Improved survival over time with immunotherapy in locally advanced and metastatic cutaneous squamous cell carcinomas.

PURPOSE: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in white-skinned populations. There is little information on the epidemiology of cSCC, and even less on advanced cases (acSCC). Therefore, we analyzed acSCC patients to describe their characteristics, management, and outcomes over time. METHODS: A single-center retrospective study was conducted over a period of 5 years, including all patients who started systemic therapy for acSCC. The patient characteristics, cSCC management, response to therapy, and survival were recorded. Patients were stratified into equal chronological periods (periods 1 and 2). A subgroup analysis was performed to compare patients who received immunotherapy (group 1) with those who did not (group 2). RESULTS: The study included 127 patients, and patient numbers increased by an average of 19.7% per year. Most patients were male (88/127), elderly (mean 81.6 years), with comorbidities, and 27.6% were immunocompromised. The median overall survival (OS) was higher in period 2 (20 months) than in period 1 (10 months) (hazard ratio [95% confidence interval] = 0.62 [0.39; 0.98], p = 0.04). The risk of progression increased with age and immunosuppression. Of the 64 patients who received second-line therapy, 38 had immunotherapy (group 1) and 26 received other therapies (group 2). Immunotherapy reduced mortality and progression by 71% (p = 0.004) and 67% (p = 0.002), respectively. CONCLUSIONS: Patients with acSCC are usually very frail and elderly. OS increased over time, with a twofold improvement between periods 1 and 2, whereas progression-free survival (PFS) did not increase. Access to immunotherapy reduced mortality in a majority of patients in period 2. Immunosuppression and advanced age were associated with lower PFS.

Real-life use of trametinib after immunotherapy failure in BRAF wild-type advanced melanoma.

BRAF V600 wild-type advanced melanomas quickly reach a therapeutic dead-end, after immunotherapy failure. Even if preclinical studies have suggested sensitivity to MEK inhibitors such as trametinib in NRAS, NF1 or GNA mutated melanoma, therapeutic options are limited for these patients. We present a retrospective monocentric study of 22 patients with advanced melanoma treated by trametinib after immunotherapy resistance. Melanomas harboured NRAS (20), NF1 (1) or GNA 11 (1) mutations. For most of them (18), anti-PD1 was associated with trametinib. A disease-control was reported in 36% of patients (8/22), with six stable diseases and two partial responses according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Median progression-free survival was 2 months (1-14) and median overall survival was 6.5 months (2-24). In patients with progressive disease (14/22), dissociated radiologic responses and clinical benefits such as pain reduction were seen in five patients. High blood level of lactate dehydrogenase (LDH) seemed associated with trametinib failure, without significance ( P = 0.06). Adverse events (grade 1-3) occurred in 91% of patients during the first weeks of treatment, mainly papulo-pustular rashes (77%), leg oedemas (36%), asthenia (18%) and diarrhoea (14%). This real-life study showed that trametinib may benefit some metastatic melanoma that progressed after chemotherapy and immune checkpoint inhibitors. Objective disease control (partial response or stable disease) using RECIST criteria was observed in 36% of patients. Because of frequent side-effects which can alter the quality of life and the short response duration, this off-label option has to be discussed with the patient. Studies with combination therapy with trametinib to improve relapse-free survival and lower side-effects are ongoing.

Integrative diagnosis of primary cutaneous large B-cell lymphomas supports the relevance of cell of origin profiling.

Primary cutaneous large B-cell lymphomas (PCLBCL) represent a diagnostic challenge because they are classified as PCLBCL, leg type (PCLBCL, LT) or primary cutaneous follicle centre lymphoma, large cell (PCFCL, LC), which differ by prognosis and therapeutic requirement. Unclassified cases with discordant clinical presentations, morphologies, and immunophenotypes may be classified into the not otherwise specified (PCLBCL, NOS) category based on ancillary molecular analyses. Cell-of-origin profiling as germinal centre (GC) type or non-GC type by immunohistochemistry is not considered reproducible because of variable CD10 expression. In a series of 55 PCLBCL cases with > 80% large cells, we reported 21 PCFCL, LC cases as GC-type and 27 PCLBCL, LT as non-GC-type; 7 cases were considered PCLBCL, NOS. Here, we demonstrate the accuracy of molecular profiling of PCLBCL as GC or non-GC type using a reverse transcriptase multiplex ligation assay (RT-MLPA). RT-MLPA classified the seven PCLBCL, NOS cases in accordance with their mutational profile. An integrative principal component analysis confirmed the main criteria and the relevance of genomic profiling of PCFCL, LC as GC-derived, and PCLBCL, LT as non-GC-derived. Both the cell-of-origin classification of PCLBCL and the integrative analysis identified two clinically relevant subgroups according to overall survival, which may help to standardize PCLBCL diagnosis and patient management.

