Bone Marrow Transplantation (2005) 35, 667–673 & 2005 Nature Publishing Group All rights reserved 0268-3369/05 $30.00 www.nature.com/bmt

Pelvic magnetic resonance imaging after bone marrow harvest – a retrospective study in 50 unrelated marrow donors

F Kroschinsky1, T Kittner2, S Mauersberger3, U Rautenberg3, U Schuler1, C Rutt3, M Laniado2 and G Ehninger1

1University Hospital Dresden, 1st Medical Department, Dresden, Germany; 2University Hospital Dresden, Department of Diagnostic Radiology, Dresden, Germany; and 3German Bone Marrow Donor Center (DKMS), Tuebingen, Germany

Summary: hematopoietic stem cells (HSC) for transplantation from allogeneic donors. In addition to the collection of adequate A total of 50 unrelated marrow donors were examined by numbers of hematopoietic progenitors, comfort and safety pelvic magnetic resonance imaging (MRI) to investigate for the donors are of the uppermost importance, especially the morphological sequelae of bone marrow harvesting in unrelated volunteers. Several studies evaluated the risks (BMH). Signal increase in T2-weighted sequences and of marrow harvesting in larger series and demonstrated contrast media enhancement in T1 sequences at the BMH as a very safe procedure,1–5 with a reported incidence operative sites were found as typical MRI morphology 4 of major, life-threatening complications of less than 0.5%. weeks after harvest (group A, n ¼ 16), corresponding to However, a substantial number of bone marrow donors edema, hyperemia and proliferative activity. Although experience side effects resulting from general or spinal tissue repair was completed in the majority of donors 1 anesthesia, loss of oxygen-transporting erythrocytes or year after BMH, about 36% of donors in group B (n ¼ 16) operative site morbidity. Pain at the collection site or in the had abnormal findings. These included a persistence of lower back is the most frequent local problem, occurring the ‘acute injury’ signal pattern (2/16, 12%), and signal with variable severity and duration in about 70–80% of the alterations due to fatty marrow conversion (4/16, 24%). donors.3,4,6,7 Furthermore, bleedings and hematomas at The proportion of MRI abnormalities increased to over the collection site,3,8 transient compressive neuropathies,2,9 70% in two-time donors (group C, n ¼ 11), which might osteomyelitis10 as well as a fracture of the ileum11 were indicate a cumulation of tissue damage after repetitive described as rare local complications of BMH. Never- harvests. If donors had experienced prolonged discomfort theless, there is no information available about acute or after BMH (group D, n ¼ 7), MRI revealed pathological persisting morphological changes in the bone and soft signals in 86%. In conclusion, the MRI morphology tissues caused by the multiple punctures, which are needed reflects the pathophysiological reactions after BMH, to collect a sufficient volume of marrow. including inflammation and tissue repair. A further The purpose of this retrospective study was to investigate prospective evaluation in a larger number of donors is the local alterations at the operative site after a BMH necessary to confirm these results and to identify the procedure by means of magnetic resonance imaging (MRI). factors which influence the extent and duration of tissue Pelvic MRI was performed in 50 selected unrelated bone damage. marrow donors with or without postsurgical complications Bone Marrow Transplantation (2005) 35, 667–673. and/or prolonged discomfort to assess the short- and long- doi:10.1038/sj.bmt.1704873 term effects of BMH to the affected tissues. Published online 21 February 2005 Keywords: bone marrow harvest; unrelated donor; mag- netic resonance imaging Patients and methods

