of lymphocyte count reduc- to the lower gestational age at delivery or preterm birth. tion or the monocyte count increase observed in a normal preg- Although there was no significant difference in CBC parame- nancy could imply a decrease in gestational age at delivery. ters according to obstetric outcomes, we found that a higher LMR LMR has been proposed as a surrogate marker for inflamma- in the second trimester was associated with a decreased gestation- tion and has prognostic value too [18-20]. Further, an abnormal al age at delivery. CBC parameters in the second trimester of preg- monocyte or lymphocyte count has been shown to have an ad- nancy could be used to predict adverse pregnancy outcomes. verse effect on the prognosis of various diseases [21,22]. In the field of obstetrics, there have been several studies regarding the as- Acknowledgments sociation between CBC parameters and obstetric complications in addition to the ability of CBC to predict preterm birth. Sargin Conflicts of interest et al. [8] investigated whether there were differences in the NLR No potential conflict of interest relevant to this article was report- and PLR between glucose intolerance (e.g., GDM patients), im- ed. paired glucose tolerance, GDM-screening-positive, and control groups. They concluded that NLR or PLR could not be used for the Author contributions screening of GDM. However, they also observed that the lympho- Conceptualization: WJS, HHC, GOC; Data duration: JMK, cyte and neutrophil counts were higher in the glucose-intolerance HMK, MJK; Investigation: HHC, JMK, MJK, HMK, GOC; group compared to those in the control group. However, Mertoglu Writing-original draft: HHC; Writing-review & editing: JMK, and Gunay [9] showed differences in NLR and PLR between glu- HMK, MJK, WJS, GOC. cose-intolerance and normal control groups in non-pregnant adults and they suggested that these markers could be used to predict pre- https://doi.org/10.12701/yujm.2020.00234 37 Cha HH et al. Complete blood cell parameters and obstetric outcomes

ORCID Int J Gynaecol Obstet 2019;144:16–20. Hyun-Hwa Cha, https://orcid.org/0000-0002-4399-7627 11. Oylumlu M, Ozler A, Yildiz A, Oylumlu M, Acet H, Polat N, et Jong Mi Kim, https://orcid.org/0000-0001-7455-6907 al. New inflammatory markers in pre-eclampsia: echocardio- Hyun Mi Kim, https://orcid.org/0000-0002-2985-9965 graphic epicardial fat thickness and neutrophil to lymphocyte Mi Ju Kim, https://orcid.org/0000-0001-9770-1580 ratio. Clin Exp Hypertens 2014;36:503–7. Gun Oh Chong, https://orcid.org/0000-0003-4887-4017 12. Daglar HK, Kirbas A, Kaya B, Kilincoglu F. The value of com- Won Joon Seong, https://orcid.org/0000-0002-8088-2554 plete blood count parameters in predicting preterm delivery. Eur Rev Med Pharmacol Sci 2016;20:801–5. References 13. Taylan M, Demir M, Kaya H, Selimoglu Sen H, Abakay O, Car- kanat AI, et al. Alterations of the neutrophil-lymphocyte ratio 1. Eo WK, Kim KH, Park EJ, Kim HY, Kim HB, Koh SB, et al. 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Indian J Hematol Blood Transfus 2012;28:144–6. phocyte ratio, monocyte count, mean platelet volume, and 18. Goto W, Kashiwagi S, Asano Y, Takada K, Takahashi K, Hatano platelet/lymphocyte ratio in endometrial cancer. Eur J Obstet T, et al. Predictive value of lymphocyte-to-monocyte ratio in Gynecol Reprod Biol 2018;226:25–9. the preoperative setting for progression of patients with breast 6. Li A, Yang S, Zhang J, Qiao R. Establishment of reference inter- cancer. BMC Cancer 2018;18:1137. vals for complete blood count parameters during normal preg- 19. Wang QX, Li SH, Ji BY, Wang HY, Li YY, Feng LL, et al. Lym- nancy in Beijing. J Clin Lab Anal 2017;31:e22150. phocyte/monocyte ratio is a novel predictor for early stage ex- 7. Gomez-Lopez N, StLouis D, Lehr MA, Sanchez-Rodriguez tranodal natural killer/T-cell lymphoma, nasal type. J Cancer EN, Arenas-Hernandez M. Immune cells in term and preterm 2017;8:1030–7. labor. Cell Mol Immunol 2014;11:571–81. 20. Zhu JY, Liu CC, Wang L, Zhong M, Tang HL, Wang H. Periph- 8. Sargin MA, Yassa M, Taymur BD, Celik A, Ergun E, Tug N. eral blood lymphocyte-to-monocyte ratio as a prognostic factor Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios: in advanced epithelial ovarian cancer: a multicenter retrospec- are they useful for predicting gestational diabetes mellitus tive study. J Cancer 2017;8:737–43. during pregnancy? Ther Clin Risk Manag 2016;12:657–65. 21. Charach G, Rogowski O, Karniel E, Charach L, Grosskopf I, 9. Mertoglu C, Gunay M. Neutrophil-lymphocyte ratio and plate- Novikov I. Monocytes may be favorable biomarker and predic- let-lymphocyte ratio as useful predictive markers of prediabetes tor of long-term outcome in patients with chronic heart failure: and diabetes mellitus. Diabetes Metab Syndr 2017;11(Suppl 1) a cohort study. Medicine (Baltimore) 2019;98:e17108. 1:S127–31. 22. Feng F, Zheng G, Wang Q, Liu S, Liu Z, Xu G, et al. Low lym- 10. Gogoi P, Sinha P, Gupta B, Firmal P, Rajaram S. Neutro- phocyte count and high monocyte count predicts poor progno- phil-to-lymphocyte ratio and platelet indices in pre-eclampsia. sis of gastric cancer. BMC Gastroenterol 2018;18:148.

38 https://doi.org/10.12701/yujm.2020.00234 Original article eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):39-46 https://doi.org/10.12701/yujm.2020.00276

Pelvic floor muscle exercise with biofeedback helps regain urinary continence after robot-assisted radical prostatectomy Yeong Uk Kim1, Dong Gyu Lee2, Young Hwii Ko3 1Department of Urology, Yeungnam Hospital, of Medicine, Daegu, Korea 2Department of Physical Medicine and Rehabilitation, Yeungnam University College of Medicine, Daegu, Korea 3Department of Urology, Yeungnam University College of Medicine, Daegu, Korea

Received: April 12, 2020 Revised: May 5, 2020 Background: To determine the benefit of pelvic floor muscle exercise (PFME) with visual biofeed- Accepted: May 7, 2020 back on promoting patient recovery from incontinence, we investigated variables associated with the early restoration of continence for patients who underwent robot-assisted radical prostatec- Corresponding author: tomy (RARP). Young Hwii Ko Methods: Of the 83 patients enrolled, 41 consecutive patients completed PFME (the exercise Department of Urology, Yeungnam group), and the other 42 consecutive patients just before the PFME program commenced (the University College of Medicine, 170 control group). The primary outcome was whether PFME engagement was associated with zero Hyeonchung-ro, Namgu, Daegu pad continence restoration within 3 months of surgery. 42415, Korea Results: Continence restoration percentages (defined as zero pads used per day) at 1, 3, and 6 Tel: +82-53-620-3694 Fax: +82-53-627-5535 months after surgery were 49.4%, 77.1%, and 94.0%, respectively. The exercise group achieved E-mail: [email protected] significantly higher recovery rates at 1 month (p=0.037), 3 months (p<0.001), and 6 months (p=023). Cox regression analysis demonstrated that a lower Gleason score (<8; hazard ratio [HR], 2.167), lower prostate specific antigen (<20 ng/dL; HR, 2.909), and engagement in PFME (HR, 3.731) were independent predictors of early recovery from postprostatectomy incontinence. Stratification by age showed that those younger than 65 years did not benefit significantly from exercise (log-rank test, p=0.08), but that their elderly counterparts, aged 65–70 years (p=0.007) and >70 years old (p=0.002) benefited significantly. Conclusion: This study suggests that postoperative engagement in PFME with biofeedback speeds up the recovery of continence in elderly patients (≥65 years old) that undergo RARP.

Keywords: Aged; Biofeedback; Prostatectomy; Urinary incontinence

Introduction bot-assisted radical prostatectomy (RARP), has resulted in RP be- coming the contemporary treatment of choice. However, postpros- Radical prostatectomy (RP) is a standard treatment for non-meta- tatectomy incontinence (PPI) remains a serious issue that dimin- static prostate cancer [1]. Increased enthusiasm for radical organ re- ishes postoperative quality of life [2]. The majority of patients expe- moval as a reliable treatment option for high-risk or locally advanced rience urinary incontinence immediately after RP, and in some cases disease, combined with the minimal invasiveness unique to ro- this incontinence is protracted. As such, urinary incontinence is a

Copyright © 2021 Yeungnam University College of Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. https://doi.org/10.12701/yujm.2020.00276 39 Kim YU et al. Pelvic floor muscle exercise helps earlier continence in the elderly major source of concern for patients requiring RP or RARP. 2. Pelvic floor muscle exercise As a postoperative intervention, pelvic floor muscle exercise Patients in the exercise group began engaging in PFME immedi- (PFME), with or without biofeedback, is known to promote mus- ately after Foley catheter removal, which was routinely performed cle contraction and hasten recovery from PPI. Although initial tri- 5 days after RARP. Patients received PFME with biofeedback on als produced promising results, systematic reviews have led to an outpatient basis for 30 minutes per week until continence was questions regarding the efficacy of PFME [3]. Furthermore, no regained or 4 weeks had elapsed. Ultrasonography was used to vi- large-scale randomized controlled trials (RCTs) have been con- sualize pelvic floor muscle contractions. Patients were asked to ducted to test the efficacy of PFME with biofeedback, although a perform 20–25 contractions with durations from 3–5 seconds at trial is underway [4]. In addition, published evidence regarding submaximal strength in the lateral decubitus, supine (with hips the efficacy of existing PFME programs for preventing and treat- flexed at 60°), and standing positions. A relaxation period of 6–10 ing PPI is inconsistent [5]. seconds was allowed between contractions. The physiotherapist In an attempt to identify factors that hasten the restoration of checked pelvic floor muscles by palpating the perineum, exam- continence, we compared outcomes between patients who en- ined contractions via ultrasonography in each position, and gaged in PFME with visual biofeedback and patients who engaged showed patients how to contract pelvic floor muscles correctly on in the Kegel exercise with verbal instructions alone. Given uncer- avoiding Valsalva maneuver. In addition, patients were asked to tainties regarding the benefits of PFME, we minimized confound- repeat the exercise at home. Patients in the control group were ing factors by using data from patients treated by a single surgeon, given verbal instructions on the Kegel exercise by a single urolo- using the same RARP technique over a period of 1 year. gist and asked to perform 50–100 exercises daily at home while lying, sitting, and standing. Material and methods 3. Outcome assessments 1. Recruitment of the exercise and study groups Postoperatively, all 83 patients were routinely followed-up in an This study was approved by the Institutional Review Board of the outpatient office at 1 week and 1, 3, and 6 months after surgery. Yeungnam University Hospital (IRB No: 2020-05-001). During each visit, patients were asked about daily pad use and the All patients that underwent RARP, performed by a single experi- last date of pad usage. Continence in this study was strictly de- enced surgeon (YHK) from September 2018 to August 2019, were fined as the cessation of pad use, regardless of the type of pad enrolled in this study. During RARP three procedures were per- used. The primary outcome of this study was the determination formed: unilateral, bilateral, or no nerve-sparing; bladder neck pres- of whether PFME with biofeedback impacts the restoration of ervation; and posterior reconstruction. The same surgical tech- continence within the 3 months following RARP. niques were used throughout the 12-month study period. The study exclusion criteria were as follows: previous pelvic radiation 4. Statistical analysis therapy, poor compliance due to psychiatric or medical problems, Group clinicopathological characteristics were compared using previous prostate surgery, and <3 months of follow-up after sur- Student t-test for continuous variables and a chi-squared test for gery. Of the 94 patients initially considered, two men that required a categorical variables. Given the well-documented association be- cardiac procedure after RARP and nine that were followed for <3 tween time and recovery from PPI, the Cox proportional hazards months were excluded. Accordingly, 83 participants constituted the model was used to identify predictors of early continence resto- study cohort. Forty-one of the 83 participants (49.4%) engaged in ration. The Kaplan-Meier method with the log-rank test was used PFME with biofeedback (the exercise group), while the other 42 to compare groups with respect to time to continence. Data were did not (the control group), as they underwent RARP using the analyzed using IBM SPSS version 19.0 (IBM Corp., Armonk, NY, same technique just before the PFME program was adopted. USA). All tests were two-sided and p-values < 0.05 were consid- In the exercise group, PFME with biofeedback was performed ered statistically significant. by a single physiotherapist (DGL) on patients that underwent RARP between March 2019 and August 2019. Patients in the Results control group underwent RARP between September 2018 and February 2019 and performed the Kegel exercise at home after 1. Participant characteristics being given oral instructions by a urologist (YHK). The characteristics of patients in the exercise (PFME with biofeedback) and the control (conventional Kegel exercise) groups

40 https://doi.org/10.12701/yujm.2020.00276 Yeungnam Univ J Med 2021;38(1):39-46 are summarized in Table 1. Continuous and categorical variables (p< 0.001), and 6 months (p= 0.023) (Table 2). Three months were similar in the two groups, except initial serum prostate spe- after surgery, all 41 patients in the exercise group had regained cific antigen (PSA) levels, which were significantly higher in the continence. Furthermore, the mean time to restored continence exercise group (p= 0.025). However, the proportions of patients was significantly shorter in the exercise group (32.4 vs. 95.3 days, with a PSA value ≥ 20 ng/dL (the cut-off for high-risk disease) p< 0.001) (Fig. 1). Other than the implementation of PFME in- was similar (p= 0.276) across groups. The proportion of patients structions, no factors differed between participants who had or with a Gleason score > 8 was marginally higher in the exercise had not regained continence after 3 months (Table 3). group (p= 0.09). 3. Multivariate analysis of early continence restoration and 2. Continence outcomes and variables associated with post-hoc analysis by age early continence restoration Cox proportional hazards analysis demonstrated that a lower Glea- Continence restoration rates for all study subjects at 1 week, and son score (<8; hazard ratio [HR], 2.167), a lower initial PSA (<20 1, 3, and 6 months after surgery were 18.1%, 49.4%, 77.1%, and ng/dL; HR, 2.909), and PFME completion (HR, 3.731) were as- 94.0%, respectively. The exercise group had higher rates of conti- sociated with continence restoration within 3 months of RARP nence restoration than controls at 1 month (p= 0.037), 3 months (Table 4). After stratifying all study subjects by age, those aged <65

Table 1. Characteristics of the patients enrolled PFME with biofeedback group Conventional Kegel exercise group Total (n= 41, 49.4%) (n= 42, 50.6%) (n= 83) p-value Age (yr) 68.4±5.98 67.7±4.90 68.1±5.44 0.561 < 65 12 (29.3) 13 (31.0) 25 0.952 65−70 16 (39.0) 17 (40.5) 33 > 70 13 (31.7) 12 (28.5) 25 Diabetes mellitus No 37 (90.2) 34 (81.0) 71 0.229 Yes 4 (9.8) 8 (19.0) 12 Coronary heart disease No 36 (87.8) 40 (95.2) 76 0.223 Yes 5 (12.2) 2 (4.8) 7 Gleason score <8 23 (56.1) 31 (73.8) 54 0.091 ≥8 18 (43.9) 11 (26.2) 29 Prostate volume (gm) 33.8±15.2 36.2±13.8 35.0±14.5 0.448 < 40 31 (75.6) 27 (64.3) 58 0.261 ≥ 40 10 (24.4) 15 (35.7) 25 Initial PSA (ng/dL) 45.4±78.7 16.8±20.5 30.9±58.6 0.025 < 20 29 (70.7) 34 (81.0) 63 0.276 ≥ 20 12 (29.3) 8 (19.0) 20 Pathological T stage ≤ pT2 19 (46.3) 24 (57.1) 43 0.325 ≥ pT3 22 (53.7) 18 (42.9) 40 Nerve-sparing procedure Non-NS 33 (80.5) 35 (83.3) 68 0.736 NS RARP 8 (19.5) 7 (16.7) 15 Adjuvant radiation No RT 39 (95.1) 40 (95.2) 79 0.98 Adjuvant RT 2 (4.9) 2 (4.8) 4 Values presented as mean±standard deviation or number (%). PFME, pelvic floor muscle exercise; PSA, prostate specific antigen; NS, nerve-sparing; RARP, robot-assisted radical prostatectomy; RT, radiation therapy. https://doi.org/10.12701/yujm.2020.00276 41 Kim YU et al. Pelvic floor muscle exercise helps earlier continence in the elderly

Table 2. Continence outcome between PFME with biofeedback and conventional Kegel exercise groups PFME with biofeedback group Conventional Kegel exercise group Total (n= 41, 49.4%) (n= 42, 50.6%) (n= 83) p-value Pad period (day) 32.4±30.3 95.3±98.5 64.2±79.4 < 0.001 Continence regain within 1 wk Zero pad 9 (22.0) 6 (14.3) 15 (18.1) 0.364 Incontinence 32 (78.0) 36 (85.7) 68 (81.9) Continence regain within 1 mo Zero pad 25 (61.0) 16 (38.1) 41 (49.4) 0.037 Incontinence 16 (39.0) 26 (61.9) 42 (50.6) Continence regain within 3 mo Zero pad 41 (100) 23 (54.8) 64 (77.1) < 0.001 Incontinence 0 19 (45.2) 19 (22.9) Continence regain within 6 mo Zero pad 41 (100) 37 (88.1) 78 (94.0) 0.023 Incontinence 0 5 (11.9) 5 (6.0) Values presented as mean±standard deviation or number (%). PFME, pelvic floor muscle exercise.

1.0 reported to last as long as 1–2 years after surgery [7]. The physiological mechanism underlying PPI is multifactorial and has been attributed, in part, to damage to the sphincter. This 0.8 structure is composed of smooth inner muscles and the rhabdo-sphincter muscle [8-10]. PPI also compromises a supporting 0.6 system, including Denonvilliers’ fascia, the puboprostatic ligament, the endopelvic fascia, and the levator ani muscle, during RP 0.4 [11]. Based on these mechanisms, many intraoperative interventions have been devised to reduce the severity and incidence of

One minus cum survival PPI. These include bladder neck preservation, posterior recon- 0.2 Control group Exercise group struction, and a nerve-sparing procedure [12-14]. PFME with or without biofeedback is a type of postoperative 0 intervention that improves urinary continence after RP. Accord- 50 100 150 200 ing to the European Association of Urology guidelines, PFME Pad period (day) with or without biofeedback is the recommended option for conservative management of PPI [15]. Theoretically, PFME im- Fig. 1. Time to urinary incontinence in all patients (log-rank test proves sphincter function by enhancing rhabdosphincter tone p <0.001). and strengthening levator ani muscles [16]. Several studies have reported on the short- and long-term effects of PFME with bio- years were found to receive no significant benefit from exercise (log- feedback. Ribeiro et al. [17] conducted an RCT of 73 patients rank test, p=0.08) (Fig. 2A). In contrast, patients ranging from 65– and demonstrated that early PFME with biofeedback after RARP 70 years of age (p=0.007) (Fig. 2B) and those older than 70 years was superior to conventional PFME, as measured by the conti- (p=0.002) (Fig. 2C) benefited significantly from PFME. nence recovery rate at 1 year after surgery (96% vs. 75%; p= 0.028). Burgio et al. [18] suggested that preoperative behavioral training Discussion can reduce time to recovery of urine control and reduce the severity of incontinence after RP. On the other hand, Bales et al. [19] The incidence of PPI has been reported to range from as low as reported that continence restoration at 1, 2, 3, and 4 months after 2% to as high as 87% with significant leakage in 0.3%–12.5% of surgery was not significantly different between biofeedback and patients at 1 month after surgery [6]. Furthermore, PPI has been control groups. Overgard et al. [20] carried out an RCT of 85 pa-

42 https://doi.org/10.12701/yujm.2020.00276 Yeungnam Univ J Med 2021;38(1):39-46

Table 3. Comparison of the patient who obtained continence within 3 months after surgery or not Continence within 3 mo Variable Total (n= 83) p-value Continence (n= 64, 77.1%) Incontinence (n= 19, 22.9%) Age (yr) 68.0±5.45 68.3±5.53 68.1±5.44 0.854 < 65 20 (31.3) 5 (26.4) 25 0.763 65−70 26 (40.6) 7 (36.8) 33 > 70 18 (28.1) 7 (36.8) 25 Diabetes mellitus No 55 (85.9) 16 (84.2) 71 0.851 Yes 9 (14.1) 3 (15.8) 12 Coronary heart disease No 58 (90.6) 18 (94.7) 76 0.571 Yes 6 (9.4) 1 (5.3) 7 Gleason score <8 41 (64.1) 13 (68.4) 54 0.726 ≥8 23 (35.9) 6 (31.6) 29 Prostate volume (gm) 34.0±15.1 38.5±12.3 35.0±14.5 0.234 < 40 47 (73.4) 11 (57.9) 58 0.195 ≥ 40 17 (26.6) 8 (42.1) 25 Initial PSA (ng/dL) 33.2±65.1 23.5±27.9 30.9±58.6 0.529 < 20 50 (78.1) 13 (68.4) 63 0.385 ≥ 20 14 (21.9) 6 (31.6) 20 Pathological T stage ≤ pT2 30 (46.9) 13 (68.4) 43 0.099 ≥ pT3 34 (53.1) 6 (31.6) 40 Nerve-sparing procedure Non-NS 54 (84.4) 14 (73.7) 68 0.288 NS RARP 10 (15.6) 5 (26.3) 15 Adjuvant radiation No RT 61 (95.3) 18 (94.7) 79 0.918 Adjuvant RT 3 (4.7) 1 (5.3) 4 PFME with biofeedback No 23 (35.9) 19 (100.0) 42 < 0.001 Yes 41 (64.1) 0 (0.0) 41 Values presented as mean±standard deviation or number (%). PSA, prostate specific antigen; NS, nerve-sparing; RARP, robot-assisted radical prostatectomy; RT, radiation therapy; PFME, pelvic floor muscle exercise.

tients and found that early continence restoration rates were simi- RP, many factors that might predispose patients to PPI, such as lar in a PFME with biofeedback group and in a control group type of surgery or number of surgeons, were not controlled. In a (46% vs. 43%, p= 0.73). Therefore, the efficacy of perioperative study by Geraerts et al. [22], RP was performed by open surgery PFME with biofeedback remains a controversial topic. or RARP and patient numbers between these two groups were We defined continence as the cessation of daily pad use. Several unequal (open= 116 vs. RARP= 54), and in a multicenter study studies defined continence as the use of a single safety or 0 pads by Floratos et al. [23], radical prostatectomies were conducted by daily [17,20], whereas others defined it based on 1 hour or 24 any of four experienced surgeons. These factors can lead to statis- hours pad test results, as recommended by the International Con- tical errors when assessing the efficacy of PFME for PPI. On the tinence Society [21]. We believe that defining continence based other hand, the present study was conducted at a single institute on pad usage is sufficient for the assessment of continence and by a surgeon who had experience with more than 200 cases. more convenient for patients than the pad test. Additionally, we investigated the independent factors including Unfortunately, in some studies of the efficacy of PFME after PFME with biofeedback for early continence restoration, based https://doi.org/10.12701/yujm.2020.00276 43 Kim YU et al. Pelvic floor muscle exercise helps earlier continence in the elderly

Table 4. Cox–continence regain within 3 months Variable (reference value) p-value OR (95% CI) Age (< 65 yr) 0.149 1.535 (0.857−2.749) Diabetes mellitus (no) 0.165 1.753 (0.793−3.873) Coronary heart disease (no) 0.952 0.968 (0.338−2.773) Gleason score (< 8) 0.040 2.167 (1.035−4.539) Prostate volume (< 40 gm) 0.342 0.743 (0.403−1.371) Initial PSA (< 20 ng/dL) 0.018 2.909 (1.197−7.072) Pathological T stage (≤ pT2) 0.917 0.965 (0.497−1.876) Nerve-sparing (yes) 0.573 0.760 (0.292−1.977) Adjuvant radiation (no) 0.735 0.798 (0.217−2.941) PFME (yes) < 0.001 3.731 (2.081−6.690) OR, odds ratio; CI, confidence interval; PSA, prostate specific antigen; PFME, pelvic floor muscle exercise.

