Clinicopathological features, MCPyV status and outcomes of Merkel cell carcinoma in solid-organ transplant recipients: a retrospective, multicentre cohort study.

BACKGROUND: The proportion of Merkel cell carcinomas (MCCs) in solid-organ transplant recipients (SOTR) harbouring Merkel cell polyomavirus (MCPyV) is unknown, as are factors affecting their outcomes. OBJECTIVE: To describe clinicopathological features of MCC in SOTR, investigate the tumoral MCPyV-status and identify factors associated with tumour outcomes. METHODS: Retrospective, international, cohort-study. MCPyV-status was investigated by immunohistochemistry and polymerase chain reaction. RESULTS: A total of 30 SOTR and 44 consecutive immunocompetent patients with MCC were enrolled. SOTR were younger at diagnosis (69 vs. 78 years, P < 0.001). Thirty-three percent of SOTR MCCs were MCPyV-positive vs. 91% of immunocompetent MCCs (P = 0.001). Solid-organ transplantation was associated with an increased cumulative incidence of progression (SHR: 3.35 [1.57-7.14], P = 0.002), MCC-specific mortality (SHR: 2.55 [1.07-6.06], P = 0.034) and overall mortality (HR: 3.26 [1.54-6.9], P = 0.002). MCPyV-positivity and switching to an mTOR inhibitor (mTORi) after MCC diagnosis were associated with an increased incidence of progression (SHR: 4.3 [1.5-13], P = 0.008 and SHR: 3.6 [1.1-12], P = 0.032 respectively) in SOTR. LIMITATIONS: Retrospective design and heterogeneity of SOTR cohort. CONCLUSIONS: MCPyV appears to play a less prominent role in the aetiopathogenesis of MCC in SOTR. SOTR have a worse prognosis than their immunocompetent counterparts and switching to an mTORi after the diagnosis of MCC does not improve progression.

Treatment approaches in immunosuppressed patients with advanced cutaneous squamous cell carcinoma.

Immunosuppression, both iatrogenic and disease-related, is associated with a greatly increased incidence of cutaneous SCC (cSCC) and with aggressive cSCC and worse disease outcomes. Consequently, rapid access to skin cancer services and prudent surgical choices, such as circumferential margin assessment, is essential when treating advanced cSCC in an immunosuppressed patient. For high-risk cancers and control of cSCC multiplicity, additional strategies should be actively considered within the multidisciplinary clinical care team. These include minimization or revision of immunosuppressive medications, systemic chemoprevention (including retinoids, nicotinamide, capecitabine) and adjuvant therapies such as radiotherapy. Unfortunately, there is a relative paucity of good evidence for many of these treatments in the immunosuppressed. Systemic treatments for metastatic cSCC are often contraindicated in organ transplant recipients, notably checkpoint inhibitor immunotherapy. There are also toxicity concerns with some conventional chemotherapies and EGFR inhibitors. Until recently, clinical trials have largely excluded immunosuppressed individuals. Development of more effective treatment for advanced cSCC in this high-risk group and prospective clinical trials are now research priorities.

Cutaneous atypical papular CD8+ lymphoproliferative disorder at acral sites in a renal transplant patient.

A 20-year-old woman presented with a 2-month history of an acute symmetrical eruption, manifesting as asymptomatic ill-defined erythematous macules and hyperkeratotic papules on the palms. The patient was a renal transplant recipient, and the lesions had developed 2 months post-transplantation. Histologically, the eruption shared features of a reactive inflammatory condition called papular eruption of atypical CD8+ lymphocytes as well as primary cutaneous acral CD8+ T-cell lymphoma (a provisional indolent entity in the new World Health Organisation classification of lymphoid neoplasms, 2016). The latter disorder has been described to occur at acral sites in immunocompetent patients, whereas the former has previously been described only in patients infected with human immunodeficiency virus. The lesions in our patient healed after topical treatment with corticosteroids and alteration of immunosuppressive therapy, supporting the role of immunosuppression in this case. We classified our patient's condition as lying in the spectrum of the aforementioned two conditions, but the relationship between both diseases remains to be clarified. Awareness of these unusual conditions may prevent the use of unnecessary aggressive therapies in similar patients.

Painful skin lesions and squamous cell carcinoma predict overall mortality risk in organ transplant recipients: a cohort study.

