Germline intergenic duplications at Xq26.1 underlie Bazex-Dupré-Christol basal cell carcinoma susceptibility syndrome.

BACKGROUND: Bazex-Dupré-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1. However, the genetic mechanism of BDCS remains an open question. OBJECTIVES: To investigate the genetic aetiology and molecular mechanisms underlying BDCS. METHODS: We ascertained multiple individuals from eight unrelated families affected with BDCS (F1-F8). Whole-exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long-range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head-tail junctions. Hi-C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. RESULTS: In eight families with BDCS, we identified overlapping 18-135-kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi-C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. CONCLUSIONS: Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic? Bazex-Dupré-Christol syndrome (BDCS) is a rare X-linked basal cell carcinoma susceptibility syndrome linked to an 11·4-Mb interval on chromosome Xq25-q27.1. Loss-of-function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add? BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1. The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene. ACTRT1 loss-of-function variants are unlikely to cause BDCS. What is the translational message? This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management. ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas.

A distinct four-value blood signature of pyrexia under combination therapy of malignant melanoma with dabrafenib and trametinib evidenced by an algorithm-defined pyrexia score.

Pyrexia is a frequent adverse event of BRAF/MEK-inhibitor combination therapy in patients with metastasized malignant melanoma (MM). The study's objective was to identify laboratory changes which might correlate with the appearance of pyrexia. Initially, data of 38 MM patients treated with dabrafenib plus trametinib, of which 14 patients developed pyrexia, were analysed retrospectively. Graphical visualization of time series of laboratory values suggested that a rise in C-reactive-protein, in parallel with a fall of leukocytes and thrombocytes, were indicative of pyrexia. Additionally, statistical analysis showed a significant correlation between lactate dehydrogenase (LDH) and pyrexia. An algorithm based on these observations was designed using a deductive and heuristic approach in order to calculate a pyrexia score (PS) for each laboratory assessment in treated patients. A second independent data set of 28 MM patients, 8 with pyrexia, was used for the validation of the algorithm. PS based on the four parameters CRP, LDH, leukocyte and thrombocyte numbers, were statistically significantly higher in pyrexia patients, differentiated between groups (F = 20.8; p = <0.0001) and showed a significant predictive value for the diagnosis of pyrexia (F = 6.24; p = 0.013). We provide first evidence that pyrexia in patients treated with BRAF/MEK-blockade can be identified by an algorithm that calculates a score.

Dealing with Corticosteroid and High-Dose Cyclosporine Therapy in a Pyoderma Gangrenosum Patient Contracting a COVID-19 Infection.

Pyoderma gangrenosum (PG) is a rare and chronic neutrophil inflammation belonging to the spectrum of autoinflammatory disorders. Immunosuppressive therapy is the cornerstone of successful treatment. However, due to the global COVID-19 pandemic, physicians struggle with therapeutic strategies during infection. This paper describes the case of a 58-year-old patient with a very painful, rapidly increasing wound on his right foot, which was diagnosed as pyoderma gangrenosum. Five weeks after the initial treatment with high-dose immunosuppressives (combination therapy with cyclosporine A and systemic methylprednisolone), he became infected with COVID-19. Reduction in the immunosuppressive dosage proved effective, as the patient recovered from COVID-19 without any complication and showed rapid wound healing.

Cutaneous Malignancies in Tattoos, a Case Series of Six Patients.

BACKGROUND: A variety of side effects following the tattooing of the skin were reported over the years. Analytical studies showed that some tattoo inks contain harmful compounds. METHODS: We presented six patient cases with cutaneous malignancies in tattooed skin and performed an extensive literature research. RESULTS: Two patients with black ink tattoos that were diagnosed with malignant melanoma raises the number of described cases to 36 patients. One of the patients developed an immunologic reaction limited to the tattoo area after treatment with a targeted immune therapy. In the other patient, the malignancy (malignant melanoma) was fatal. Basal cell carcinoma was seen in four patients with tattoos containing varying ink colors (black, green, red). This increased the number of described patient cases to 18. Although some ink components and their cleavage products have carcinogenic properties, epidemiological evidence for a causative correlation fails. Further epidemiologic studies on tattoos and malignancies, as well as on the appearance of naevi in tattoos, are necessary. Determining the type of mutation might be helpful to separate sun-induced tumors from skin cancers due to other pathogenic mechanisms.