Age <65 yr Age 65-70 yr Age >70 yr 1.0 1.0 1.0 0.8 0.8 0.8

0.6 0.6 0.6

0.4 0.4 0.4

0.2 0.2 0.2 Control group Control group Control group

One minus cum survival Exercise group One minus cum survival Exercise group One minus cum survival Exercise group 0 0 0 50 100 150 200 50 100 150 200 50 100 150 200 A Pad period (day) B Pad period (day) C Pad period (day)

Fig. 2. (A) Time to urinary incontinence in men under 65 years of age (log-rank test p =0.08). (B) Time to urinary incontinence in men between 65 to 70 years of age (log-rank test p=0.007). (C) Time to urinary incontinence in men over 70 years of age (log-rank test p=0.002). on the days of pads used. In the majority of previous studies on feedback for patients with PPI is more effective in elderly men. the effectiveness of PFME with biofeedback, predictive factors, The present study has a number of limitations that deserve con- such as age, receipt of a nerve-sparing procedure, and type of sur- sideration. First, the number of patients enrolled was relatively gery, were not considered. We believe that it will be statistically small and the study was inherently limited by its retrospective de- persuasive to establish the relationship between early continence sign. However, by adopting data derived from a single surgeon’s restoration and other clinic-pathological factors for PPI, including experience, we sought to minimize the influence of potential co- PFME with biofeedback, because these factors could also affect variates. Second, we focused on early recovery, and did not inves- PPI recovery rates. tigate the long-term effects of PFME with biofeedback, because In our study, PFME with biofeedback had a more positive im- experience has shown that the benefits of PFME with biofeed- pact on PPI in elderly men (> 70 years old) than in younger men. back manifest during the earlier stages of recovery. Third, In a systematic review of factors that contribute to PPI, age was self-questionnaires, such as the International Prostate Symptom found to have a negative impact on continence rate after RP [24]. Score or International Consultation on Incontinence Question- Simard and Tu [25] reported that pelvic floor muscle rehabilita- naire, were not used, although the majority of recent studies have tion with physiotherapy was effective in elderly women with uri- used self-questionnaires to determine outcomes. Therefore, we nary incontinence. However, no study has addressed the relation- suggest that further larger-scale studies be conducted to assess the ship between age and the efficacy of PFME with biofeedback. efficacy of PFME with biofeedback, especially in elderly men. Based on the results of this study, we suggest that PFME with bio- In conclusion, PFME with visual biofeedback was found to be

44 https://doi.org/10.12701/yujm.2020.00276 Yeungnam Univ J Med 2021;38(1):39-46 an effective intervention for promoting early continence resto- Bruskewitz RC. A prospective study of quantification of urinary ration (within 3 months) in patients that suffered from urinary in- incontinence and quality of life in patients undergoing radical continence after RARP. Furthermore, this study showed that retropubic prostatectomy. Urology 1996;48:433–40. PFME with biofeedback more effectively results in early conti- 7. Sanda MG, Dunn RL, Michalski J, Sandler HM, Northouse L, nence restoration, after RARP, in elderly men. Hembroff L, et al. Quality of life and satisfaction with outcome among prostate cancer-survivors. N Engl J Med 2008;358: Acknowledgments 1250–61. 8. Chao R, Mayo ME. Incontinence after radical prostatectomy: Conflicts of interest detrusor or sphincter causes. J Urol 1995;154:16–8. No potential conflict of interest relevant to this article was report- 9. Desautel MG, Kapoor R, Badlani GH. Sphincteric inconti- ed. nence: the primary cause of post-prostatectomy incontinence in patients with prostate cancer. Neurourol Urodyn 1997;16:153– Author contributions 60. Conceptualization: all authors; Formal analysis: YUK; Methodol- 10. Ficazzola MA, Nitti VW. The etiology of post-radical prostatec- ogy: DGL; Project administration, Supervision: YHK; Investiga- tomy incontinence and correlation of symptoms with urody- tion: YUK; Writing-original draft: YUK; Writing-review & edit- namic findings. J Urol 1998;160:1317–20. ing: YHK. 11. Kojima Y, Takahashi N, Haga N, Nomiya M, Yanagida T, Ishibashi K, et al. Urinary incontinence after robot-assisted radi- ORCID cal prostatectomy: pathophysiology and intraoperative tech- Yeong Uk Kim, https://orcid.org/0000-0002-8783-9567 niques to improve surgical outcome. Int J Urol 2013;20:1052– Dong Gyu Lee, https://orcid.org/0000-0002-4787-4448 63. Young Hwii Ko, https://orcid.org/0000-0002-9150-4292 12. Srivastava A, Chopra S, Pham A, Sooriakumaran P, Durand M, Chughtai B, et al. Effect of a risk-stratified grade of nerve-spar- References ing technique on early return of continence after robot-assisted laparoscopic radical prostatectomy. Eur Urol 2013;63:438–44. 1. Yossepowitch O, Eggener SE, Bianco FJ Jr, Carver BS, Serio A, 13. Freire MP, Weinberg AC, Lei Y, Soukup JR, Lipsitz SR, Prasad Scardino PT, et al. Radical prostatectomy for clinically localized, SM, et al. Anatomic bladder neck preservation during robot- high risk prostate cancer: critical analysis of risk assessment ic-assisted laparoscopic radical prostatectomy: description of methods. J Urol 2007;178:493–9. technique and outcomes. Eur Urol 2009;56:972–80. 2. Ficarra V, Novara G, Rosen RC, Artibani W, Carroll PR, Costel- 14. Rocco F, Carmignani L, Acquati P, Gadda F, Dell'Orto P, Rocco lo A, et al. Systematic review and meta-analysis of studies re- B, et al. Early continence recovery after open radical prostatec- porting urinary continence recovery after robot-assisted radical tomy with restoration of the posterior aspect of the rhabdo- prostatectomy. Eur Urol 2012;62:405–17. sphincter. Eur Urol 2007;52:376–83. 3. Chang JI, Lam V, Patel MI. Preoperative pelvic floor muscle ex- 15. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De ercise and postprostatectomy incontinence: a systematic review Santis M, et al. EAU-ESTRO-SIOG guidelines on prostate can- and meta-analysis. Eur Urol 2016;69:460–7. cer. Part 1: screening, diagnosis, and local treatment with cura- 4. Averbeck MA, Marcelissen T, Anding R, Rahnama'i MS, Sahai tive intent. Eur Urol 2017;71:618–29. A, Tubaro A. How can we prevent postprostatectomy urinary 16. Anderson CA, Omar MI, Campbell SE, Hunter KF, Cody JD, incontinence by patient selection, and by preoperative, peroper- Glazener CM, et al. Conservative management for postprosta- ative, and postoperative measures? International Consultation tectomy urinary incontinence. Cochrane Database Syst Rev on Incontinence-Research Society 2018. Neurourol Urodyn 2015;1:CD001843. 2019;38:119–26. 17. Ribeiro LH, Prota C, Gomes CM, de Bessa J Jr, Boldarine MP, 5. Hodges PW, Stafford RE, Hall L, Neumann P, Morrison S, Dall'Oglio MF, et al. Long-term effect of early postoperative Frawley H. Reconsideration of pelvic floor muscle training to pelvic floor biofeedback on continence in men undergoing radi- prevent and treat incontinence after radical prostatectomy. Urol cal prostatectomy: a prospective, randomized, controlled trial. J Oncol 2019;24:1–18. Urol 2020;184:1034–9. 6. Jonler M, Madsen FA, Rhodes PR, Sall M, Messing EM, 18. Burgio KL, Goode PS, Urban DA, Umlauf MG, Locher JL, https://doi.org/10.12701/yujm.2020.00276 45 Kim YU et al. Pelvic floor muscle exercise helps earlier continence in the elderly

Bueschen A, et al. Preoperative biofeedback assisted behavioral breugel B, De Groef A, et al. Influence of preoperative and post- training to decrease post-prostatectomy incontinence: a ran- operative pelvic floor muscle training (PFMT) compared with domized, controlled trial. J Urol 2006;175:196–201. postoperative PFMT on urinary incontinence after radical 19. Bales GT, Gerber GS, Minor TX, Mhoon DA, McFarland JM, prostatectomy: a randomized controlled trial. Eur Urol 2013; Kim HL, et al. Effect of preoperative biofeedback/pelvic floor 64:766–72. training on continence in men undergoing radical prostatecto- 23. Floratos DL, Sonke GS, Rapidou CA, Alivizatos GJ, Deliveliotis my. Urology 2000;56:627–30. C, Constantinides CA, et al. Biofeedback vs verbal feedback as 20. Overgard M, Angelsen A, Lydersen S, Morkved S. Does physio- learning tools for pelvic muscle exercises in the early manage- therapist-guided pelvic floor muscle training reduce urinary in- ment of urinary incontinence after radical prostatectomy. BJU continence after radical prostatectomy? A randomized con- Int 2002;89:714–9. trolled trial. Eur Urol 2008;54:438–48. 24. Heesakkers J, Farag F, Bauer RM, Sandhu J, De Ridder D, Stenzl 21. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, A. Pathophysiology and contributing factors in postprostatecto- Lee J, et al. An International Urogynecological Association my incontinence: a review. Eur Urol 2017;71:936–44. (IUGA)/International Continence Society (ICS) joint report 25. Simard C, Tu LM. Long-term efficacy of pelvic floor muscle re- on the terminology for female pelvic floor dysfunction. Int Uro- habilitation for older women with urinary incontinence. J Ob- gynecol J 2010;21:5–26. stet Gynaecol Can 2010;32:1163–6. 22. Geraerts I, Van Poppel H, Devoogdt N, Joniau S, Van Cleynen-

46 https://doi.org/10.12701/yujm.2020.00276 Original article eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):47-52 https://doi.org/10.12701/yujm.2020.00325 Evaluation of craniofacial morphology in short-statured children: growth hormone deficiency versus idiopathic short stature Ki Bong Kim1,*, Eun-Kyong Kim2,*, Kyung Mi Jang3, Min Seon Kim4, Eun Young Park1 1Department of Dentistry, Yeungnam University College of Medicine, Daegu, Korea 2Department of Dental Hygiene, College of Science and Technology, Kyungpook National University, Sangju, Korea 3Department of Pediatrics, Yeungnam University College of Medicine, Daegu, Korea 4Department of Dentistry, Yeungnam University Hospital, Daegu, Korea

Received: May 7, 2020 Revised: June 5, 2020 Background: Short stature is defined as a height below the 3rd percentile or more than two stan- Accepted: June 11, 2020 dard deviations below the mean for a given age, sex, and population. There have been inconsistent results regarding craniofacial morphology in short-statured children. This study aimed to an- Corresponding author: alyze the differences between short-statured children with growth hormone deficiency, idiopath- Eun Young Park ic short-statured children, and normal children. Department of Dentistry, Yeungnam Methods: Thirty-one short-statured children with growth hormone deficiency, 32 idiopathic University College of Medicine, 170 short-statured children, and 32 healthy children were enrolled in this study. The measurements of Hyeonchung-ro, Nam-gu, Daegu their craniofacial structures from lateral cephalograms were evaluated. 42415, Korea Results: There were statistically significant differences among the three groups seven variables Tel: +82-53-620-3282 Fax: +82-53-629-1772 (anterior cranial base length, posterior cranial base length, total cranial base length, upper poste- E-mail: [email protected] rior facial height, posterior total facial height, mandibular ramus length, and overall mandibular length) in the linear measurement and five variables (saddle angle, gonial angle, mandibular *These authors contributed equally plane angle, position of mandible, and maxilla versus mandible) in the angular measurement. to this work. Conclusion: Compared to the control group, many linear and angular measurements of the craniofacial structures were significantly different in the two short-statured groups (p <0.05). Treat- ment plans by orthodontists should include these craniofacial structure characteristics.

Keywords: Child; Growth; Mandible; Maxilla; Orthodontists

Introduction In Korea, parents with growing children are often concerned about their child’s final height. In a survey conducted by the Kore- Heightism is a newly invented word that combines “height” and an Society of Pediatric Endocrinology, found that Korean parents “ism”, and it refers to the privilege enjoyed by those with tall stat- considered the ideal final height of their children to be over 175 cm ure. Nicholas Herpin, a French sociologist, says in his book ‘Le and less than 180 cm (46.6%, 178/382 persons), with over 180 cm Pouboir des grands’ that a man’s big height works in favor of his sta- (42.7%, 163/382 persons) for males, and over 165 cm to less than tus, salary, love, marriage, and many other factors, and his height is 170 cm (54.6%, 532/975 persons), followed by 160 cm to less a power [1]. than 165 cm (36.5%, 356/975 persons) for females. This exceeds

Table 1. Twelve cephalometric landmarks Name Abbreviation Description Sella S The center of the sella turcica Nasion N The most anterior point of the frontonasal suture Subspinale A The most posterior point on the curvature from the anterior nasal spine to the crest of the maxillary alveolar process Supraentale B The most posterior point on the curvature of the mandible between pogonion and the crest of the mandibular alveolar process Pogonion Pog The most anterior point on the contour of chin Gnathion Gn A bony point by bisecting line of angle formed by facial plane and mandibular plane Menton Me The most inferior point on the symphyseal outline Gonion Go A bony point by bisecting line of angle formed by ramal plane and mandibular plane Articulare Art The point of intersection of the inferior cranial base surface basioccipital and the posterior surface of the mandibular condyle Basion Ba The most inferior posterior point on the anterior margin of the foramen magnum Posterior nasal spine PNS The most posteior point on the bony hard palate Anterior nasal spine ANS The most anterior point on the maxilla at the level of the palate

48 https://doi.org/10.12701/yujm.2020.00325 Yeungnam Univ J Med 2021;38(1):47-52

Table 2. Linear and angular craniofacial measurements Measurement Abbreviation Cephalometric landmark S Linear a) N Anterior cranial base length ACB N-S Posterior cranial base lengtha) PCB S-Ba Total cranial base length TCB N-Ba Art Upper anterior facial heighta) UAFH N-ANS Ba PNS Upper posterior facial height UPFH S-PNS a) ANS Lower anterior facial height LAFH ANS-Me Anterior total facial heighta) ATFH N-Me A Posterior total facial height PTFH S-Go Go Maxillar lengtha) MaxL ANS-PNS Mandibular ramus lengtha) MandRL Art-Go Mandibular corpus lengtha) MandCL Go-Pog B Overall mandibular length OMandL Art-Pog Pog Angular a) Me Gn Saddle angle SA N-S-Art Gonial angle GA Art-Go-Me a) Fig. 1. Cephalometric landmarks. S, sella; N, nasion; Ba, basion; Mandibular plane angle MPA S-N-Go-Gn Art, articulare; PNS, posterior nasal spine; ANS, anterior nasal Position of maxillaa) SNA S-N-A spine; Go, gonion; A, subspinale; B, supraentale; Pog, pogonion; Position of mandiblea) SNB S-N-B Me, menton; Gn, gnathion. Maxilla/mandiblea) ANB A-N-B Posterior position of mandible PPMand S-N-Art-Go ured subjects and the chart records of the normal subjects. a)For these variables, norms are given in Broadbent et al. [15],1975.

2) Cephalometric analysis In all participants, lateral cephalograms were taken by a single den- males and 16 females, mean age, 10.31± 1.82 years; and 32 NC, 17 tist and a single dental hygienist with their teeth in maximum ha- males and 15 females, mean age, 10.31± 1.82 years, respectively. bitual intercuspation with relaxed lips and face positioned with the Camper’s plane parallel to the ground. Twelve cephalometric refer- 2. Cephalometric analysis ence points were identified (Table 1, Fig. 1). Then, using these, 12 Comparison of the linear and angular craniofacial variables among linear and seven angular cephalometric measurements were taken the SS-HD, SS-I, and NC groups are shown in Tables 4 and 5. to evaluate the craniofacial morphology (Table 2) [15]. Regarding the linear measurements, there were significant differences in seven variables among the SS-HD, SS-I, and NC groups 3) Statistical analysis (p<0.05). In the two groups, mandibular ramus length (MandRL) Statistical analysis was performed using IBM SPSS version 19.0 were 36.10±0.57 and 37.22±0.67, and overall mandibular length (IBM Corp., Armonk, NY, USA). According to the variables, a fre- (OMandL) were 96.50±0.79 and 99.52±0.75, respectively. There quency analysis and multivariate analysis of variance (ANOVA) were all statistically significant (p<0.05). Significant differences be- with Bonferroni correction were used to compare the characteris- tween the SS-HD and NC groups were apparent at anterior cranial tics of the groups. A p-value of < 0.05 was considered statistically base length (ACB), posterior cranial base length (PCB), total crani- significant. al base length (TCB), upper posterior facial height (UPFH), posterior total facial height (PTFH), MandRL, and mandibular corpus Results length (MandCL) (p<0.05). Significant differences between the SS-I group and NC group were apparent at ACB, PCB, UPFH, 1. Demographic characteristics of the study subjects MandRL, and MandCL (p<0.05). A total of 95 children participated in this study, and the general and Regarding the angular measurements, there were significant dif- physical characteristics of each group are shown in Table 3. The ferences in five variables among the SS-HD, SS-I, and NC groups number, sex, and age of each group were as follows: 31 SS-HD, 16 (p<0.05). In the two groups, gonial angle (GA) were 127.39 ± 0.51 males and 15 females, mean age, 10.35±1.84 years; 32 SS-I, 16 and 125.38± 0.28, position of mandible (SNB) were 75.03± 0.42 https://doi.org/10.12701/yujm.2020.00325 49 Kim KB et al. Craniofacial morphology in the short-statured children

Table 3. Demographic characteristics of subjects Group Variable Total (n= 95) SS-HD (n= 31) SS-I (n= 32) NC (n= 32) Sex Male 16 (51.6) 16 (50.0) 17 (53.1) 49 (51.6) Female 15 (48.4) 16 (50.0) 15 (46.9) 46 (48.4) Age (yr) 10.35±1.84 10.31 ±1.82 10.31 ±1.82 10.33±1.81 Values are presented as number (%) or mean±standard deviation. SS-HD, short-statured children with growth hormone deficiency; SS-I, idiopathic short-statured children; NC, normal children.

