Search

The maternal mode of mitochondrial DNA (mtDNA) inheritance is central to human genetics. Recently, evidence for bi-parental inheritance of mtDNA was claimed for individuals of three pedigrees that suffered mitochondrial disorders. We sequenced mtDNA using both direct Sanger and Massively Parallel Sequencing in several tissues of eleven maternally related and other affiliated healthy individuals of a family pedigree and observed mixed mitotypes in eight individuals. Cells without nuclear DNA, i.e. thrombocytes and hair shafts, only showed the mitotype of haplogroup (hg) V. Skin biopsies were prepared to generate ρ° cells void of mtDNA, sequencing of which resulted in a hg U4c1 mitotype. The position of the Mega-NUMT sequence was determined by fluorescence in situ hybridization and two different quantitative PCR assays were used to determine the number of contributing mtDNA copies. Thus, evidence for the presence of repetitive, full mitogenome Mega-NUMTs matching haplogroup U4c1 in various tissues of eight maternally related individuals was provided. Multi-copy Mega-NUMTs mimic mixtures of mtDNA that cannot be experimentally avoided and thus may appear in diverse fields of mtDNA research and diagnostics. We demonstrate that hair shaft mtDNA sequencing provides a simple but reliable approach to exclude NUMTs as source of misleading results.

IL-17 blockers are among the newer anti-psoriatic treatment options and little is known about the interclass switching. We have thus initiated a multi-center, multi-national, retrospective study to assess the treatment response of patients who were switched from one IL-17 blocker to another. Analysis consisted of data from patients with moderate-to-severe psoriasis who did not respond satisfactorily to one of the available IL-17 blockers (secukinumab, ixekizumab, brodalumab) and were subsequently switched to another drug of this class. After 12 weeks of treatment, patients' PASIs were evaluated. Treatment success was defined as reaching PASI 75 after 12 weeks. Topical treatment was allowed and used in all patients. 26 patients were included (13 male, 13 female) and 29 switches were evaluated. Overall, 29 switches in 21 patients were evaluated. 18 patients changed their therapy from secukinumab to ixekizumab, or in 7 cases to brodalumab. Brodalumab was used in 3 cases after failure of treatment with ixekizumab. Only in one case, non-response of brodalumab resulted in a therapy switch to secukinumab. In 15 (52%) cases, PASI 75 was reached. In 6 (20%) patients, the switch led to a PASI 50 response. No success of treatment was seen among 8 (28%) participants. When patients fail to respond or do not tolerate an IL-17 blocker, switching to another anti-IL-17A/RA is a promising viable option. Larger studies are needed to confirm our results.

This retrospective multicentre analysis from the Psoriasis Registry Austria (PsoRA) was conducted to determine drug effectiveness and survival of anti-tumour necrosis factor alpha (anti-TNF-α) agents in patients with moderate-to-severe chronic plaque psoriasis over a 9-year period. Data on 1,019 treatment cycles with adalimumab (n = 460), etanercept (n = 501), and/or infliximab (n = 58) administered to 827 patients (272 women, 555 men) were available for analysis. Compared with etanercept, adalimumab and infliximab showed superior short-term effectiveness. Intention-to-treat-calculated median drug survivals for adalimumab (1,264 days) and etanercept (1,438 days) were similar to each other (p = 0.74), but significantly superior to that of infliximab (477 days) (p = 7.0e-07 vs. adalimumab and p=2.2e-07 vs. etanercept, respectively). Their drug survival rates at 36 months were 51.6%, 56.0%, and 22.6%, respectively. Survival rates correlated significantly with effectiveness for adalimumab and etanercept, but not for infliximab.