BACKGROUND: Organ transplant recipients (OTRs) have a highly increased risk of cutaneous squamous cell carcinomas (SCCs). Sensation of pain in cutaneous tumours is a powerful patient-reported warning signal for invasive SCCs in OTRs. OBJECTIVES: To investigate the impact of painful vs. painless skin lesions and SCC vs. other skin lesions on the overall mortality risk in OTRs. METHODS: We followed 410 OTRs from 10 different centres across Europe and North America between 2008 and 2015. These patients had been enrolled in an earlier study to define clinically meaningful patient-reported warning signals predicting the presence of SCC, and had been included if they had a lesion requiring histological diagnosis. Cumulative incidences of overall mortality were calculated using Kaplan-Meier survival analysis, and risk factors were analysed with Cox proportional hazard analysis. RESULTS: There was an increased overall mortality risk in OTRs who reported painful vs. painless skin lesions, with a hazard ratio (HR) of 1·6 [95% confidence interval (CI) 0·97-2·7], adjusted for age, sex and other relevant factors. There was also an increased overall mortality risk in OTRs diagnosed with SCC compared with other skin lesions, with an adjusted HR of 1·7 (95% CI 1·0-2·8). Mortality due to internal malignancies and systemic infections appeared to prevail in OTRs with SCC. CONCLUSIONS: We suggest that OTRs have an increased overall mortality risk if they develop painful skin lesions or are diagnosed with cutaneous SCC.

N-Acetylcysteine in the treatment of trichotillomania: remarkable results in two patients.

BACKGROUND: The management of trichotillomania is challenging. The limited efficacy and side-effects of pharmacological medications and difficulty in long-term maintenance of behavioural therapies necessitates alternative treatment options. A dysregulated glutamatergic system has been implicated in the pathophysiology of trichotillomania. A limited number of reports indicate that N-acetylcysteine (NAC), a glutamate modulator, may be a promising treatment for this disorder. OBJECTIVES: We report two patients with trichotillomania for whom treatment with NAC was successful. METHODS: The first patient was a 30-year-old female, and the second patient was a 14-year-old girl, both who were diagnosed with trichotillomania and prescribed NAC (1200 mg/d, p.o.). RESULTS: Hair pulling behaviour subsided within 2 months and 2 weeks of initiating NAC in the first and second patient, respectively. Complete hair regrowth was observed after 4 and 6 months of NAC treatment in the first and second patient, respectively. No side-effects related to NAC were noted. CONCLUSION: NAC could be a well-tolerated and effective treatment option for trichotillomania.

Swelling Mechanisms of UO2 Lattices with Defect Ingrowths.

The swelling that occurs in uranium dioxide as a result of radiation-induced defect ingrowth is not fully understood. Experimental and theoretical groups have attempted to explain this phenomenon with various complex theories. In this study, experimental lattice expansion and lattice super saturation were accurately reproduced using a molecular dynamics simulation method. Based on their resemblance to experimental data, the simulation results presented here show that fission induces only oxygen Frenkel pairs while alpha particle irradiation results in both oxygen and uranium Frenkel pair defects. Moreover, in this work, defects are divided into two sub-groups, obstruction type defects and distortion type defects. It is shown that obstruction type Frenkel pairs are responsible for both fission- and alpha-particle-induced lattice swelling. Relative lattice expansion was found to vary linearly with the number of obstruction type uranium Frenkel defects. Additionally, at high concentrations, some of the obstruction type uranium Frenkel pairs formed diatomic and triatomic structures with oxygen ions in their octahedral cages, increasing the slope of the linear dependence.

Cutaneous lymphoproliferative disorders in organ transplant recipients: update 2014.

Post-transplant lymphoproliferative disorders (PTLD) are lymphoid or plasmacytic proliferations that develop after solid organ, bone marrow or stem cell transplantation. PTLD are the leading cause of cancer-related mortality and graft loss in both pediatric and adult solid organ transplant recipients (ORT). These disorders comprise a spectrum ranging from usually EBV-driven, mostly B-cell polyclonal proliferations to B- and T-cell lymphomas indistinguishable from their counterparts occurring in immunocompetent individuals. PTLD usually present in extranodal sites; isolated skin involvement of PTLD is rare. A recent multicenter European case series showed that primary cutaneous T-cell PTLD are more common than primary cutaneous B-cell PTLD, and along with its folliculotropic variant, mycosis fungoides (MF) is the most frequent form of posttransplant primary cutaneous T-cell lymphoma (CTCL). This case series also disclosed that primary cutaneous CD30+ lymphoproliferative disorders is the second most common posttransplant CTCL subtype, indicating that the spectrum of primary CTCL in OTR is similar to that in the general population. However, in contrast with the immunocompetent individuals, the prognosis of primary cutaneous CD30+ anaplastic large T-cell lymphoma is worse than posttransplant MF and than its counterpart in the general population which has an excellent prognosis. The recent case series indicated that the spectrum of primary cutaneous B-cell PTLD differs significantly from cutaneous B-cell lymphoma in the general population, with a predominance of EBV-associated forms. Currently, the best therapeutic intervention(s) for primary cutaneous PTLD remains unknown.