A total of 50 adult, unrelated bone marrow donors from the German Bone Marrow Donor Center (Deutsche Bone marrow harvesting (BMH) from the posterior– Knochenmarkspenderdatei, DKMS, Tuebingen, Germany) superior iliac crest is a standard procedure to obtain were included in this MRI study. They had undergone BMH in one out of eight different German collection centers, either 4 weeks (group A, n ¼ 16) or 1 year (group B, n ¼ 16) before study entry. The donors in groups A and B Correspondence: Dr F Kroschinsky, Medizinische Klinik und were randomly selected and asked for study participation Poliklinik I, Universita¨ tsklinikum der TU Dresden, D-01307 Dresden, by the donor center. Furthermore, donors after a second Fetscherstrae 74, Germany; E-mail: [email protected] BMH (group C, n ¼ 11), and donors with a postsurgical Received 23 August 2004; accepted 13 December 2004 complication or prolonged discomfort (group D, n ¼ 7), Published online 21 February 2005 were examined. These participants were all donors with Pelvic MRI after marrow harvest F Kroschinsky et al 668 these selection criteria (two-time donor, complication) from lower limbs. Medical history and examination were the entirety of 2447 volunteers of the DKMS, who performed by a hematologist experienced in the field of underwent a BMH between May 1992 and July 2003. The marrow harvesting. protocol was approved by the Institutional Review Board MRI was performed at a 1.5 T superconductive magnet of the University Hospital Dresden, Germany. Written (Magnetom Vision, Siemens, Erlangen, Germany) using a informed consent was obtained from all participants. body phased-array coil. The study protocol included The harvests were performed between December 1994 transverse T2- (turbo inversion recovery modulus (TIRM)) and January 2003. All collection centers used common and T1-weighted (spin echo (SE)) sequences. The slice harvest procedures. Marrow had been aspirated exclusively thickness was 5 mm, with an interslice gap of 0.5 mm. In from the posterior–superior iliac crest, which was entered patients, who underwent BMH 4 weeks before MRI, through a skin puncture or a small skin incision. A slightly contrast medium (Gd-DTPA, Magnevist, Schering, Berlin, different technique was used in one of the collection Germany) was administered intravenously via an ante- centers, making 16–33 punctures or incisions in a larger cubital vein at a dosage of 0.1 mmol/kg, followed by a area above the posterior–superior iliac crests (six out of the saline flush of 20 ml. In this group, the axial T1-weighted 50 donors). During the harvests, donors were in the prone sequence was repeated after contrast medium administra- position and under general anesthesia. The volume of tion, applying a fat suppression technique. Total imaging harvested marrow per single aspiration varied from a few to time was 20 min approximately. MRI scans were assessed 20 ml. Demographic data and harvest parameters of the by two radiologists experienced in musculoskeletal diag- study population are listed in Table 1. nostics and the hematologist, who had also performed the At the time of MRI, donors were asked to describe clinical evaluation. The scans were specifically searched for postsurgical complaints, especially severity and duration bone and soft tissue injuries, sacroiliac joint (SIJ) damage, of pain, need for analgesic medication and/or limitations marrow morphology and signal alterations after applica- in normal life activities using a standardized questionnaire. tion of the contrast medium. Primary data entry was Severity of maximum pain within 48 h after the harvest performed electronically as free text using MedoraCOM was classified by the donors on a scale from 0 to 4 (0 – no software (GEHealthcare, Fairfield, USA). After comple- pain, 1 – mild, 2 – moderate, 3 – severe, 4 – very severe tion of recruitment, morphology, frequency and interpreta- pain). In a nonstandardized free interview, the donors were tion of the observed MRI findings in the different groups explored for details of BMH-related problems. Physical were evaluated systematically. Mann–Whitney test was examination included the inspection of the operative employed for the comparison of independent samples, and sites, an investigation of the mobility of the lower spinal a P-value less than 0.05 was considered as statistically column, as well as motility, sensibility and reflexes of the significant.

Table 1 Characteristics of study population

Group A Group B Group C Group D donors 4 weeks donors 1 year two-time donors with after harvest after harvest donors prolonged side effects

Number (n)1616117 Gender (male/female) 14/2 9/7 8/3 4/3 Median age at harvest (range) (years) 31 (20–54) 32 (24–43) 31 (22–39) 35 (26–50) Body weight at harvest, mean (range) (kg) 81 (64–100) 76 (58–107) 74 (55–97) 84 (70–99) Volume of collected marrow Harvest mean (range) (ml) 1173 (580–1664) 1092 (560–1500) 845 (500–1433) 1132 (552–1400) Harvest mean (range) (ml) 805 (300–1175)

Maximum pain at the collection site within 48 h after harvest,a number of donors (%) No 0 (0) 0 (0) 1 (9) 0 (0) Mild 3 (19) 1 (6) 1 (9) 0 (0) Moderate 5 (31) 5 (32) 7 (64) 2 (28) Severe 6 (37) 9 (56) 1 (9) 4 (57) Very severe 2 (13) 1 (6) 1 (9) 1 (15)

Number of days after harvest with any pain Mean 12 4 5 171 Median 10 1 4 60 Range (0–30) (0–14) (0–14) (30–730)

Number of days needed for complete recovery (from any complaints) Mean 16 19 13 n.r. in five donors Median 14 14 8 Range (4 – n.r.) (5–49) (2–37)

aThe second harvest in two-time donors; n.r. – not reached.