Risk Factors for Relapse after Intentional Discontinuation of Immune Checkpoint Inhibitors in Melanoma Patients.

Immune checkpoint inhibitors (ICIs) have tremendously changed the therapeutic landscape of melanoma since they are associated with a durable response, allowing for intentional discontinuation of therapy after complete or partial remission. However, a subset of patients develops a relapse after cessation of ICI treatment and may not respond to reinduction of ICIs. The aim of the present study was to identify risk factors for relapse after intentional discontinuation of ICI therapy. Patients with intentional discontinuation of ICI therapy for metastatic or unresectable melanoma from 5 German university hospitals were analyzed retrospectively. Clinicopathologic and follow-up data of 87 patients were collected and analyzed by univariate and multivariate Cox proportional-hazards models. The following parameters were associated with relapse after cessation of ICI treatment in the univariate Cox regression analysis: concurrent radiotherapy and ICI, best overall response, and presence of brain metastases. Duration of treatment, type of primary tumor, body mass index, programmed-death ligand 1 expression, and lactate dehydrogenase levels did not significantly influence the risk for relapse. In the multivariate analysis, partial remission [hazard ratio 4.217 (95% confidence interval: 1.424-12.49), P=0.009] and stable disease [3.327 (1.204-9.19), P=0.02] were associated with a significant decrease in progression-free survival compared with complete remission. Concurrent radiotherapy and ICI [3.619 (1.288-10.168), P=0.015] are additional independent risk factors for decreased progression-free survival upon ICI discontinuation, whereas the presence of brain metastasis did not reach statistical significance on multivariate analysis.

Cutaneous Vasculitis in a Patient With COVID-19.

We describe a 43-year-old patient with coronavirus disease 2019 who developed a bullous hemorrhagic rash that progressed to necrotic lesions. Histopathology confirmed a vasculitis of small- and medium-sized cutaneous vessels.

Immune checkpoint inhibition therapy for advanced skin cancer in patients with concomitant hematological malignancy: a retrospective multicenter DeCOG study of 84 patients.

BACKGROUND: Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy. METHODS: This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS). RESULTS: 84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin's lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002). CONCLUSIONS: ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.

Mutation analysis of multiple pilomatricomas in a patient with myotonic dystrophy type 1 suggests a DM1-associated hypermutation phenotype.

Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disease which results from an expansion of repetitive DNA elements within the 3' untranslated region of the DMPK gene. Some patients develop multiple pilomatricomas as well as malignant tumors in other tissues. Mutations of the catenin-ß gene (CTNNB1) could be demonstrated in most non-syndromic pilomatricomas. In order to gain insight into the molecular mechanisms which might be responsible for the occurrence of multiple pilomatricomas and cancers in patients with DM1, we have sequenced the CTNNB1 gene of four pilomatricomas and of one pilomatrical carcinoma which developed in one patient with molecularly proven DM1 within 4 years. We further analyzed the pilomatrical tumors for microsatellite instability as well as by NGS for mutations in 161 cancer-associated genes. Somatic and independent point-mutations were detected at typical hotspot regions of CTNNB1 (S33C, S33F, G34V, T41I) while one mutation within CTNNB1 represented a duplication mutation (G34dup.). Pilomatricoma samples were analyzed for microsatellite instability and expression of mismatch repair proteins but no mutated microsatellites could be detected and expression of mismatch repair proteins MLH1, MSH2, MSH6, PMS2 was not perturbed. NGS analysis only revealed one heterozygous germline mutation c.8494C>T; p.(Arg2832Cys) within the ataxia telangiectasia mutated gene (ATM) which remained heterozygous in the pilomatrical tumors. The detection of different somatic mutations in different pilomatricomas and in the pilomatrical carcinoma as well as the observation that the patient developed multiple pilomatricomas and one pilomatrical carcinoma over a short time period strongly suggest that the patient displays a hypermutation phenotype. This hypermutability seems to be tissue and gene restricted. Simultaneous transcription of the mutated DMPK gene and the CTNNB1 gene in cycling hair follicles might constitute an explanation for the observed tissue and gene specificity of hypermutability observed in DM1 patients. Elucidation of putative mechanisms responsible for hypermutability in DM1 patients requires further research.