Pain identifies squamous cell carcinoma in organ transplant recipients: the SCOPE-ITSCC PAIN study.

Organ transplant recipients (OTR) are at high risk for cutaneous squamous cell carcinomas (SCC). We aimed to define clinically meaningful patient-reported warning signals predicting the presence of invasive SCC.Patient-reported signs and symptoms of 812 consecutively biopsied skin lesions from 410 OTR were determined by questionnaire and physical examination and related to the subsequent biopsy-proven diagnoses. Receiver-operating characteristic (ROC) curve analyses were used as a measure of distinction between the predictive values of patient-reported warning signals and the occurrence of SCC. Pain was an independent predictive patient-reported warning signal for a biopsy-proven invasive SCC. The odds ratio from the fully adjusted model predicting SCC was 4.4(95% confidence interval: 2.4­8.2). Higher scores on the visual analog scale (VAS) for pain were associated witha greater likelihood for the presence of SCC compared to none or mild pain. The for scores on the VAS from 1to 3, 4 to 6 and 7 to 10 were 4.9 (2.2­10.5), 2.3 (0.96­5.5)and 16.5 (3.6­75.8), respectively. Pain is the most powerful patient-reported warning signal for invasive cutaneous SCC in OTR. Empowerment of patients by education could accelerate diagnosis and treatment of cutaneous SCC.

Primary cutaneous posttransplant lymphoproliferative disorders in solid organ transplant recipients: a multicenter European case series.

Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)-classified according to the WHO-EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty-seven percent of patients had a kidney transplant. Twenty-four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV-associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV-negative. Sixteen (45.7%) patients died after a median follow-up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30(+) lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30(+) LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30(+) LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV-associated cutaneous B cell LPD predominates in OTR.

Isotretinoin has no negative effect on attention, executive function and mood.

BACKGROUND: According to some animal data, impairments in learning and memory are seen with isotretinoin. Isotretinoin has been shown to affect human brain metabolism, but the data on human neural functions is lacking. OBJECTIVES: To evaluate whether isotretinoin treatment affects cognitive functions, causes depression and anxiety or alters anger level and anger expression. METHODS: Neuropsychological tests of attention and executive functions, behavioural tests measuring anger and depression and measures assessing acne severity were applied to 63 severe and/or resistant acne patients from four medical centres including one primary care institute and three university hospitals at the beginning, at the end of first month, third month and at end of treatment with isotretinoin. RESULTS: From a total of 63 patients, 15 missed the final visit and 48 were evaluated. Overall, 11 (six women, five men) and five (all women) patients reported anger and depression, respectively, during treatment. Eleven of these 16 patients improved spontaneously. No detrimental effects of isotretinoin treatment on either executive functions or mood were found. Several executive functions and control of anger trait were found to be improved. Clearing of acne was obtained in 94.6% of patients. LIMITATIONS: Improvement of several measures may be related to learning effect of repeated testing. Investigating brain functions is a complex process and various methods can be used. CONCLUSION: The test battery used in this study, which is commonly used to evaluate mental status both in adults and children, did not show any negative effect of isotretinoin on executive functional parameters in acne patients.

Vertical vs. transverse sections of scalp biopsy specimens: a pilot study on the comparison of the diagnostic value of two techniques in alopecia.

