Dabrafenib plus trametinib in unselected advanced BRAF V600-mut melanoma: a non-interventional, multicenter, prospective trial.

OBJECTIVE: The efficacy of combined BRAF and MEK inhibition for BRAF V600-mutant melanoma in a broad patient population, including subgroups excluded from phase 3 trials, remains unanswered. This noninterventional study (DATUM-NIS) assessed the real-world efficacy, safety and tolerability of dabrafenib plus trametinib in Austrian patients with unresectable/metastatic melanoma. METHODS: This multicenter, open-label, non-interventional, post-approval, observational study investigated the effectiveness of dabrafenib plus trametinib prescribed in day-to-day clinical practice to patients ( N  = 79) with BRAF V600-mutant unresectable/metastatic melanoma with M1c disease (American Joint Committee on Cancer staging manual version 7), ECOG > 1, and elevated serum lactate dehydrogenase (LDH). The primary endpoint was 6-, 12- and 18-month progression-free survival (PFS) rates. Secondary endpoints were median PFS, disease control rate and overall survival (OS). RESULTS: The 6-, 12- and 18-month PFS rates were 76%, 30.6% and 16.2%, respectively. Subgroup analysis showed a significant PFS benefit in the absence of lung metastasis. The median PFS and OS were 9.1 (95% CI, 7.1-10.3) months and 17.9 (95% CI, 12.7-27.8) months, respectively. The 12- and 24-month OS rates were 62.7% and 26.8%, respectively. Subgroup analyses showed significant OS benefits in the absence of bone or lung metastasis and the presence of other metastases (excluding bone, lung, brain, liver and lymph nodes). Furthermore, S100 and Eastern Cooperative Oncology Group performance status (ECOG PS) showed a significant impact on survival. No new safety signals were observed. CONCLUSION: Despite an unselected population of melanoma patients with higher M1c disease, ECOG PS > 1 and elevated LDH, this real-world study demonstrated comparable efficacy and safety with the pivotal phase 3 clinical trials for dabrafenib-trametinib.

Real-world outcomes using PD-1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland.

BACKGROUND: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. METHODS: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence. RESULTS: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. CONCLUSIONS: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk.

Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.

BACKGROUND: Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%. OBJECTIVES: The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting. METHODS: Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020. RESULTS: 88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%). CONCLUSION: This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.

Long-term Therapeutic Success of Intravenous Rituximab in 26 Patients with Indolent Primary Cutaneous B-cell Lymphoma.

Systemic monotherapy with rituximab is a well-known treatment approach for primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone lymphoma. Both have excellent prognosis despite high relapse rates. To investigate the long-term effectiveness and clinical outcome of intravenous rituximab at a dose of 375 mg/m2 once weekly, data for 26 patients (17 primary cutaneous follicle centre lymphoma and 9 primary cutaneous marginal zone lymphoma) were analysed retrospectively. Complete remissions occurred in 20 (77%) and partial remissions in 6 patients (23%), demonstrating an overall response rate of 100%. The relapse rate was 52.9% in primary cutaneous follicle centre lymphoma and 88.9% in primary cutaneous marginal zone lymphoma. Ongoing complete remissions after therapy with rituximab were observed in 9 patients (34.6%) with a median progression-free survival of 161 months (13.4 years). These results confirm that intravenous rituximab is an effective and well-tolerated treatment with durable responses in a relevant percentage of patients at a median follow-up of 148 months (12.3 years).

Clinical melanoma characteristics and survival-a single-center retrospective study between 2000 and 2010.