Aseptic cystitis induced by nivolumab and ipilimumab combination for metastatic melanoma.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma. Combination of ICI with ipilimumab cytotoxic T-lymphocyte antigen-4 and nivolumab [anti-programmed cell death-1 (PD-1)] improves tumoral response compared to anti-PD1 monotherapy in melanoma patients, but is associated with more severe and multiple immune-related adverse events. We report the first case of aseptic cystitis induced by ipilimumab and nivolumab combination in a 61-year-old melanoma patient. She described after two infusions, diarrhea, pollakiuria, intense bladder pain, urinary urgency, and nocturia. Repeated negative urine culture tests led to perform cystoscopy. Mucosal bladder biopsies showed lymphocytic T-cells infiltration in intraepithelial and in subepithelial connective tissue, which were consistent with the diagnosis of immune-related aseptic cystitis. Aseptic cystitis is a rare and poorly known side-effect related to ICI. Only four other cases with anti-PD1 monotherapy were found in literature, only in Japanese patients. It simulates bacterial cystitis with negative urinary tests, and is often associated with atypical symptoms like diarrhea, which may delay the diagnosis. Oral steroids appear to be the most efficient therapeutic options.

Leishmania naiffi and lainsoni in French Guiana: Clinical features and phylogenetic variability.

In French Guiana, five species are associated with Cutaneous Leishmaniasis (CL). Though infections with Leishmania guyanensis, L. (V.) braziliensis and L. (L.) amazonensis have been extensively described, there are few available clinical and genetic data on L. (V.) lainsoni and L. (V.) naiffi. We determined the clinical and epidemiological features of all cases of CL due to L. (V.) naiffi and L. (V.) lainsoni diagnosed in French Guiana between 2003 and 2019. Phylogenetic analysis was performed by sequencing a portion of HSP70 and cyt b genes. Five cases of L. naiffi and 25 cases of L. lainsoni were reported. Patients infected by L. (V.) lainsoni were usually infected on gold camps, mostly along the Maroni river (60%), while L. naiffi was observed in French patients infected on the coast (100%). A high number of pediatric cases (n = 5; 20%) was observed for L. (V.) lainsoni. A mild clinical course was observed for all cases of L. (V.) naiffi. HSP70 and cyt b partial nucleotide sequence analysis revealed different geographical clusters within L. (V.) naiffi and L. (V.) lainsoni but no association were found between phylogenetic and clinical features. Our data suggest distinct socio-epidemiological features for these two Leishmania species. Patients seem to get infected with L. (V.) naiffi during leisure activities in anthropized coastal areas, while L. (V.) lainsoni shares common features with L. (V.) guyanensis and braziliensis and seems to be acquired during professional activities in primary forest regions. Phylogenetic analysis has provided information on the intraspecific genetic variability of L. (V.) naiffi and L. (V.) lainsoni and how these genotypes are distributed at the geographic level.

Acquired Lymphangioma Circumscriptum of the Penis Treated by Electrocoagulation.

Lymphangioma circumscriptum (LC) is a vascular malformation resulting from a developmental anomaly of the superficial lymphatic system of the skin. It is benign albeit uncommon. LC less frequently occurs on the penis. LC may be either congenital or acquired. Acquired cases appear to develop most frequently after interventions in the area or underlying pathologies. It is often mistaken for genital warts or molluscum contagiosum. We report here about a case of LC misdiagnosed with genital warts for 15 years. A biopsy eventually provided histopathological evidence. Various treatments are available for LC including surgical excision (which is the gold standard), CO2 laser ablation, cryotherapy, flash lamp pulsed dye laser, and electrocoagulation therapy. For our patient, one session of electrocoagulation was performed under local anesthesia. This treatment allowed an almost complete regression of the lesion without recurrence after 3 years of follow-up. Electrocoagulation may be an efficient treatment for LC in locations that may be surgically challenging such as penis.

Mutations of the B-Cell Receptor Pathway Confer Chemoresistance in Primary Cutaneous Diffuse Large B-Cell Lymphoma Leg Type.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) preferentially involves the lower limb in elderly subjects. A combination of polychemotherapy and rituximab has improved prognosis. However, about 50% of patients will experience progression or relapse without any predictive biologic marker of therapeutic response. The mutational profile of PCLBCL-LT has highlighted mutations contributing to constitutive NF-κB and B-cell receptor (BCR) signaling pathways but has not demonstrated clinical utility. Therefore, the mutational status of 32 patients with PCLBCL-LT (14 patients with complete durable response and 18 patients with relapsing or refractory disease) was determined with a dedicated lymphopanel. Tumor pairs at diagnosis and relapse or progression were analyzed in 14 relapsing or refractory patients. Patients with PCLBCL-LT harboring one mutation that targets one of the BCR signaling genes, CD79A/B or CARD11, displayed a reduced progression-free survival and specific survival (median 18 months, P = 0.002 and 51 months, P = 0.03, respectively, whereas median duration in the wild-type group was not reached) and were associated with therapeutic resistance (P = 0.0006). Longitudinal analyses revealed that MYD88 and CD79B were the earliest and among the most mutated genes. Our data suggest that evaluating BCR mutations in patients with PCLBCL-LT may help to predict first-line therapeutic response and to select targeted therapies.