MAPKinase inhibition after failure of immune checkpoint blockade in patients with advanced melanoma - An evaluation of the multicenter prospective skin cancer registry ADOREG.

OBJECTIVES: Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30-40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. METHODS: Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. RESULTS: We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2-2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4-7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2-20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. CONCLUSIONS: BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.

Complete Metabolic Response in FDG-PET-CT Scan before Discontinuation of Immune Checkpoint Inhibitors Correlates with Long Progression-Free Survival.

Checkpoint inhibitors have revolutionized the treatment of patients with metastasized melanoma. However, it remains unclear when to stop treatment. We retrospectively analyzed 45 patients (median age 64 years; 58% male) with metastasized melanoma from 3 cancer centers that received checkpoint inhibitors and discontinued therapy due to either immune-related adverse events or patient decision after an (18F)2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with a low-dose CT scan (FDG-PET-CT) scan without signs for disease progression. After a median of 21 (range 1-42) months of immunotherapy an FDG-PET-CT scan was performed to evaluate disease activity. In these, 32 patients (71%) showed a complete metabolic response (CMR) and 13 were classified as non-CMR. After a median follow-up of 34 (range 1-70) months, 3/32 (9%) of CMR patients and 6/13 (46%) of non-CMR patients had progressed (p = 0.007). Progression-free survival (PFS), as estimated from the date of last drug administration, was significantly longer among CMR patients than non-CMR (log-rank: p = 0.001; hazard ratio: 0.127; 95% CI: 0.032-0.511). Two-year PFS was 94% among CMR patients and 62% among non-CMR patients. Univariable Cox regression showed that metabolic response was the only parameter which predicted PFS (p = 0.004). Multivariate analysis revealed that metabolic response predicted disease progression (p = 0.008). In conclusion, our findings suggest that patients with CMR in an FDG-PET-CT scan may have a favorable outcome even if checkpoint inhibition is discontinued.

PET/CT in malignant melanoma: a two-tiered healthcare system? Updated healthcare situation regarding initial staging of malignant melanoma with PET/CT.

BACKGROUND: Patients with stage IIC malignant melanoma are recommended to undergo cross-sectional imaging for initial staging. PET/CT is superior to other methods regarding its diagnostic accuracy of the tumor spread in stage III. So far there is no meaningful data on the nationwide availability, usage and cost recovery of this imaging technique. PATIENTS AND METHODS: Questionnaires on the healthcare situation in 2018 were sent to all German dermatology clinics and PET/CT centers in March and April 2019. RESULTS: 61.2 % of the dermatology clinics (71/115) and 48.2 % of the PET/CT centers (77/160) took part in the survey. A total of 22,645 patients with malignant melanoma were seen in these clinics in 2018. 16.8 % of the patients with stage IIC melanoma received a PET/CT for primary staging. The costs of this examination were covered for all statutory and privately insured patients in 40 % and 68 % of dermatology clinics (20/50 and 34/50), respectively. 68.0 % (34/50) of all dermatology clinics reported relevant changes of treatment according to PET/CT findings. Long examination periods by the health insurance companies and the time required to submit the application were the most common reasons for dermatology clinics to reject a request for PET/CT. Relevant incidental findings were reported in 90.2 % (47/51) of all PET/CT centers. CONCLUSIONS: There are clear differences in the nationwide availability and cost coverage of PET/CT in primary staging for stage IIC melanoma. For these reasons, a two-tiered healthcare system may be assumed.

Clear cell acanthoma.

Clear cell acanthoma is a rarely diagnosed tumor with variable clinical morphology that is usually only recognized by its histopathological features. The primary lesion is a red papule a few millimeters in diameter that often occurs as a single lesion on the lower extremities. In dermoscopy, resemblance of the vessels to a string of pearls is a largely specific finding of clear cell acanthoma. In contrast to the initially uncharacteristic clinical findings, histopathology of clear cell acanthomas is characterized by a typical compact, well-demarcated acanthosis consisting of pale-staining, PAS-reactive keratinocytes. As etiology and pathogenesis are both unclear, nosology of clear cell acanthoma is also controversial, with an ongoing debate as to its classification as cutaneous neoplasia or reactive inflammatory dermatosis.

Lymphomatoid papulosis.

Lymphomatoid papulosis (LyP) is characterized by a varied clinical presentation that includes erythema, papules, pustules, vesicles, plaques, nodules and ulcerations. While its biological course is typically marked by spontaneous regression, the histopathological findings of LyP are consistent with cutaneous T-cell lymphoma. Provided patients do no develop a secondary lymphoma, they exhibit unusually high 10-year survival rates (> 90 %), which is a typical feature of LyP. To date, the etiology and pathogenesis of LyP have not been elucidated. One particular subtype of LyP is known to be associated with chromosome 6p25.3 rearrangement (DUSP22-IRF4 translocation). Treatment is guided by the clinical presentation. In addition to a wait-and-see approach, recommended options include topical corticosteroids and PUVA therapy.

Randomised controlled trial to evaluate the influence of mHealth and eHealth skin cancer prevention education among young organ transplant recipients: the HIPPOlino intervention study.