Table 4. Comparison for the linear craniofacial variables among SS-HD, SS-I, and NC groups Group Linear (mm) p-value SS-HD (n= 31) SS-I (n= 32) NC (n= 32) ACB 64.41±0.43a 65.09±0.40a 67.64±0.37b < 0.001 PCB 44.01±0.54a 44.89±0.37a 46.70±0.55b < 0.001 TCB 99.40±0.84a 100.77±0.62ab 102.66±0.64b 0.006 UAFH 51.71±0.50 51.97±0.53 53.31±0.51 0.065 UPFH 46.13±0.28a 46.31±0.23a 48.28±0.41b < 0.001 LAFH 64.24±0.63 64.80±0.54 64.34±0.54 0.764 ATFH 114.65±0.75 115.41±0.81 116.33±0.78 0.318 PTFH 66.74±0.75a 67.30±0.69a 70.77±0.89b < 0.001 MaxL 44.56±0.47 44.98±0.55 46.16±0.43 0.061 MandRL 36.10±0.57a 37.22±0.67b 41.50±0.64c < 0.001 MandCL 69.11±0.67 70.58±0.50 72.69±0.56 0.064 OMandL 96.50±0.79a 99.52±0.75b 99.78±0.83b 0.007 Values are presented as mean±standard error. SS-HD, short-statured children with growth hormone deficiency; SS-I, idiopathic short-statured children; NC, normal children; ACB, anterior cranial base length; PCB, posterior cranial base length; TCB, total cranial base length; UAFH, upper anterior facial height; UPFH, upper posterior facial height; LAFH, lower anterior facial height; ATFH, anterior total facial height; PTFH, posterior total facial height; MaxL, maxillar lenghth; MandRL, mandibular ramus length; MandCL, mandibular corpus length; OMandL, overall mandibular length. p-value of MANOVA, Bonferroni correction (a

Table 5. Comparison for the angular craniofacial variables among SS-HD, SS-I, and NC groups Group Angular (°) p-value SS-HD (n= 31) SS-I (n= 32) NC (n= 32) SA 126.92±0.61b 126.03±0.43ab 124.42±0.56a 0.006 GA 127.39±0.51b 125.38±0.28a 124.14±0.49a < 0.001 MPA 36.65±0.40b 35.83±0.30b 33.55±0.51a < 0.001 SNA 79.42±0.28a 79.75±0.35ab 80.58±0.26b 0.022 SNB 75.03±0.42a 76.47±0.36b 78.38±0.29c < 0.001 ANB 4.39±0.17c 3.28±0.13b 2.22±0.13a < 0.001 PPMand 87.19±0.51 86.16±0.34 86.45±0.38 0.201 Values are presented as mean±standard error. SS-HD, short-statured children with growth hormone deficiency; SS-I, idiopathic short-statured children; NC, normal children; SA, saddle angle; GA, gonial angle; MPA, mandibular plane angle; SNA, position of maxilla; SNB, position of mandible; ANB, maxilla versus mandible; PPMand, posterior position of mandible. p-value of MANOVA, Bonferroni correction (a

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Discussion tures were significantly smaller in both growth hormone-deficient and idiopathic short-statured children. Orthodontic treatment Mechanisms that regulate the growth and development of cranio- plans should be modified to include these craniofacial structure facial regions are expressed by the complex interaction of genes, characteristics. hormones, nutrition, and epigenetic factors. Interference with these mechanisms can cause changes in growth patterns [16,17]. Acknowledgments The relationship between the development of the craniofacial structures and body structures has been shown in various growth Conflicts of interest studies [18-20]. The study by Chung et al. [21] reported that No potential conflict of interest relevant to this article was report- growth retardation in short stature children affected not only their ed. height but also their craniofacial growth. In this study, we classified short-statured children into two groups, Author contribution growth hormone deficient or idiopathic, and compared the charac- Conceptualization, Data curation: all authors; Formal analysis, teristics of their craniofacial growth with NC. Methodology: EYP, KBK, EKK; Project administration: EYP, This study found that both short-statured children with growth KBK; Investigation: all authors; Resources: EYP, KBK, MSK; hormone deficiency and idiopathic short-statured children were Software: EYP, EKK; Supervision: EYP; Validation: EYP, KBK, affected not only in terms of height but also craniofacial growth. EKK; Visualization, Writing–original draft, Writing–review & edit- Compared to the control group, almost all of the craniofacial struc- ing: EYP, KBK. ture measurements were significantly different. There was a more disproportionate growth of the cranial base, and jaw which result- ORCID ed in facial retrognathia in the two short-statured groups. Ki Bong Kim, https://orcid.org/0000-0002-3974-3050 Both short-statured groups had a shorter cranial base length. Eun-Kyong Kim, https://orcid.org/0000-0001-9582-1415 This was consistent with the results of van Erum et al. [22], but in- Kyung Mi Jang, https://orcid.org/0000-0002-2226-9268 consistent with the results of Spiegel et al. [10], Kjellberg et al. Min Seon Kim, https://orcid.org/0000-0002-3205-6725 [13], and Poole et al. [23]. Eun Young Park, https://orcid.org/0000-0002-1860-5425 The PTFH, MandRL, and OMandL values of the two short-statured groups were higher than the control group. This References could be seen in the small mandible and reduced posterior facial height, which might cause the mandible to rotate in short-statured 1. Herpin N. Le pouvoir des grands: de l’influence de la taille des children. Contrastingly, the GA and MPA values of the two hommes sur leur statut social. Paris: Découverte; 2006. short-statured groups were lower than the control group. This 2. You JB. “My son should be 175cm and daughter 165cm or could also be seen by the growth pattern of the mandible rotating more”… Parents worry about discrimination [Internet]. Jung- clockwise in short-statured children. This incongruity of the upper Ang Ilbo; 2020 Oct 21 [cited 2020 Jun 10]. https://news.joins. and lower jaws can lead to skeletal malocclusion, thereby requiring com/article/18905427. orthodontic treatment for tooth occlusion, oral function, and tem- 3. Barstow C, Rerucha C. Evaluation of short and tall stature in poromandibular joint issues. The growth pattern of both jaws children. Am Fam Physician 2015;92:43–50. should also be considered at this time. 4. Cox LA. The biology of bone maturation and ageing. Acta Pae- There are several limitations to this study. All subjects should be diatr Suppl 1997;423:107–8. investigated according to sex and age because there are differences 5. Cao F, Huang HK, Pietka E, Gilsanz V. Digital hand atlas and between males and females, and the time and amount of growth web-based bone age assessment: system design and implemen- with age [24]. Besides, the number of participants included in this tation. Comput Med Imaging Graph 2000;24:297–307. study was rather small. Therefore, further studies should be con- 6. Bilgili Y, Hizel S, Kara SA, Sanli C, Erdal HH, Altinok D. Accu- ducted with more children that are analyzed according to sex and racy of skeletal age assessment in children from birth to 6 years age, as well as the short stature cause. Despite these limitations, this of age with the ultrasonographic version of the Greulich-Pyle at- study is significant in that it identified differences in the develop- las. J Ultrasound Med 2003;22:683–90. ment of craniofacial structures in short-statured children. 7. Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M. In conclusion, most of the measurements of craniofacial struc- Utah Growth Study: growth standards and the prevalence of https://doi.org/10.12701/yujm.2020.00325 51 Kim KB et al. Craniofacial morphology in the short-statured children

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52 https://doi.org/10.12701/yujm.2020.00325 Original article eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):53-59 https://doi.org/10.12701/yujm.2020.00773 Effect of in vitro testicular spermatozoa culture on pregnancy outcomes: an experience at a single university hospital Jisun Lee1, Jung Hyeon Yoo2, Jae Hun Lee3, Hyun Soo Ahn4, Kyung Joo Hwang3, Miran Kim3 1Department of Obstetrics and Gynecology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea 2Department of Obstetrics and Gynecology, Bundang Jaeseng Hospital, Seongnam, Korea 3Department of Obstetrics and Gynecology, Ajou University School of Medicine, Suwon, Korea 4Department of Urology, Ajou University School of Medicine, Suwon, Korea

Received: September 16, 2020 Revised: November 2, 2020 Background: There are no guidelines for the optimal incubation time or temperature to improve Accepted: November 5, 2020 pregnancy outcomes in testicular sperm extraction-intracytoplasmic sperm injection (TESE-ICSI) cycles. We aimed to evaluate whether a 24-hour in vitro culture of testicular spermatozoa affects Corresponding author: pregnancy outcomes in TESE-ICSI cycles. Miran Kim Methods: This was a retrospective study of 83 TESE-ICSI cycles using testicular spermatozoa in Department of Obstetrics and 46 couples with male partners suffering from nonobstructive or obstructive azoospermia. Sperm Gynecology, Ajou University School retrieval was performed either on the oocyte retrieval (OR) day (65 cycles in 33 couples; group A) of Medicine, 164 Worldcup-ro, or on the day before OR (18 cycles in 13 couples; group B) followed by in vitro culture for 24 Yeongtong-gu, Suwon 16499, Korea hours. The clinical characteristics and pregnancy outcomes, including the number of retrieved Tel: +82-31-219-5250 Fax: +82-31-219-5245 oocytes, fertilization rates, embryo transfer rates, implantation and clinical pregnancy rates, were E-mail: [email protected] compared between the two groups. Results: There were no differences in terms of clinical characteristics except for the levels of luteinizing hormone (LH) in males. Group B had higher LH levels than group A (4.56±1.24 IU/L vs. 3.67± 1.07 IU/L, p =0.017). Group B showed higher fertilization rate (72.4%± 32.1% vs. 59.2%±21.7%, p=0.045), implantation rate (35.0%±34.1% vs. 14.0%±21.5%, p=0.010), pregnancy rate per cycle (80% vs. 39%, p=0.033), and clinical pregnancy rate per cycle (80% vs. 37.5%, p=0.024) than those of group A. Conclusion: Testicular sperm retrieval performed on the day before OR followed by in vitro culture can potentially improve pregnancy outcomes.

Keywords: Azoospermia; Intracytoplasmic sperm injections; Testicular sperm retrieval

Introduction plied for the treatment of obstructive and nonobstructive azoospermia. In vivo, spermatozoa are released from the seminiferous Almost 20% of men with infertility suffer from azoospermia [1,2]. tubules and reach epididymal sites where they acquire progressive Assisted fertilization with testicular sperm extraction (TESE) and motility and fertilization potential [3]. However, in TESE cycles, it intracytoplasmic sperm injection (ICSI) has been successfully ap- is difficult to find sufficient number of motile sperms because tes-

Copyright © 2021 Yeungnam University College of Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. https://doi.org/10.12701/yujm.2020.00773 53 Lee J et al. Effect of in vitro testicular spermatozoa culture on pregnancy outcomes ticular spermatozoa show motility only for a short period of time on at least two separate semen analyses confirmed the diagnosis of after testicular biopsy and may become immotile due to depletion azoospermia. of metabolic resources [4]. Clinical characteristics, including male age, female age, type of Sperm motility refers to the movement of sperm and is often azoospermia, follicle-stimulating hormone (FSH) level, type of used as a clinical parameter to evaluate sperm viability in ICSI cy- ovulation induction, etiology of infertility, total gonadotropin dose cles. It has been reported that only 3% of testicular spermatozoa are (IU), and pregnancy outcomes, were included in the analysis. motile after a biopsy [5]. In vitro culture of spermatozoa has been Clinical pregnancy was defined as the presence of a gestational sac suggested as a way to improve sperm motility in TESE-ICSI cycles. with fetal heartbeat confirmed by ultrasonography. The implanta- The efficacy of cryopreserved spermatozoa was first evaluated by tion rate was analyzed as the number of gestational sacs with fetal Oates et al. [6], who achieved a pregnancy rate of 40% per couple heartbeat per embryo transferred. using cryopreserved spermatozoa. However, studies on in vitro maturation of sperm and its effects on clinical pregnancy outcomes 2. Ovarian stimulation and oocyte retrieval show conflicting results. The ovarian stimulation protocol was individualized according to Hu et al. [7] reported that sperms extracted on the day before the patients’ age, diagnosis, and ovarian reserve. Different stimula- oocyte retrieval (OR) showed increased motility, consequently re- tion protocols included long gonadotropin-releasing hormone sulting in a higher fertilization rate. On the contrary, Karacan et al. (GnRH) agonist and short GnRH antagonist using recombinant [8] reported that the timing of TESE does not affect the outcomes FSH (Follitrope, LG Life Sciences Ltd., Seoul, Korea; Menopur, of ICSI-embryo transfer (ET) cycles. More importantly, there are Ferring Pharmaceuticals, Lausanne, Switzerland), and/or human no specific guidelines suggesting a suitable incubation time or tem- menopausal gonadotropin (IVF-C, LG Life Sciences Ltd). Trans- perature to improve sperm motility and pregnancy outcomes in vaginal sonography was used to monitor follicle growth every 2 TESE-ICSI cycles. days until the dominant follicle grew to approximately 16–18 mm. Hosseini and Khalili [9] studied the changes in sperm motility Ovulation was triggered by injecting 10,000 IU of human chorion- at different time intervals in an in vitro culture of spermatozoa and ic gonadotropin (hCG; Pregnyl, Merck & Co. Inc., Haarlem, the observed that sperm motility significantly increased after 24 hours Netherlands) intramuscularly when the mean diameter of the lead- but began to decline at day 2 of culture. Therefore, we aimed to ing follicle reached ≥18 mm or when urine luteinizing hormone evaluate whether a 24-hour in vitro culture of testicular spermato- (LH) was positive. zoa affects outcomes of TESE-ICSI cycles. We compared the clini- Thirty-six hours after hCG administration, OR was performed cal characteristics and pregnancy outcomes between TESE-ICSI through vaginal ultrasonography-guided punctures of the ovarian cycles with fresh testicular spermatozoa obtained on the day of OR follicles. Following the OR, patients received either intramuscular and those with in vitro cultured spermatozoa retrieved on the day injection of progesterone (Sugest, 50 mg; Sanzyme Ltd., Hyder- before OR. abad, India) once a day or vaginal progesterone (Utrogestan, 200 mg; Besins Healthcare Ltd., London, UK) for luteal support until Materials and methods 2 weeks after the procedure when the pregnancy was confirmed by analyzing serum hCG, and continued to receive the injection 1. Patients thereafter. This was a retrospective study of patients with successful TESE-ICSI cycles with TESE performed either on the day of OR or 24 hours 3. Testicular sperm extraction and in vitro culture of before OR between January 2001 and December 2015 at Ajou Uni- spermatozoa versity Hospital, Suwon, Korea. Clinical characteristics and preg- Testicular sperm extraction was performed by a urology specialist nancy outcomes were evaluated by reviewing the medical records. either on the day of OR or 24 hours before the day of OR. After This study was approved by the Institutional Review Board (IRB) sterilization of the scrotal skin, 1% lidocaine was injected locally of Ajou University Hospital (IRB No: AJIRB-MED-MDB-16-038). into the underlying tunics, and an incision was made to remove a The informed consent from the patients was waived from the IRB. 3-mm segment of testicular tissues. The initial examination for the A total of 83 TESE-ICSI cycles in 46 couples were included in the presence of spermatozoa was performed under an inverted study. All male partners with obstructive azoospermia or nonob- phase-contrast microscope (Diaphot 300/N88, Nikon, Tokyo, Ja- structive azoospermia, including chemotherapy exposure or vari- pan). Individual spermatozoa were observed carefully with a high cocele, underwent repeated semen analyses; the absence of sperms magnification under the microscope to evaluate any sign of sperm

54 https://doi.org/10.12701/yujm.2020.00773 Yeungnam Univ J Med 2021;38(1):53-59 motility, such as twitching of the head or tail. The suspension was status of the embryo, ET was performed 3 to 5 days following OR. then transferred to a test tube if spermatozoa were noticed. The bi- The number of embryos transferred was determined by the Kore- opsy samples were then independently minced using sterile nee- an Ministry of Health and Welfare, depending on the female part- dles and dissected into small pieces in a sterile Petri dish. ner’s age and embryo development. Embryos with multiple nuclei TESE spermatozoa were accompanied by red blood cells or cytoplasmic abnormalities were discarded. Progesterone was (RBCs), debris, testicular cells, and a large number of dead or im- administered either intramuscularly (Sugest, 50 mg) once a day or motile spermatozoa that have detrimental effects on existing mo- vaginally (Utrogestan, 200 mg) for luteal support until 2 weeks af- tile spermatozoa. The biopsy tissues were then centrifuged with an ter the procedure when the pregnancy was confirmed by analyzing RBC lysis buffer for 5 minutes at 300× g to eliminate these cells. In serum hCG and continued thereafter. group A (TESE performed on the day of OR), the tissue was cen- Clinical pregnancy was defined as the presence of a gestational trifuged twice at 300× g for 5 minutes, and the pellet was placed in sac with a fetal heartbeat confirmed by ultrasonography. The im- the Sydney IVF fertilization medium (Cook Medical, Blooming- plantation rate was analyzed as the ratio between the number of ton, IN, USA) containing10% human serum albumin. In group B gestational sacs and the number of transferred embryos. The deliv- (TESE performed on the day before OR), the extracted tissues ery rate was defined as the ratio between the number of deliveries were incubated in the same IVF fertilization medium and cultured and the number of ETs. for 24 hours at 37°C in 6% CO2 and 5% O2 balance. Centrifugation of the biopsy samples in group B was performed on the day of the 6. Statistics OR. The pH and temperature of the culture medium and incuba- Quantitative variables are described using means and standard devia- tor were controlled daily and maintained throughout the study. tions, and qualitative variables are shown as percentages. The data were first tested for normality, and then the differences between 4. Intracytoplasmic sperm injection procedure groups were compared using an independent t-test or Mann-Whit- Using sterile 23-gauge needles, the testicular spermatozoa were ney U test depending on the distribution. Pearson chi-square test or prepared for oocyte insemination by squeezing the biopsy tissues Fisher exact test was used to determine the association between two to identify the tubules and release spermatozoa. The tubules were categorical variables. Data were analyzed using IBM SPSS version placed in Quinn’s Sperm Washing Medium (SAGE In Vitro Fertil- 25.0 (IBM Corp., Armonk, NY, USA). A p-value of less than 0.05 ization, Trumbull, CT, USA) containing gentamicin and 5.0 mg/ was considered statistically significant. mL human serum albumin. One drop of sperm washing medium was replaced with a 7% polyvinylpyrrolidone medium, and five Results drops were replaced with the sperm washing medium. Motile spermatozoa with forward progression were transferred from the Group A consisted of 65 cycles in 33 patients and group B consist- sperm suspension drop to the polyvinylpyrrolidone drop using an ed of 18 cycles in 13 patients. The clinical characteristics of both injection needle with an inside diameter of 12 to 15 µm. The sper- groups are shown in Table 1. The two groups were comparable in matozoa were then immobilized and stored in the polyvinylpyrro- terms of age of male and female partners, basal FSH and an- lidone drop. After this, assisted fertilization by ICSI was performed ti-Müllerian hormone levels, and the number of stimulation days. as previously described [10]. The distribution of type of azoospermia, etiology of infertility, and type of ovulation induction also showed no difference between the 5. Evaluation of the outcomes of intracytoplasmic sperm two groups. Although statistically insignificant, the total dose of injection gonadotropin used for group B was slightly higher than that used Fertilization was assessed 17 to 19 hours after ICSI, and embryo for group A (2,387.5± 500.3 IU vs. 2,130± 490.4 IU, p= 0.053). cleavage and quality were evaluated 2 to 5 days after OR. The crite- Table 2 describes the ICSI outcomes and pregnancy outcomes of ria for embryo grading were based on the gross morphological ap- groups A and B. The numbers of retrieved oocytes and good-quali- pearance on light microscopy [11]. The zygotes were cultured in ty oocytes were not significantly different between the two groups the media (cleavage medium 10% human serum albumin; Cook (16.8±11.3 vs. 14.5±7.6, p =0.608; 14.7±9.7 vs. 12.4±6.7,

Medical) under oil in a 6% CO2 and 5% O2 incubator. The embry- p=0.235). However, the fertilization rate was significantly higher in os were transferred into Pronase solution (Sigma-Aldrich, St. Lou- group B than in group A (72.4%±32.1% vs. 59.2%±21.7%, is, MO, USA) under oil for 60 seconds to soften the zona pellucida p =0.045). Group B also showed higher implantation rate and then transferred to fresh cleavage medium. Depending on the (35.0%±34.1% vs. 14.0%±21.5%, p=0.010), pregnancy rate per https://doi.org/10.12701/yujm.2020.00773 55 Lee J et al. Effect of in vitro testicular spermatozoa culture on pregnancy outcomes

Table 1. Clinical characteristics in groups A and B Variable Group A Group B p-value No. of cycle/couple 65/33 18/13 Age (yr) Female 31.1±3.4 31.1±3.2 0.925b) Male 34.3±3.8 35.6±6.4 0.284 Basal FSH (IU/L) Female 5.3±1.7 4.2±2.2 0.304 Male 4.8±2.9 4.3±1.6 0.966 AMH in females (ng/mL)a) 4.2±2.5 4.7±2.7 0.657 Basal LH in males (IU/L) 3.6±1.1 4.6±1.2 0.017 Type of azoospermia 0.658 Obstructive 58 (89.2) 16 (88.9) Nonobstructive 7 (10.8) 1 (5.6) Etiology of infertility Only male factor 42 (64.6) 11 (61.1) 1.000 Male factor+anovulation 1 (1.5) 1 (5.6) 0.389c) Male factor+tubal factor 4 (6.1) 0 0.572 Male factor+endometriosis 13 (20.0) 5 (27.8) 0.524 Type of ovulation induction FSH+GnRH antagonist 14 (21.5) 2 (11.1) 0.502 FSH+GnRH agonist 15 (23.1) 8 (44.4) 0.084 Pure FSH 8 (12.3) 3 (16.7) 0.697 FSH+hMG 28 (43.1) 5 (27.8) 0.286 Total gonadotropin dose (IU) 2,130.0±490.4 2,387.5±500.3 0.053 Duration of stimulation (day) 8.6±4.1 9.0±1.2 0.336 Values are presented as number only, mean±standard deviation, or number (%). Group A, testicular sperm extraction (TESE) performed on the day of oocyte retrieval (OR); group B, TESE performed on the day before OR. FSH, follicle-stimulating hormone; LH, luteinizing hormone; AMH, anti-Müllerian hormone; GnRH, gonadotropin-releasing hormone; hMG, human menopausal gonadotropin. a)The number of patients with available AMH levels was 9 for each group. b)Mann-Whitney test. c)Fisher exact test. cycle (80% vs. 39%, p= 0.033), and clinical pregnancy rate per cy- There are various factors known to influence pregnancy out- cle (80% vs. 37.5%, p=0.024) than those of group A. The inci- comes following TESE-ICSI cycles, such as paternal age, maternal dence of miscarriage, ectopic pregnancy, and live birth and cryo- age, male testosterone, sperm motility, and/or type of azoospermia preservation rates were comparable between the two groups. [12-14]. Among these factors, the motility of spermatozoa is emphasized as an important predictive factor for successful fertiliza- Discussion tion by ICSI [15]. In vitro maturation of spermatozoa has been suggested as a way to improve sperm motility, thereby improving In the present study, we compared the outcomes of TESE-ICSI cy- pregnancy outcomes in TESE-ICSI cycles [16-19]. In a study by cles with fresh spermatozoa obtained on the day of OR and Balaban et al. [20], the fertilization rate increased from 42.1% to TESE-ICSI cycles with spermatozoa obtained 24 hours before 68.8% after in vitro culture of spermatozoa with improved sperm OR. The number of retrieved oocytes, fertilized eggs, and cleaved motility. Similarly, in our study, group B showed a higher fertiliza- embryos were comparable between the two groups. On the other tion rate than group A (72.4% vs. 59.2%, p= 0.045) due to in vitro hand, TESE-ICSI cycles with spermatozoa obtained 24 hours be- maturation of spermatozoa. The exact mechanism behind im- fore OR showed higher fertilization rate, implantation rate, preg- proved testicular sperm motility after in vitro culture is not yet nancy rate, and clinical pregnancy rate than those of TESE-ICSI clear. Some studies have suggested that co-culture with all testicu- cycles with fresh spermatozoa. These results indicate that in vitro lar cells, including Sertoli, Leydig, and germ cells, may enhance maturation of spermatozoa for 24 hours resulted in improved preg- sperm maturation [4]. In addition, the washing procedure before nancy outcomes compared to fresh spermatozoa. the culture also eliminates inhibitory factors, which activates the

