Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial.

AIM: ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAFV600-mutated melanoma. METHODS: In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed. RESULTS: Of 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37-0.84; PStratified=0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; PStratified=0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53-78 versus 58%; 95%CI, 45-70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively. CONCLUSION: In patients with BRAFV600-mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT.

[Metastasized occult melanomas?]. / "Okkulte" metastasierte Melanome?

CASE REPORTS: We present two patients who were referred to us from other hospitals for further therapy as metastasized occult melanoma patients with extensive stage III and stage IV disease, respectively. On thorough clinical examination, we found a slightly thickened nail plate on the right thumb with barely visible pigmentation and a tiny skin-colored tumor at the proximal nail fold of a 60-year-old man. In a 60-year-old woman, we saw an anatomically almost hidden small nonpigmented tumor on the labia majora close to the posterior commissure. The patients were histologically diagnosed with an ulcerated acrolentigineous melanoma and a nodular mucosal melanoma, respectively. CONCLUSION: With these two case reports we want to emphasize that although extensive radiographic and invasive diagnostic procedures to detect a primary in patients with suspected melanoma of unknown primary are no longer recommended by current guidelines, repeated and thorough clinical examinations can sometimes revise the diagnosis metastasized "occult" melanoma.

Perianal streptococcal dermatitis in adults: its association with pruritic anorectal diseases is mainly caused by group B Streptococci.

AIM: Although perianal streptococcal dermatitis (PSD) is well known in children, it has only rarely been documented in adults. The incidence and necessity for treatment may be underestimated. We have retrospectively identified adult patients with perianal streptococcal dermatitis. METHOD: Patients with streptococcal anal dermatitis were identified from a prospective office database. Treatment was with oral antibiotics according to the organism sensitivity. Additional concomitant anorectal disease was treated according to standard guidelines. Patients were compared with a control group, without eczema or erythema, for the presence of ß-haemolysing Streptococci on perianal swab. Demographic and microbiological data were assessed and compared between and within treatment and control groups. RESULTS: Fifty-three (22 female) patients older than 20 (mean = 49) years of age were diagnosed with perianal streptococcal dermatitis between 2005 and 2009. In most cases group B ß-haemolytic Streptococci were found. Fifty patients received antibiotics for 14 days. In 28 of 33 patients who had a post-treatment swab, the result was negative. Five patients showed Streptococci of different groups in the post-treatment swab. Of the 50 patients, 21 (42%) had no further anorectal complaint and 29 (58%) required continuing treatment for another anorectal condition. In the control group ß-haemolysing Streptococcus was found in 34%. Men over 60 years of age more often required no further anorectal treatment compared with women (P < 0.05). CONCLUSION: Perianal streptococcal dermatitis occurs in adult patients more often than reported. It is mainly caused by group B ß-haemolysing Streptococcus. Its diagnosis is important because it can cause serious systemic infections, especially in the elderly and in newborns. Antibiotics resolve the condition in a high proportion of patients.

[Histamine intolerance mimics anorexia nervosa]. / Histaminintoleranz imitiert Anorexia nervosa.

Histamine intolerance is a clinically heterogeneous disease. We present a woman who suffered from weight loss, diarrhea, abdominal pain, headache, flushing and bronchial asthma for several years. When placed on a histamine-poor diet, she experienced weight gain and improvement of other all signs and symptoms, supporting the diagnosis of histamine intolerance. Therefore, this disease should be included in the differential diagnosis of anorexia nervosa.

Allergic and non-allergic periorbital dermatitis: patch test results of the Information Network of the Departments of Dermatology during a 5-year period.

Periorbital dermatitis is common and can be due to the external use of ophthalmic drugs. We evaluated patch test results of the Information Network of the Departments of Dermatology. During a 5-year period (1995-99), of a total 49,256 patch-tested patients, 1053 (2.1%) were eventually diagnosed as allergic periorbital contact dermatitis (APD) and 588 (1.2%) as non-allergic periorbital dermatitis (NAPD). Patient characteristics between APD, NAPD and other cases (OCs) differed with respect to sex (19.7% male in both periorbital groups versus 36.3% in OCs), atopic dermatitis (10.4% in APD versus 60.2% in NAPD versus 16.9% in OCs) and age, APD being substantially more often (68.2%) aged 40 and above than NAPD (52.6%). Several of the top allergens in OCs [such as fragrance mix, Myroxylon pereirae resin (balsam of Peru), lanolin alcohol and potassium dichromate] caused significantly fewer positive test reactions in both periorbital groups. In contrast, thimerosal, phenylmercuric acetate, sodium disulfite, gentamicin sulfate, phenylephrine hydrochloride and benzalkonium chloride tested positively significantly more often in APD but not in NAPD, verifying them as true ophthalmic allergens. Finally, in 42 cases (4%) of APD patients, additional allergens were identified by testing of the patients' own substances (mostly beta-blockers, oxybuprocaine and dexpanthenol), supporting the necessity of testing with ophthalmic drugs as is where individual substances are not readily available.

Reactive perforating collagenosis associated with scabies in a diabetic.

