Med. Surg. J. – Rev. Med. Chir. Soc. Med. Nat., Iaşi – 2020 – vol. 124, no. 3

PHARMACY REVIEWS

LITERATURE REVIEW OF ORAL TREATMENT OF MELLITUS

Mousa Sha’at1, Cristina Mihaela Ghiciuc2, Alexandra Bujor1*, D. V. Timofte2, Alina Ștefanache1, Lăcrămioara Ochiuz1 “Grigore T. Popa” University of Medicine and Pharmacy Iasi 1. Faculty of Pharmacy 2. Faculty of Medicine *Corresponding author. E-mail: [email protected]

LITERATURE REVIEW OF ORAL TREATMENT OF TYPE 2 DIABETES MELLITUS (Abstract): Type 2 non--dependent diabetes mellitus (T2DM), the most common form of diabetes that affects more than 90% of diabetic patients, is characterized by insulin re- sistance, β-pancreatic cells dysfunction, and increased hepatic glucose synthesis. The aim of the present paper was to review data on the efficacy of conventional oral dosage forms com- pared to controlled oral drug delivery systems for treating diabetes. Although the number of oral antidiabetic drugs has significantly increased in recent years, clinically there are still important limitations in terms of therapeutic efficacy, tolerability, and adverse effects, par- ticularly regarding weight gain and medium and long-term glucose control. The last genera- tion of oral pharmaceutical formulations such as modified-release tablets overcame some limitations, while injectable formulations with -like peptide-1 receptor agonists sig- nificantly increased the effectiveness of anti-diabetic and significantly reduced diabetes-specific comorbidities. extended-release formulation seems to be more effective than metformin conventional-release formulation in improving glyco-metabolic control, lipid profile, and levels of some adipocytokines in T2DM. Sustained-release glipiz- ide formulation increases the compliance compared to immediate-release because it seems to achieve similar glucose control with decreased insulin secretion and to decrease the frequency of hypoglycemic episodes. modified release formulation seems to be effective and safe in T2DM with suboptimal glycemic control. Modified release formula- tions generate other advantages such as increasing treatment compliance, lowering the dose of drug substance, and even reducing side effects. Keywords: NON-INSULIN- DEPENDENT DIABETES MELLITUS, CONVENTIONAL RELEASE ORAL PHARMA- CEUTICAL DOSAGE FORMS, MODIFIED RELEASE ORAL PHARMACEUTICAL DOSAGE FORMS.

Diabetes mellitus is a metabolic genet- al metabolism. The diagnostic criteria ically or inherited disorder, with chronic defined by the standard diagnostic criteria evolution, characterized initially by dis- proposed by IDF and World Health Or- ruption of glucose metabolism, subse- ganization (WHO) for the patient with quently associated with suffering and diabetes mellitus include a venous blood disturbance of lipidic, protidic and miner- glucose higher than 126 mg/dL or 7.0