56 https://doi.org/10.12701/yujm.2020.00773 Yeungnam Univ J Med 2021;38(1):53-59

Table 2. Pregnancy outcomes of TESE-ET cycles in groups A and B Variable Group A Group B p-value No. of oocytes retrieved 14.5±7.6 16.8±11.3 0.608a) No. of good oocytes 12.4±6.7 14.7±9.7 0.235 No. of fertilized eggs 7.0±3.7 10.7±8.8 0.211a) Fertilization rate (%) 59.2±21.7 72.4±32.1 0.045 No. of embryos cleaved 5.1±2.1 8.1±7.0 0.102a) No. of good embryos 2.8±1.5 2.1±1.3 0.097 No. of embryos transferred 3.8±1.5 2.5±1.4 0.001 Implantation rate (%) 14.0±21.5 35.0±34.1 0.010a) Pregnancy rate per cycle 25 (38.5) 12 (66.7) 0.033 Clinical pregnancy rate per cycle 24 (36.9) 12 (66.7) 0.024 No. of miscarriages 4 (6.2) 1 (5.6) 1.000b) No. of ectopic pregnancies 1 (1.5) 0 1.000b) No. of of live births 13 (20.0) 2 (11.1) 0.040 Cryopreservation rate 18 (27.7) 9 (50.0) 0.074 Values are presented as mean±standard deviation or number (%). Group A, testicular sperm extraction (TESE) performed on the day of oocyte retrieval (OR); group B, TESE performed on the day before OR. a)Mann-Whitney test. b)Fisher exact test. essential factors required for enhanced motility [12]. However, a More recently, Karacan et al. [8] compared the fertilization rates long-term culturing may decrease sperm motility because of the between ICSI-ET cycles with fresh testicular spermatozoa ob- gradual degeneration of testicular somatic cells. tained on the same day or the day before OR with frozen-thawed Despite collective evidence to support sperm retrieval before spermatozoa. They observed no difference between the groups in OR and have sperm cultured before ICSI, there are no guidelines terms of pregnancy outcomes with a fertilization rate of 68.7%– to suggest suitable incubation times. Determination of appropriate 70%, implantation rate of 13.4%–16.5%, and clinical pregnancy sperm retrieval timing and incubation times before the ICSI proce- rate of 30.9%–31.3%. dure is critical. Various incubation time periods have been suggest- Contrary to the results of Karacan et al. [8], our study showed ed as an optimal time to improve sperm motility and pregnancy significantly higher implantation rate, pregnancy rate per cycle, and outcomes. Wu et al. [21] observed that after a 24-hour in vitro cul- clinical pregnancy rate per cycle in ICSI cycles using in vitro culture, the number of motile sperm showed a remarkable increase tured spermatozoa than in those with fresh spermatozoa (35.0% vs. and reached a maximum motility rate between 48 and 72 hours. 14.0%, p=0.010; 80% vs. 39%, p=0.033; 80% vs. 37.5%, p=0.024, Hu et al. [7] also investigated the feasibility of performing testicu- respectively). In the study by Karacan et al. [8], the baseline charac- lar biopsies 24 hours prior to OR and observed that after in vitro teristics between the two groups were not different. On the con- culture, the overall fertilization rate was 58%, the implantation rate trary, group A in our study included a higher proportion of female was 20%, and the clinical pregnancy rate was 45%. In another infertility patients along with azoospermic male partners than study, Hosseini and Khalili [9] observed that sperm motility group B. This may have influenced group B to have a higher num- changed from 13% immediately after biopsy to 76% at 24 hours ber of retrieved oocytes and fertilized eggs, consequently leading to and 15% at 72 hours of culture, suggesting that 1 day of culture is improved pregnancy outcomes compared to those of group A. an ideal in vitro culture time to optimize sperm motility in azo- Another possible explanation may be the different hormone lev- ospermic TESE samples. However, the results of these studies only els of male partners between the two groups. Although statistically implied that in vitro culture may enhance sperm motility but failed insignificant, group A had higher basal FSH levels than group B to provide evidence for the effect on pregnancy outcomes. (4.8±2.9 IU/L vs. 4.3±1.67 IU/L, p=0.966). The baseline LH Levran et al. [18] first reported the outcomes of TESE-ICSI us- levels in group B, however, were higher than those in group A ing testicular spermatozoa obtained on the day of OR or the day (4.56±1.24 IU/L vs. 3.67±1.07 IU/L, p=0.017). There have before OR. They obtained similar fertilization rates (61.7% vs. been conflicting reports on the association between hormonal lev- 58.9%) and clinical pregnancy rates (34.8% vs. 29.2%) in their els and the chance of sperm retrieval. Salehi et al. [22] reported analysis of 47 IVF-ICSI cycles using testicular spermatozoa re- that high levels of FSH are significantly associated with lower trieved on the day of or on the day before oocyte aspiration [18]. chances of sperm retrieval in azoospermic men. On the other https://doi.org/10.12701/yujm.2020.00773 57 Lee J et al. Effect of in vitro testicular spermatozoa culture on pregnancy outcomes hand, some studies have shown that serum FSH concentration is iting: JHY, KJH, MK. not an independent predictive factor for sperm retrieval because FSH concentration is controlled by various endocrine and para- ORCID crine factors [23,24]. The discrepancies in male FSH and LH lev- Jisun Lee, https://orcid.org/0000-0002-2870-3176 els observed in our study might have resulted from the small num- Jung Hyeon Yoo, https://orcid.org/0000-0002-7593-7581 ber of the study population in group B. If the number of cycles Jae Hun Lee, https://orcid.org/0000-0003-2103-8078 were equivalent between the two groups, the baseline hormonal Hyun Soo Ahn, https://orcid.org/0000-0002-9764-2004 levels could have different values. Nonetheless, our data suggest Kyung Joo Hwang, https://orcid.org/0000-0001-7073-9124 that the baseline male hormone levels might have influenced the Miran Kim, https://orcid.org/0000-0001-5553-5334 pregnancy outcomes in TESE-ICSI cycles. Our study has several limitations. The uneven sample size of References groups A and B makes it difficult to extrapolate significant statistical importance. Moreover, although we have shown that fertiliza- 1. Coetzee K, Ozgur K, Berkkanoglu M, Bulut H, Isikli A. Reliable tion rate, implantation rate, and pregnancy rates were significantly single sperm cryopreservation in Cell Sleepers for azoospermia improved with in vitro cultured spermatozoa, we are unable to pro- management. Andrologia 2016;48:203–10. vide data for any change in sperm motility before and after in vitro 2. Bocca S, Moussavi V, Brugh V, Morshedi M, Stadtmauer L, culture. Any changes in sperm motility were only observed by the Oehninger S. ICSI outcomes in men undergoing TESE for azo- laboratory technician, and the recorded data were not provided. ospermia and impact of maternal age. Andrologia 2017;49: Another limitation is the effect of different controlled ovarian hy- e12617. perstimulation (COH) protocols on pregnancy outcomes. It is 3. Moore HD, Akhondi MA. In vitro maturation of mammalian known that different COH protocols may influence pregnancy spermatozoa. Rev Reprod 1996;1:54–60. outcomes. Because we aimed to evaluate the effect of in vitro cul- 4. Angelopoulos T, Adler A, Krey L, Licciardi F, Noyes N, Mc- ture of spermatozoa on pregnancy outcomes and the number of Cullough A. Enhancement or initiation of testicular sperm mo- each COH protocol for groups A and B was too small, we did not tility by in vitro culture of testicular tissue. Fertil Steril 1999; compare the pregnancy outcomes according to the COH protocol. 71:240–3. Nevertheless, our study provides enough evidence to support the 5. Lacham-Kaplan O, Trounson A. The effects of the sperm motil- previous findings that in vitro culture of spermatozoa in TESE-IC- ity activators 2-deoxyadenosine and pentoxifylline used for SI cycles may significantly improve pregnancy outcomes. Further sperm micro-injection on mouse and human embryo develop- studies with large sample sizes are needed to make definitive statement. Hum Reprod 1993;8:945–52. ments in this regard. 6. Oates RD, Lobel SM, Harris DH, Pang S, Burgess CM, Carson In conclusion, a sperm extraction procedure can be performed RS. Efficacy of intracytoplasmic sperm injection using inten- on the day before egg retrieval without compromising the risk of tionally cryopreserved epididymal spermatozoa. Hum Reprod pregnancy. Although the mechanism is yet unknown, the in vitro 1996;11:133–8. culture of sperm before OR may improve clinical outcomes, espe- 7. Hu Y, Maxson WS, Hoffman DI, Ory SJ, Licht MR, Eager S. cially for patients undergoing TESE-ICSI for azoospermia. Clinical application of intracytoplasmic sperm injection using in vitro cultured testicular spermatozoa obtained the day before Acknowledgments egg retrieval. Fertil Steril 1999;72:666–9. 8. Karacan M, Alwaeely F, Erkan S, Çebi Z, Berberoğlugil M, Batu- Conflicts of interest kan M, et al. Outcome of intracytoplasmic sperm injection cy- No potential conflict of interest relevant to this article was report- cles with fresh testicular spermatozoa obtained on the day of or ed. the day before oocyte collection and with cryopreserved testicular sperm in patients with azoospermia. Fertil Steril 2013; Author contributions 100:975–80. Conceptualization: JL, JHY, HSA, KJH, MK; Data curation: JL, 9. Hosseini A, Khalili MA. Improvement of motility after culture JHL, HSA, KJH; Formal analysis: JL, JHL, KJH, MK; Funding ac- of testicular spermatozoa: the effects of incubation timing and quisition, Validation: JHY; Resources: JL, HSA, KJH, MK; Super- temperature. Transl Androl Urol 2017;6:271–6. vision: KJH, MK; Writing-original draft: JL; Writing-review & ed- 10. Bechoua S, Berki-Morin Y, Michel F, Girod S, Sagot P, Fauque P.

58 https://doi.org/10.12701/yujm.2020.00773 Yeungnam Univ J Med 2021;38(1):53-59

Outcomes with intracytoplasmic sperm injection of cryopre- man A. Timing of testicular sperm retrieval procedures and in served sperm from men with spinal cord injury. Basic Clin An- vitro fertilization-intracytoplasmic sperm injection outcome. drol 2013;23:14. Fertil Steril 2001;76:380–3. 11. Scott RT Jr, Hofmann GE, Veeck LL, Jones HW Jr, Muasher SJ. 19. Windt ML, Coetzee K, Kruger TF, Menkveld R, van der Merwe Embryo quality and pregnancy rates in patients attempting JP. Intracytoplasmic sperm injection with testicular spermato- pregnancy through in vitro fertilization. Fertil Steril 1991;55: zoa in men with azoospermia. J Assist Reprod Genet 2002;19: 426–8. 53–9. 12. Schwarzer JU, Fiedler K, v Hertwig I, Krüsmann G, Würfel W, 20. Balaban B, Urman B, Sertac A, Alatas C, Aksoy S, Mercan R, et Schleyer M, et al. Sperm retrieval procedures and intracytoplas- al. In-vitro culture of spermatozoa induces motility and increas- matic spermatozoa injection with epididymal and testicular es implantation and pregnancy rates after testicular sperm ex- sperms. Urol Int 2003;70:119–23. traction and intracytoplasmic sperm injection. Hum Reprod 13. Park YS, Lee SH, Lim CK, Choi HW, An JH, Park CW, et al. Pa- 1999;14:2808–11. ternal age as an independent factor does not affect embryo qual- 21. Wu B, Wong D, Lu S, Dickstein S, Silva M, Gelety TJ. Optimal ity and pregnancy outcomes of testicular sperm extraction-in- use of fresh and frozen-thawed testicular sperm for intracyto- tracytoplasmic sperm injection in azoospermia. Andrologia plasmic sperm injection in azoospermic patients. J Assist Re- 2018;51:e13187. prod Genet 2005;22:389–94. 14. Meijerink AM, Cissen M, Mochtar MH, Fleischer K, Thoonen 22. Salehi P, Derakhshan-Horeh M, Nadeali Z, Hosseinzadeh M, I, de Melker AA, et al. Prediction model for live birth in ICSI us- Sadeghi E, Izadpanahi MH, et al. Factors influencing sperm re- ing testicular extracted sperm. Hum Reprod 2016;31:1942–51. trieval following testicular sperm extraction in nonobstructive 15. Hessel M, Robben JC, D’Hauwers KW, Braat DD, Ramos L. azoospermia patients. Clin Exp Reprod Med 2017;44:22–7. The influence of sperm motility and cryopreservation on the 23. Bryson CF, Ramasamy R, Sheehan M, Palermo GD, Rosen- treatment outcome after intracytoplasmic sperm injection fol- waks Z, Schlegel PN. Severe testicular atrophy does not affect lowing testicular sperm extraction. Acta Obstet Gynecol Scand the success of microdissection testicular sperm extraction. J 2015;94:1313–21. Urol 2014;191:175–8. 16. Zhu J, Tsirigotis M, Pelekanos M, Craft I. In-vitro maturation of 24. Ramasamy R, Padilla WO, Osterberg EC, Srivastava A, Reifsny- human testicular spermatozoa. Hum Reprod 1996;11:231–2. der JE, Niederberger C, et al. A comparison of models for pre- 17. Liu J, Tsai YL, Katz E, Compton G, Garcia JE, Baramki TA. Out- dicting sperm retrieval before microdissection testicular sperm come of in-vitro culture of fresh and frozen-thawed human tes- extraction in men with nonobstructive azoospermia. J Urol ticular spermatozoa. Hum Reprod 1997;12:1667–72. 2013;189:638–42. 18. Levran D, Ginath S, Farhi J, Nahum H, Glezerman M, Weiss-

https://doi.org/10.12701/yujm.2020.00773 59 Case report eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):60-64 https://doi.org/10.12701/yujm.2020.00290 Cushing syndrome in pregnancy, diagnosed after delivery Han Byul Kim1, Mi Kyung Kim2, El Kim3, Keun Soo Ahn4, Hye Soon Kim2, Nam Kyung Kim5 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Raphael Hospital, Daegu, Korea 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University Dongsan Hospital, Daegu, Korea 3Department of Neurosurgery, Keimyung University Dongsan Hospital, Daegu, Korea 4Department of Surgery, Keimyung University Dongsan Hospital, Daegu, Korea 5Park Kyung Dae Clinic of Internal Medicine, Gyeongju, Korea

Received: April 21, 2020 Revised: May 11, 2020 Cushing syndrome (CS) is rare in pregnancy, and few cases have been reported to date. Women Accepted: May 12, 2020 with untreated CS rarely become pregnant because of the ovulatory dysfunction induced by hypercortisolism. It is difficult to diagnose CS in pregnancy because of its very low incidence, the Corresponding author: overlap between the clinical signs of hypercortisolism and the physiological changes that occur Hye Soon Kim during pregnancy and the changes in hypothalamus-pituitary-adrenal axis activity that occur Division of Endocrinology and during pregnancy and limit the value of standard diagnostic testing. However, CS in pregnancy is Metabolism, Department of Internal associated with poor maternal and fetal outcomes; therefore, its early diagnosis and treatment Medicine, Keimyung University are important. Here, we report two patients with CS that was not diagnosed during pregnancy, in Dongsan Hospital, 56 Dalseong-ro, Jung-gu, Daegu 41931, Korea whom maternal and fetal morbidity developed because of hypercortisolism. Tel: +82-53-258-2982 Fax: +82-53-258-7982 Keywords: Complication; Cushing syndrome; Hypercortisolism; Pregnancy E-mail: [email protected]

Introduction 1. Case 1 A 37-year-old women presented with bilateral flank pain and Cushing syndrome (CS) is rare in pregnancy, with only about 220 weight gain. She became pregnant in 2013 and underwent cesare- cases having been reported to date. Women with untreated CS an section at 35 weeks of gestation because of pulmonary arterial rarely become pregnant because CS is associated with a high preva- hypertension. A 1,720-g infant was delivered, but after delivery, the lence of ovulatory disturbances, which are induced by cortisol ex- patient gained 14 kg and reported persistent bilateral flank pain cess [1]. Furthermore, even if pregnancy occurs, hypercortisolism over a 5-month period. The patient had a 3-year history of hyper- is associated with higher incidences of maternal and fetal complica- tension and dyslipidemia, and was taking atenolol (50 mg), nifed- tions; therefore, the early diagnosis and treatment of CS are im- ipine (60 mg), and atorvastatin (10 mg) once daily. On admission, portant [2]. Here, we report two cases of CS that was diagnosed her blood pressure was 130/70 mmHg and her body mass index within the 12 months following delivery. (BMI) was 36.9 kg/m2. She showed Cushingoid features, including truncal obesity, striae cutis, and buffalo hump. Her morning Cases plasma cortisol concentration was 22.04 μg/dL and her plasma ad- renocorticotrophic hormone (ACTH) concentration was 12.07 This study was approved by the Institutional Review Board of the pg/mL. Her plasma renin activity, plasma aldosterone concentra- Keimyung University Dongsan Hospital (IRB No: 2020-05-007). tion, and aldosterone-to-renin ratio were within the normal ranges, and the concentrations of other adrenal hormones were unremark-

60 https://doi.org/10.12701/yujm.2020.00290 Yeungnam Univ J Med 2021;38(1):60-64 able. A low-dose dexamethasone suppression test demonstrated livered a 2,200-g female infant by cesarean section during the 37th autonomous cortisol excess (Tables 1-3). Contrast-enhanced ab- week. She returned to the hospital 8 months after delivery be- dominal computed tomography revealed a 35× 28 mm hypoatten- cause she had not experienced menstruation, even after stopping uating nodule in the right adrenal gland (Fig. 1), and in venous and breastfeeding, and had gradually gained weight and noticed multi- delayed phases showed significant enhancement and rapid wash- ple bruises. Her blood pressure was 170/106 mmHg and her BMI out, which was consistent with a cortical adenoma. We, therefore, was 24.6 kg/m2. On physical examination, she had a moon face, diagnosed adrenal CS. A laparoscopic right adrenalectomy was buffalo hump, multiple bruises, and abdominal striae. Laboratory performed and pathological examination revealed that the mass investigations revealed morning plasma cortisol and ACTH con- was an adrenal cortical adenoma. On the day of surgery, 200 mg of centrations suggestive of ACTH-dependent hypercortisolism intravenous hydrocortisone was administered to avoid an adrenal (Tables 1, 2). Low-dose dexamethasone suppression testing was crisis, and the dose was gradually tapered off. Four months after not associated with a reduction in plasma cortisol concentration, the surgery, the patient resumed menstruation. The patient’s body but high-dose dexamethasone suppression testing was, which was mass decreased from 92.6 kg before surgery to 70 kg 6 months lat- consistent with a diagnosis of Cushing disease (CD) (Table 3). er. Long-term follow-up of the patient showed that her blood pres- Pituitary magnetic resonance imaging revealed a 3×4×6 mm hy- sure had improved. She was able to stop taking antihypertensive pointense nodule on the left side of the pituitary gland (Fig. 2). drugs and hydrocortisone 2 years after surgery. Endonasal pituitary adenomectomy was performed via an endonasal transsphenoidal approach, and the pathological finding was 2. Case 2 an ACTH-producing pituitary adenoma (World Health Organi- A 34-year-old woman attended our outpatient department be- zation grade I). One day following surgery, her plasma ACTH cause of weight gain and easy bruising. She was diagnosed with concentration had decreased from 68.48 to 20.43 pg/mL. In addi- gestational diabetes during her 25th week of gestation and she de- tion, her plasma cortisol concentration had decreased to 1.18 µg/

Table 1. Summary of the clinical characteristics of the reported cases Principal Physical BMI Blood pressure Maternal Pregnancy Case complaint examination (kg/m2) (mmHg) Imaging result Diagnosis outcome outcome Management 1 Bilateral flank Truncal obesity, 36.9 140/100 Right adrenal Adrenal Cushing Pulmonary arterial LBW (1,720 g)a), Laparoscopic pain, weight striae cutis, adenoma syndrome hypertension preterm birth right adre- gain buffalo hump (35× 28 mm) (35+1 wk)b) nalectomy 2 Weight gain Moon face, buf- 24.6 170/106 Pituitary mi- Cushing disease Gestational diabetes LBW (2,200 g)a) Pituitary ade- falo hump, croadenoma nomectomy purple striae (3× 4× 6 mm) via a TSA BMI, body mass index; LBW, low birth weight; TSA, transsphenoidal approach. a)Weight at birth less than 2,500 g, regardless of gestational age. b)Babies born alive before 37 weeks of pregnancy.