Bone Marrow Transplantation Pelvic MRI after marrow harvest F Kroschinsky et al 669 Results the posterior–superior spines, the adjacent muscles (gluteus maximus and gluteus minimus) and the connecting soft Group A (donors 4 weeks after BMH) tissues. After administration of contrast medium, enhance- ment was observed in the T1-weighted sequences in the All 16 donors experienced pain on the day of marrow affected area (Figure 1b). In nine cases (56%) the signal harvest and the day after the procedure. The maximum alterations affected the sacroiliac joint or crossed to the pain was described as severe or very severe in eight donors lateral mass of the sacrum, but there was no increase in (50%), while the symptoms were mild to moderate in the pain intensity or duration observed in these donors remaining donors. None of the donors reported to have (Figure 4c). required analgesics. The median time with temporary discomfort at physical exertion or movement was 10 days (Table 1). Five donors reported persisting problems at the Group B (donors 1 year after BMH) time of MRI. Apart from a positive Lase´ gue’s sign (701)in The grading of postsurgical pain in the donors who were one donor and a slight painful swelling at the operative site examined 1 year after BMH was similar to those in group A in another donor, the physical examinations did not reveal (Table 1). Six donors used analgesics (paracetamol) after any pathological findings. the harvest. At study evaluation, all donors in this cohort Morphological changes in the bone and/or overlying soft were free of discomfort as well as motoric and/or sensory tissues could be seen in all of the 16 donors. MRI showed a dysfunctions. MRI showed abnormal findings in six out of signal increase in T2-weighted (Figure 1a), and a signal 16 donors (36%). Persisting hyperintense signal intensity in decrease in T1-weighted images (not shown) in the ilium at T2 sequences was found in two donors (12%) in the posterior–superior iliac spines and the sacroiliac joints, respectively. A different pattern with signal decrease in T2- weighted images with fat suppression and signal increase in T1-weighted images in the iliac bone was seen in four cases (24%) (Figure 2).

Group C (donors after two harvest procedures) The interval between the second BMH and MRI ranged from 11 months to 8.5 years. Interviews and physical examinations of the donors did not reveal any persisting problems related to the harvest procedures. The majority of donors in this group reported that there was no or only slight pain during the first 48 h after the harvest (Table 1). Only one of them required paracetamol. Four out of 11 donors described an increased discomfort after the second harvest compared to first BMH. One donor had suffered from a unilateral sciatic neuralgia with pain and prickle paresthesias due to a gluteal hematoma. Morphological changes in MRI were seen in eight out of 11 (73%) donors, which is about twice as much as in the donors of group B. As in group B donors, there was a signal decrease in fat-suppressed T2-weighted images, and a signal increase in T1-weighted images in six out of 11 (55%) participants. In addition, scleroses were detected in two cases (18%) in the posterior–superior iliac crest or along the aspiration ducts. In four donors (36%), the alterations indicated an affection of the sacroiliac joint.

Group D (donors with prolonged discomfort) Medical histories and MRI findings of the donors of this group are summarized in Table 2 and Figure 3. MRI scans showed abnormal findings in six donors (86%). A definite Figure 1 Pelvic MRI from a 25-year-old female bone marrow donor 4 postsurgical complication had occurred in three donors weeks after harvest. Typical hyperintense signal alterations at the poster- (one sacroiliitis, two hematomas), whereas three other ior–superior iliac spines in the fat-suppressed T2-weighted sequence. There donors experienced prolonged pain and/or reduced daily is only slight hyperintensity in the adjacent gluteus muscle (a). The fat- activities. Only in the donor, in whom the sacroiliitis had suppressed T1-weighted image after application of contrast medium demonstrates enhancement of numerous tubular structures marking the been diagnosed, MRI demonstrated a specific (unilateral) way of the aspiration needles. Note also minimal enhancement of overlying morphology. In an obese female donor who has suffered soft tissues (b). from low back pain for about 2 years (UPN P32) after

Bone Marrow Transplantation Pelvic MRI after marrow harvest F Kroschinsky et al 670

Figure 2 A 28-year-old asymptomatic male donor 5 years after the second harvest. The fat-suppressed T2-weighted image shows irregular areas of hypointense signal intensity in the iliac crest and the lateral mass of the sacrum bilaterally (a) that correspond to hyperintense signals in the plain T1-weighted image without fat suppression (b). The pattern of signal alteration indicates a crossing of the sacroiliac joint during the harvest.