Reactive perforating collagenosis (RPC) in adults commonly manifests in patients with diabetes mellitus. Pruritus and consequent induced scratching have been identified as the bases for the evolution of this skin disease. We present the unusual case of a 55-year-old female diabetic with characteristic umbilicated skin lesions and a long history of scabies. Histology from a crusty nodule revealed transepidermal elimination of collagen. Following antiscabietic treatment, two courses of oral doxycycline demonstrated beneficial effects in controlling the perforating skin disorder.

[Condylomata acuminata gigantea. Surgical and combined immunomodulatory therapy]. / Condylomata acuminata gigantea. Chirurgische und kombinierte immunmodulierende Therapie.

A 50-year-old female developed extensive condylomata acuminata in the genitoanal region over a period of 12 years. She presented with multiple, verrucous lesions involving the whole genitoanal area plus the adjacent perineum and gluteal region which made it impossible to identify the anatomical structures. Proctoscopy was normal. Serology for infectious diseases was negative. Several biopsies showed no signs of malignant transformation. Tumor excision under general anaesthesia was incomplete. Therefore, adjunctive therapy with immunomodulatory agents was administered, utilizing local application of imiquimod cream (3 x weekly) for 3 months and subcutaneous injections of interferon-alpha-2a (3 million IU 3 x weekly) for 5 months. This treatment regimen resulted in complete remission of all skin lesions with only discrete superficial scarring but no significant loss of anatomical structures or functions. During a 1-year follow-up the patient showed no sign of relapse.

[Sentinel lymph node excision (SLNE) and positron emission tomography in the staging of stage I-II melanoma patients]. / Schildwächterlymphknotenexzision (SLKE) und Positronenemissionstomographie (PET).Staginguntersuchungen bei Melanompatienten in den klinischen Stadien I-II (nach DDG): Erfahrungen aus der Hautklinik Dortmund.

BACKGROUND AND OBJECTIVE: Sentinel lymph node excision (SLNE) and positron emission tomography (PET) were evaluated in the staging of 51 Stage I and II melanoma patients (staged according to the guidelines of the German Dermatological Society). PATIENTS/METHODS AND RESULTS: Tumor thickness ranged from 1.0 mm to 6.0 mm (median: 1.5 mm; mean: 2.07 mm). At least one sentinel lymph node (SLN) was excised in all patients; 80 SLN were excised from 69 lymphatic drainage areas. Positive SLN were detected in 6 patients (11.8%). Additional positive lymph nodes were not detected in any of these patients in the following complete lymph node dissection of the affected lymph node basin. Preoperative PET was performed in 40 patients and did not detect any of the micrometastases that were subsequently found by SLNE. During the follow up of 7-40 months (mean 21.9 months) 3 patients experienced tumor progression; 2 of 3 had a positive SLN. CONCLUSIONS: According to the current literature SLNE is recommended in primary tumors greater than 1 mm thickness. PET cannot be expected to give additional information in the staging of stage I-II patients.

Patient with trisomy 6 mosaicism.

Trisomy 6 and trisomy 6 mosaicism were found in chorionic villi cell culture and short term incubation in a prenatal diagnosis at 12 weeks of gestation in a pregnancy with a growth retarded fetus showing nuchal translucency. The child was born in the 25th gestational week with a number of malformations including heart defects, deep-set ears, cleft right hand, cutaneous syndactylies, and overlapping toes of irregular shape and length. Trisomy 6 was not found in peripheral blood lymphocytes but was confirmed in umbilical cord fibroblasts. Currently, at the age of 2-3/4 years, the development of the child is relatively normal despite considerable growth delay. At the age of two years, she developed a papular erythema clinically suggestive of epidermal nevi. Cytogenetic analysis of fibroblast cultures derived from skin from a right hand finger and the inguinal area confirmed the presence of a trisomy 6 mosaicism. This is the first observation of a liveborn with trisomy 6 mosaicism.

Allelic loss at the neurofibromatosis type 1 (NF1) gene locus is frequent in desmoplastic neurotropic melanoma.

Mutations of the tumour-suppressor gene NF1 (neurofibromatosis 1) have been observed in neurofibromas and neurofibrosarcomas of patients with von Recklinghausen's disease and in sporadic nerve sheath tumours. In contrast, melanoma, another tumour type of neuroectodermal origin, rarely shows NF1 alterations. Desmoplastic neurotropic melanoma (DNM) is an uncommon melanoma subtype that shares morphological characteristics with nerve sheath tumours. Therefore, we analysed 15 DNM and 20 melanomas without morphological features of desmoplasia or neuroid differentiation (common melanomas) for loss of heterozygosity (LOH) at the NF1 locus and flanking regions. Allelic loss was detected in 10/15 (67%) DNM but only in 1/20 (5%) common melanomas. LOH was most frequently observed at marker IVS38, located in intron 38 of NF1. These data suggest a role for NF1 in the pathogenesis of DNM and support an earlier hypothesis that exon 37 might encode a functional domain. DNM may represent an interesting tumour model tor the further elucidation of the cellular functions and tumour-suppressive potential of neurofibromin.

11q23 allelic loss is associated with regional lymph node metastasis in melanoma.