Table 2. Laboratory data of the reported cases Fasting plasma glucose Plasma sodium Plasma potassium Plasma ACTH Basal plasma cortisol 24-Hr urine cortisol Case (70–99 mg/dL) (136–145 mmol/L) (3.5–5.0 mmol/L) (10–60 pg/mL) (9.4–26.1 μg/dL) (1.49–8.20 μg/day) 1 100 148 3.2 12.07 22.04 40.02 2 99 140 3.8 149.20 48.97 85.87 ACTH, adrenocorticotropic hormone.

Table 3. Results of dexamethasone suppression testing Case 1 Case 2 Variable Low-dose dexamethasone test Low-dose dexamethasone test High-dose dexamethasone test Basal 24 hr 48 hr Basal 24 hr 48 hr Basal 24 hr 48 hr Serum cortisol (µg/dL) 14.85 15.02 21.22 25.99 13.71 8.95 24.63 1.10 1.91 24-Hr urine-free cortisol (µg/day) 40.02 35.48 38.51 28.08 14.41 1.51 25.78 2.93 1.12 17-OHCS (mg/dL) 30.2 27.8 30.1 22 18 9 20 8 6 17-OHCS, 17-hydroxycorticosteroids. https://doi.org/10.12701/yujm.2020.00290 61 Kim HB et al. Cushing syndrome in pregnancy, diagnosed after delivery

A B

Fig. 1. (A) Abdominal computed tomography reveals a 35×28 mm, hypoattenuating mass (arrow) in the right adrenal gland. (B) The excised right adrenal gland shows a well circumscribed, yellowish mass.

A B

Fig. 2. (A) Pituitary magnetic resonance imaging shows a 3×4×6 mm, hypointense nodule (arrow) in the left side of the pituitary gland. (B) The intraoperative photograph shows a grayish pink nodule (arrow) in the left side of the pituitary gland. dL, and thus hydrocortisone treatment was initiated. The patient’s Discussion blood pressure had normalized, and antihypertensive medication and hydrocortisone administration were stopped 3 months after When women are diagnosed with CS less than 12 months after surgery. delivery, they are empirically considered to have had active CS during pregnancy, with a high probability of concomitant hyper-

62 https://doi.org/10.12701/yujm.2020.00290 Yeungnam Univ J Med 2021;38(1):60-64 cortisolism during pregnancy [3]. Herein, we have reported two nancy and one neonate was born preterm and both were a low patients in whom CS was diagnosed 5 and 8 months after deliv- birth weight. ery, which is consistent with them having had active CS during The management of pregnant women with CS is similar to that pregnancy. of non-pregnant patients. For both ACTH-independent and Chronic hypercortisolemia inhibits both the action of gonado- ACTH-dependent CS, surgical treatment should ideally be per- tropin-releasing hormone (GnRH) in the gonads and GnRH se- formed during the second trimester, before the 24th week of gesta- cretion from the hypothalamus [1]. Therefore, women with un- tion. For ACTH-independent CS, which accounts for 55% of the treated CS rarely become pregnant. In those who do become cases of CS during pregnancy, adrenal surgery appears to be more pregnant, 55% have ACTH-independent CS, whereas ACTH-in- successful than medical therapy. For pregnant women with CD, dependent CS accounts for a relatively small proportion in transsphenoidal surgery or medical therapy (generally using non-pregnant women [3]. It has been suggested that in CD, there metyrapone) have both been used [10]. In addition to the specific is hypersecretion of cortisol and androgens, which interferes with treatment of CS, any comorbidities should be treated, including di- the gonadal axis, causing amenorrhea in over 70% of patients, abetes and hypertension [2]. After the surgical treatment of both whereas adrenal tumors almost exclusively hypersecrete cortisol of the patients reported herein, their symptoms resolved. [4]. Therefore, the second patient reported herein, in which CD As in the cases reported herein, the diagnosis of CS during preg- had likely been present during pregnancy, had a relatively rare con- nancy is difficult because of its low incidence, the overlapping clini- dition. cal signs, and the changes that occur in the HPA axis during nor- The diagnosis of CS in pregnancy is quite difficult for many rea- mal pregnancy. However, because CS is associated with higher in- sons. First, due to its very low incidence, a high degree of clinical cidences of maternal and fetal complications, early diagnosis is im- suspicion is required [1]. Second, the clinical signs of hypercorti- portant. Therefore, when pregnant women present with suspicious solism (weight gain, fatigue, hypertension, and hyperglycemia) symptoms, such as pathological fracture, physicians should consid- overlap with the physiological changes that characterize pregnancy er whether they might be hypercortisolemic. [2,5]. Therefore, CS is often not diagnosed until the second trimester [6]. However, although many of the symptoms overlap, the Acknowledgments occurrence of pathological fracture should provoke a CS work-up [7]. In the present patients, the symptoms reported are common Conflicts of interest features of pregnancy, meaning that it would have been difficult to No potential conflict of interest relevant to this article was report- diagnose CS earlier. ed. The diagnosis of CS during pregnancy is also hampered by the changes in the hypothalamic-pituitary-adrenal (HPA) axis that Author contributions normally occur [8]. Plasma ACTH and cortisol concentrations Conceptualization: all authors; Data curation: HBK; Formal anal- and urinary free cortisol (UFC) concentration are high during ysis: HSK; Methodology: MKK; Resources: EK, KSA, NKK; Su- normal pregnancies, which makes biochemical diagnosis more pervision: HSK; Validation: MKK; Writing-original draft: HBK; challenging [8]. However, a recent study showed that late-night Writing-review & editing: HSK, MKK. salivary cortisol concentration is higher in patients with CS than in pregnant women [9]; therefore, the use of a combination of UFC ORCID and late-night salivary cortisol is recommended for the diagnosis of Han Byul Kim, https://orcid.org/0000-0002-5024-7496 CS during pregnancy. Mi Kyung Kim, https://orcid.org/0000-0001-5750-3598 CS during pregnancy is associated with poor maternal and fetal El Kim, https://orcid.org/0000-0002-7664-6030 outcomes [2]. Patients with active CS tend to deliver earlier than Keun Soo Ahn, https://orcid.org/0000-0001-8738-8009 those whose CS has been corrected and are more likely to undergo Hye Soon Kim, https://orcid.org/0000-0001-6298-3506 cesarean section. They also more frequently experience complica- Nam Kyung Kim, https://orcid.org/0000-0002-5363-6817 tions of pregnancy, including gestational diabetes, hypertension, and preeclampsia. In addition, fetal complications, such as fetal References loss, fetal distress, preterm birth, and low birth weight, are more frequent in the presence of active maternal CS [3]. In both the pa- 1. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, Perry LA, tients reported here, maternal complications occurred during preg- Grossman AB, Besser GM, et al. Menstrual abnormalities in https://doi.org/10.12701/yujm.2020.00290 63 Kim HB et al. Cushing syndrome in pregnancy, diagnosed after delivery

women with Cushing’s disease are correlated with hypercorti- 7. Brue T, Amodru V, Castinetti F. Management of endocrine dis- solemia rather than raised circulating androgen levels. J Clin En- ease. Management of Cushing’s syndrome during pregnancy: docrinol Metab 1998;83:3083–8. solved and unsolved questions. Eur J Endocrinol 2018;178: 2. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s R259–66. syndrome during pregnancy: personal experience and review of 8. Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal the literature. J Clin Endocrinol Metab 2005;90:3077–83. axis in pregnancy: challenges in disease detection and treat- 3. Caimari F, Valassi E, Garbayo P, Steffensen C, Santos A, Corcoy ment. Endocr Rev 2005;26:775–99. R, et al. Cushing’s syndrome and pregnancy outcomes: a sys- 9. Lopes LM, Francisco RP, Galletta MA, Bronstein MD. Deter- tematic review of published cases. Endocrine 2017;55:555–63. mination of nighttime salivary cortisol during pregnancy: com- 4. Polli N, Pecori Giraldi F, Cavagnini F. Cushing’s syndrome in parison with values in non-pregnancy and Cushing’s disease. Pi- pregnancy. J Endocrinol Invest 2003;26:1045–50. tuitary 2016;19:30–8. 5. Aron DC, Schnall AM, Sheeler LR. Cushing’s syndrome and 10. Sammour RN, Saiegh L, Matter I, Gonen R, Shechner C, Co- pregnancy. Am J Obstet Gynecol 1990;162:244–52. hen M, et al. Adrenalectomy for adrenocortical adenoma caus- 6. Andreescu CE, Alwani RA, Hofland J, Looijenga LH, de Herd- ing Cushing’s syndrome in pregnancy: a case report and review er WW, Hofland LJ, et al. Adrenal Cushing’s syndrome during of literature. Eur J Obstet Gynecol Reprod Biol 2012;165:1–7. pregnancy. Eur J Endocrinol 2017;177:K13–20.

64 https://doi.org/10.12701/yujm.2020.00290 Case report eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):65-69 https://doi.org/10.12701/yujm.2020.00269 Development of donepezil-induced hypokalemia following treatment of cognitive impairment Dongryul Kim1, Hye Eun Yoon1, Hoon Suk Park2, Seok Joon Shin1, Bum Soon Choi2, Byung Soo Kim2, Tae Hyun Ban2 1Division of Nephrology, Department of Internal Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea 2Division of Nephrology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea

Received: April 11, 2020 Revised: May 7, 2020 Donepezil is a cholinesterase inhibitor used extensively to treat Alzheimer disease. The increased Accepted: May 14, 2020 cholinergic activity is associated with adverse effects, therefore gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common. Hypokalemia is a rare adverse event that Corresponding author: occurs in less than 1% of donepezil-treated patients. Although hypokalemia of mild and moder- Tae Hyun Ban ate grade does not present serious signs and symptoms, severe hypokalemia often results in Division of Nephrology, Department prolonged hospitalization and mortality. Herein, we report a case of hypokalemia developed af- of Internal Medicine, Eunpyeong St. ter the initiation of donepezil therapy for cognitive impairment. Mary’s Hospital, The Catholic University of Korea, 1021 Tongil-ro, Eunpyeong-gu, Seoul 03312, Korea Keywords: Alzheimer disease; Cognitive dysfunction; Donepezil; Hypokalemia Tel: +82-2-2030-4356 Fax: +82-2-2030-4641 E-mail: [email protected]

Introduction sis, and arrhythmia have been reported in a few patients [7,8]. Ac- cording to the FDA, hypokalemia is a rare adverse event that oc- Hypokalemia is a common electrolyte disturbance in clinical prac- curs in less than 1% of donepezil-treated patients [9,10]. tice. The major causes of hypokalemia include gastrointestinal loss Notably, hypokalemia exhibits non-specific symptoms such as and medications such as diuretics [1,2]. Most cases are asymptom- general weakness, fatigue, dyspepsia, myalgia, tingling sensation, atic and mild, but some patients develop severe hypokalemia re- muscle cramps, and spasms; hence, it can be difficult to diagnose sulting in arrhythmias and patient death. About 20% of inpatients without laboratory investigations. Therefore, clinicians sometimes experience hypokalemia during hospitalization [3], and among fail to recognize the signs and symptoms of hypokalemia. Accord- these cases, severe hypokalemia was sometimes associated with ingly, a rare case of hypokalemia induced by medication is signifi- prolonged hospitalization and increased mortality [4]. cant. Herein, we report a case of hypokalemia developed after initi- Donepezil is the second approved acetylcholinesterase inhibitor ating donepezil as a treatment for cognitive impairment. for the treatment of mild to moderate Alzheimer disease by the United States Food and Drug Administration (FDA), extensively Case used worldwide [5]. As donepezil is generally tolerated, most adverse events are gastrointestinal symptoms, including vomiting and The study was approved by the Institutional Review Board of the diarrhea [6]. However, rare adverse events such as lupus, psycho- Catholic University of Korea (IRB No: PC20ZASI0046) with

A B

Fig. 1. Abdominal computed tomography scan. (A) Both adrenal glands (arrows) show no abnormalities. (B) Both kidneys (arrows) show no abnormal findings.

66 https://doi.org/10.12701/yujm.2020.00269 Yeungnam Univ J Med 2021;38(1):65-69 dL), which were within the normal range, revealing no mineral creased and was modified to oral potassium agents. On the third corticoid excess. Plasma renin activity was determined as 0.19 ng/ day after donepezil cessation, his serum potassium level recovered mL/hr (range, 0.3–2.9 ng/mL/hr), aldosterone concentration was to 3.5 mmol/L under oral potassium supplementation of 32 mEq/ 14.93 pg/mL (range, 29.9–158.8 pg/mL), and the aldosterone/re- day (Fig. 2). During hypokalemia evaluation and correction, pneu- nin ratio was 7.86, indicating hyporeninemic hypoaldosteronism. monia was properly controlled. Finally, he was able to maintain se- However, unlike Liddle syndrome, the serum sodium level was rum potassium of 3.3 mmol/L under oral potassium supplementa- normal at 140 mmol/L. The serum magnesium level was normal tion of 32 mEq/day and was discharged on the ninth day of hospi- at 2.4 mg/dL, which was far from that observed in Gitelman syn- talization. At the time of discharge, the results of blood chemistry drome. Hence, no obvious cause of hypokalemia was determined. and spot urine chemistry were as follows: serum creatinine, 0.73 During investigations analyzing the possible cause of hypokale- mg/dL; serum potassium, 3.5 mmol/L; serum magnesium, 2.3 mia, he underwent potassium supplementation using intravenous mg/dL; serum osmolality, 295 mOsm/kg; urine creatinine, 120.6 and oral formulations. Until the fourth day of hospitalization, his mg/dL; potassium, 46.7 mEq/L; osmolality, 330 mOsm/kg. Ad- serum potassium level demonstrated difficulty increasing beyond ditionally, the following values were determined: urine potassium/ 3.0 mmol/L despite sufficient potassium administration (Fig. 2). creatinine ratio, 38.7 mEq/g; fractional excretion of potassium, As the hypokalemia was poorly corrected, clinicians suspected oth- 8.1%; TTKG, 11.9. er causes of hypokalemia. A thorough review of the therapeutic Conversely, in the past, he had presented a systolic BP of less agents prescribed for cognitive dysfunction was conducted. On ex- than 130 mmHg and diastolic BP of 80 mmHg during several vis- amining possible adverse effects, we identified evidence suggesting its to the outpatient clinic, with no history of medication-related that donepezil causes hypokalemia as a rare adverse event [9,10]. hypertension. However, for 24 hours after hospitalization, BP was Therefore, donepezil was immediately discontinued. Thereafter, continuously confirmed as 160/90 mmHg or more, including a his potassium demand, supplemented intravenously, gradually de- maximum of 185/105 mmHg, and amlodipine 5 mg was initiated.

Potassium supplementation withdrawal Potassium supplementation IV 65 mmol + PO 48 mmol Donepezil 4.5 140 withdrawal IV supplementation discontinued, Potassium supplementation (mmol/day) PO 32 mmol only 120 4.1 Donepezil start 100

3.7 80

60 3.3

Serum potassium (mmol/L) 2.9 20

2.5 0 -7 ... 1 2 3 4 5 6 7 8 9 ... 14 Hospitalization (day)

Total intake [IV fluid] 1,350 2,510 3,700 2,460 2,970 2,500 3,230 1,450 (mL/day) [1,150] [1,600] [1,850] [1,100] [850] [1,100] [900] [200] Serum potassium Total output 1,750 2,000 3,100 1,700 1,800 2,200 2,200 1,700 (mL/day) Potassium supplementation

Fig. 2. Summary of serum potassium level, potassium supplementation, total intake, and total output per day. IV, intravenous; PO, per oral. https://doi.org/10.12701/yujm.2020.00269 67 Kim D et al. Donepezil induced hypokalemia

As BP measurements were above 140/90 mmHg on average after that renal potassium wasting would recover after its withdrawal. the addition of amlodipine 5 mg, the patient was additionally pre- Unfortunately, the follow-up study did not achieve demonstrate an scribed olmesartan 20 mg on the fifth day of hospitalization. Finally, improvement in renal potassium wasting. Based on previous rein the outpatient clinic follow-ups, serum potassium was measured ports, we speculated the possible reasons by which recovery from as 4.5 mmol/L, and oral potassium agents were withheld. renal potassium wasting may vary from 2 days to 3 months [15,16]. Therefore, the patient may require further time for recovery. None- Discussion theless, this case was significant as it confirmed the progression of hypokalemia recovery, necessitating a decrease in the daily amount This case report presents the rare development of hypokalemia of potassium supplementation after the withdrawal of donepezil. with donepezil, an agent used to treat cognitive dysfunction. The A limitation of this case report is that we have not done addition- most common cause of hypokalemia is gastrointestinal losses, fol- al research regarding how donepezil affects the renal ion channels. lowed by medications such as diuretics [1,2]. Additionally, various Further case reports and research would assist in determining the conditions lead to hypokalemia. For example, the following factors mechanism by which donepezil causes renal potassium wasting. result in the development of renal potassium wasting: malignant Although donepezil demonstrates rare serious adverse events, hypertension, renal artery stenosis, renin-secreting tumors that can symptoms during early therapy require a differential diagnosis for increase renin, adrenal hyperplasia, Cushing syndrome, medica- hypokalemia. tion including diuretics, magnesium deficiency, Gitelman syndrome, and chronic metabolic acidosis [3]. However, it is difficult Acknowledgments to implicate donepezil, used for cognitive dysfunction therapy, as a causative agent. If this patient had multiple prescriptions, donepez- Conflicts of interest il was probably not considered a major cause of hypokalemia. No potential conflict of interest relevant to this article was report- Donepezil is a cholinesterase inhibitor, mainly prescribed for ed. Alzheimer disease. By inhibiting acetylcholinesterase, donepezil improves behavioral and cognitive symptoms, including confu- Author contributions sion, aggression, and psychosis [11,12]. In several studies, donepe- Conceptualization: all authors; Data curation: DK, THB, HSP; zil has demonstrated improved cognitive functions in patients with Formal analysis: DK, THB, HEY, BSC, BSK; Investigation: DK, dementia, but it had some adverse effects [13]. The adverse effects THB, HEY, HSP; Methodology, Project administration: THB; Su- were associated with increased cholinergic activity, and the gastro- pervision: THB, BSC, BSK; Validation: THB, SJS, BSC, BSK; intestinal system was mainly affected. Therefore, nausea, vomiting, Writing-original draft: DK; Writing-review & editing: DK, THB, and diarrhea were the most common symptoms, as well as insom- HEY, HSP, SJS. nia, abnormal dreams, hepatotoxicity, and cardiovascular adverse events [14]. Hypokalemia was one of the rare adverse effects. ORCID The mechanism by which donepezil causes hypokalemia re- Dongryul Kim, https://orcid.org/0000-0002-1322-1887 mains unclear. In this case, based on TTKG, potassium excretion Hye Eun Yoon, https://orcid.org/0000-0002-6347-7282 continued under donepezil therapy. Therefore, we hypothesized Hoon Suk Park, https://orcid.org/0000-0002-1102-5460 the mechanism by which donepezil caused renal potassium wast- Seok Joon Shin, https://orcid.org/0000-0001-7642-2849 ing. This finding may be due to the action of donepezil on the ion Bum Soon Choi, https://orcid.org/0000-0002-1412-9951 channels in the renal tubule or Henle’s loop. Donepezil could po- Tae Hyun Ban, https://orcid.org/0000-0002-2884-4948 + + - tentially inhibit the Na -K -2Cl cotransporter in the thick ascending limb of Henle’s loop, suppressing potassium reabsorp- References tion. Additionally, it could be postulated that donepezil stimulates the renal outer medullary potassium channel to excrete potassi- 1. Crop MJ, Hoorn EJ, Lindemans J, Zietse R. Hypokalaemia and um. As another hypothesis, donepezil could affect the sodium subsequent hyperkalaemia in hospitalized patients. Nephrol channel epithelium in the principal cell of the collecting tubule. Dial Transplant 2007;22:3471–7. Thereafter, potassium appeared to be secreted into the lumen to 2. Widodo D, Setiawan B, Chen K, Nainggolan L, Santoso WD. maintain electrolyte balance. Although the mechanism by which The prevalence of hypokalemia in hospitalized patients with in- donepezil induces hypokalemia remains unclear, we anticipated fectious diseases problem at Cipto Mangunkusumo Hospital,