BACKGROUND: Using both vertical and transverse sections is preferred for histopathological diagnosis of alopecia. However, in cases in which only a single biopsy is taken, it is not clear which type of sectioning is better. AIM: To compare the diagnostic value of transverse and vertical sections. METHODS: In total, 53 patients with alopecia were enrolled in the study. Two biopsies were taken from each patient, and cut into either transverse or vertical sections. The clinical and histopathological findings were evaluated together for the definitive diagnosis. After the study period, a pathologist randomly re-evaluated the sections. We compared the histopathological diagnoses with the definitive diagnoses, and determined the sensitivity and specificity of each method. RESULTS: A definitive diagnosis was made for 47 patients (88.7%). Of these, 30 (63.8%) had noncicatricial and 17 (36.2%) had cicatricial alopecia, and the diagnosis was made by transverse and vertical sections for 43 (91.5%) and 39 (88%), respectively (P > 0.05; sensitivity; 91.5% vs. 82%). All 30 patients with noncicatricial alopecia were diagnosed by transverse sections, and 25 (83.3%) of the 30 were diagnosed with vertical sections (P = 0.05; sensitivity 100% vs. 83.3%). Of the 17 patients with cicatricial alopecia, 13 (76.5%) and 14 (82.4%) patients were diagnosed by transverse and vertical sections, respectively (P > 0.05; sensitivity 76.5% vs. 82.4%). Five patients with lichen planopilaris were diagnosed by vertical sections, and one by transverse sections. There were several limitations to the study: (i) statistical subtype analysis could be performed only for alopecia areata; (ii) no conclusion could be drawn about the interobserver reliability of two sections; and (iii) having the pathologist-blinded study performed retrospectively might have caused a recall bias. CONCLUSION: If only a single biopsy specimen is available, it may be preferable to have transverse sections in cases of suspected noncicatricial alopecia, and vertical sections in cases of suspected lichen planopilaris. Either type of sectioning is suitable for cicatricial alopecia when lichen planopilaris is clinically unlikely.

Viral oncogenesis and its role in nonmelanoma skin cancer.

In recent years, the contribution of viruses to cutaneous oncogenesis has steadily gained recognition. The archetype is human herpesvirus 8, which is well established as the causative agent in Kaposi sarcoma. Other viruses believed to play a role in nonmelanoma skin cancer include human papillomavirus and the recently described Merkel cell polyomavirus. We review the mechanisms by which these three viruses interact with the host cell, ultraviolet radiation and immunosuppression to result in carcinogenesis.

In vitro antifungal susceptibility of dermatophyte strains causing tinea pedis and onychomycosis in patients with non-insulin-dependent diabetes mellitus: a case-control study.

BACKGROUND: The efficacy of antifungal treatment may be reduced and/or delayed in diabetic patients. To date, no study has investigated the in vitro antifungal susceptibility of dermatophytes in this patient group. OBJECTIVE: We aimed to determine the dermatophyte species causing tinea pedis and onychomycosis, and in vitro susceptibility of these dermatophytes to terbinafine, itraconazole, and fluconazole in patients with non-insulin-dependent diabetes mellitus. We compared the findings in diabetic patients with those in non-diabetic individuals. MATERIALS AND METHODS: One hundred patients with non-insulin-dependent diabetes mellitus and 100 otherwise healthy controls clinically suspected with tinea pedis and/or onychomycosis were included. Skin scrapings and/or nail clippings were taken and cultured on Sabouraud dextrose agar, mycobiotic agar, and dermatophyte test medium. In vitro antifungal susceptibility tests were carried out according to the Clinical and Laboratory Standards Institute (CLSI) M-38P protocol with some modifications. RESULTS: Fifty-seven samples of 54 diabetics and 50 samples of 50 controls grew dermatophytes. In both groups, Trichophyton rubrum was the most common isolate. Mean MIC values of terbinafine, itraconazole, and fluconazole for all of the isolated dermatophyte strains were similar in two groups (P>0.05). The difference in mean MIC values of three antifungals for T. rubrum and T. mentagrophytes between two groups was not statistically significant (P>0.05). CONCLUSIONS: Dermatophyte types causing tinea pedis and onychomycosis, their frequency patterns, and in vitro activity of three antifungals against dermatophytes in diabetics are similar to the non-diabetics. Terbinafine is the most active agent in vitro in both groups.

Comparison of the two techniques for measurement of the density of Demodex folliculorum: standardized skin surface biopsy and direct microscopic examination.