482 Literature review of oral treatment of type 2 diabetes mellitus mmol/L at fasting (fasting for at least 8 rently living with diabetes and 700 million hrs.) obtained for two separate tests or by adults are estimated with diabetes for 2045 more than 200 mg/dL (11.1 mmol/L) (5). It is important to mention that the inci- measured at any time of the day in pa- dence of diabetes has significantly in- tients with symptoms of hyperglycemia or creased in developing countries compared hyperglycemic crisis. Another diagnostic to the developed ones. According to the criterion is the glucose tolerance test, results of the PREDATORR study finalized which requires the administration of a in 2014, which aimed to assess the preva- defined amount of glucose (75 g) followed lence of diabetes in the adult population of by blood glucose level test after two Romania, more than 11% of Romania's hours; in this case, a glycemia higher than population is affected by diabetes. In 2014, 200 mg/dL confirms the diagnosis of dia- there were registered over 875,000 diabetic betes mellitus. Last but not least, glyco- patients and in 2015 there was an increase sylated hemoglobin value above 6.5% (48 with 8.73% in the number of patients, mmol/mol) completes the biochemical reaching approximately one million diag- status of the diabetic patient (1-3). Diabe- nosed patients (6). tes mellitus, according to its etiopatholo- This fact has contributed to the approval gy, is classified as: type 1 diabetes (auto- of innovative antidiabetic molecules, thus immune β-pancreatic cells destruction), ensuring effective monitoring of antidiabet- type 2 diabetes (progressive loss of insulin ic medication, especially in patients for secretion), gestational diabetes (usually whom conventional antidiabetic medication diagnosed in the second or third trimester does not provide a rigorous and stable gly- of pregnancy in previously clinically cemic control. Nowadays, the pharmaco- healthy patients). There are also other logical therapy of T2DM includes the fol- types of diabetes such as neonatal diabe- lowing therapeutic classes: insulin, bigua- tes due to exocrine pancreatic disorders nides, sulphonylureas (hypoglycemic sul- (cystic fibrosis and pancreatitis) and iat- famides), methylglinides, thiazolidinedi- rogenic diabetes as a result of chronic ones (glitazones), α-glucosidase inhibitors, glucocorticoid administration in transplant dipeptidyl peptidase 4 (DPP-4), sodium- patients and HIV/AIDS immunosup- glucose co-transporter 2 inhibitors (SGLT2 pressed patients (2, 3). inhibitors) and glucagon-like peptide 1 T2DM is the metabolic disorder with (GLP-1) receptor agonists (4, 7). the highest incidence and is considered a Most conventional pharmaceutical dos- worldwide public health issue. According age forms of oral antidiabetic drugs are to World Health Organization (WHO) sta- characterized by low bioavailability, short tistics, the number of diabetes patients half-life, and the need to be taken more increased from 108 million in 1980 to 422 times a day, resulting in poor patient ad- million in 2014 and it is estimated to in- herence. Therefore, more research has been crease to 642 million diabetic patients in made in developing new controlled oral 2040 (4). According to the 2019 edition of drug delivery systems. The aim of the pre- the International Diabetes Federation (IDF) sent paper was to review data on the effica- Diabetes Atlas, 463 million adults are cur- cy of conventional oral dosage forms com-

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pared to controlled oral drug delivery sys- The current dosage forms for oral anti- tems for treating diabetes. diabetic drugs are presented in first table.

TABLE I Dosage forms for oral antidiabetic drugs Therapeutic Strength Pharmaceutical Renal Hepatic ANMDMR EMA Drug name Brand name Elderly class (mg) form impairment impairment approval approval film-coated 1000 SIOFOR® tablet 500; prolonged- 750; SIOFOR® release tablet 1000 film-coated 1000 METFOGAMMA® tablet Metformin film-coated SRI NO YES   500 MEGUAN® tablet 500; film-coated 850; GLUCOPHAGE® tablet 1000 500; GLUCOPHAGE prolonged- 750; XR® release tablet 1000 1,75; GLIBENCLAMID tablet 3,5; 5 ARENA SRI SLD YES   3,5 MANINIL® tablet modified 60 DIAPREL MR® release tablet 80 ESQUEL® tablet Gliclazide prolonged- SRI SLD YES   derivatives 30 GLYCLADA® release tablet modified 60; 90 GLYCLADA® release tablet 1; 2; 3; AMARYL® tablet SRI SLD YES  4; 6 30 GLURENORM® tablet YES SLD YES   0,5 DUVIE® tablet   Thiazolidine- 15 tablet diones TORRENT Pioglitazone YES NO YES   (glitazones) 15; 30; ACTOS® tablet 45 Alpha- glucosidase 50; 100 GLUCOBAY® tablet SRI YES YES   inhibitors MRI=12,5 mg Dipeptidyl 6,25; film-coated VIPIDIA® ESRD; YES YES   Peptidase-4 12,5; 25 tablet SRI=6,25 (DPP-4) mg Inhibitors film-coated 5 TRAJENTA® YES YES YES   tablet