Correlative Monitoring of Immune Activation and Tissue Damage in Malignant Melanoma-An Algorithm for Identification of Tolerance Breakage During Immune Checkpoint Inhibitor Therapy of Cancer.

We describe an innovative approach for identification of tolerance breakage during immune checkpoint inhibitor therapy in malignant melanoma. Checkpoint inhibitor therapy enhances the immunologic clearance of cancer by suppressing pathways which induce immune suppression and tolerance. We posit that by analyzing temporal correlations of key markers of immune activation and tissue damage it would be possible to detect the onset of anticancer immune reaction as well as of immunologic adverse effects which might become crucial for optimization as well as safety of immune checkpoint inhibitor treatment. We analyzed time courses of routine laboratory values of serum tumor markers as well as of markers of immune activation in 17 patients with metastasized malignant melanoma receiving checkpoint inhibition and weekly laboratory controls. A parallel serum level increase of interleukin-6 and the tumor marker S100B could be identified in 13 patients, suggesting that the onset of tolerance breakage under checkpoint inhibition may be identified and measured. Immune-related adverse events in the patients were also accompanied by a peak of IL-6. In six patients, the onset of a putative anticancer immune reaction and the beginning of immunologic adverse events occurred in the same treatment cycle; in six patients the immunologic adverse reactions took place in separate cycles.

[Anal herpes simplex virus infections]. / Anale Herpes-simplex-Virus-Infektionen.

BACKGROUND: Herpes simplex virus (HSV) type 1 and type 2 may infect the anal region and induce aphthous ulcers. HSV-induced proctitis may be severe with fever, anal pain, anal bleeding, and diarrhea. OBJECTIVES: The pathogenic agents and treatment are reviewed. MATERIALS AND METHODS: A review of the current literature was performed. RESULTS: The shift to later primary infections with HSV1 and changes towards more frequent oro-genital and oro-anal sex has increased the incidence of HSV1-induced primary anal infections. Due to frequent recurrences, HSV2 remains the most common cause of anal HSV infection. Anal and genital HSV infections are a risk factor for subsequent HIV infection. In case of suspicion, pathogen detection by polymerase chain reaction (PCR) should be performed and other sexually transmitted diseases should be excluded. HSV proctitis may mimic inflammatory bowel disease. Treatment should include antiviral medication as in genital herpes simplex. CONCLUSIONS: HSV may induce perianal infections, anal infections and HSV proctitis. Diagnosis of HSV1 and HSV2 using PCR is recommended. Anal and genital HSV infections are a risk factor for subsequent HIV infection. The risk is higher for HSV2 infection due to more frequent recurrences.

Surgical Site Infections After Dermatologic Surgery in Immunocompromised Patients: A Single-Center Experience.