Objectives To assess demographical and clinical data in a Middle‐European cohort of patients with Adamantiades–Behçet's disease (ABD), together with the use of medication in adherence to international guidelines. Methods In a retrospective cohort study, in‐ and outpatients of an Austrian secondary and tertiary university hospital center were analyzed independent from the medical discipline involved. After ethics approval, screening for ABD‐patients in the clinical information system resulted in 1821 documents from 1997 to 2016. Patients fulfilling the International Criteria for Behçet's Disease were included, and ABD symptoms and signs together with medical interventions for immunosuppression, anticoagulation and pain management were identified by individual chart reviews and evaluated for conformity with international recommendations. Results A total of 76 ABD patients were identified with 39.1% Austrian and 37.0% Turkish origin. Genital aphthae and skin manifestations were more frequent, neurological, gastrointestinal and vascular manifestations less frequent in ABD patients of Turkish origin living in Austria compared to those living in Turkey (each P

Background: Wells’ syndrome is defined as an inflammatory disorder with the histopathological presence of eosinophilic infiltrates and flame figures in the absence of vasculitis. Eosinophilic leukocytoclastic vasculitis shows eosinophilic infiltrates in combination with vasculitic changes. And Churg Strauss Syndrome comprises all three characteristics – eosinophilic infiltrates, vasculitis and flame figures. Objective: To determine whether these three diseases are distinct entities or different manifestations of a similar clinicopathologic process. Method: Histopathological samples and clinical courses of 17 patients with eosinophilic infiltrates, flame figures and clinical features of Wells’ syndrome were re-evaluated. Histopathologically, we focused on the presence or absence of vasculitic features. Clinically, we included only patients who were diagnosed with Wells’ syndrome at least once in the course of their disease. Results: 4 patients were finally diagnosed with Wells’ syndrome, 5 with eosinophilic leukocytoclastic vasculitis and 6 with Churg Strauss syndrome. Further, we had one case of an overlap between Wells’ syndrome and eosinophilic vasculitis and one case of Wegener granulomatosis. Vasculitic features were found in the samples of all patients. Conclusions: Histologically, we find vasculitic features in typical presentations of Wells’ syndrome. Clinically, we find typical features of Wells’ syndrome in patients finally diagnosed with eosinophilic leukocytoclastic vasculitis or Churg Strauss syndrome. Furthermore, we have observed and formerly reported 3 patients with progression from Wells’ syndrome to Churg Strauss syndrome. Thus, we assume that eosinophilic leukocytoclastic vasculitis might form a bridge between Wells’ syndrome and Churg Strauss syndrome.

In this retrospective pilot study, the DNA-methylation status of genes that have been demonstrated to be involved in melanoma carcinogenesis was analyzed in order to identify novel biomarkers for the risk assessment of melanoma patients. We analyzed DNA extracted from punch-biopsies from 68 formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Using MethyLight PCR, we examined 20 genes in specimens from a training set comprising 36 melanoma patients. Selected candidate genes were validated in a test set using FFPE tissue samples from 32 melanoma patients. First, we identified the TNFRSF10D DNA-methylation status (TNFRSF10D methylated vs. unmethylated) as a prognostic marker for overall (p = 0.001) and for relapse-free survival (p = 0.008) in the training set. This finding was confirmed in the independent test set (n = 32; overall survival p = 0.041; relapse-free survival p = 0.012). In a multivariate Cox-regression analysis including all patients, the TNFRSF10D DNA-methylation status remained as the most significant prognostic parameter for overall and relapse-free survival (relative-risk (RR) of death, 4.6 (95% CI: 2.0–11.0; p < 0.001), RR of relapse, 7.2 (95% CI: 2.8–18.3; p < 0.001)). In this study, we demonstrate that TNFRSF10D DNA-methylation analysis of a small tissue-punch from archival FFPE melanoma tissue is a promising approach to provide prognostic information in patients with melanoma.