484 Literature review of oral treatment of type 2 diabetes mellitus

Therapeutic Strength Pharmaceutical Renal Hepatic ANMDMR EMA Drug name Brand name Elderly class (mg) form impairment impairment approval approval film-coated 2,5; 5 ONGLYZA® ESRD YES YES   tablet 25; 50; film-coated JANUVIA® ESRD YES YES   100 tablet MRI; SRI; 50 GALVUS® tablet ESRD= NO YES   50 mg 5; 10 GLUFAST® tablet orally disinte- - - -   5; 10 GLUFAST OD® grating tablet Methylglinides 60; 120; film-coated STARLIX® YES SLD YES   180 tablet 0,5; 1; 2 RENEOS® tablet YES YES YES   100; film-coated ≥75 INVOKANA® YES YES   300 tablet years film-coated 5; 10 FORXIGA® YES YES YES   SGLT-2 tablet Inhibitors film-coated 10; 25 JARDIANCE® YES YES YES   tablet film-coated ≥75 5; 15 STEGLATRO® ESRD YES   tablet years ANMDMR: National Agency for Medicines and Medical Devices of Romania; EMA: European Medicines Agency; ESRD: end-stage renal disease; MR: modified-release; MRI: moderate renal impairment; SRI: severe renal impairment; SLD: severe liver disease; XR: extended-release.

Biguanides - from conventional gees/sugar-coated pills (100 mg bufor- formulations to modified release min/dragee) by the German pharmaceutical Since the active substance called phen- company Grünenthal. Unfortunately, this formin (fig. 1a) was firstly discovered in the active molecule did not offer maximum 1920s in the Galega officinalis plant extract therapeutic results, being responsible for the (French lilac), the biguanides became the same adverse effects as the first therapeutic class of oral antidiabetic molecule, which is the reason why it was agents used in the treatment of diabetes. withdrawn from the therapeutic use (9). This compound was approved for therapeu- An important moment in the develop- tic use only in October 1977 in the United ment of oral antidiabetics was the introduc- States (US) but did not reach a major thera- tion of metformin (dimethyl HCl) peutic success and was withdrawn a few molecule into therapy (fig. 2). It started to years later due to the increased incidence of be used in European patient therapy in the lactic acidosis as an adverse reaction (8). mid-twentieth century, more precisely in Researches in this field continued and in 1957, and it was approved by the Food and 1957 scientists Shapiro, Parrino, and Freed- Drug Administration (FDA) in the US in man synthesized 1-butylbiguanide (bufor- 1995 (3). Metformin is the first-choice oral min) (fig. 1b), registered under the name of antidiabetic drug in the management of Silubin® formulated in delayed-release dra- T2DM across all age groups.

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a b Fig. 1. Chemical Structure of (a) phenformin (b) (10)

commercial name of metformin convention- al-release tablets, Glucophage® (8, 11, 12). It has been shown that metformin alone reduces glycosylated hemoglobin by about 1.5% and is currently available as tablets with the immediate-release profile (IR) or extended-release profile (XR). The new studies of metformin pharmaceutical for- mulations revealed major benefits for lipid metabolism. Moreover, it was shown that prolonged-release tablets improved the glycemic control of diabetes patients. Re- ducing the frequency of administration at once per day in case of metformin XR for- Fig. 2. Chemical Structure of metformin mulations it was noticed an improved gas- hydrochloride 3-(diaminomethylidene)- trointestinal tolerability through gradual 1,1-dimethylguanidine; hydrochloride (10) and a controlled release of the active sub- stance. Furthermore, by reducing the num- In the development of metformin clinical ber of daily doses compliance to therapy studies, French clinician Jean Sterne was the increased significantly and the number and first diabetes specialist to introduce the intensity of reported adverse reactions were molecule into therapy and gave the first also diminished (13-15).

486 Literature review of oral treatment of type 2 diabetes mellitus

In the Nomenclature of Medicinal Prod- antidiabetic drugs were intensively devel- ucts for Human Use of the Romanian Na- oped. Usually, this class of oral antidia- tional Agency for Medicines and Medical betic agents is recommended only in nor- Devices (ANMDMR), 50 pharmaceutical mal weight or lean patients with greater forms with metformin used in T2DM thera- insulin deficiency, since β-pancreatic cells py are registered as single drug or as associ- are still functional to secrete insulin and to ations under different concentrations. Cur- lower plasma glucose levels. It is im- rently, metformin is the cheapest and most portant to note that they may be associated commonly used oral antidiabetic drug (16). with other oral antidiabetics, such as met- formin or , but their use Sulfonylureas derivatives - becomes more and more limited due to from conventional formulations safety issues and emergence of new oral to modified release antidiabetics. The loss of β-pancreatic cell Following the synthesis of hypoglyce- function does not allow the usage of anti- mic sulfonylureas derivatives, diabetic sulfamides in the therapy of pa- and , which were also the tients with type 1 or advanced stages of first representatives, this class of oral type 2 diabetes (17, 18).