Genetic alterations of the long arm of chromosome 11 have been implicated in melanoma pathogenesis, and we recently identified two distinct regions of common allelic loss in chromosomal band 11q23. To establish the point in time of melanoma tumorigenesis at which these two putative tumor suppressor loci become relevant, we investigated allelic loss [loss of heterozygosity (LOH)] in both chromosomal regions in tumors of progressing patients. We analyzed 102 tumor samples from 23 patients for whom at least two (10 patients) or three (13 patients) tumor samples from different clinical progression steps (such as primary tumor and/or in-transit metastasis and/or regional lymph node metastasis and/or distant metastasis) were available. We detected no 11q23 LOH at any stage in 3 of 23 patients and detected LOH at all stages tested in 8 of 23 patients. In 8 of the remaining 12 (67%) patients with 11q23 LOH at some stage during tumor progression, we found this to occur first at regional lymph node metastasis. Two of these patients retained constitutional heterozygosity in several in-transit metastases that developed up to 7 months after lymph node metastases that already had loss. We therefore conclude that 11q23 LOH is associated with regional lymph node metastasis in melanoma. Finally, we detected an allele shift restricted to a histomorphologically distinct part of a primary melanoma and found that the same parental chromosome was affected by allelic loss in a subsequently occurring lymph node metastasis. These findings support our conclusion and give additional evidence for the hypothesis of molecular heterogeneity of early tumor cell populations in melanoma.

Guttate psoriasis triggered by perianal streptococcal dermatitis in a four-year-old boy.

Perianal streptococcal dermatitis (PSD) is a superficial bacterial infection usually with group A beta-hemolytic streptococci. PSD is often misdiagnosed for long periods and patients are subjected to treatments for a variety of differential diagnoses without success. We report a 4-year-old boy with PSD who presented to our clinic with guttate psoriasis for 2 reasons: first, to make dermatologists aware of PSD and second, to emphasize the necessity to examine patients, particularly pediatric patients, with guttate psoriasis very thoroughly and swab both the pharynx and perianal and/or perigenital areas even when they are, or seem to be, asymptomatic for bacterial infections. Once PSD has been diagnosed, systemic antibiotic therapy with penicillin, erythromycin, roxithromycin, or azithromycin (probably augmented by topical mupirocin ointment) should be the treatment of choice. Therapy should be monitored by posttreatment perianal and throat swabs as well as a urine analysis to monitor for poststreptococcal glomerulonephritis.

[Malignant melanoma of the skin. Pathogenesis, clinical aspects and prognosis]. / Das maligne Melanom der Haut. Pathogenese, Klinik und Prognose.

Cutaneous malignant melanoma is not among the most frequent cancer types at an incidence of 10-12/100,000 persons/year in Central Europe. However, the number of melanomas has doubled within the last 10-15 years. This increase is higher than that of most other malignancies. It has been attributed to an increased UV-light exposure, whereby the latency period probably reaches decades. Persons at high risk for melanoma were identified in various studies: those from families with other melanoma patients and those who have more than 50 benign nevi, atypical nevi and actinic freckles. The majority of melanomas develops de novo and not from preexisting nevi. Treatment of choice is complete surgical excision of the tumors. Prognosis of these patients is mainly determined by tumor thickness. Metastatic spread occurs most frequently within lymph vessels, local recurrences as well as regional metastases significantly impairing the prognosis. From long-term experience in Australia it is evident that the dilemma "melanoma" can only be addressed effectively by rigorous prophylaxis and early diagnosis of the tumors.

The p44S10 locus, encoding a subunit of the proteasome regulatory particle, is amplified during progression of cutaneous malignant melanoma.

Gene amplification is frequently present in human tumors, although specific target genes relevant to many amplified loci remain unidentified. An expression cloning assay enabled identification of a candidate oncogene derived from human chromosome 3p14.1. The cDNA retrieved from morphologically transformed cells contained the full-length protein coding region and detected an abundant transcript in the same cells. Sequence analysis revealed identity with the wild-type sequence of p44S10, a highly conserved subunit of the 26S proteasome that exhibits similarity to the Arabidopsis fus6/cop11 family of signaling molecules. p44S10 gene copy number and mRNA expression were increased in association with segmental 1.8 - 11-fold chromosomal gains in cutaneous malignant melanoma cell lines (5/13; 40%) and tumors (2/40; 5%), and in breast cancer MCF-7 cells. Likewise, malignant progression of human radial growth phase WM35 melanoma cells was associated with amplification and increased expression of endogenous p44S10, and increased expression of p44S10 was sufficient to induce proliferation of WM35 cells in vivo. The results demonstrate segmental copy number gains within chromosome 3p in cutaneous malignant melanoma and suggest that deregulation of a proteasome regulatory particle subunit may contribute to the malignant phenotype.

Retiform hemangioendothelioma: another tumor associated with human herpesvirus type 8?

Retiform hemangioendothelioma is a rare low-grade angiosarcoma of the skin. It shares some clinical characteristics with Kaposi's sarcoma, a tumor with known human herpesvirus 8 (HHV-8) association. We report a case of retiform hemangioendothelioma in which we detected HHV-8 DNA sequences.