Importance Psoralen-UV-A (PUVA) photochemotherapy is standard first-line treatment for skin-limited, early-stage mycosis fungoides capable of producing high initial complete response (CR) rates. However, much remains unknown about PUVA's therapeutic mechanisms, optimal duration and frequency of treatment, dose escalation, or use as maintenance therapy. Objectives To evaluate low-dose, low-frequency PUVA, and whether maintenance treatment extends disease-free remission in patients with mycosis fungoides. Design, setting, and participants This prospective randomized clinical trial with defined PUVA dosing regimen was carried out in 5 centers (Graz, Vienna, Hietzing, Innsbruck, and Salzburg) across Austria. Patients with stage IA to IIA mycosis fungoides (n = 27) were enrolled in the study beginning March 13, 2013, with the last patient enrolled March 21, 2016. These patients were treated with oral 8-methoxypsoralen followed by UV-A exposure 2 times per week for 12 to 24 weeks until CR. Patients with CR were randomized to PUVA maintenance for 9 months (14 total exposures) or no maintenance. The study was conducted from April 27, 2012, to July 27, 2018. Data analysis of the primary end point was of the intention-to-treat population, and the secondary end point analysis was of the evaluable population. Main outcomes and measures Efficacy of the PUVA regimen was determined by the rate of CR as defined by a modified severity-weighted assessment tool (mSWAT) score reduction to 0. Levels of proinflammatory molecules in serum and histologic features and percentage of clonal T cells in skin were assessed to search for biomarkers of clinical response. Results In 27 patients with mycosis fungoides, 19 (70%) were male with mean (range) age 61 (30-80) years. At baseline, patients with CR had a mean (range) mSWAT score of 18.6 (1-66) compared with 16.8 (3-46) in patients with partial response. The 12- to 24-week PUVA induction regimen reduced the mSWAT score in all patients and led to CR in 19 (70%) of 27 patients and a low mean cumulative UV-A dose of 78.5 J/cm2. The subsequent standardized 9-month PUVA maintenance phase prolonged median (range) disease-free remission from 4 (1-20) months to 15 (1-54) months (P = .02). High density of histologic infiltrate and high percentage of clonal TCR sequences in skin biopsy specimens at baseline were inversely associated with therapeutic response. No severe adverse effects were seen during the PUVA induction or maintenance phase. Conclusions and relevance This proof-of-concept study identifies potential biomarkers for therapeutic response to PUVA in mycosis fungoides; it also demonstrates that low-dose, low-frequency PUVA appears to be highly effective, and maintenance treatment may extend disease-free remission. Trial registration ClinicalTrials.gov identifier: NCT01686594.

Purpose: We compared the efficacy of human Langerhans cells (LC) as tumor immunogens in vivo with monocyte-derived dendritic cells (moDC) and investigated how interleukin 15 (IL15) supports optimal DC-stimulated antitumor immunity. Experimental Design: American Joint Committee on Cancer stage III/IV melanoma patients participated in this first clinical trial comparing melanoma peptide-pulsed LC with moDC vaccines (NCT00700167, www.ClinicalTrials.gov). Correlative studies evaluated mechanisms mediating IL15 support of DC-stimulated antitumor immunity. Results: Both DC vaccines were safe and immunogenic for melanoma antigens. LC-based vaccines stimulated significantly greater tyrosinase–HLA-A*0201 tetramer reactivity than the moDC-based vaccines. The two DC subtypes were otherwise statistically comparable, in contrast to extensive prior data in vitro showing LC superiority. LCs synthesize much more IL15 than moDCs and stimulate significantly more antigen-specific lymphocytes with a cytolytic IFN-γ profile even without exogenous IL15. When supplemented by low-dose IL15, instead of IL2, moDCs stimulate 5 to 6 logs more tumor antigen–specific effector memory T cells (TEMRA) over 3 to 4 weeks in vitro. IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T cells. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity. Conclusions: MoDC-based vaccines will require exogenous IL15 to achieve clinical efficacy. Alternatively, LCs can couple the endogenous production of IL15 with potent T-cell stimulatory activity. Optimization of full-length tumor antigen expression for processing into multiple immunogenic peptides for presentation by both class I and II MHC therefore merits emphasis to support more effective antitumor immunity stimulated by LCs. Clin Cancer Res; 17(7); 1984–97. ©2011 AACR.