BACKGROUND: In daily dermatological practice, many dermatologists do not include demodicosis in their differential diagnoses, or the diagnosis of demodicosis is frequently masked by other skin diseases such as papulopustular or erythematotelangiectatic rosacea, seborrhoeic dermatitis, perioral dermatitis and contact dermatitis. There are two methods for measurement of the density of Demodex folliculorum (Dd): standardized skin surface biopsy (SSSB) and direct microscopic examination of fresh secretions from sebaceous glands (DME). No study has been reported in the literature comparing the diagnostic value of these two techniques. OBJECTIVES: To compare the value of the two techniques, SSSB and DME, for the measurement of Dd in patients with suspected demodicosis. METHODS: Mite density was investigated using SSSB and DME in 37 patients with facial skin lesions suggesting demodicosis. Two samples, one for SSSB and one for DME, were obtained from a cheek lesion of each patient. RESULTS: Twenty-three (62%) patients were diagnosed with demodicosis according to their clinical manifestations combined with a high Dd (Dd > 5 mites cm(-2)) with SSSB and/or DME. In all the patients, the mean Dd measured with SSSB was higher than that with DME (22.9 +/- 5.9 and 2.2 +/- 0.8, respectively; P = 0.001). Also, among the 23 patients with demodicosis, the mean Dd measured using SSSB was higher than the mean Dd with DME (36.5 +/- 8.3 and 3.4 +/- 1.2, respectively; P = 0.0001). CONCLUSIONS: We recommend the use of SSSB for the measurement of Dd as more patients with demodicosis can be diagnosed with this method compared with the DME method.

Patch testing in allergic contact dermatitis: is it useful to perform the cosmetic series in addition to the European standard series?

BACKGROUND: Cosmetics are the causative agents in 8-15% of patients suspected of having allergic contact dermatitis. Patch testing with standard series identifies 70-80% of the responsible allergens in all contact dermatitis; however, many important cosmetic-related allergens may be missed by using standard series alone. OBJECTIVE: The aim of this study was to determine the value of using cosmetic series in addition to the European standard series in patients with suspected allergic contact dermatitis. METHODS: In this prospective study, 93 consecutive patients suspected of having allergic contact dermatitis were patch tested with the European standard series, and simultaneously with cosmetic series. Positive allergic reactions were further interpreted as clinically relevant or irrelevant. The clinically relevant reactions were subsequently stratified into three subgroups: (i) reactions only to allergen/allergens in the European standard series; (ii) reactions only to allergen/allergens in cosmetic series; and (iii) reactions both to allergen/allergens in the European standard and cosmetic series. RESULTS: A total of 74 positive reactions were observed in 93 patients. However, only 46 (62.2%) of the total positive reactions were found to be clinically relevant. Of all the clinically relevant positive reactions, 27 (58.7%) were caused by the allergens in the European standard series; 19 (41.3%) were caused by the allergens in cosmetic series. Of the 93 patients tested, 44 (47.3%) had at least one positive allergic reaction, 30 (68.2%) of whom had clinically relevance. Of the 30 patients with clinically relevant positive tests, 16 (53.3%) reacted only to allergens in the European standard series; nine (30%) reacted only to cosmetic series allergens; and five (16.7%) reacted both to the European standard and cosmetic series allergens. Among the 45 cosmetic series allergens tested, 15 (33.3%) gave positive reactions of which 14 (93.3%) of those were found to be clinically relevant. The clinically relevant cosmetic series allergens which were found to be over the critical incidence of 1% included methyldibromo glutaronitrile, Euxyl K400, and isopropyl myristate. CONCLUSION: Patch testing with cosmetic series in addition to the European standard series increased the capability to detect the relevant allergen/allergens, particularly in patients with a suspicion of cosmetic allergy. However, it is not practical and cost-effective to test those patients routinely with all 45 allergens in the cosmetic series. As the European baseline series which includes methyldibromo glutaronitrile is now widely used as the guideline minimum set of allergens for routine diagnostic patch test investigations, we additionally recommend Euxyl K400 and isopropyl myristate as the candidates for patch testing.

Oxidant/antioxidant status in recurrent aphthous stomatitis.

OBJECTIVE: Recurrent aphthous stomatitis (RAS) is a common oral mucosal disorder characterized by recurrent, painful oral aphthae, and oxidative stress presumably contributes to its pathogenesis. The study was performed to evaluate the involvement of oxidant toxicity in this disorder. METHODS: Patients with RAS (n = 26) and age- and sex-matched healthy control subjects (n = 20) were included in this study. Following an overnight fast, blood specimens were obtained. Plasma malondialdehyde concentrations and erythrocytes glutathione peroxidase activities were determined. Also, plasma vitamin E and selenium levels were detected. Mann-Whitney U-test was performed for statistical evaluation. RESULTS: Oxidative stress was confirmed by the significant elevation in plasma malondialdehyde levels and by the significant decrease in glutathione peroxidase activities, vitamin E and selenium levels (P < 0.001). CONCLUSIONS: Our results indicated that lipid peroxidation and the inadequacy of the defense system seem to play a crucial role in the pathogenesis of recurrent aphthous stomatitis.