68 https://doi.org/10.12701/yujm.2020.00269 Yeungnam Univ J Med 2021;38(1):65-69

Jakarta. Acta Med Indones 2006;38:202–5. FDA; 2012 [cited 2020 Feb 20]. https://www.accessdata.fda. 3. Unwin RJ, Luft FC, Shirley DG. Pathophysiology and manage- gov/drugsatfda_docs/label/ 2012/020690s035,021720s008, ment of hypokalemia: a clinical perspective. Nat Rev Nephrol 022568s005lbl.pdf. 2011;7:75–84. 10. eHealthMe. Will you have hypokalemia with Donepezil? (a 4. Paltiel O, Salakhov E, Ronen I, Berg D, Israeli A. Management study of FDA data) [Internet]. eHealthMe; 2020 [cited 2020 of severe hypokalemia in hospitalized patients: a study of quali- Feb 20]. https://www.ehealthme.com/ds/donepezil/hypoka- ty of care based on computerized databases. Arch Intern Med lemia/. 2001;161:1089–95. 11. Li XL, Hu N, Tan MS, Yu JT, Tan L. Behavioral and psychologi- 5. Li HC, Luo KX, Wang JS, Wang QX. Extrapyramidal side effect cal symptoms in Alzheimer’s disease. Biomed Res Int 2014; of donepezil hydrochloride in an elderly patient: a case report. 2014:927804. Medicine (Baltimore) 2020;99:e19443. 12. Seltzer B. Donepezil: a review. Expert Opin Drug Metab Toxi- 6. Arai H, Hashimoto N, Sumitomo K, Takase T, Ishii M. Disease col 2005;1:527–36. state changes and safety of long-term donepezil hydrochloride 13. Dunn NR, Pearce GL, Shakir SA. Adverse effects associated administration in patients with Alzheimer’s disease: Japan-Great with the use of donepezil in general practice in England. J Psy- Outcome of Long-term trial with Donepezil (J-GOLD). Psy- chopharmacol 2000;14:406–8. chogeriatrics 2018;18:402–11. 14. Jackson S, Ham RJ, Wilkinson D. The safety and tolerability of 7. Cubeddu LX. Drug-induced inhibition and trafficking disrup- donepezil in patients with Alzheimer’s disease. Br J Clin Phar- tion of ion channels: pathogenesis of QT abnormalities and macol 2004;58(Suppl 1):1–8. drug-induced fatal arrhythmias. Curr Cardiol Rev 2016;12: 15. Tabish M, Mahendran M, Ray A, Vikram NK. Colistin-induced 141–54. acquired Bartter-like syndrome: an unusual cause of meltdown. 8. Manzo C, Putignano S. Drug-induced lupus erythematosus as- BMJ Case Rep 2020;13:e232630. sociated with donepezil: a case report. Age Ageing 2015;44: 16. Min HK, Kim EO, Lee SJ, Chang YK, Suh KS, Yang CW, et al. 1062–3. Rifampin-associated tubulointersititial nephritis and Fanconi 9. US Food and Drug Administration (FDA). Highlights of pre- syndrome presenting as hypokalemic paralysis. BMC Nephrol scribing information: Aricept [Internet]. Silver Spring (MD): 2013;14:13.

https://doi.org/10.12701/yujm.2020.00269 69 Case report eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):70-73 https://doi.org/10.12701/yujm.2020.00304 Co-existence of relapsing polychondritis and Crohn disease treated successfully with infliximab Hye-In Jung1, Hyun Jung Kim1, Ji-Min Kim2, Ju Yup Lee1, Kyung Sik Park1, Kwang Bum Cho1, Yoo Jin Lee1 1Division of Gastroenterology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea 2Division of Rheumatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea

Received: April 28, 2020 Revised: May 16, 2020 Relapsing polychondritis (RP) is a rare, progressive immune-mediated systemic inflammatory dis- Accepted: May 25, 2020 ease of unknown etiology, characterized by recurrent inflammation of cartilaginous structures. Approximately 30% of RP cases are associated with other autoimmune diseases. However, the Corresponding author: co-occurrence of RP and Crohn disease (CD) has rarely been reported. Herein, we present a Yoo Jin Lee 35-year-old woman diagnosed with RP and CD, who was refractory to initial conventional medi- Department of Internal Medicine, cations, including azathioprine and glucocorticoid, but who subsequently responded to infliximab Keimyung University School of (IFX). For both diseases, remission was sustained with IFX. There has been no previous report re- Medicine, 1035 Dalgubeol-daero, garding the successful treatment of co-existing RP and CD with IFX. Dalseo-gu, Daegu 42601, Korea Tel: +82-53-258-7739 Keywords: Crohn disease; Inflammatory bowel diseases; Infliximab; Relapsing polychondritis Fax: +82-53-258-4341 E-mail: [email protected]

Introduction 05-064). The patient provided written informed consent for publication of clinical details and images. Relapsing polychondritis (RP) is a rare, immune-mediated A 35-year-old woman with polyarthralgia and intermittent fever multi-systemic disease characterized by inflammation of multiple for a 2-month duration was referred to our rheumatology clinic. cartilaginous tissues, particularly those in the ear, nose, tracheo- She presented with pain in multiple joints, including both hands, bronchial tree, and eye [1,2]. Although the pathogenesis of RP re- both wrists, right ankle, and both knees, and reported that the mains unclear, an immunological mechanism is considered to be pain was most prominent in both metacarpophalangeal and prox- crucial [1]. Accordingly, nearly 30% of RP reportedly coexists with imal interphalangeal joints. The patient was not on any medica- other autoimmune inflammatory disorders, including rheumatoid tion and had no prior illness. Laboratory tests revealed that C-re- arthritis, systemic lupus erythematosus, and Sjogren’s syndrome active protein was elevated to 6.32 mg/dL (range, 0–0.5 mg/dL), [3]. However, the co-occurrence of RP and Crohn disease (CD) is erythrocyte sedimentation rate was increased to 120 mm/hr rare, and the treatment strategy for such cases remains uncertain. (range, women < 25 mm/hr), hemoglobin was decreased to 10.4 Herein, we present a first report of co-existing RP and CD success- g/dL (range, 11–15 g/dL). Her rheumatoid factor was marginally fully treated with infliximab (IFX). elevated to 25.2 IU/mL (range, ≤ 20 IU/mL); however, anti-cy- clic citrullinated peptide antibody and antinuclear antibody were Case absent. All other biochemical parameters, leukocyte count, and electrolyte values were within normal limits. X-rays of multiple This study was approved by the Institutional Review Board of the joints were normal without evidence of erosion. Keimyung University Dongsan Hospital (IRB No: DSMC 2020- On physical examination, she presented bilateral injected con-

70 https://doi.org/10.12701/yujm.2020.00304 Yeungnam Univ J Med 2021;38(1):70-73 junctiva (Fig. 1), as well as bilateral auricular redness and tender- the terminal ileum, cecum, and ascending colon, favoring a diag- ness, with sparing of the earlobes (Fig. 2). Ophthalmological ex- nosis of CD. Brownish, discolored colonic mucosa was observed, amination revealed bilateral episcleritis. An auricular biopsy was which was considered melanosis coli associated with the intake of performed, and various inflammatory cells were observed in the aloe vera (Fig. 4). Histological analyses of the colonoscopic biop- chondro-dermal junction (Fig. 3). Based on auricular cartilage in- sy revealed chronic inflammation. Her calprotectin level was flammation, ocular inflammation, and seronegative arthritis, she > 1,000 μg/g (range, < 50 μg/g). Collectively, the patient was fi- was diagnosed with RP according to the RP diagnostic criteria nally diagnosed with RP co-existing with CD. documented by Michet et al. [4]. After discontinuing NSAID therapy, she was treated with me- Initial treatment was started with a low-dose steroid (predniso- salazine (4 g/day), azathioprine (50 mg/day), and intravenous lone 10 mg) and non-steroidal anti-inflammatory drugs (IV) high-dose corticosteroid. With high-dose corticosteroid (NSAIDs) at the outpatient clinic. Three months later, she visited treatment, both CD- and RP-related symptoms were markedly the emergency department with fever, abdominal pain, and inter- improved. However, after tapering steroid treatment, she com- mittent hematochezia occurring for a month. A detailed interview plained of mild, fluctuating, but persisting abdominal pain, diar- focusing on gastrointestinal manifestations revealed that she had rhea, bilateral auricular pain, and polyarthritis. Despite mainte- been experiencing intermittent vague abdominal pain and diar- nance therapy comprising azathioprine and repeated steroid res- rhea 3–4 times per week for one year. She had self-diagnosed her cue therapy, flare-ups occurred twice in 6 months; thus, IV IFX (5 symptoms as irritable bowel syndrome and had often consumed mg/kg) was initiated. Following induction therapy with IFX, all aloe vera as a folk remedy. Interestingly, she reported that her ab- symptoms, including abdominal pain, diarrhea, auricular pain, dominal pain had repeatedly worsened, several times along with and arthralgia, were improved. Eighteen months after treatment the exacerbation of RP-related symptoms, such as arthralgia, con- with IFX, the colonoscopy showed that only ulcer scars and a few junctival injection, and bilateral auricular tenderness. Colonosco- inflammatory pseudopolyps remained. She had no RP recurrence py revealed multiple discontinuous ulcers with skipped lesions in and was confirmed to have reached not only a clinical but also an endoscopic remission with IFX.

Discussion

RP is a long-lasting, systemic inflammatory disease presenting diverse clinical manifestations, with a flaring‒remitting course [3].

Fig. 1. Photo of patient's eye. Bilateral conjunctival injection is observed. Ophthalmologic examination presents corneal ulcer and iritis.

A B Fig. 3. Microscopic finding of auricular biopsy. The microscopic Fig. 2. Photos of both ears. The bilateral erythema of both finding of an auricular lesion shows perivascular infiltration auricles with sparing of the ear lobes (A, right; B, left) indicates of lymphocytes in a background of fibrous connective tissue bilateral auricular chondritis. (hematoxylin and eosin stain, ×200). https://doi.org/10.12701/yujm.2020.00304 71 Jung HI et al. Co-existence of relapsing polychondritis and Crohn disease

both wrists, right ankle, and both knees, with episcleritis and unique auricular chondritis appeared simultaneously, which con- curred with the criteria (B) of Michet et al. [4]. Although the etiology of RP remains unclear, an autoimmune RP hypothesis is supported owing to its frequent association with other autoimmune diseases, as well as the effectiveness of corticosteroid and immunosuppressant treatments [2]. As both RP and A B IBD are immune-mediated diseases, they can theoretically appear together. Reportedly, RP has been introduced as one of the ex- tra-intestinal manifestations (EIMs) of IBD, but compared to other EIMs, such as peripheral and axial arthropathies, erythema no- dosum, and pyoderma gangrenosum, RP is an extremely rare EIM of IBD [8,9]. Furthermore, RP is easily overlooked by clinicians, owing to its non-specific and unusual manifestations [2]. Howev- er, proper diagnosis and treatment of RP are essential, as it can C D cause severe functional complications, including deafness, loss of vision, balance disturbance, and airway obstruction [3,10]. Fig. 4. Colonoscopic findings. Multiple discontinuous ulcers are Owing to a lack of data, standardized RP treatment guidelines are present in the terminal ileum (A, B), cecum, and ascending colon yet to be established. Currently, the treatment strategy remains em- (C, D). Melanosis coli is observed probably due to the previous pirical, based on existing case reports. The treatment goal is symp- history of aloe vera consumption (C, D). tomatic control and the long-term inhibition of immune-mediated pathogenic mechanisms [1]. Thus, empirical tailored therapy, according to the severity of disease activity and organ involvement, As RP is an extremely rare disease, with an estimated prevalence has been provided [10]. Mild forms of RP with the involvement of a few cases per million [5], supporting data are extremely limit- of the external ear, nose, or joints are managed with NSAIDs, col- ed. To date, no specific laboratory or histological markers are chicine, dapsone, and low-dose corticosteroids, while severe RP available for RP, the diagnosis of RP is challenging and based on forms, with organ-threatening complications, require high-dose clinical findings [1]. The criteria suggested by Michet et al. [4] are corticosteroids [2]. Immunomodulators, such as azathioprine, the most commonly used for the diagnosis of RP and consist of methotrexate, and cyclosporine, have been used as steroid-sparing the following: (A) two or more major criteria (auricular chondri- therapy [1]. Although evidence is extremely limited, biologics tis, nasal chondritis, laryngotracheal chondritis), (B) one or more have been suggested as a secondary treatment for patients refrac- of the previously mentioned major and two or more minor crite- tory to conventional therapies. According to a review of reports ria (ocular inflammation, such as conjunctivitis, keratitis, episcleri- concerning RP treated with biologics, 62 patients with active RP tis, and uveitis; hearing loss; vestibular dysfunction; seronegative were treated with anti-tumor necrosis factor alpha (anti-TNFα) inflammatory arthritis). The most frequent clinical feature of RP agents; in 28, the treatment was effective, but six patients experi- is auricular chondritis, causing unilateral or bilateral inflammation enced only partial effects, and 28 reported no effect [11]. In the in the cartilage, with sparing of the earlobe. The second frequent IFX group, remission or partial remission was achieved in 18 of 31 manifestation is joint pain [2]. These findings were unequivocally patients [11]. demonstrated in our current case. Regarding polyarthritis, our Although a few cases regarding the co-existence of RP and IBD case differed from the clinical features of inflammatory bowel dis- have been documented, most have reported the co-existence of ease (IBD)-related spondyloarthritis. There are two types of RP and ulcerative colitis, with the co-occurrence of CD extremely IBD-related peripheral arthritis: oligoarticular and polyarticular rare. To date, we have found only one case report in English type [6]. The oligoarticular type involves less than five joints, pre- through a PubMed search in March 2020; this patient showed dominantly affecting the lower extremities. In contrast, the poly- resolution of RP with a mild form of CD after mesalazine treat- articular type involves more than five small joints (predominantly ment [12]. In our case, a 35-year-old woman with RP and CD had upper limbs), with symmetric distribution and unrelated with recurring symptoms, with flare-ups following conventional treat- IBD activity [6,7]. In this case, polyarthritis affecting both hands, ment but responded well to IFX therapy. Following IFX treat-

72 https://doi.org/10.12701/yujm.2020.00304 Yeungnam Univ J Med 2021;38(1):70-73 ment, both clinical and endoscopic remission was achieved and et al. Relapsing polychondritis: an update on pathogenesis, clin- RP-related symptoms improved. No previous report has de- ical features, diagnostic tools, and therapeutic perspectives. Curr scribed the successful treatment of co-existing RP and CD with Rheumatol Rep 2016;18:3. IFX. 3. Rednic S, Damian L, Talarico R, Scire CA, Tobias A, Costedo- In conclusion, clinicians should be aware that both RP and IBD at-Chalumeau N, et al. Relapsing polychondritis: state of the art can co-exist in patients. Additionally, anti-TNFα agents could be a on clinical practice guidelines. RMD Open 2018;4(Suppl treatment of choice for RP patients with IBD who are refractory 1):e000788. to conventional immunosuppressive therapy. 4. Michet CJ Jr, McKenna CH, Luthra HS, O’Fallon WM. Relaps- ing polychondritis: survival and predictive role of early disease Acknowledgments manifestations. Ann Intern Med 1986;104:74–8. 5. Horvath A, Pall N, Molnar K, Kovats T, Surjan G, Vicsek T, et Conflicts of interest al. A nationwide study of the epidemiology of relapsing poly- No potential conflict of interest relevant to this article was report- chondritis. Clin Epidemiol 2016;8:211–30. ed. 6. Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropathies in inflammatory bowel disease: their articular distribution Author contributions and natural history. Gut 1998;42:387–91. Conceptualization: all authors; Formal analysis: JMK, JYL, KSP, 7. Rodriguez-Reyna TS, Martinez-Reyes C, Yamamoto-Furusho KBC, YJL; Methodology: HIJ, HJK, YJL; Investigation: HIJ, JK. Rheumatic manifestations of inflammatory bowel disease. HJK, YJL; Resources: HIJ, HJK, YJL; Supervision: JMK, JYL, World J Gastroenterol 2009;15:5517–24. KSP, KBC, YJL; Writing-original draft: HIJ, HJK, YJL; Writ- 8. Fousekis FS, Saridi M, Albani E, Daniel F, Katsanos KH, Kasta- ing-review & editing: all authors. nioudakis IG, et al. Ear involvement in inflammatory bowel disease: a review of the literature. J Clin Med Res 2018;10:609–14. ORCID 9. Vavricka SR, Schoepfer A, Scharl M, Lakatos PL, Navarini A, Hye-In Jung, https://orcid.org/0000-0003-0047-9042 Rogler G. Extraintestinal manifestations of inflammatory bowel Hyun Jung Kim, https://orcid.org/0000-0001-6205-4897 disease. Inflamm Bowel Dis 2015;21:1982–92. Ji-Min Kim, https://orcid.org/0000-0002-3894-3413 10. Mathian A, Miyara M, Cohen-Aubart F, Haroche J, Hie M, Pha Ju Yup Lee, https://orcid.org/0000-0003-0021-5354 M, et al. Relapsing polychondritis: a 2016 update on clinical Kyung Sik Park, https://orcid.org/0000-0003-1874-9936 features, diagnostic tools, treatment and biological drug use. Kwang Bum Cho, https://orcid.org/0000-0003-2203-102X Best Pract Res Clin Rheumatol 2016;30:316–33. Yoo Jin Lee, https://orcid.org/0000-0003-1799-0146 11. Kemta Lekpa F, Kraus VB, Chevalier X. Biologics in relapsing polychondritis: a literature review. Semin Arthritis Rheum References 2012;41:712–9. 12. Touma DJ, Gross EJ, Karmody CS, Fawaz KA. Relapsing poly- 1. Borgia F, Giuffrida R, Guarneri F, Cannavo SP. Relapsing polychondritis in association with Crohn's disease. Am J Otolaryn- chondritis: an updated review. Biomedicines 2018;6:84. gol 1996;17:424–6. 2. Vitale A, Sota J, Rigante D, Lopalco G, Molinaro F, Messina M,

https://doi.org/10.12701/yujm.2020.00304 73 Case report eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):74-77 https://doi.org/10.12701/yujm.2020.00297 Transpedal lymphatic embolization for lymphorrhea at the graft harvest site after coronary artery bypass grafting Jung Guen Cha1, Sang Yub Lee2, Jihoon Hong1, Hun Kyu Ryeom2, Gab Chul Kim2, Young Woo Do3 1Department of Radiology, Kyungpook National University Hospital, Daegu, Korea 2Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Korea 3Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kyungpook National University, Daegu, Korea

Received: April 26, 2020 Revised: June 22, 2020 Lymphorrhea is a rare but potentially severe complication that occurs after various surgical pro- Accepted: June 23, 2020 cedures. Untreated lymphorrhea may lead to wound dehiscence, infection, and prolonged hospital stay. Currently, there is no standard effective treatment. Early management usually includes Corresponding author: leg elevation, drainage, and pressure dressing. However, these methods are associated with pro- Sang Yub Lee longed recovery and high recurrence rates. We report a case of lymphorrhea from a calf wound Department of Radiology, School of after endoscopic great saphenous vein (GSV) harvesting for coronary artery bypass grafting Medicine, Kyungpook National (CABG). The patient presented with intractable oozing from the postoperative wound on the right University, 130 Dongdeok-ro, Jung- calf. Lymphorrhea persisted for 6 weeks despite negative-pressure wound therapy with a gu, Daegu 41944, Korea long-acting somatostatin. We performed unilateral pedal lymphangiography that confirmed Tel: +82-53-200-5390 wound lymphorrhea, followed by glue embolization. No recurrence was observed after 8 months Fax: +82-53-422-2677 E-mail: [email protected] of follow-up. This case report demonstrates the successful use of lymphangiography with glue embolization in the control of lymphorrhea after GSV harvesting for CABG.

Keywords: Lymphangiography; Lymphatic system; Therapeutic embolization; Therapeutics

Introduction pedal lymphangiography and subsequent N-butyl cyanoacrylate (NBCA) embolization of the injured lymphatic vessel, which was Lymphorrhea is a lymphatic leakage from wounds resulting from found to be effective. trauma of the lymphatic vessels; 10% to 16% of patients develop lymphorrhea after vein graft harvesting for arterial bypass surgery Case [1]. Anatomically, large lymphatic vessels lie adjacent to the great saphenous vein (GSV) and are prone to injury during GSV har- This study was approved by the Institutional Review Board of vesting [2]. Kyungpook National University Hospital (IRB No. 2020-05- When lymphorrhea is persistent and intractable despite conser- 078). The patient provided written informed consent for publica- vative treatment including low-fat diet with medium-chain trition of clinical details and images. glycerides, total parenteral nutrition, drainage, somatostatin, and A 63-year-old male patient underwent endoscopic GSV har- negative-pressure wound therapy (NPWT), it can cause wound vesting for coronary artery bypass grafting (CABG) due to isch- dehiscence, infection, and consequently prolonged hospital stay. emic heart disease. He had a history of hypertension, diabetes Here, we report a purely percutaneous approach for the treat- mellitus, and chronic kidney disease. After GSV harvesting, the ment of persistent and intractable lymphorrhea using unilateral patient developed wound oozing on the medial side of the right

74 https://doi.org/10.12701/yujm.2020.00297 Yeungnam Univ J Med 2021;38(1):74-77 calf. This was managed conservatively with NPWT. During the tion of the surrounding soft tissue were performed to expose a subsequent 6 weeks, the oozing continued. Therefore, direct ped- lymphatic vessel with blue staining. Then, the isolated lymphatic al lymphangiography and percutaneous embolization were re- vessel was cannulated using a 26-gauge (G) LG needle (Cook, quested. Bloomington, IN, USA). After accessing the lymphatic vessel, 2 to The patient was transferred to the interventional radiology suite 3 mL of contrast agent (Lipiodol; Guerbet, Paris, France) was in- and placed in the supine position on the operating table. The foot jected at a rate of 0.2–0.4 mL/min using an injection pump. Serial ipsilateral to the leakage site was selected, and 0.5 mL of methy- fluoroscopic images were obtained until the interrupted lymphat- lene blue was injected intradermally into the web spaces of the ic vessel leaking into the calf wound was identified. Then, we per- right foot. After waiting for 10 minutes, the injected methylene formed embolization of the culprit lymphatic vessel through ini- blue was released through the medial calf wound, thereby con- tially cannulated 26-G LG needle at the foot dorsum using NBCA firming lymphorrhea (Fig. 1). and lipiodol mixture in a ratio of 1:4 (Fig. 2). To prevent recur- A transverse cutaneous incision at the foot dorsum and dissec- rence, after additional cannulation of the midportion of the culprit

A B

Fig. 1. Photographs of pedal lymphangiography. (A) Photograph of the foot during the subcutaneous injection of methylene blue into the web space. (B) Photograph of the medial calf shows injected methylene blue seeping through the wound (arrows), confirming lymphorrhea.