Background Cheilitis granulomatosa and Melkersson–Rosenthal syndrome are both rare and benign diseases. Because of their granulomatous character, a relationship to Crohn's disease has been suggested. Furthermore, because of their unknown aetiology, treatment is difficult, and evaluation of response is hampered by the natural tendency to spontaneous resolution and recurrence. Objectives and methods To evaluate gastrointestinal involvement by clinical history, conventional endoscopy, and capsule endoscopy as well as to compare efficacy of treatment modalities on a series of 14 patients, one of the biggest collectives reported. Results Four patients (4 of 14) were previously, simultaneously, or subsequently diagnosed with Crohn's disease. In six patients (6 of 14) with minor gastrointestinal symptoms as flatulence, occasional constipation, diarrhoea, or admixture of mucus with the stool, we could not detect any signs of inflammatory bowel disease by capsule endoscopy. Nine patients received clofazimine, and eight patients responded to treatment (four complete responses, four partial responses). Two patients were successfully treated with infliximab. Systemic methylprednisone was not successful in two patients. Conclusion Close to 30% of patients showed an association of cheilitis granulomatosa and Crohn's disease. Forty-three per cent of patients reported minor gastrointestinal irregularities without any detectable changes of Crohn's disease. Clofazimine seems to be an effective treatment, although long-term application is necessary with frequent aggravation in the beginning. Infliximab, an effective drug in Crohn's disease, could be a promising treatment option for severe cases.

Sweet syndrome is a neutrophilic dermatosis defined by diagnostic criteria that include the lack of evidence for leukocytoclastic vasculitis. Because of the clinicopathological similarities on the one hand and the strict exclusion on the other hand, we were interested in a systematic evaluation of the relationship between these two diseases. We investigated the clinical and histopathological characteristics of 31 patients with Sweet syndrome, comparing our cases with 32 cases of leukocytoclastic vasculitis (including seven cases of urticarial vasculitis) and tried to place them in the background of published cases. There is a close relationship between Sweet syndrome and leukocytoclastic vasculitis in terms of clinical appearance, histopathological pattern, triggers, disease course, and response to treatment. The majority of the cases (23/31; 74%) showed histologic evidence of vasculitis, including nuclear dust, extravasation of erythrocytes, fibrin in and around vessel walls, and degeneration of collagen. Although one original criterion for Sweet syndrome is the absence of vasculitis, we propose that vasculitic changes should not exclude the diagnosis of Sweet syndrome. In contrast, Sweet syndrome can demonstrate vasculitis and may, similarly to urticarial vasculitis, be regarded a variant of leukocytoclastic vasculitis. Clinicopathologic characteristics with acute onset of juicy papules, plaques mostly on the face, shoulder, and trunk, and prominent edema probably reflect modifications of the pathogenetic process based on location and disease acuity.

Indeterminate cell histiocytosis is a rare disorder, in which the predominant cells have the characteristics of both Langerhans cells and macrophages. We, in this study, describe 18 patients and compare them with those previously published. Most patients were adults with either solitary or multiple red-brown papules or nodules. While most lesions were confined to the skin, both conjunctival and bony involvement was seen. Histologically, the lesions showed patterns resembling those described for xanthogranulomas, with predominantly oncocytic (nine patients), spindled (five patients), scalloped (two patients) or vacuolated (two patients) macrophages. The accompanying infiltrate was mainly lymphocytic, although eosinophils and occasionally plasma cells were seen. All lesions were positive for macrophage markers, such as KP1 (CD68) and Ki-M1p, as well as for S-100 protein and showed variable reactivity for CD1a. No Birbeck granules were seen ultrastructurally in one patient. Some patients shared features with sinus histiocytosis with massive lymphadenopathy. It is unclear whether this disorder is a separate entity or represents various macrophage disorders identified at various time points in the inflammatory response. Ratzinger G, Burgdorf WHC, Metze D, Zelger BG, Zelger B. Indeterminate cell histiocytosis: fact or fiction? A clinicopathological series of 18 patients.

Cutaneous larva migrans (CLM, creeping eruption) is a skin disease commonly seen in travelers returning from the tropics. The lesions are caused by intradermal migration of animal hookworm larvae which cannot mature in humans. While the typical serpiginous skin lesions are easily diagnosed and treated with albendazole or ivermectin, unusual presentations can be misdiagnosed and cause prolonged morbidity. We present 3 cases of CLM, which were difficult to diagnose and/or treat.Case 1 is a 34-year old Caucasian male who presented with itchy papular lesions on the soles of both feet and was initially treated for plantar psoriasis.Case 2 is a 54-year old Caucasian male who suffered from extensive follicular larva migrans on the buttocks for several months and was only cured after repeated courses of albendazole and ivermectin.Case 3 is a 29-year old Caucasian male with pruritic inflammatory papules on the trunk. Despite extensive diagnostic procedures including skin biopsies and tissue cultures the correct diagnosis was only made later during the course of the illness. After treatment for CLM with albendazole (800 mg/d for 3 days) and after resolution of perifocal edema and inflammation the typical serpiginous tracks became more obvious. They responded rapidly to anthelminthic treatment.These cases highlight the importance of careful history taking and work-up in individuals presenting with atypical skin lesions. In case of exposure to CLM empiric anthelminthic treatment might be considered.