a b Fig. 3. Chemical Structure of (a) gliclazide and (b) glimepiride (10)

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Sulfonylureas derivatives generically high potency and the therapeutic dose is called sulfamides are classified into two expressed in units of milligrams of the ac- major classes: first generation (chlorpropa- tive substance, but the maximum hypogly- mide, , tolbutamide), second- cemic effect is not superior to tolbutamide. generation (glibenclamide, , Sulfamides and their metabolites have sig- gliclazide (fig. 3 a) gliquidone, ) nificant renal excretion, which is why cau- and, according to some authors, third gener- tion is recommended in elderly patients and ation glimepiride (fig. 3 b) (tab. I). The in patients with impaired renal function to second generation of sulphonylureas has a avoid severe hypoglycemia (8, 19).

TABLE II Sulfonylureas antidiabetic drugs - pharmacological characteristics Oral antidiabetic drug Usual daily dose (mg) Duration of action (hrs.) T1/2 (hrs.) Chlorpropamide 100-500 24-72 35 Tolazamide 100-1,000 12-18 7 Tolbutamide 500-3,000 6-10 7 Glibenclamide 2.5-15 12-16 5 Glibornuride 12.5-100 8-12 8 Gliclazide 80-240 6-12 10 Gliquidone 15-120 5-7 1.5-2 Glisoxepide 2-16 8-24 1.7 Glyburide 1.25-10 24 7-10 Glipizide 2.5-10 10-24 2-4 Glimepiride 3-6 12-12 7

Sustained-release glipizide formulation surprisingly found that these two molecules increases the compliance compared to im- caused a decrease in blood glucose, but mediate-release glipizide because it seems high hepatotoxicity though (20). In addi- to achieve similar glucose control with tion to the hypoglycemic effect, thiazoli- decreased insulin secretion and to decrease dinediones have a various number of phar- the frequency of hypoglycemic episodes macological advantages, including decreas- (21). Gliclazide modified release formula- ing the rate of albumin excretion, modula- tion seems to be effective and safe in tion of insulin resistance syndrome, lower- T2DM with suboptimal glycemic control ing blood pressure, and improving the glu- (22). cose tolerance threshold (7). Based on the scientific observations of Oral antidiabetic drugs formulated these two substances ( and only as conventional drug release forms ), a new class of oral antidia-  Thiazolidinediones (glitazones) betics, called derivatives, The development of thiazolidinediones has been developed. They are acting as started from the observations of the clofi- agonists of peroxisome proliferator- brate, ciglitazone and troglitazone deriva- activated receptors (PPAR). The main rep- tives (fig. 4) which were studied for their resentatives of this therapeutic class are therapeutic effect on lipid profile; it was pioglitazone and lobeglitazone (19).

488 Literature review of oral treatment of type 2 diabetes mellitus

Fig. 4. Chemical structure of thiazolidinediones (10)

Pioglitazone (Actos®), the most used T2DM therapy. Even though the chemical from this group, was authorized by the structure of lobeglitazone is similar to European Medicines Agency (EMEA, pioglitazone and , lobeglita- EMA) in October 2000 in T2DM in adult zone was conceptually designed by modifi- patients, particularly those who are over- cation of the rosiglitazone structure with a weight, and it is used as an adjunct to diet substituted pyrimidine. Unlike Pioglita- and exercise to improve glycemic control. zone, which is an agonist on both PPAR- Another derivative, Rosiglitazone (Avan- alpha and PPAR-gamma, Lobeglitazone is dia®) (fig. 5 a), authorized by EMEA in a selective agonist only on PPAR-alpha. July 2000, was suspended in September Lobeglitazone has a p-methoxy phenoxy 2010 because the benefits no longer out- group at the 4-position of the pyrimidine weighed the cardiovascular risks (23). moiety leading to a more potent activity Lobeglitazone, a novel thiazolidinedi- than the reference compounds (pioglitazone one derivative, was approved in 2013, only and rosiglitazone), with reduced side ef- in South Korea, and it is recommended in fects (fig. 5 b) (24).