A B C D

Fig. 2. Percutaneous lymphatic vessel embolization. (A) Photograph of the lymphatic vessel puncture site and transverse incision on the right foot dorsum. (B) Spot radiograph of the calf shows puncture needle (white arrow), normal ascending lymphatic vessel (black arrow), and lipiodol leakage into the calf wound (dashed arrow). (C) Spot radiograph reveals embolized culprit lymphatic vessel using N-butyl cyanoacrylate and lipiodol mixture (mixture ratio, 1:4). Note that additional lymphatic vessel is accessed with needle (white arrow), and additional lymphatic embolization is performed to prevent recurrence. (D) Photograph of the calf wound reveals polymerized glue cast released through the wound. https://doi.org/10.12701/yujm.2020.00297 75 Cha JG et al. Lymphatic embolization for CABG harvest site lymphatic vessel, further embolization was performed using the aged lymphatic channels were on the anteromedial side. Thus, in- same NBCA and lipiodol mixture (Fig. 2C). During percutane- jecting it into the web space was sufficient to reveal lymphorrhea. ous NBCA embolization, polymerized glue cast was released Lymphatic vessel cannulation with a fine needle is challenging. through the wounds (Fig. 2D). After embolization, initially can- Usually, the lymphatic vessel diameter is smaller than that of a nulated proximal lymphatic vessels (Fig. 2A) at the transverse in- conventional fine needle (26 G). To increase the accuracy of the cision site of the foot dorsum were ligated. After successful embo- puncture, parallel advancement of the needle along the lymphatic lization, the oozing finally stopped. However, despite emboliza- vessel is important. In this method, the needle tip can cannulate tion and wound management for 2 months, the patient under- the lymphatic vessel wall multiple times, and slow injection of went skin grafting for prolonged wound exposure and wound de- contrast materials can enable accurate puncture. hiscence. Then, the patient was discharged from the hospital. In summary, we presented a case of successful percutaneous lymphatic vessel embolization with NBCA for intractable lym- Discussion phorrhea at the graft harvest site after CABG. Understanding the lymphatic anatomy and relevant techniques is essential for this We described an approach for the management of refractory type of procedure. lymphorrhea using pedal lymphangiography and subsequent NBCA embolization. As in our case, conservative management Acknowledgments is recommended before invasive treatment. Conservative options include low-fat diet with medium-chain triglycerides, total Conflicts of interest parenteral nutrition, drainage, somatostatin, and NPWT. How- No potential conflict of interest relevant to this article was report- ever, lymphorrhea involves a large amount of output and diffi- ed. cult-to-find leakage site and can be refractory to conservative treatment. In such cases, surgical or interventional management Funding has been the standard of care. However, several patients with This research was supported by the Basic Science Research Pro- lymphorrhea are not eligible for surgery because of various rea- gram through the National Research Foundation of Korea (NRF) sons. Furthermore, the surgical approach requires imaging funded by the Ministry of Education, Science and Technology workup to ascertain the exact location of the leak. Compared (NRF- 2017R1C1B5075931). with surgery, lymphangiography with or without embolization can be performed as a diagnostic and therapeutic test. More- Author contributions over, lymphangiography is superior to surgery in terms of mini- Conceptualization, Investigation: all authors; Formal analysis: mal invasiveness. JGC, SYL, JH; Methodology: JGC, SYL, HKR, GCK; Resources: Currently, pedal lymphangiography has been replaced with the JH, HKR, YWD; Supervision: SYL; Writing-original draft: JGC; less cumbersome and more feasible intranodal lymphangiogra- Data curation, Writing-review & editing: JGC, SYL. phy. The intranodal approach has recently been introduced and remarkably reduced time and effort compared with the conven- ORCID tional pedal lymphangiography approach [3-5]. However, intran- Jung Guen Cha, https://orcid.org/0000-0002-2519-2120 odal lymphangiography cannot be performed at the below-the- Sang Yub Lee, https://orcid.org/0000-0001-8529-8229 knee level because the lowest lymph node is present in the popli- Jihoon Hong, https://orcid.org/0000-0003-3389-244X teal area [6]. Hun Kyu Ryeom, https://orcid.org/0000-0003-4327-8777 In conventional pedal lymphangiography, the web space is usu- Gab Chul Kim, https://orcid.org/0000-0001-7963-7538 ally recognized as the standard injection site. However, this ap- Young Woo Do, https://orcid.org/0000-0001-9725-9163 proach does not always allow visualization of complete lower leg lymphatics. Shinaoka et al. [6] reported that injection into this References web space demonstrates lymphatic vessels only in the anteromedial group. The anteromedial and posteromedial groups did over- 1. Unno N, Yamamoto N, Suzuki M, Tanaka H, Mano Y, Sano M, lap in the leg; however, the anterolateral and posterolateral groups et al. Intraoperative lymph mapping with preoperative vein were independent. Therefore, with respect to the region, the site mapping to prevent postoperative lymphorrhea following para- of methylene blue injection should be modified. In our case, dam- malleolar bypass surgery in patients with critical limb ischemia.

76 https://doi.org/10.12701/yujm.2020.00297 Yeungnam Univ J Med 2021;38(1):74-77

Surg Today 2014;44:436–42. nary experience in children. J Vasc Interv Radiol 2011;22: 2. Heitink MV, Schurink GWH, de Pont CDJM, van Kroonen- 1300–5. burgh MJPG, Veraart JCJM. Lymphedema after greater saphe- 5. Nadolski GJ, Itkin M. Feasibility of ultrasound-guided intranod- nous vein surgery. Eur J Vasc Endovasc Surg 2009;38:656. al lymphangiogram for thoracic duct embolization. J Vasc Interv 3. Kos S, Haueisen H, Lachmund U, Roeren T. Lymphangiogra- Radiol 2012;23:613–6. phy: forgotten tool or rising star in the diagnosis and therapy of 6. Shinaoka A, Koshimune S, Suami H, Yamada K, Kumagishi K, postoperative lymphatic vessel leakage. Cardiovasc Intervent Boyages J, et al. Lower-limb lymphatic drainage pathways and Radiol 2007;30:968–73. lymph nodes: a CT lymphangiography cadaver study. Radiolo- 4. Rajebi MR, Chaudry G, Padua HM, Dillon B, Yilmaz S, Arnold gy 2020;294:223–9. RW, et al. Intranodal lymphangiography: feasibility and prelimi-

https://doi.org/10.12701/yujm.2020.00297 77 Case report eISSN 2384-0293 Yeungnam Univ J Med 2021;38(1):78-82 https://doi.org/10.12701/yujm.2020.00759 Pancreatic metastasis from malignant phyllodes tumor of the breast Seung Eun Lee1, Young Kyung Bae2, Joon Hyuk Choi2 1Department of Radiology, Yeungnam University College of Medicine, Daegu, Korea 2Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea

Received: September 7, 2020 Revised: October 30, 2020 Pancreatic metastasis from malignant phyllodes tumor (PT) of the breast is rare, and only a few Accepted: November 5, 2020 cases have been reported in the literature. Here, we report a case of pancreatic metastasis from malignant PT of the breast in a 48-year-old woman. She had had three episodes of recurrence of Corresponding author: malignant PT in her right breast. She presented with epigastric pain for 2 months. Computed to- Seung Eun Lee mography and magnetic resonance imaging revealed a 6 cm-sized, well-defined, heterogeneous Department of Radiology, mass with peripheral enhancement in the body of the pancreas. Endoscopic ultrasonogra- Yeungnam University College of phy-guided fine-needle aspiration was performed, and the pathologic report suggested spindle Medicine, 170 Hyunchung-ro, Nam- cell mesenchymal neoplasm. Subsequently, surgical excision was performed, and the mass was gu, Daegu 42415, Korea confirmed as a metastatic malignant PT. The imaging findings are discussed and the literature is Tel: +82-53-620-4129 Fax: +82-53-653-5484 briefly reviewed in this report. E-mail: [email protected] Keywords: Breast; Neoplasm metastasis; Pancreas ; Phyllodes tumor

Introduction Board (IRB) of the Yeungnam University Hospital (IRB No: 2020-05-053) and the requirement of informed consent from pa- Phyllodes tumors (PTs) are rare fibroepithelial neoplasms of the tient was waived by IRB. breast that account for 0.3% to 1% of all breast neoplasms [1]. PTs A 48-year-old woman presented with epigastric pain for 2 can be classified as benign, borderline, or malignant based on their months. The patient had previously suffered three episodes of re- histologic characteristics [2]. Malignant PTs have greater risk of currence of malignant PT in her right breast. She underwent right distant metastasis than benign PTs. Distant metastases occur in breast-conserving surgery with negative resection margins for ma- 10% to 20% of patients with malignant PTs [2,3]. The lungs and lignant PT 7 years ago in 2013, and right nipple areolar skin spar- bones are the most common sites of metastases via hematogenous ing mastectomy for recurrent malignant PT in 2015. She subse- spread [1,4]. The pancreas is an unusual site for metastasis, and quently underwent wide excision for recurrent malignant PT in only a few case reports were found in the literature [5-10]. Due to 2018 (Fig. 1). their rarity, the imaging findings of pancreatic metastases from PTs After 18 months from the last surgery, she was hospitalized with are extremely rare. Herein, we report a case of malignant PT that epigastric pain and abdominal computed tomography (CT) (Fig. 2) metastasized to the pancreas. and magnetic resonance (MR) imaging (Fig. 3) showed a 6 cm- sized heterogeneous enhancing mass involving the body of the Case pancreas. Her laboratory data, including the levels of the tumor markers carcinoembryonic antigen and carbohydrate antigen 19-9, This retrospective study was approved by the Institutional Review were within normal range.

78 https://doi.org/10.12701/yujm.2020.00759 Yeungnam Univ J Med 2021;38(1):78-82

Endoscopic ultrasonography-guided fine-needle aspiration was were similar to those of the primary malignant PT of the breast performed (Fig. 4), and the pathologic report suggested spindle (Fig. 5) and the tumor cells were positive for CD34. The final diag- cell mesenchymal neoplasm. Based on her history of malignant PT nosis was metastatic malignant PT. Following discussions with pa- of her right breast, metastatic malignant PT was strongly suspect- tient, she chose to proceed with adjuvant therapy with an immuno- ed. modulatory substance (Mesima; Han Kook Shin Yak, Nonsan, Ko- Open distal pancreatectomy with splenectomy was performed, rea), which enhances immunologic activities and anticancer effects. and severe mesenteric adhesions surrounding the tumor were not- There was no evidence of recurrence during the first 4 months after ed during the surgery. Histologic findings of the pancreatic tumor surgery, but a long-term follow-up is now required.

Discussion

PTs are rare fibroepithelial neoplasms of the breast exhibit a wide range of clinical characteristics. The World Health Organization classifies PTs as benign, borderline, or malignant based on their histologic characteristics, including tumor margins, mitotic activity, degree of cellular atypia, stromal cellularity, and stromal over- B growth [2]. Histologically, PTs contain both epithelial and stromal components, and they have large leaf-like projections accompanied by high degree of increased stromal proliferation and cellularity. The stromal component has various histologic appearances that are correlated with metastasis and local recurrence [5]. In this case, the stromal overgrowth, high stromal cellularity, significant nuclear atypia of stromal cells, and the high mitotic count of 11 per 10 A C high-power fields could have led to distant metastasis. Distant metastases occur in 10% to 20% of patients with malig- Fig. 1. Radiologic and pathologic findings of recurrent malignant nant PTs. The most common sites of metastases are the lungs and phyllodes tumor of the breast in a 48-year-old woman. (A) bones [2,3]. However, several unusual metastatic sites, including du- Mammography of the right breast reveals an oval, circumscribed, odenum, brain, nasal cavity, skin, oral cavity, skeletal muscle, mandi- hyperdense mass in the right inner breast, above the implant, with an approximate size of 3.6 cm. (B) Ultrasonography reveals ble, and maxilla, have also been reported [11-13]. Metastasis to pan- a 3.6×3.0×2.0 cm-sized, oval, microlobulated, hypoechoic mass creas is rare, and only a few cases have been reported [5-10]. at the 3 o’clock location of the periareolar area. (C) The recurred In the literature, the clinical symptoms of the previously report- breast mass shows stromal overgrowth and hypercellularity. The stromal cells are spindle-shaped and show significant nuclear ed cases of pancreatic metastases from malignant PTs, were ob- atypia. Benign epithelial component is present (hematoxylin and structive jaundice, abdominal or back pain, hematemesis and inter- eosin stain, ×100). mittent tarry stools or steatorrhea. The mean age was 46 years

* *

A B C

Fig. 2. Computed tomography imaging findings of pancreatic metastasis from malignant phyllodes tumor of the breast. Precontrast (A), arterial (B), and portal (C) phase of contrast-enhanced abdominal computed tomography show a 6 cm-sized, well-defined heterogeneous mass involving the body of the pancreas. The mass reveals central cystic or necrotic portion (asterisk) and internal septa (arrow). The mass shows progressive, peripheral, and septal enhancement. https://doi.org/10.12701/yujm.2020.00759 79 Lee SE et al. Pancreatic metastasis from malignant phyllodes tumor of the breast

A B C

D E F

Fig. 3. Magnetic resonance imaging findings of pancreatic metastasis from malignant phyllodes tumor of the breast. The mass shows low signal intensity on T1-weighted image (A) and high signal intensity and internal septa with low signal intensities (arrows) on T2- weighted images (B, C). (D–F) Dynamic studies after the administration of gadolinium show thick irregular peripheral enhancement and septal enhancement with central poorly enhancing areas.

had three episodes of recurrence, and metastasis was detected after 18 months from the last surgery. Therefore, the duration between diagnosis and the initial therapy was long, but the duration between diagnosis and the last surgery was comparable to what was reported for the previous cases. Imaging findings were included in six case reports in the literature reviewed; six included CT images and only one included MR images (in Japanese) [5-10]. To our knowledge, this is the first report to discuss the MR imaging findings of pancreatic metastasis from PT in the English literature. Previous reports demonstrated hypodense mass (relatively to the pancreas) or peripheral enhancing mass with central low-density area on CT images [5-10]. There was a reported case accompanied by retroperitoneal hemorrhage on CT images [10]. The only MR images (in Japanese) presented Fig. 4. Endoscopic ultrasonography (EUS) finding of pancreatic metastasis from malignant phyllodes tumor of the breast. EUS in the available reports demonstrated a mass involving the pancre- revealed a 6-cm mixed and heterogeneous hypoechoic mass in the atic head and body with low signal intensity on T1-weighted image body of the pancreas. (T1WI) and high signal intensity on T2-weighted images. On MR cholangiopancreatography, the distal common bile duct was com- (range, 34–57 years) and the time to diagnosis from primary thera- pressed by the mass, and the upstream biliary duct was dilated [9]. py was 3 years (range, 8 months–6 years). In our case, the patient In our case, the lesion appeared as an exophytic mass involving the presented with epigastric pain for 2 months, and her age was with- pancreatic body without pancreatic or biliary duct dilatation. The in the range of previously reported cases. The time to diagnosis mass revealed central cystic or necrotic portion and internal septa. from primary therapy was approximately 6.5 years, which was the The mass showed progressive peripheral and septal enhancement longest interval noted in the literature. However, our patient had on dynamic studies of CT and MR imaging. The preoperative dif-

80 https://doi.org/10.12701/yujm.2020.00759 Yeungnam Univ J Med 2021;38(1):78-82

A B C

Fig. 5. (A) Gross photograph of the pancreatic tumor shows a 6.0×5.0-cm, grayish white, myxoid and solid cut surface with hemorrhage. (B) Histologic photographs of the pancreatic tumor show proliferation of spindle-shaped tumor cells in the myxoid stroma. (C) The tumor cells have elongated hyperchromatic nuclei, with fascicular pattern (hematoxylin and eosin stain, x100 [B] and x200 [C]).

ferential diagnoses included pancreatic metastasis, solid pseudo- ic mass in the patient with history of malignant PT of the breast. papillary neoplasm, and neuroendocrine tumor with cystic degeneration. Solid pseudopapillary neoplasms are often difficult to dif- Acknowledgments ferentiate from other solid tumors of the pancreas when they are small, and the cystic changes are insignificant. Solid pseudopapil- Conflicts of interest lary neoplasms usually contain hemorrhage that may have high sig- No potential conflict of interest relevant to this article was report- nal intensity on T1WI; however, the mass showed homogeneous ed. low signal intensity on T1WI in this case. Neuroendocrine tumors show more rapid enhancement during the arterial phase due to an Author contributions abundant vascular supply, but in our case, there was progressive en- Conceptualization, Project administration: SEL; Data curation: all hancement on dynamic studies [14]. The radiologic findings of authors; Writing-original draft: SEL, JHC; Writing-review & edit- pancreatic metastases are usually similar to those of primary carci- ing: all authors. nomas, but they are nonspecific, so the past history of malignancy is helpful for diagnosis. ORCID The standard treatment for distant metastases from PTs has not Seung Eun Lee, https://orcid.org/0000-0001-6693-4752 been established yet, because of lack of large prospective studies. Young Kyung Bae, https://orcid.org/0000-0002-6689-9413 Due to the low incidence of metastatic PTs, only a small number of Joon Hyuk Choi, https://orcid.org/0000-0002-8638-0360 retrospectively analyzed cases have been reported. Furthermore, treatment options, including surgery, radiotherapy, hormone ther- References apy, and chemotherapy, remain limited. In previous case reports, patients underwent chemotherapy with a diverse regimen [5-10]. 1. Telli ML, Horst KC, Guardino AE, Dirbas FM, Carlson RW. Bednar et al. [8] reported that patients with isolated pancreatic me- Phyllodes tumors of the breast: natural history, diagnosis, and tastasis from breast cancer who undergo resection have the poten- treatment. J Natl Compr Canc Netw 2007;5:324–30. tial for prolonged postresection survival. They suggested that defi- 2. Mishra SP, Tiwary SK, Mishra M, Khanna AK. Phyllodes tu- nite curative pancreatic resection can be a viable treatment option mor of breast: a review article. ISRN Surg 2013;2013:361469. for patients with isolated metastasis to the pancreas. In our case, 3. Zhou ZR, Wang CC, Yang ZZ, Yu XL, Guo XM. Phyllodes tu- the patient had metastasis only to the pancreas, and she underwent mors of the breast: diagnosis, treatment and prognostic factors surgical resection. The prognosis of patients with distant metasta- related to recurrence. J Thorac Dis 2016;8:3361–8. ses from PTs is poor, with an average survival time of less than 2 4. Kessinger A, Foley JF, Lemon HM, Miller DM. Metastatic cys- years [2,15]. tosarcoma phyllodes: a case report and review of the literature. J In summary, we report a case of pancreatic metastasis from ma- Surg Oncol 1972;4:131–47. lignant PT of the breast. Although it is rare, metastatic PT should 5. Amir RA, Rabah RS, Sheikh SS. Malignant phyllodes tumor of be considered in differential diagnosis when evaluating a pancreat- the breast with metastasis to the pancreas: a case report and re- https://doi.org/10.12701/yujm.2020.00759 81 Lee SE et al. Pancreatic metastasis from malignant phyllodes tumor of the breast

view of literature. Case Rep Oncol Med 2018;2018:6491675. 11. Asoglu O, Karanlik H, Barbaros U, Yanar H, Kapran Y, Kecer M, 6. Ang TL, Ng VW, Fock KM, Teo EK, Chong CK. Diagnosis of a et al. Malignant phyllode tumor metastatic to the duodenum. metastatic phyllodes tumor of the pancreas using EUS-FNA. World J Gastroenterol 2006;12:1649–51. JOP 2007;8:35–8. 12. Karczmarek-Borowska B, Bukala A, Syrek-Kaplita K, Ksiazek 7. Bachert SE, Stewart RL, Samayoa L, Massarweh SA. Malignant M, Filipowska J, Gradalska-Lampart M. A rare case of breast phyllodes tumor metastatic to pancreas. Breast J 2020;26: malignant phyllodes tumor with metastases to the kidney: case 1627–8. report. Medicine (Baltimore) 2015;94:e1312. 8. Bednar F, Scheiman JM, McKenna BJ, Simeone DM. Breast 13. Khangembam BC, Sharma P, Singla S, Singhal A, Dhull VS, Bal cancer metastases to the pancreas. J Gastrointest Surg 2013; C, et al. Malignant phyllodes tumor of the breast metastasizing 17:1826–31. to the vulva: (18)F-FDG PET-CT demonstrating rare metasta- 9. Serikawa M, Sasaki T, Kobayashi K, Itsuki H, Kamigaki M, Min- sis from a rare tumor. Nucl Med Mol Imaging 2012;46:232–3. ami T, et al. Malignant phyllodes tumor metastatic to the pan- 14. Low G, Panu A, Millo N, Leen E. Multimodality imaging of creas: a case report. Nihon Shokakibyo Gakkai Zasshi 2012; neoplastic and nonneoplastic solid lesions of the pancreas. Ra- 109:795–803. diographics 2011;31:993–1015. 10. Yukawa M, Watatani M, Isono S, Shiono H, Hasegawa H, Okaji- 15. Mituś JW, Blecharz P, Walasek T, Reinfuss M, Jakubowicz J, Kul- ma K, et al. Pancreatic metastasis from phyllodes tumor pre- pa J. Treatment of patients with distant metastases from phyl- senting initially as acute retroperitoneal hemorrhage. Int Canc lodes tumor of the breast. World J Surg 2016;40:323–8. Conf J 2013;2:238–42.