Wells syndrome has been described as an inflammatory disorder based on typical clinical appearance combined with the histopathological presence of eosinophilic infiltrates and flame figures in the absence of vasculitis. Churg-Strauss syndrome, on the other hand, is primarily a diffuse, necrotizing vasculitis but is also typically displaying eosinophils and flame figures. Despite several parallels, the present understanding of these two diseases excludes any pathogenetic relationship. We describe the clinical course and histopathological appearance of three patients who had initially been diagnosed with Wells syndrome that developed into Churg-Strauss syndrome during the course of their disease. The clinical presentation of all three patients led to the diagnosis of Wells syndrome by independent specialists. Histopathology showed an eosinophilic infiltrate and flame figures next to features of leukocytoclastic vasculitis. Detailed examination revealed asthma bronchiale and additional symptoms indicating Churg-Strauss syndrome. The initial diagnosis of Wells syndrome had to be revised to Churg-Strauss syndrome. We conclude that Wells syndrome could be the starting point of a pathogenetic process that might reach its maximum in Churg-Strauss syndrome. As a clinical consequence, patients with Wells syndrome should be evaluated and followed for Churg-Strauss syndrome.

Chondrodermatitis nodularis chronica helicis is a rather common condition which substantially affects quality of life causing pain and sleeping disturbances. Surgical treatment is connected with a tendency to recurrence. Mechanical pressure is probably the main etiological factor.A prospective study was performed with 18 patients that were offered a non-surgical treatment using a self-made bandage of foam plastic which they applied during the night. Of these, 12 performed the treatment including follow-up; 6 patients initially also consented, but they did not return after the initial visit.11 patients reported substantial reduction of pain within the first month; after an average of 1.75 months they were free of pain. All 8 patients with initial sleeping problems caused by pain reported undisturbed sleep after only one month. In 11 patients the lesions receded satisfactorily, in 9 patients completely, in 2 patients leaving small asymptomatic residual lesions. Recurrences appeared in 3 patients with 2 of them having been surgically pretreated at the same location.We recommend conservative treatment using protective padding as first line treatment for chondrodermatitis nodularis chronica helicis. The successful outcome achieved only by relief of pressure supports pressure as the main etiological factor in the development of the disease.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucencephalopathy (CADASIL) is a rare vascular disorder affecting mainly the central nervous system with transient ischaemic attacks, strokes, psychiatric symptoms and dementia. It is a progressive familial disease owing to mutations in the Notch3 gene. Clinically apparent skin involvement is usually absent. Electron microscopy of seemingly uninvolved skin reveals characteristic granular deposits in the basal lamina of vessels and adnexals. We report on a case of CADASIL with generalized haemorrhagic macules and patches. Typical neurological symptoms as well as classical findings in histopathology and electron microscopy confirmed the diagnosis. Immunofluorescence showed an increased number of vessels with walls markedly thickened by deposits of fibrin, complement and immunoglobulins. This method could serve as an additional method for accurate diagnosis of CADASIL.

We report on three exceptional courses of sinus histiocytosis Rosai-Dorfman. Patient one developed regional lymph-node disease subsequent to two independent malignancies in the right head and neck region. Patient two suffered from extensive extranodal disease with more than 100 mucocutaneous lesions over 17 years, which spontaneously resolved. Patient three showed exclusively extranodal disease, including bilateral conjunctival/scleral lesions, before he developed lung cancer. Our cases are unique for three reasons: the association of the disease with solid malignancies in two cases, the extent and persistence of exclusively extranodal disease in one patient and the appearance of thus far undescribed conjunctival/scleral lesions.