489 Mousa Sha’at et al.

Fig. 5. Chemical Structure of (a) rosiglitazone (b) lobeglitazone (10)

 Alpha-glucosidase inhibitors insulin preparations are not able to provide The beginning of the '90s is marked by adequate glycemic control. the introduction of a new therapeutic class for patients with T2DM, α-glucosidase inhibitors, whose mechanism of action is delayed the absorption of dietary carbohy- drates in the gastrointestinal tract, which generates the reduction in plasma glucose levels. Three drugs belong to this class, namely , acarbose, and , that were clinically approved in the US. In Romania, are used only the 50 and 100 mg film-coated tablets of acarbose (fig. 6), under the name Glucobay® (7, 17). Voglibose, an unauthorized α-glucosidase inhibitor in Europe, is successfully used in Asia though. This compound was discovered in Japan in 1981, and since 1994 it has been used as an oral antidiabetic drug in T2DM therapy. Voglibose is used for lowering post- prandial blood glucose levels when either diet and/or lifestyle-related exercise, and other hypoglycemic agents (sulphonylureas) or Fig. 6. Chemical Structure of acarbose (10)

490 Literature review of oral treatment of type 2 diabetes mellitus

This active substance produces an in- resent one of the newest T2DM therapy creased release of glucagon-like peptide 1 classes used as monotherapy. This thera- (GLP-1), which is an insulinotropic hor- peutic class includes drugs, such as mone, known to enhance insulin secretion sitagliptin (fig. 7), saxagliptin, vildag- and insulin sensitivity. Voglibose has a liptin, alogliptin, linagliptin, , major advantage to acarbose, namely, it has , , , no inhibitory activity against lactase and dutogliptin, and omarigliptin (27-29). so, it does not cause lactose intolerance. In DPP-4 inhibitors have various mecha- 2004, voglibose orodispersible tablets nisms of action to control hyperglycemia, (VODT - Voglibose oral disintegrated tab- by stimulating the secretion of insulin let) were introduced into Japan, which from beta-cells, decreasing the secretion allowed easier and faster administration of of glucagon from pancreatic alpha-cells, medication, in comparison with conven- and at the same time reducing the produc- tional oral tablets. The launch of VODT tion of glucose by the liver. The number made a significant contribution to diabetic of drugs doses administered per day is care by improving patient compliance. The correlated with the half-life of the active development of VODT formulation brings substance. Thus, the sitagliptin, alogliptin, important benefits to patients with swal- saxagliptin and linagliptin are adminis- lowing problems, elderly patients as well as tered in a single daily dose, while vildag- in emergencies when the patient has no liptin, with a lower half-life, is recom- access to water (25, 26). mended for twice-daily administration. DPP-4 inhibitors may be used in combina-  Dipeptidyl Peptidase-4 tion with insulin with the great advantage (DPP-4) Inhibitors of reducing the likelihood of developing Dipeptidyl peptidase-4 inhibitors rep- hypoglycemia (3, 20).

Fig. 7. Chemical Structure of sitagliptin (10)

DPP-4 inhibitors are safe, orally active,  Methylglinides and highly tolerable, mainly in elderly Methylglinides form a class of drugs patients, due to their minimal risk for hy- used to treat T2DM and include active poglycemic events. substances, like repaglinide (fig. 8),