BACKGROUND: Immunosuppression is often considered as an indication for antibiotic prophylaxis to prevent surgical site infections (SSI) while performing skin surgery. However, the data on the risk of developing SSI after dermatologic surgery in immunosuppressed patients are limited. PATIENTS AND METHODS: All patients of the Department of Dermatology and Allergology at the University Hospital of RWTH Aachen in Aachen, Germany, who underwent hospitalization for a dermatologic surgery between June 2016 and January 2017 (6 months), were followed up after surgery until completion of the wound healing process. The follow-up addressed the occurrence of SSI and the need for systemic antibiotics after the operative procedure. Immunocompromised patients were compared with immunocompetent patients. The investigation was conducted as a retrospective analysis of patient records. RESULTS: The authors performed 284 dermatologic surgeries in 177 patients. Nineteen percent (54/284) of the skin surgery was performed on immunocompromised patients. The most common indications for surgical treatment were nonmelanoma skin cancer and malignant melanomas. Surgical site infections occurred in 6.7% (19/284) of the cases. In 95% (18/19), systemic antibiotic treatment was needed. Twenty-one percent of all SSI (4/19) were seen in immunosuppressed patients. CONCLUSION: According to the authors' data, immunosuppression does not represent a significant risk factor for SSI after dermatologic surgery. However, larger prospective studies are needed to make specific recommendations on the use of antibiotic prophylaxis while performing skin surgery in these patients.

Cutaneous Basal Cell Carcinoma with Lymph Node and Pulmonary Metastases.

Basal cell carcinoma (BCC) is the most common skin cancer. Metastatic BCC is an extraordinary rare finding observed in only 0.5% of all cases. Until the introduction of the small molecule hedgehog inhibitor vismodegib, patients with metastatic BCC were treated with chemotherapy, most frequently platinum-based with mixed responses to therapy. We present the case of a 55-year-old Caucasian man who suffered from BCC on his left arm with lymph node and pulmonary metastases. Sonic hedgehog blockade with vismodegib only induced a short remission, and the patient succumbed to the cancer.

Cancer heterogeneity: converting a limitation into a source of biologic information.

Analysis of spatial and temporal genetic heterogeneity in human cancers has revealed that somatic cancer evolution in most cancers is not a simple linear process composed of a few sequential steps of mutation acquisitions and clonal expansions. Parallel evolution has been observed in many early human cancers resulting in genetic heterogeneity as well as multilineage progression. Moreover, aneuploidy as well as structural chromosomal aberrations seems to be acquired in a non-linear, punctuated mode where most aberrations occur at early stages of somatic cancer evolution. At later stages, the cancer genomes seem to get stabilized and acquire only few additional rearrangements. While parallel evolution suggests positive selection of driver mutations at early stages of somatic cancer evolution, stabilization of structural aberrations at later stages suggests that negative selection takes effect when cancer cells progressively lose their tolerance towards additional mutation acquisition. Mixing of genetically heterogeneous subclones in cancer samples reduces sensitivity of mutation detection. Moreover, driver mutations present only in a fraction of cancer cells are more likely to be mistaken for passenger mutations. Therefore, genetic heterogeneity may be considered a limitation negatively affecting detection sensitivity of driver mutations. On the other hand, identification of subclones and subclone lineages in human cancers may lead to a more profound understanding of the selective forces which shape somatic cancer evolution in human cancers. Identification of parallel evolution by analyzing spatial heterogeneity may hint to driver mutations which might represent additional therapeutic targets besides driver mutations present in a monoclonal state. Likewise, stabilization of cancer genomes which can be identified by analyzing temporal genetic heterogeneity might hint to genes and pathways which have become essential for survival of cancer cell lineages at later stages of cancer evolution. These genes and pathways might also constitute patient specific therapeutic targets.

Electrochemotherapy in advanced skin tumors and cutaneous metastases - a retrospective multicenter analysis.

