Lipase elevation and type 1 diabetes mellitus related to immune checkpoint inhibitor therapy - A multicentre study of 90 patients from the German Dermatooncology Group.

AIM: Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear. PATIENTS AND METHODS: Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres. RESULTS: We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1-181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels. CONCLUSION: Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency.

Retrospective Analysis of Checkpoint Inhibitor Therapy-Associated Cases of Bullous Pemphigoid From Six German Dermatology Centers.

Immune-related adverse events (irAEs) are a class-effect of checkpoint inhibitors (CIs). The development of a Bullous pemphigoid (BP)-like blistering disease, driven by autoantibodies against the hemidesmosomal protein BP180, is a potentially serious irAE whose incidence seems to be increasing. We therefore set out to characterize the clinical and (immuno)histopathological features and treatment responses of cases of BP which developed during or after CI therapy collated in six German tertiary referral centers between 2014 and 2018. We identified twelve cases of BP which emerged during and/or after CI therapy. The time interval between the initiation of CI therapy and the diagnosis of BP was 3-74 weeks (median: 23 weeks). Age at the time of diagnosis of BP varied between 62 and 80 years (median: 76 years). The clinical presentation of the patients was diverse but the severity was relatively mild when compared to that seen in most cases of spontaneous BP. Only four patients met all of the immunopathological criteria recommended in the European guidelines for the diagnosis of BP. Topical corticosteroid treatment was sufficient to achieve disease control in most patients. CI therapy could be continued in 8 out of 12 patients. In summary, our study indicates that cases of BP during or after CI therapy bear several peculiarities distinguishing them from spontaneous BP. Given the diversity of the clinical presentation of CI-induced BP the application of existing diagnostic algorithms developed for spontaneous BP can be utilized to uncover the frequency and features of CI-induced BP and to develop and optimize management algorithms.

Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis.

Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.

Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: an open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study.

AIM: Both low-dose interferon (IFN) alfa-2b and pegylated interferon (Peg-IFN) alfa-2b have been shown to be superior to observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. Peg-IFN facilitates prolongation of treatment, which could provide additional benefit. This multicentre, open-label, randomised, phase 3 trial compared standard low-dose interferon IFN and prolonged treatment with Peg-IFN. PATIENTS AND METHODS: Patients with resected melanoma ≥1.5mm thick and without clinically detectable node metastases were randomised 1:1 to treatment with IFN 3 MU subcutaneously (SC) three times weekly for 18 months or Peg-IFN 100 µg SC once weekly for 36 months. Sentinel lymph node dissection (SLND) was optional. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS) and adverse events (AEs) grade 3-4. RESULTS: Of 898 patients enrolled, 896 (443 Peg-IFN, 453 IFN) were eligible for evaluation (median follow-up 4.7 years). SLND was performed in 68.2% of patients. There were no statistical differences between the two arms for the primary outcome of DFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.73-1.15) or the secondary outcomes of DMFS (HR 1.02, 95% CI 0.80-1.32) and OS (HR 1.09, 95% CI 0.82-1.45). Peg-IFN was associated with higher rates of grade 3-4 AEs (47.3% versus 25.2%; p<0.0001) and discontinuations (54.3% versus 30.4%) compared with IFN. CONCLUSION: This trial did not show superiority for adjuvant Peg-IFN over conventional low-dose IFN in melanoma patients without clinically detectable nodes. ClinicalTrials.gov identifier: NCT00221702.

Perianal streptococcal dermatitis: an important differential diagnosis in pediatric patients.

Perianal streptococcal dermatitis is an infectious disease that predominantly affects younger children and is mostly caused by Group A beta-hemolytic streptococci. Although patients are mostly seen primarily by their pediatrician or family physician, the diagnosis is not infrequently established just after referral to a dermatologist or colorectal surgeon. We report a case series of 124 children, aged 14 years or younger, who were seen at our office for anorectal complaints between February 2003 and September 2006. Twenty-one of 124 patients (16 percent) were diagnosed with perianal streptococcal dermatitis on the basis of a positive perianal swab by microbiologic analysis. Perianal streptococcal dermatitis was the most frequent infectious disease in that age group in our practice. Sixteen (of 21, 76 percent) patients were male, and the mean age was 6.3 years. One course of systemic antibiotic treatment augmented by additional local antiseptic ointment in selected cases cured all patients within 10 to 14 days. One patient presented with a new perianal streptococcal dermatitis episode five months after treatment and was successfully retreated with an oral antibiotic. With this report, we wish to alert the colorectal community of the diagnosis because it may be underdiagnosed in our practices and thereby lead to prolonged discomfort, protracted disease, and potentially harmful sequelae for these typically very young patients.

Allergic contact dermatitis due to beta-blockers in eye drops: a retrospective analysis of multicentre surveillance data 1993-2004.

Topically applied ophthalmic drugs are a potential cause of allergic contact dermatitis of the periorbital region. The objectives of this study were to assess the frequency and spectrum of contact allergy to topically applied beta-blocker containing eye drops. Data of the Information Network of Departments of Dermatology (IVDK) collected between 1993 and 2004 was analysed. Out of 112,430 patch-tested patients, 332 had been tested with their own topical anti-glaucoma eye drops containing different beta-blockers because of suspected allergic contact dermatitis. The frequency of positive test reactions was related to exposure intensity, as estimated by annual prescription rates in Germany. A total of 43/332 (12.95%) showed at least one positive patch test reaction. Positive reactions were observed to products containing timolol (n = 21), metipranolol (n = 13) and levobunolol (n = 11) without conceivable cross-reactivity. Whereas exposure to beta-blocker-containing eye drops remained stable over the years, as estimated by the prescription rates, a slight, non-significant increase in positive patch-reactions to these substances was noted. This is the first systematic analysis of a large set of data on patients' own beta-blocker topical medications, the results indicating that contact allergy should be considered as important, if rare, adverse event caused by this family of drugs.