Table 2 Donors with postsurgical complications and/or prolonged discomfort

UPN Gender Age Harvest Interval Medical history MRI diagnosis (years) volume harvest– (ml) MRI (days)

P32 F 33 552 604 Back pain since harvest, reduced live Fluid retention in the facet joints L4/5, activities, intermittent tramadol synovial cyst of 8 mm P33 M 39 1240 49 Readmission 1 week after harvest due Unilateral sacroiliitis with abnormal to progressive pain at the right gluteal signals in the right sacroiliac joint and region, ischialgia, CRP elevation and the articulating bones (Figure 3a and b) fever, analgetic and antimicrobial treatment P34 M 26 1350 110 Lower back pain since harvest, Local edema in bone and adjacent soft intermittent paracetamol tissues P35 F 32 1400 41 Lower back pain since harvest, Marked signal alterations and intermittent tramadol and paracetamol, enhancement in both posterior–superior reduced fitness to work, positive iliac spines, sacroiliac joints and the soft Lasegue’s sign at 501 tissues (Figure 3c and d) P36 F 35 990 214 Prolonged pain, no analgesics No abnormal findings P37 M 50 1000 71 Prolonged pain in left pelvis due to Circumscript enhancement in the left hematoma, no analgesics gluteus maximus muscle nearby the sacroiliac joint P38 M 37 1395 182 Organized hematoma right access site, Fatty marrow degeneration at the surgical revision 42 days post harvest posterior–superior iliac spines, normal soft tissues

BMH, the MRI findings were compatible with a degen- P ¼ 0.008). In group B, the mean volume of harvested erative facet joint arthrosis. marrow was not different between donors with and without MRI changes (1123 vs 1073 ml, P ¼ 0.958), whereas the Influence of donor weight and harvest volume on symptoms mean cumulative harvest volume in two-time donors was and MRI changes slightly higher in those with abnormal MRI findings compared to donors without signal alterations (1756 vs Based on the analyses of donors in groups A, B and C, no 1370 ml, P ¼ 0.376). correlation could be shown between harvest volume (Figure 4a and b) as well as body weight (data not shown) and intensity or duration of postsurgical discomfort. Further- Discussion more, the comparison of the mean body weight of donors with and without MRI changes in cohorts B and C did not To our knowledge, this is the first study which analyzed the reveal a relevant difference (73 vs 78 kg, P ¼ 0.458). In morphological alterations in the tissues affected by BMH. contrast, the mean body weight of donors with an Multiple marrow aspirations inevitably result in major alteration of the SIJ (group A, B and C) was higher than trauma to the (sacro)iliac bones and the adjacent soft those of donors without such a damage (83 vs 72 kg, tissues.

Bone Marrow Transplantation Pelvic MRI after marrow harvest F Kroschinsky et al 671

Figure 3 Pelvic MRI of donors with postsurgical complications or prolonged discomfort (for medical history, see Table 2). UPN P33 (a, b) The fat- suppressed T2-weighted image shows a persisting marked signal increase in the right ilium and the lateral mass of the sacrum, as well as an irregular sacroiliac joint (a). After administration of contrast medium, enhancement occurs in the same area (T1-weighted, fat-suppressed sequence, b). UPN P35 (c, d): The fat-suppressed T2-weighted image (c) and the fat-suppressed contrast-enhanced T1-weighted scan (d) demonstrate signal increase of both iliac crests, affecting also the overlying soft tissues. There is a cystic lesion (arrow) of less than 10 mm in diameter in the left lateral mass of the sacrum, which was interpreted as a small hematoma or seroma.

There are no investigations regarding the specific suggested inflammatory and regenerative changes (‘acute pathophysiology of bone injury due to BMH. Nevertheless, injury pattern’). by analogy with (noninfectious) osteomyelitis,12 the con- The tissue repair has resulted in a restitutio ad integrum in sequences might include a destruction of bone trabeculae, the majority of donors 1 year after BMH. Nevertheless, vasodilatation, hematoma, edema, migration of cellular about 36% of the study participants in group B had immune effectors, cytokine release, as well as the activation abnormal MRI findings. In two cases, there was a of osteoclasts and osteoblasts. persisting increase of signal intensity in T2-weighted MRI is a suitable modality for the detection of acute sequences, which was interpreted as an ongoing bone bone injury due to its capability to demonstrate anatomical repair. After a surgical intervention due to fracture or details and pathological changes of bone, bone marrow and osteomyelitis, similar signal intensities and enhancement surrounding soft tissues with high sensitivity and excellent pattern may also persist for up to 12 months.15,16 In four spatial resolution. Gadolinium-enhanced imaging is helpful other donors (24%), MRI showed a different morphology in the discrimination of fibrovascular scars from inflam- with signal decrease in T2-weighted and signal increase in matory active foci.13,14 T1-weighted images (Figure 2), reflecting a local replace- Edema pattern on T2-weighted sequences and contrast ment of hematopoietic tissue by fat marrow. The propor- media enhancement after intravenous gadolinium due to tion of donors with fatty marrow conversion and scleroses hyperemia and increased endothelial permeability were as residual MRI abnormalities (‘long-term pattern’) in- found as a typical MRI morphology in donors 4 weeks creased to over 70% in two-time donors. Although data after harvest (group A, Figure 1) and corresponds to the from MRI changes after the first harvest in these donors do