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Items pertaining to 1051-1053 (http://crossmark.crossref.org/dialog/?doi=10.3346/ manuscripts submitted for publication, as well as letters or other jkms.2017.32.7.1051&domain=pdf&date_stamp=2017-06-05). forms of communication regarding the editorial management of YUJM, all correspondences and business communications should ii iii be sent to: comments made by referees. The revised manuscript should be re- Joon Hyuk Choi, M.D., Ph.D., Editor-in-Chief submitted via the web system. Failure to resubmit the revised manu- Yeungnam University Journal of Medicine script within 2 months without any notice from the corresponding Yeungnam University College of Medicine author is regarded as a withdrawal. The corresponding author must 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea indicate clearly what alterations have been made in response to the Tel: +82-53-640-6832, Fax: +82-53-651-0394 referee's comments point by point. Acceptable reasons should be E-mail: [email protected] given for noncompliance with any recommendation of the referees. Homepage: https://www.e-yujm.org Copyrights and creative commons attribution license Peer review process The manuscript, when published, will become the property of the YUJM reviews all manuscripts received. A manuscript is previewed journal. All published papers become the permanent property of for its format and academic relevancy, and then rejected or sent to the Yeungnam University College of Medicine and must not be the 2 (or more) relevant investigators available for review of the con- published elsewhere without written permission. Copyrights of tents. The editor selects peer referees by recommendation of the all published materials are owned by the Yeungnam University editorial board members or from the board's specialist database. College of Medicine. They also follow the Creative Commons At- The identities of the reviewers and authors will not be revealed tribution Non-Commercial License (https://creativecommons. (double blinded review). All the radiologic images and pathologic org/licenses/by-nc/4.0/). (microscopic) images are reviewed by radiologist or pathologist for appropriateness. A manuscript containing statistical analysis will be reviewed by a statistical editor. Upon completion of the review, authors will receive notifica- tion of the Editor's decision by e-mail with comments offered by the reviewers. Revised manuscripts must be submitted within 3 months of the date on the decision letter. Acceptance of manuscripts is based on many factors, including Manuscript preparation the importance, originality, and priority of the research. Accep- tance of the manuscript is decided based on the critiques and rec- Review article ommended decision of the referees. A referee may recommend Review articles are usually solicited by the Editor-in-Chief. How- “accept”, “minor revision”, “major revision”, or “reject.” If there is a ever, unsolicited Reviews will be also considered. Authors should marked discrepancy in the decisions between two referees or be- contact the Editor-in-Chief in advance to determine the appropri- tween the opinions of the author and referee(s), the editor may ateness of their review articles for publication. All Review articles send the manuscript to another referee for additional comments will undergo peer review. An abstract is required whereas Materi- and a recommended decision. The reviewed manuscripts are re- als and methods section and a Results section are not required. turned back to the corresponding author with comments and rec- The length of review articles is limited to 5,000-8,000 words with ommended revisions. Names and decisions of the referees are a maximum of 100 references. Also, there should be no more than masked. A final editor's decision on acceptance or rejection for 3 authors. publication is forwarded to the corresponding author from the editorial office. Original article The usual reasons for rejection are topics that are too specific Original articles should begin with the title page followed by an and target audience that is too limited, insufficient originality, seri- abstract; a list of key words; an Introduction, Materials and meth- ous scientific flaws, poor quality of illustrations, or absence of a ods, Results, Discussion, References (no more than 30), and ta- message that might be important to readers. Rarity of a disease bles and/or illustrations. condition is itself not an acceptable justification for a case report. The peer review process takes usually 2–4 weeks after the manu- 1) Title page script submission. The tile page should contain the following information: (1) ti- Revisions are usually requested to take account of criticisms and tle (less than 150 characters, including spaces); (2) author list iv v (first name, middle name, and last name); (3) name of the in- Results stitutions at which the work was performed; (4) acknowledge- This should include a concise textual description of the data ment of research support; (5) name, address, telephone, fax presented in tables and figures. number, and e-mail address of the corresponding author; (6) running title (less than 50 characters, including spaces). Discussion This section includes the new and important aspects of the 2) Abstract study and the conclusions. The data should be interpreted Abstract must be organized and formatted according to the fol- concisely. Speculation is permitted, but it must be supported lowing headings: Background, Methods, Results, and Conclu- by the data presented by the authors. sion. The abstract length is typically no more than 250 words. References 3) Keywords References should be numbered consecutively in the order in List 3-6 keywords from the list provided in Index Medicus un- which they are first mentioned in the text, with numbers in der "Medical Subject Heading (MeSH)." square brackets before any closing punctuation. They should be listed on a separate document under the heading "Referenc- 4) Text es," and double-spaced. Reference format should conform to The text of manuscripts must have the following sections: In- that set forth in "Uniform Requirements for Manuscripts Sub- troduction, Materials and methods, Results, and Discussion. mitted to Biomedical Journals. 5th ed." (JAMA 1997;277:927- The body of the manuscript should be written as concisely as 34). Titles of journals should be abbreviated according to the possible. All pages of the manuscript should be numbered. Index Medicus style. Introduction This should provide a context or background for the study and Reference style: states the specific purpose or research objective of or hypothe- Journal articles sis tested by the study. This may include mention of papers List all authors when six or less; when seven or more, list the most closely related to the article, and of the problem. first six and add et al. Vega KJ, Pina I. Heart transplantation is associated with an in- Materials and methods creased risk for pancreatobiliary disease. Ann Intern Med Explanation of the experimental methods should be concise 1996;124:980-3. but sufficient to allow other workers to reproduce the results. Verbalis JG. Renal physiology of nocturia. Neurourol Urodyn This provides the technical information, apparatus (the manu- 2014;33(Suppl 1):S6-9. facturer's name and brief address) and procedures. Give references and brief descriptions for the methods that have been Book published. Describe statistical methods with enough detail to Ringsven MK, Bond D. Gerontology and leadership skills for enable a reader with access to the original data to verify the re- nurses. 2nd ed. Albany (NY): Delmar Publishers; 1996. ported results. Define statistical terms, abbreviations, and most Luzikov VN. Mitochondrial biogenesis and breakdown. Galkin symbols. AV, translator; Roodyn DB, editor. New York: Consultants Bu- Ensure correct use of the terms sex (when reporting biologi- reau; 1985. p. 362 cal factors) and gender (identity, psychosocial or cultural factors), and, unless inappropriate, report the sex or gender of Book chapter study participants, the sex of animals or cells, and describe the Phillips SJ, Whisnant JP. Hypertension and stroke. In: Laragh methods used to determine sex or gender. If the study was JH, Brenner BM, editors. Hypertension: pathophysiology, di- done involving an exclusive population, for example in only agnosis, and management. 2nd ed. New York: Raven Press; one sex, authors should justify why, except in obvious cases 1995. p. 465-78. (e.g., prostate cancer). Authors should define how they determined race or ethnicity and justify their relevance. Web resources Polgreen PM, Diekema DJ, Vandeberg J, Wiblin RT, Chen YY, David S, et al. Risk factors for groin wound infection after fem- iv v oral artery catheterization: a case-control study. Infect Control the abstract section, but each term must be identified the first Hosp Epidemiol [Internet]. 2006 [cited 2007 Jan 5];27:34-7. time it is mentioned. http://www.journals.uchicago.edu/ICHE/journal/issues/ v27n1/2004069/2004069.web.pdf 9) Unit of measurement Testa J. The Thomson Reuters journal selection process [In- Measurements of length, height, weight, and volume should be ternet]. Philadelphia: Thomson Reuters; 2012 [cited 2013 Sep reported in metric units (meter, kilogram, or liter) or their dec- 30]. http://wokinfo.com/essays/journal-selection-process imal multiples. Temperature should be in degrees Celsius. Au- thors must consult the information for authors for the particu- 5) Tables lar journal and should report laboratory information in both Tables should fit within a single page. The Table's legend may the local and International System of Units (SI). include any pertinent notes and must include definitions of all abbreviations and acronyms that have been used in the Table. Case report For footnotes, the following symbols should be used in this se- Case reports should consist of an Abstract, Keywords, Introduction, quence: a), b), c), d), e), f), g), h), etc. Authors are obligated to Case, Discussion, and References (no more than 20). Case reports indicate the significance of their observations by appropriate should have fewer than nine authors. The abstract should be con- statistical analysis. cisely written (no more than 250 words).

6) Illustrations Permission Figures must be cited consecutively using Arabic numerals. Au- thors must submit illustrations as electronic files. Acceptable fig- If any portion of a manuscript has been previously published, the ure file formats are JPEG, TIFF, and PPT/PPTX. Each figure original source must be acknowledged, and the written permis- needs to be prepared in a resolution higher than 300 dpi with sion from the copyright holder to reproduce the material must be good contrast and sharpness. The file size of each submitted fig- submitted. It is the responsibility of the author to request permis- ure should not exceed 10 MB per figure. If the patient's photo- sion from the publisher for any material that is being reproduced. graph is presented in a paper, it should be manipulated to make it This requirement applies to text, illustrations, and tables. difficult to recognize. Patients introduced in the manuscripts should be informed and aware that their photographs, video- Article processing charges tapes, and other images (imaging records) will be released by the authors, and the authors should attach the Authorization and Manuscripts that have accepted will be charged 200,000 won. The Release Form available at the YUJM website (https://www.e-yu- surcharge for color figures is none. jm.org/authors/ethics.php) including each patient’s signature. If the patient is a minor, a written consent of the guardian must be Author change submitted. If the addition or deletion of authors or changes in the order of 7) Legends for tables and illustrations authorship is required, the correspondent author must complete Typed legends that use double-spacing should start on a sepa- the authorship change form and submit it to the editorial board rate page with Arabic numerals corresponding to the Tables or with the signature of all existing authors and new authors. When Illustrations. When symbols, arrows, numbers, or letters are there is a request for change by the author, the editorial committee used to identify parts of the Tables or Illustrations, they should convenes an ethics committee and judges whether it is appropri- be individually identified and explained clearly in the legend. ate. If a new author should be added or an author should be delet- ed after the submission, it is the responsibility of the correspond- 8) Abbreviations ing author to ensure that all of the authors concerned are aware of Authors should limit the use of abbreviations to an absolute and agree to the change in authorship. The YUJM has no respon- minimum. Abbreviations are not to be used in titles. Abstracts sibility for such changes. may contain abbreviations for terms mentioned many times in

vi vii Research and publication ethics

Research ethics The YUJM asks referees to let its editor know of any conflicts of interest before reviewing a particular manuscript. All of the manuscripts should be prepared based on strict observa- tion of research and publication ethics guidelines recommended Authorship by the Council of Science Editors (http://www.councilscienceedi- tors.org), International Committee of Medical Journal Editors Each author is expected to have made substantial contribution to (ICMJE, http://www.icmje.org), World Association of Medical the conception or design of the work; or the acquisition, analysis, Editors (WAME, http://www.wame.org), and the Korean Associ- or interpretation of data; or the creation of new software used in ation of Medical Journal Editors (KAMJE, https://www.kamje. the work; or have drafted the work or substantively revised it; or.kr/en/main_en). All studies involving human subjects or hu- AND to have approved the submitted version (and any substan- man data must be reviewed and approved by a responsible Institu- tially modified version that involves the author’s contribution to tional Review Board (IRB). Please refer to the principles embodied the study); AND to have agreed both to be personally account- in the Declaration of Helsinki (https://www.wma.net/poli- able for the author’s own contributions and to ensure that ques- cies-post/wma-declaration-of-helsinki-ethical-principles-for-med- tions related to the accuracy or integrity of any part of the work, ical-research-involving-human-subjects/) for all investigations in- even ones in which the author was not personally involved, are volving human materials. Animal experiments also should be re- appropriately investigated, resolved, and the resolution docu- viewed by an appropriate committee (IACUC) for the care and mented in the literature. use of animals. Also studies with pathogens requiring a high degree Those who do not meet the above criteria should be acknowl- of biosafety should pass review of a relevant committee (IBC). The edged as contributors instead of authors. The corresponding au- approval should be described in the Methods section. For studies thor is responsible for completing this information at submission, of humans including case reports, state whether informed consents and it is expected that all authors will have reviewed, discussed, were obtained from the study participants. The editor of YUJM and agreed to their individual contribution ahead of this time. may request submission of copies of informed consents from hu- When a large, multicenter group has conducted the work, the man subjects in clinical studies or IRB approval documents. The group should identify the individuals who accept direct responsi- YUJM will follow the guidelines by the Committee on Publication bility for the manuscript. When submitting a manuscript au- Ethics (COPE, http://publicationethics.org) for settlement of any thored by a group, the corresponding author should clearly indi- misconduct. cate the preferred citation and identify all individual authors as well as the group name. Journals generally list other members of Conflicts of interest the group in the Acknowledgements. Acquisition of funding, collection of data, or general supervision of the research group alone The corresponding author of an article is asked to inform the Edi- does not constitute authorship. tor of the authors' potential conflicts of interest possibly influencing the research or interpretation of data. A potential conflicts of Contributor Roles Taxonomy (CRediT) interest should be disclosed in the cover letter even when the au- • Conceptualization thors are confident that their judgments have not been influenced • Data curation in preparing the manuscript. Such conflicts may include financial • Formal analysis support or private connections to pharmaceutical companies, po- • Funding acquisition litical pressure from interest groups, or academic problems. Dis- • Investigation closure form shall be same with ICMJE Uniform Disclosure Form • Methodology for Potential Conflicts of Interest (http://www.icmje.org/coi_dis- • Project administration closure.pdf). The Editor will decide whether the information on • Resources the conflicts should be included in the published paper. In partic- • Software ular, all sources of funding for a study should be explicitly stated. • Supervision vi vii • Validation tions of the primary version. • Visualization • The secondary version informs readers, peers, and documenting • Writing - original draft agencies that the paper has been published in whole or in part • Writing - review & editing elsewhere—for example, with a note that might read, "This article is based on a study first reported in the (journal title, with Redundant publication and plagiarism full reference)"—and the secondary version cites the primary reference. Redundant publication is defined as “reporting (publishing or at- • The title of the secondary publication should indicate that it is a tempting to publish) substantially the same work more than once, secondary publication (complete or abridged republication or without attribution of the original source(s).” Characteristics of translation) of a primary publication. Of note, the United States reports that are substantially similar include the following: (a) “at National Library of Medicine (NLM) does not consider trans- least one of the authors must be common to all reports (if there lations as "republications" and does not cite or index them when are no common authors, it is more likely plagiarism than redun- the original article was published in a journal that is indexed in dant publication),” (b) “the subjects or study populations are the MEDLINE. same or overlapped,” (c) “the methodology is typically identical or nearly so,” and (d) “the results and their interpretation generally Registration of the clinical trial research vary little, if at all.” When submitting a manuscript, authors should include a letter Clinical trial defined as “any research project that prospectively as- informing the editor of any potential overlap with other already signs human subjects to intervention and comparison groups to published material or material being evaluated for publication and study the cause-and-effect relationship between a medical inter- should also state how the manuscript submitted to YUJM differs vention and a health outcome” should be registered to the prima- substantially from other materials. If all or part of your patient ry registry to be prior publication. YUJM accepts the registration population was previously reported, this should be mentioned in in any of the primary registries that participate in the WHO Inter- the Methods, with citation of the appropriate reference(s). national Clinical Trials Portal (http://www.who.int/ictrp/en/), The duplication will be checked through crosscheck (https:// NIH ClinicalTrials.gov (http://www.clinicaltrials.gov), ISRCTN app.ithenticate.com) or eTBLAST (https://helioblast.heliotext. Resister (www.ISRCTN.org), or the Clinical Research Informa- com) before submission. If duplicate publication related to the pa- tion Service (CRIS), Korea CDC (https://cris.nih.go.kr/cris/in- pers of this journal is detected, the manuscripts may be rejected, dex.jsp). The clinical trial registration number shall be published the authors will be announced in the journal, and their institutes at the end of the abstract. will be informed. There will also be penalties for the authors. Data sharing statement Secondary publication YUJM accepts the ICMJE Recommendations for data sharing It is possible to republish manuscripts if the manuscripts satisfy the statement policy (http://icmje.org/icmje-recommendations. condition of secondary publication of the Uniform Requirements pdf). All manuscripts reporting clinical trial results should submit for Manuscripts Submitted to Biomedical Journals by International a data sharing statement following the ICMJE guidelines from 1 Committee of Medical Journal Editors (ICMJE), available from July 2018. Authors may refer to the editorial, “Data Sharing state- http://www.icmje.org. These are: ments for Clinical Trials: A Requirement of the International • The authors have received approval from the editors of both Committee of Medical Journal Editors,” in JKMS Vol. 32, No. journals (the editor concerned with the secondary publication 7:1051-1053 (http://crossmark.crossref.org/dialog/?- must have access to the primary version). doi=10.3346/jkms.2017.32.7.1051&domain=pdf&date_ • The priority for the primary publication is respected by a publi- stamp= 2017-06-05). cation interval negotiated by editors of both journals and the authors. Process to manage the research and publication • The paper for secondary publication is intended for a different misconduct group of readers; an abbreviated version could be sufficient. • The secondary version faithfully reflects the data and interpreta- When the Journal faces suspected cases of research and publication viii ix misconduct such as a redundant (duplicate) publication, plagiarism, The Editorial Board of YUJM will discuss the suspected cases and fabricated data, changes in authorship, undisclosed conflicts of in- reach a decision. YUJM will not hesitate to publish errata, corrigen- terest, an ethical problem discovered with the submitted manu- da, clarifications, retractions, and apologies when needed. script, a reviewer who has appropriated an author’s idea or data, For the policies on research and publication ethics not stated in complaints against editors, and other issues, the resolving process the Instructions, Guidelines on Good Publication (http://publica- will follow the flowchart provided by the Committee on Publica- tionethics.org) or Good Publication Practice Guidelines for Medi- tion Ethics (http://publicationethics.org/resources/flowcharts). cal Journals (http://kamje.or.kr) can be applied.

viii ix Research and publication ethics form

Affiliation:

Author’s name (please print):

Manuscript title:

All authors pledges that we follow the basic standards of research and publication ethics in the submission process to Yeungnam Univer- sity Journal of Medicine

Check Yes if Research subject, research object and size, setting of controls, and the methods of data collection are suitable for the □ Yes □No research ethics.

Check Yes if Authors should ensure that their submitted manuscripts are not against publication ethics such as fabrication, □ Yes □No falsification or plagiarism.

Check Yes if In clinical research involving human, informed consent from patient should be conducted and written in the method □ Yes □No section of the manuscript.

Check Yes if All clinical research involving human and animal subjects to be approved by the author’s Institutional Review Board □ Yes □No (IRB) or equivalent committees.

Check Yes if This study is conducted in compliance with the Declaration of Helsinki and this comment is written in the method □ Yes □No section of the manuscript.

Check Yes if All Authors must disclose all relationships that could be viewed as potential conflicts of interest. This relationship □ Yes □No also includes any potential conflicts of interest with all material, products, and companies in the manuscript.

Check Yes if Authors should confirm that the submitted work is not under consideration or accepted for publications elsewhere, □ Yes □No and would not be submitted in any other journals after acceptance.

Check Yes if Duplicate publication, which includes ‘imalas publication’, ‘plagiarism’, and ‘salami publication’, is strictly not □ Yes □No conducted.

If the rationale provided by the authors remains unsatisfactory in the judgment of the editors, the manuscript will be rejected or retracted. The authors will not be allowed to subsequently submit their research to Yeungnam University Journal of Medicine. The authors should keep the above mentioned disadvantages in mind.

Date:

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x Copyright transfer agreement

The author(s) submit manuscript with the following title

In consideration of editors and publisher’s effort in reviewing and editing our/my Article, the undersigned authors hereby transfer, convey, and assign all copyrights in the Article to the Editorial Board of the Yeungnam University Journal of Medicine (YUJM). The copyright transfer covers the right to print, publish, distribute and sell throughout the world the said contribution and parts thereof, including all revisions or versions and future editions, in all forms and media.

The authors certify that I have participated in the intellectual content, the analysis of data, and the writing of the Article, to take public responsibility for it The authors reviewed the final version of the Article, believe it represents valid work and approve it for publication The authors certify that none of the material in the manuscript has been published previously, is included in another manuscript The authors also certify that the Article has not been accepted for publication elsewhere, nor have they assigned any right or interest in the Article to any third party. The authors will obtain and include with the manuscript written permission from any respective copyright owners for the use of any text, figures, and tables that have been previously published. The authors agree that it is their responsibility to pay fees charged for permissions.

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xi Patient photographic and videographic consent, authorization and release form

I am informed and aware of photographs, videotapes and other images (imaging records) taken by Dr. or his designee(s) of myself or any parts of my body regarding surgical procedures carried out by Dr. . I understand and consent that such imaging records may and will be used by Dr. as reference in diagnosing and treating other patients in the future. I further consent to the release and transfer of copyright ownership by Dr. to Yeungnam University Journal of Medicine of such imaging records. I understand that by consenting on release of my imaging records, these may and will be used in upcoming issue or issues of the journal, as well as on the journal website, or any other print or electronic media for the purpose of informing medical professionals or other readers about surgical methods. I understand that when these imaging records are included in any articles, medical information regarding sex, age, operative date and treatment results may and will be included together. But I, nor any member of my family, will be identied by name in any publication, and any information that may aid in identifying me or my family will not be exposed. (In case of facial photographs, the photo is cropped to only necessary parts in order to make individual identication impos- sible.) I understand that whether I consent on this form or not, it bears no consequences whatsoever on any future actions, and that there will be no eect on the medical treatment I receive from Dr. or any subordinates. I grant this consent as a voluntary contribution in the interest of public education, and certify that I have read the above Con- sent, Authorization and Release form and fully understand its terms. I understand that, if I do not revoke this authorization, it will expire ten years from the date written below.

I hereby transfer in above-mentioned terms, the copyright of my imaging records to

Dr. .

20 . . .

Name: Signature:

Hospital: Department:

Designated Doctor: Signature:

xii