Disseminated hyperkeratotic and granulomatous nodules in a child with fatal Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis is a rare and potentially fatal syndrome associated with a variety of genetic, malignant, autoimmune, or infectious conditions. The importance of cutaneous presentations of this syndrome has only recently been brought forward. We report the first case of Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis presenting with papulonodular and granulomatous skin lesions. A girl of African origin developed several umbilicated papules on her extremities and face at the age of 18 months. She was born in Germany, had never visited Africa, and was otherwise healthy. Over the next 5 months the lesions progressed in size and number and became hyperkeratotic. Histopathologic analysis of early lesions revealed a superficial lympho- and plasmacellular dermatitis with some features of panniculitis. Later biopsy specimens from nodular lesions showed the formation of tuberculoid granulomas in the deep dermis. At the age of 23 months she became severely ill, rapidly developing high fever, hepatosplenomegaly, icterus, pancytopenia, and ascites. On the basis of bone marrow and lymph node biopsies, the diagnosis of hemophagocytic lymphohistiocytosis was established. However, this phenomenon could not be detected in any of the skin specimens. An active Epstein-Barr virus infection was diagnosed by polymerase chain reaction in blood, lymphoid tissue, and skin. Despite chemotherapy with etoposide and cortisone, the girl expired 14 days after clinical onset of her systemic disease.

[Histological diagnosis of onychomycosis]. / Histologische Diagnose der Onychomykose.

It is mandatory to establish a firm diagnosis before starting systemic antimycotic therapy because of potential side effects and relatively high therapy costs. Direct microscopy and fungal culture are the most widely employed diagnostic tools. Not infrequently, a strong clinical suspicion cannot be proven by even repeated direct microscopic examinations and fungal cultures. In these cases histologic examination is a simple alternative. We identified 32 cases of histopathologically proven onychomycosis; of the 29 where a fungal culture was performed, only 14 (48%) were positive. Direct microscopy was performed only in 12 cases since most had repeatedly negative direct microscopy results before being referred to us; 5 cases (42%) were positive. Histopathology for onychomycosis has several advantages in addition to its sensitivity--particularly in difficult to diagnose cases: lack of the danger of contamination, a permanent preparation with the possibility to demonstrate fungal invasion of the nail organ and to identify other or concomitant nail disorders, simplicity of the procedure; quicker results as compared to fungal culture. Exact specification of the fungus is not possible with histology. Even though histological examination is not mentioned in the current guidelines for onychomycosis of the German Dermatological Society, it should be kept in mind as a simple but sensitive diagnostic tool.

[Vancomycin-induced linear IgA dermatosis]. / Vancomycin-induzierte lineare IgA-Dermatose.

Linear IgA disease is a rare autoimmune bullous skin disorder that may be idiopathic or drug-induced. The mechanisms of loss of self-tolerance to target antigens of the dermo-epidermal junction are unclear and may be variable. Regardless of the etiology, the clinical presentation is quite heterogeneous. Frozen sections of a blister roof are helpful in early diagnosis to rule out full-thickness epidermal necrosis or subcorneal separation as seen in toxic epidermal necrosis or staphylococcal scaled skin syndrome, respectively. Drug-induced cases of linear IgA disease typically resolve quickly once the causative agent is withdrawn. Vancomycin is the best-documented insiting drug in the literature. The significance of further associations such as malignancy or different autoimmune diseases is uncertain. Review of medication exposures after diagnosis is crucial in identifying possible offending agents. We present a patient with vancomycin-induced linear IgA disease in whom the drug was immediately discontinued because of the characteristic clinical presentation and rapid histopathological examination. The development of new blisters stopped within 24 hours and the skin healed within 2 weeks.

Absence of HHV-8 DNA in hobnail hemangiomas.

BACKGROUND: Hobnail hemangioma (HH) is a rare subtype of hemangioma that shares the morphological feature of hobnail endothelia with retiform hemangioendothelioma (RHE) and has to be considered in the differential diagnosis of Kaposi sarcoma. Since DNA of the human herpesvirus type 8 (HHV-8) has been detected in more than 90% of Karposi sarcomas and could recently be demonstrated in RHE, we sought to detect HHV-8 DNA in HH. METHODS AND RESULTS: DNA from 12 HH was extracted and subjected to polymerase chain reaction analysis for HHV-8 DNA using two independent protocols with a single set of primers and a nested PCR approach, respectively. PCR amplification was performed using the LightCycler as well as using a thermocycler. HHV-8 DNA could not be detected in HH, although each sample contained DNA adaequately preserved for PCR reactions, as determined by amplification of the beta actin gene. CONCLUSIONS: HHV-8 appears to play no rule in the pathogenesis of HH. Absence of HHV-8 DNA in HH might be important in the differential diagnosis to other vascular tumours, in particular Kaposi sarcoma.