BACKGROUND AND OBJECTIVES: Once classic treatments such as chemotherapy or radiation therapy have been exhausted, only few therapeutic options remain for extensive skin tumors or cutaneous metastases. In such cases, electrochemotherapy may be considered as alternative therapy. PATIENTS AND METHODS: In this retrospective study, clinical features, treatment response, and adverse effects were evaluated in 56 patients treated with electrochemotherapy at six German dermatology departments. RESULTS: The mean age of the patient cohort (14 men, 42 women) was 69.3 years. Included were 20 patients with skin metastasis of advanced malignant melanoma, 13 patients with breast cancer metastases, 15 patients with primary squamous cell carcinoma of the skin or cutaneous metastases of other carcinoma types, and 8 patients with cutaneous lymphoma or sarcoma. The overall response rate was 44.6% (10.7% complete response; 33.9% partial response). By contrast, 31 (55.4%) patients did not respond (12.5% had stable disease; 42.9%, tumor progression). Patients with melanoma and cutaneous lymphoma or sarcoma responded significantly better than those with carcinoma. Roughly one quarter of patients showed an improvement in tumor-related exudation, fetor, and chronic bleeding. CONCLUSION: Showing only few adverse effects, electrochemotherapy was effective in about one half of the patients with advanced tumors. Treatment response appears to depend on the tumor entity.

Use of aesthetic rhinoplasty procedures in reconstructive nasal surgery.

Resection of cancer often involves the excision of underlying hard tissue, and some procedures in aesthetic rhinoplasty can be used in reconstructive nasal surgery to increase the margin of safety while still achieving an acceptable aesthetic and functional outcome. We have used techniques from aesthetic rhinoplasty to shape the nasal framework. Osteotomy and formation of the tip were used in 17 patients with defects (ranging from 1 to 3.5 cm in size) from the nasal root to the tip of the nose. After the underlying bony or cartilaginous framework, or both, had been removed, the resulting open roof deformity had to be corrected by osteotomy of the bony nasal wall and the tip shaped by excision and suturing, including insertion of the tip graft and columellar strut graft. After this, and narrowing of the nose, the defect was smaller and could be closed with local tissue without tension. There were no deformities in the contour, and patency of the airway was maintained. Patients were satisfied with both the aesthetic and functional results. Although the margin of safety was increased, shaping the nasal framework reduced the size of the defect, which allowed tension-free closure with a local flap. The operation requires a thorough knowledge of procedures used in aesthetic rhinoplasty.

A systems approach defining constraints of the genome architecture on lineage selection and evolvability during somatic cancer evolution.

Most clinically distinguishable malignant tumors are characterized by specific mutations, specific patterns of chromosomal rearrangements and a predominant mechanism of genetic instability but it remains unsolved whether modifications of cancer genomes can be explained solely by mutations and selection through the cancer microenvironment.It has been suggested that internal dynamics of genomic modifications as opposed to the external evolutionary forces have a significant and complex impact on Darwinian species evolution. A similar situation can be expected for somatic cancer evolution as molecular key mechanisms encountered in species evolution also constitute prevalent mutation mechanisms in human cancers. This assumption is developed into a systems approach of carcinogenesis which focuses on possible inner constraints of the genome architecture on lineage selection during somatic cancer evolution. The proposed systems approach can be considered an analogy to the concept of evolvability in species evolution.The principal hypothesis is that permissive or restrictive effects of the genome architecture on lineage selection during somatic cancer evolution exist and have a measurable impact. The systems approach postulates three classes of lineage selection effects of the genome architecture on somatic cancer evolution: i) effects mediated by changes of fitness of cells of cancer lineage, ii) effects mediated by changes of mutation probabilities and iii) effects mediated by changes of gene designation and physical and functional genome redundancy. Physical genome redundancy is the copy number of identical genetic sequences. Functional genome redundancy of a gene or a regulatory element is defined as the number of different genetic elements, regardless of copy number, coding for the same specific biological function within a cancer cell. Complex interactions of the genome architecture on lineage selection may be expected when modifications of the genome architecture have multiple and possibly opposed effects which manifest themselves at disparate times and progression stages.Dissection of putative mechanisms mediating constraints exerted by the genome architecture on somatic cancer evolution may provide an algorithm for understanding and predicting as well as modifying somatic cancer evolution in individual patients.