OBJECTIVES: To determine whether a multicomponent sun protection intervention programme (mHealth) for young organ transplant recipients (OTR) leads to a higher increase of preventive knowledge and behavioural change than an e-learning education programme (eHealth). DESIGN: Randomised controlled trial with one preintervention baseline survey and three follow-up surveys after 6 weeks, 6 and 12 months. Comparison of two different intervention schedules with a control group (CG). SETTING: Multicomponent sun protection trainings in Germany, the Netherlands and Austria between June 2013 and September 2015. PARTICIPANTS: 137 OTRs (5-22 years of age, 61 females/76 males) participated in the study. INTERVENTIONS: (A) Intervention group 1 (IG1): personal training with subsequent forwarding of individual ultraviolet index-dependent sun protection recommendations via short message service (SMS); (B) intervention group 2 (IG2): e-learning training without SMS; (C) CG: regular information letters, online training after 1 year. OUTCOME MEASURES: Key questions were used to form a knowledge and a behavioural score. Behavioural strategies and knowledge were quantified through self-administered questionnaires. RESULTS: Analyses 6 weeks after the intervention showed a higher knowledge increase in both IG compared with the CG (IG1 to CG: OR 12.64, 95% CI 4.20 to 38.20; IG2 to CG: OR 2.59, 95% CI 0.95 to 7.04). Sun protection behaviour improved slightly but not significantly in both IG (IG1 to CG: OR 2.56, 95% CI 0.93 to 7.00; IG2 to CG: OR 1.22, 95% CI 0.45 to 3.32). One year after the intervention, no behavioural changes were observed in either IG compared with the CG. IG1 but not IG2 still scored significantly higher in sun protection knowledge than the CG 1 year after intervention (IG1 to CG: OR 4.46, 95% CI 1.48 to 13.43; IG2 to CG: OR 1.41, 95% CI 0.51 to 3.93). CONCLUSIONS: This multicomponent sun protection programme provides a promising strategy to increase sun protection knowledge and possibly also protective behaviour in young OTR. TRIAL REGISTRATION NUMBER: DRKS00011393.

Primary cutaneous diffuse large B-cell lymphoma, NOS and leg type: Clinical, morphologic and prognostic differences.

BACKGROUND AND OBJECTIVES: Primary cutaneous diffuse large B-cell lymphoma, NOS (PCLBCL/NOS) is a rare PCLBCL. Only few data are available for this tumor. The aim of this study was to identify clinical and/or immunohistochemical markers (in addition to Bcl-2) that characterize PCLBCL/NOS, assist in differentiating it from PCLBCL, leg type (PCLBCL/LT) and help to assess the clinical course/prognosis. PATIENTS AND METHODS: Bcl-2- PCLBCL/NOS) cases (n = 14 were compared with Bcl-2+ PCLBCL/LT cases (n = 29). RESULTS: PCLBCL/NOS patients were younger, predominantly male and had better survival rates than patients with PCLBCL/LT. Patients with PCLBCL/NOS presented more often with larger plaques limited to one or two contiguous body regions, whereas PCLBCL/LT cases often presented with disseminated lesions. Neoplastic cells had a higher proliferation rate (Ki67) in PCLBCL/LT patients. The tumor microenvironment of PCLBCL/NOS had a more prominent CD3+ infiltrate. Overall survival data for the whole cohort (n = 37) revealed that female gender and Bcl-2 expression correlated with a worse survival rate. Bcl-6 expression and centroblastic subtype correlated with better outcomes. None of the other markers studied (e.g. GCB/non-GCB subtype) correlated with survival rate. CONCLUSIONS: PCLBCL/NOS and PCLBCL/LT differ in their clinical behavior and outcomes. Bcl-2 still seems to be the best marker for discriminating between these two subgroups. Bcl-2, female gender and Bcl-6 represent prognostic markers for PCLBCL.

Cutaneous and systemic plasmocytosis.

Cutaneous and systemic plasmacytosis is a rare disorder observed mainly in Japanese that features an infiltration of mature plasma cells in various organ systems. In addition to the skin, lymph nodes and bone marrow are regularly affected. Laboratory tests show a polyclonal hypergammaglobulinemia. The cutaneous morphology is characterized by red to dark brown macules, papules and plaques a few centimeters in diameter, usually distributed symmetrically on the face, neck and back. Etiology and pathogenesis are not known. It is speculated that a reactive dysfunction of plasma cells may be triggered by various stimuli, such as interleukin 6. Treatment of cutaneous and systemic plasmacytosis is difficult. A standardized treatment concept does not yet exist. Topical corticosteroids and calcineurin inhibitors are mainly used.

Acquired reactive perforating dermatosis.

Acquired reactive perforating dermatosis is characterized by umbilicated erythematous papules and plaques with firmly adherent crusts. Histopathological examination shows a typical cup-shaped ulceration in the epidermis containing cellular debris and collagen. There is transepidermal elimination of degenerated material with basophilic collagen bundles. The etiology and pathogenesis of acquired reactive perforating dermatosis are unclear. Metabolic disorders and malignancies are associated with this dermatosis. Associated pruritus is regarded as a key pathogenic factor. Constant scratching may cause a repetitive trauma to the skin. This pathogenesis may involve a genetic predisposition. The trauma may lead to degeneration of the collagen bundles. Treatment of acquired reactive perforating dermatosis follows a multimodal approach. Apart from the treating any underlying disease, treatment of pruritus is a major goal. Systemic steroids and retinoids, as well as UVB phototherapy are well-established treatment options. Some patients may also benefit from oral allopurinol.

Clinical variants of lichen planus.

Lichen planus is characterized by lichenoid, polygonal papules with fine white lines, called Wickham striae. Lesions most commonly occur on the limbs and on the dorsal aspect of the trunk. At the same time often leukoplakia of mucous membranes as well as nail disorders are seen. There are numerous variants of lichen planus which can be distinguished from the classical form on the basis of morphology and distribution of the lesions. The typical primary lesion of lichen planus may be replaced by other forms, such as patches, hyperkeratoses, ulcerations, or bullous lesions. Moreover, distribution patterns of these lesions may vary and include erythrodermic, inverse or linear arrangements. In contrast to these numerous clinical features, histologic findings remain characteristic in the variants, so that the diagnosis can be made securely. Differential diagnoses of lichen planus include diverse dermatoses such as bullous pemphigoid or paronychia.