Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG.

BACKGROUND: Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy. METHODS: Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC-V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK. CONCLUSIONS: In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.

Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG.

BACKGROUND: Despite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM. METHOD: We assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Of 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p<0.001; HR for CRT: 0.424, 95% CI 0.210 to 0.855, p=0.016), maximal size of brain metastases (HR for MBM >1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, p<0.001; for PD-1 vs BRAF+MEK: 4.587 95% CI 1.3 to 16.8, p=0.022 for OS). Regarding therapy sequencing, patients treated with ICB as first-line therapy and BRAF+MEK as second-line therapy showed an improved OS (HR for CTLA-4+PD-1 followed by BRAF+MEK: 0.370, 95% CI 0.157 to 0.934, p=0.035; HR for PD-1 followed by BRAF+MEK: 0.290, 95% CI 0.092 to 0.918, p=0.035) compared with patients starting with BRAF+MEK in first-line therapy. There was no significant survival difference when comparing first-line therapy with CTLA-4+PD-1 ICB with PD-1 ICB. CONCLUSIONS: In patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS.

German S1 guidelines for the diagnosis and treatment of perianal dermatitis (anal eczema).

Perianal dermatitis (anal eczema, perianal eczema) is one of the most common proctological conditions. It may occur as a sequela or a presenting symptom of various proctological, dermatological, allergic or pathogen-induced disorders. The three main types of anal eczema are irritant-toxic, atopic and allergic contact dermatitis. Adequate and successful treatment requires a comprehensive diagnostic workup to determine disease etiology and includes treatment/elimination of causative factors as well as nonpharmacological interventions (avoidance of aggravating factors). In addition, adjuvant topical anti-inflammatory and/or specific symptomatic treatment may be required. The present guidelines contain recommendations for the diagnostic and therapeutic management of perianal dermatitis. Target users of these guidelines are clinicians in the fields of dermatology and proctology, as well as all other specialties involved in the management of patients with perianal dermatitis, both in hospital and office-based settings.

Large Nasal Defects with Exposed Cartilage: The Folded Transposition Flap as an Innovative Alternative to the Paramedian Forehead Flap.

BACKGROUND: Skin cancer removal surgery involving the tip or dorsum of the nose often results in large-sized defects with exposure of cartilage. In such cases, the paramedian forehead flap is a frequently used reconstruction technique; however, this method is complex and can result in a cosmetically unsatisfying outcome. OBJECTIVE: To describe the folded transposition flap as an aesthetically pleasing alternative to the paramedian forehead flap for large nasal defects with exposed cartilage. METHODS: The folded transposition flap is a 2-stage surgical modification of the transposition flap. In the first stage, an overlong axial cheek pedicle is used to cover the defect. In the second stage, the flap is thinned and the nasal scars are revised. RESULTS: All 4 patients experienced aesthetically pleasing results. CONCLUSION: The folded transposition flap is an alternative for reconstructing large surgical defects of the nasal tip or distal dorsum of the nose.

Impact of extended lymphadenectomy on morbidity and regional recurrence-free survival in melanoma patients.

Introdurction: Current guidelines for malignant melanoma do not set a concrete cutoff limit for the number of lymph nodes to be resected during regional lymph node dissection (LND). Here, we investigate if extended LND (ext-LND) has an impact on surgical morbidity and oncological outcome in melanoma patients. MATERIAL AND METHODS: A total of 245 melanoma patients receiving axillary or inguinal LND in curative intention were investigated retrospectively. Ext-LND was defined as axillary LND with 20 or more and inguinal LND with 10 or more resected lymph nodes. Surgical morbidity and regional recurrence-free survival were investigated. RESULTS: Ext-LND did not lead to increased surgical morbidity in the overall study collective. After ext-LND, 55.4% of the patients experienced one of the investigated complications compared to 46.2% in the limited LND group (p = .2113). There was no difference in the occurrence of lymphatic fistula, wound infection, severe bleeding or neurological complications. In addition, patients with positive lymph node status showed improved regional recurrence-free survival following ext-LND (p = .0425). CONCLUSION: Ext-LND can be considered a quality marker of LND in melanoma patients.

Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients.

BACKGROUND: Inguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients. METHODS: A retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated. RESULTS: A total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected. CONCLUSIONS: The results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional.

Vermilion Reconstruction with Genital Mucosa.

Functional and aesthetical reconstruction, especially of the upper lip after ablative tumor surgery, can be very challenging. The skin of the lip might be sufficiently reconstructed by transpositional flaps from the nasolabial or facial area. Large defects of the lip mucosa, including the vestibule, are even more challenging due to the fact that flaps from the inner lining of the oral cavity often lead to functional impairments. We present a case of multiple vermilion and skin resections of the upper lip. At the last step, we had to resect even the whole vermilion mucosa, including parts of the oral mucosa of the vestibule, leaving a bare orbicularis oris muscle. To reconstruct the mucosal layer, we used a mucosal graft from the labia minora and placed it on the compromised lip and the former transpositional flaps for the reconstructed skin of the upper lip with very good functional and aesthetic results.

p53 regulation by TRP2 is not pervasive in melanoma.

p53 is a central tumor suppressor protein and its inhibition is believed to be a prerequisite for cancer development. In approximately 50% of all malignancies this is achieved by inactivating mutations in the p53 gene. However, in several cancer entities, including melanoma, p53 mutations are rare. It has been recently proposed that tyrosinase related protein 2 (TRP2), a protein involved in melanin synthesis, may act as suppressor of the p53 pathway in melanoma. To scrutinize this notion we analyzed p53 and TRP2 expression by immunohistochemistry in 172 melanoma tissues and did not find any correlation. Furthermore, we applied three different TRP2 shRNAs to five melanoma cell lines and could not observe a target specific effect of the TRP2 knockdown on either p53 expression nor p53 reporter gene activity. Likewise, ectopic expression of TRP2 in a TRP2 negative melanoma cell line had no impact on p53 expression. In conclusion our data suggest that p53 repression critically controlled by TRP2 is not a general event in melanoma.

Low risk of contamination with human papilloma virus during treatment of condylomata acuminata with multilayer argon plasma coagulation and CO2 laser ablation.

Multilayer argon plasma coagulation (APC) is a new effective method for the treatment of genital warts. We assessed the generation of aerosols containing human papilloma virus (HPV) DNA during treatment of genital warts with multilayer APC and with CO2 laser ablation. Surveillance petri dishes, swabs from the glasses and nasolabial folds of the operating physician, and swabs taken from the suction units used during CO2 laser ablation were tested by HPV PCR. HPV DNA corresponding to patient derived HPV types of genital warts was not found in any of the petri dishes and swabs obtained during APC treatment. HPV DNA was detected in none of the petri dishes obtained during CO2 laser treatment, but in suction filters. In conclusion, both CO2 laser ablation with plume suction and APC treatment seem to have a low risk of HPV contamination of the operation room.

Dermal schwannoma (neurilemmoma): a peculiar foreign body reaction?

Schwannoma is usually a subcutaneous benign neoplasm that derives from nerve sheath. Pain and neurologic symptoms are uncommon, and exclusively dermal tumors are very rare. Solitary schwannoma has a traumatic origin in some cases, and rarely occur as a part of neurofibromatosis or schwannomatosis. An association of deeply located schwannoma with foreign material has been reported in very few cases. To our knowledge, we present the first case of a painful dermal schwannoma in association to foreign material.