Bone Marrow Transplantation Pelvic MRI after marrow harvest F Kroschinsky et al 672 a 4 Nevertheless, we think that the detection of fat marrow conversion is a real sequel of harvest but not a physio- logical phenomenon. We conclude this from the size and 3 morphology of the alterations and their localization in the areas, which are typically affected by the harvesting 2 procedure. Although the assessment of postsurgical pain and recovery time might be biased in part by a long period Degree of pain 1 between procedure and MRI, the results are comparable to what is known from other reports.3–6 Therefore, the study includes a representative population of bone marrow 0 0 500 1000 1500 2000 donors. The number of study participants in each cohort b is too small for a grading of morphological changes and a 30 statistical correlation of the experienced discomfort, but we do not assume a strong association between complaints and 25 tissue injury. This is based on the observation that there 20 were donors in whom MRI demonstrated extensive signal alterations without having a higher-than-average discom- 15 fort and vice versa. The persistence of an abnormal MRI morphology in any pain any 10 donors of groups B and C was independent of the donor’s body weight and the volume of harvest. However, the mean Number of days with 5 cumulative volume of harvested marrow in two-time 0 donors was higher in those with MRI changes compared 0 500 1000 1500 2000 to donors with normal scans, but this difference was not statistically significant. MRI findings indicated an affection Volume of harvested marrow (ml) of the SIJ in a substantial number of donors, with an c increased risk in donors with a higher body weight. 16 Nevertheless, SIJ damage did not lead to an increase in 14 pain intensity or duration (Figure 4c). 12 In addition to the examination of nature and course of 10 tissue damage after BMH, the study also included all 8 DKMS donors with harvest-related complications and/or 4 prolonged side effects (group D). Although there might be 6 a (small) number of unreported cases, the proportion of 4 2 seven out of 2447 donations (0.3%) confirms again that BMH is, in general, a very safe procedure. Only in one 2 Degree of pain (median) donor of this cohort, MRI revealed a specific finding which 0 Days with symptoms (median) was compatible to the diagnosis of a unilateral sacroiliitis. W/O withW/O with W/O with In the other examinations, MRI detected a bone and soft SIJ afection tissue morphology similar to those in groups A, B and C, or Maximum pain Number of Recovery even failed to detect abnormal findings. These results and within 48 hours days with from all after BMH any pain symptoms the fact that age and harvest volumes in group D donors were not different from the other cohorts might reflect an Figure 4 Influence of harvest volume and SIJ affection on procedure- interindividual different tissue vulnerability and pain related symptoms. The harvest volume did not influence either the degree of pain (0 – no pain, 1 – mild, 2 – moderate, 3 – severe, 4 – very severe pain) sensation. That intraoperative events do not alone account within 48 h (a, n ¼ 50, all donors), or the number of days with any pain after for the postsurgical pain is also suggested by a study which the BMH (b, n ¼ 42, donors of groups A–C). An affection of the SIJ during reported significantly more pain after BMH in related than the harvest procedure, which was detectable in a substantial number of in unrelated donors.20 donors, had also no impact on postsurgical pain and time for complete Although there is a steady increase in the use of recovery (c). This analysis was carried out in all donors of groups A–C which had an abnormal MRI scan (n ¼ 30; without SIF affection, n ¼ 18; peripheral blood progenitor cells (PBPC) for allogeneic with SIJ affection, n ¼ 12). Boxes and lines represent medians and ranges. transplantation, it is improbable that classical BMH will become completely obsolete in the future. Certainly, two recently published randomized studies21,22 dispelled the initial concern of a higher incidence of graft-versus-host not exist for a direct comparison, the results might indicate disease after PBPC allografting, but priming with granu- a cumulation of tissue damage caused by repetitive harvest locyte colony-stimulating factor (G-CSF) before BMH was procedures. described to expand the number of progenitor cells in The appearance of normal human bone marrow in MRI harvested marrow, resulting in a more rapid engraftment is heterogeneous and the distribution of cellular and after transplantation.23–25 Furthermore, in randomized fatty components is variable due to age and gender.17–19 comparisons symptom burden in BM donors was not

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