The aim of this study was to characterize clinical, histological, and outcome features of primary melanoma in 1329 patients managed at a single-center institution between 2000 and 2010. Parameters included age at diagnosis, sex, tumor location, histology, stage, Breslow thickness, and sentinel lymph node status among others. The mean age at diagnosis was 59.1 ± 16.7 years. Women were significantly younger than men when diagnosed (57.2 vs. 61.0 years; p < 0.001). Most melanomas (83%) were diagnosed on typically sun-exposed skin areas. Superficial spreading melanoma (39.5%) was the most frequent histological subtype. The median Breslow thickness was significantly higher for men compared to women (1.10 mm vs. 0.90 mm; p = 0.018). 38.3% of patients with positive and 12.9% of patients with negative sentinel biopsies progressed. Five-year survival analysis for a sub-cohort of 577 patients showed better 5­year overall survival for woman compared to men (75.8% vs. 63.6%; p = 0.025). Our findings indicate differences in patient characteristics between men and women, and underscore the importance of early melanoma detection to prevent disease progression.

Tumor-associated B-cells induce tumor heterogeneity and therapy resistance.

In melanoma, therapies with inhibitors to oncogenic BRAFV600E are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications.Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.

Searching for the Chokehold of NRAS Mutant Melanoma.

Up to 18% of melanomas harbor mutations in the neuroblastoma rat-sarcoma homolog (NRAS). Yet, decades of research aimed to interfere with oncogenic RAS signaling have been largely disappointing and have not resulted in meaningful clinical outputs. Recent advances in disease modeling, structural biology, and an improved understanding of RAS cycling as well as RAS signaling networks have renewed hope for developing strategies to selectively block hyperactive RAS function. This review discusses direct and indirect blocking of activated RAS with a focus on current and potential future therapeutic approaches for NRAS mutant melanoma.

Phrynoderma and acquired acrodermatitis enteropathica in breastfeeding women after bariatric surgery.

BACKGROUND AND OBJECTIVES: Women who have undergone bariatric surgery are susceptible to nutritional deficiencies in subsequent pregnancies. We highlight the importance of dermatologists in the early recognition of cutaneous signs of malnutrition occurring in this specific clinical setting. PATIENTS AND METHODS: We compare clinical characteristics of two young women with dermatological signs of combined post-gestational nutritional deficiencies following Roux-en-Y gastric bypass surgery. RESULTS: Patient 1 exhibited follicular papules on the extremities, perianal eczema, perlèche, alopecia, and depigmentation of hair. Patient 2 showed erythematous plaques in genitoanal and acral areas, perlèche, diffuse alopecia, and depigmentation of hair. Based on clinical and histopathological findings, decreased vitamin A (patient 1) and zinc levels (patient 2), we diagnosed phrynoderma and acquired acrodermatitis enteropathica, respectively. Comparison of the two patients revealed that both (i) were lacking follow-up after gastric bypass surgery, (ii) developed skin lesions as primary symptoms with (iii) mixed clinical manifestations due to combined deficiencies, and (iv) experienced initial symptoms during lactation suggesting a causal relationship. CONCLUSIONS: Our observations highlight the potentially increased risk of women to develop post-gestational dermatological manifestations of malnutrition following bariatric surgery. The awareness of dermatologists with respect to this emerging, susceptible patient group may help avert damage to mother and child.

Value of micromorphometric criteria of sentinel lymph node metastases in predicting further nonsentinel lymph node metastases in patients with melanoma.

Patients with metastases in the sentinel node (SN) are advised to undergo complete lymph node dissection, although the majority of them will have no further metastatic disease. Some of these patients undergo unnecessary surgery. In this study, we tried to predict the likelihood of further non-SN metastases on the basis of earlier published micromorphometric classifications of SN metastases. Metastases in the SN were re-evaluated on the basis of the microanatomic location of the lesions according to the Dewar's criteria, the S-classification of SN, and tumor burden in accordance with the Rotterdam criteria. The results of these classifications were correlated with the presence of further non-SN metastases. Specimens of 124 positive-SN basins and subsequent complete lymph node dissection were investigated. Further metastases in non-SNs were found in 30 lymph node basins (24.2%). All of the above-mentioned classification systems were significantly correlated with non-SN tumor status. Especially, in patients with SN metastases in subcapsular location, a maximum depth of invasion of less than 0.3 mm (stage I according to the S-classification) or metastases of less than 0.1 mm in diameter had a very low probability of further non-SN metastases (0-5%). The validity of earlier published classifications of SN metastases-based on the micromorphometric criteria in predicting non-SN status was confirmed. Especially, in patients with subcapsular metastases, SI stage metastases or metastases of less than 0.1 mm had a very low risk of further non-SN metastases.