491 Mousa Sha’at et al. nateglinide and mitiglinide, with a mecha-  Sodium-glucose co-transporter nism of action to stimulate pancreatic se- 2 (SGLT-2) inhibitors cretion of insulin. Phlorizin, a dihydroalcohol which was found primarily in fruits of the Pyrus com- munis (pear), but also in some closely re- lated species such as cherries and apples, is the first model for synthetic analogs of SGLT-2 inhibitors. This compound was studied as an antidia- betic therapeutic agent as a non-selective SGLT-1 and SGLT-2 inhibitor, but it was not an effective drug because when orally con- sumed, it was nearly entirely converted into phloretin by hydrolytic enzymes in the small intestine. So, all the attention of researchers has since focused on the synthesis of selec- tive therapeutic compounds SGLT-2 for T2DM treatment (30). In January 2019, the Committee for Me- dicinal Products for Human Use of EMEA approved a new therapeutic indication for the dapagliflozin molecule (fig. 9 a), thus becom- Fig. 8. Chemical Structure of repaglinide (10) ing the first oral antidiabetic drug used in type 1 diabetes mellitus as an adjuvant to Methylglinides have a short half-life and insulin in patients with the body mass ≥27 2 are absorbed very rapidly from the gastroin- kg/m , when insulin monotherapy does not testinal tract and therefore are recommended provide adequate glycemic control (31). to be given 15 minutes before a meal. Among the most commonly used com- Methylglinides have the advantage that they pounds in the European Union are dapagli- can be used in patients who are allergic to flozin 5 and 10 mg film-coated tablets, sulphonylureas, and may reduce the risk of canagliflozin 100 and 300 mg film-coated hypoglycemia, even if they induce similar tablets, and empagliflozin 10 and 25 mg weight gain to sulphonylureas. In case of film-coated tablets. inadequate glycemic control, they may be Empagliflozin (fig. 9 b) is the first anti- combined with metformin or thiazolidinedi- diabetic drug with clinical trials in reducing the risk of cardiovascular mortality. The ones. Repaglinide was introduced into ther- ® apy in 1997 as a benzoic acid derivative. EMPA-REG OUTCOME study demon- Repaglinide can be administrated to patients strated a 38% reduction of cardiovascular mortality risk in patients with T2DM as with renal impairment, due to their excretion compared with the placebo group. Thus, via feces. In 2001, EMEA approved the empagliflozin became the first oral antidia- nateglinide molecule as 60, 120 and 180 mg betic medicine administrated as monother- film-coated tablets marketed under the brand apy, approved by the EMEA for the reduc- name Starlix® (7, 19). tion of cardiovascular risk (32).

492 Literature review of oral treatment of type 2 diabetes mellitus

a b Fig. 9. Chemical Structure of dapagliflozin (a) empagliflozin (b) (10)

CONCLUSIONS monotherapy. In recent decades, oral antidiabetic drugs Modified release formulations generate for T2DM has undergone a remarkable evo- advantages such as increasing treatment lution from simple molecules with a hypo- compliance, lowering the dose of drug glycemic effect that has been accidentally substance, and even reducing side effects. discovered to complex polypeptides with All advances in the development of antidi- multiple mechanisms of action. Although abetic medication have significantly con- most oral antidiabetic substances are formu- tributed to increasing the quality of life of lated into conventional (immediate) release the diabetic patient, yet T2DM remains a tablets, a significant number of modified- public health problem and a scourge affect- release formulations have been introduced ing more and more patients. over the past decade, encompassing one or more drug substances thereby providing CONFLICT OF INTERESTS associated medication as an effective thera- There are no conflicts of interest. All py in the case of patients refractory to authors contributed equally to this paper.

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NONEWSUTĂ ȚI

REGARDING LYNCH / MUIR-TORRE SYNDROMES

A “cancer predisposing syndrome” later labeled as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome, was firstly described by Warthin, about one century ago. An increased predisposition to the development of multiple familial tumors is described as characteristic of this syndrome where visceral and cutaneous malignancies may appear at an early age namely endometrial, gastric, small bowel, ureteral and renal pelvis, ovarian, hepatobiliary tract, pancreatic, brain (Turcot Syndrome) and sebaceous glands (Muir-Torre Syndrome). The latter, a variant of Lynch Syndrome, is characterized by the presence of se- baceous skin adenomas, carcinomas and/or keratoacanthomas associated with visceral ma- lignancies. Both Lynch Syndrome and Muir-Torre Syndrome have been recognized due to germline mutations in mismatch repair genes MLH1, MSH2 and MSH6. To date, 56 Lynch Syndrome founder mutations dependent on MLH1, MSH2 and, although less frequently found, MSH6 and PMS2 are described. Some of these founder mutations, principally of MSH2 gene, have been described to cause Muir-Torre phenotype and have been traced in large and outbreed Muir-Torre Syndrome families living in different US and European terri- tories. Due to the evidences of highly specific Muir-Torre phenotypes related to the presence of widespread MSH2 founder mutations, preliminary search for these MSH2 common muta- tions in individuals carrying sebaceous tumors and/or keratoacanthomas, at early age or in association to visceral and familial tumors, permits cost-effective and time-saving diagnostic strategies for Lynch/Muir-Torre Syndromes (Ponti G, Manfredini M, Tomasi A, Pellacani G. Muir-Torre Syndrome and founder mismatch repair gene mutations: A long gone historical genetic challenge. Gene 2016; 589(2): 127-132).

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