Molecular cytogenetic evidence of t(14;18)(IGH;BCL2) in a substantial proportion of primary cutaneous follicle center lymphomas.

In contrast to nodal follicular lymphoma, limited data exist on genetic changes in primary cutaneous follicular lymphoma (primary cutaneous follicle center lymphoma according to WHO-EORTC). The detection rate of the BCL2 rearrangement, representing the characteristic t(14;18)(q32;q21) underlying follicular lymphoma, by polymerase chain reaction (PCR) has been reported to vary over a wide range (0%-41%), and only a few cases have been studied by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). In this study, 27 primary cutaneous follicle center lymphomas were analyzed by FISH and the results compared with those obtained by PCR. FISH demonstrated translocations affecting the immunoglobulin heavy chain locus (IGH) in 14 of 27 cases (52%): a t(14;18)(q32;q21) involving BCL2 was found in 11 cases (41%), a t(3;14)(q27;q32) affecting BCL6 in 2 cases (7%), and in 1 case the partner gene of IGH could not be identified. Interestingly, PCR did not detect BCL2 rearrangement in any case. These data suggest that the t(14;18)(q32;q21) frequently occurs in primary cutaneous follicular lymphoma. The reason(s) why BCL2 rearrangements escape the detection by PCR is (are) not clear but could be due to BCL2 mutations, breakpoints outside the amplified DNA, or a high load of somatic mutations.

S-classification of sentinel lymph node biopsy predicts the results of complete regional lymph node dissection.

The purpose of this study was to identify melanoma patients with positive sentinel lymph nodes (SLNs) at increased risk for further metastases in this specific lymph node basin. A series of consecutive patients with primary malignant melanoma stage I and II were evaluated retrospectively. The results of SLN biopsy in 26 patients with positive SLNs were compared with those of complete regional lymph node dissection (RLND) using the recently published S-classification of SLNs. The results of S-classification of SLNs were correlated with the outcome of complete RLND. There was a significant correlation between the S stage of positive SLNs and the results of complete RLND (P=0.02). Only patients with SIII stage (n=4) SLNs were found to have further metastases in the residual lymph node basin. The present study indicates that patients with SI stage and SII stage SLNs rarely have further metastases in the specific lymph node basin.

Antineutrophil cytoplasmic autoantibody-negative antiproteinase 3 syndrome presenting as vasculitis, endocarditis, polyneuropathy and Dupuytren's contracture.

Antiproteinase 3 antibodies (antiPR3) are assumed to be subtypes of antineutrophil cytoplasmic autoantibodies (ANCA), with a high specificity for active Wegener's granulomatosis and microscopic polyangiitis. Thus, antiPR3 positivity in ELISA, together with negativity in indirect immunofluorescence (IIF) is a rare finding. A 56-year-old man with Dupuytren's contracture and polyneuropathy was admitted for leukocytoclastic vasculitis. Echocardiography, performed because of fever and dyspnea, detected aortic valve endocarditis. Because of severe aortic insufficiency the valve was replaced. Blood cultures and bacteriologic investigations of the explanted valve were negative. AntiPR3 were elevated (123-163 U/ml; normal <6 U/ml), together with negativity in IIF. This case shows that antiPR3 elevation with negative ANCA may be associated with vasculitis, endocarditis, polyneuropathy and Dupuytren's contracture. A causal relationship between the clinical presentation and antiPR3 elevation is likely. In order not to miss such cases of vasculitis, combined screening by IIF and ELISA is recommended in selected cases.