Radiotherapy and prognostic factors in adnexal carcinomas: A retrospective study of 657 patients from the French CARADERM network.

BACKGROUND: Cutaneous adnexal carcinomas are a heterogeneous group of rare neoplasms. Surgical excision is the first-line treatment in localized stage. The use and effectiveness of radiotherapy have not been thoroughly evaluated in these neoplasms. OBJECTIVES: The present work analyses prognostic factors on outcomes in skin adnexal carcinomas, based on data from the CARADERM (CAncers RAres DERMatologiques) database. METHODS: Data were collected retrospectively including demographic data, tumour types and therapeutic characteristics of all patients included in the CARADERM database, with at least one informative follow-up visit. Analyses were performed on three populations: patients with complete resection of the primary tumour (ADJ/primary population), patients achieving complete remission after complete resection of a recurrent tumour (ADJ/recurrent population) and patients with unresectable locally advanced or metastatic tumours (ADV/MET population). Overall and recurrence/progression-free survivals at 3-year were analysed using Cox regression models. RESULTS: Radiotherapy did not affect overall survival (OS) in the ADJ/primary population. Adjusted recurrence-free survival (RFS) was significantly lower in the radiotherapy group in ADJ/primary group. Older patients had significantly poorer OS and RFS. Tumour size and immunosuppression were significantly associated with poorer RFS only. Radiotherapy had no effect on OS and RFS in the ADJ/recurrent population. Age was the only factor associated with a poorer OS. Radiotherapy was significantly associated with longer progression-free survival (PFS) in age-sex adjusted analysis in the ADV/MET population, without effect on OS. CONCLUSIONS: Our study shows that age, tumour size and immunosuppression are significantly associated with survival in localized adnexal carcinomas. Radiotherapy may improve PFS in the ADV/MET population but not in localized and recurrent carcinomas after complete excision.

Impact of systemic therapies in metastatic melanoma of unknown primary: A study from MELBASE, a French multicentric prospective cohort.

BACKGROUND: Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied. OBJECTIVE: To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP). METHODS: Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed. RESULTS: Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P = .73 and P = .93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type. LIMITATIONS: No record of standard diagnostic criteria of MUP used in the participating centers. CONCLUSIONS: Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies.

Risk of irAEs in patients with autoimmune diseases treated by immune checkpoint inhibitors for stage III or IV melanoma: results from a matched case-control study.

OBJECTIVE: To quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma. METHODS: Case-control study performed on a French multicentric prospective cohort of patients with melanoma, matched for irAE risk factors and oncological staging. Risk of irAE was assessed by logistic regression. RESULTS: 110 patients with pAID were included and matched with 330 controls, from March 2013 to October 2020. Over a median follow-up period of 7.2 months for cases and 6.9 months for controls, the ORs of developing all-grade and grade ≥3 irAEs among cases compared with controls were 1.91 (95% CI (1.56 to 2.27)) and 1.44 (95% CI (1.08 to 1.82)), respectively. Patients with pAID had an increased risk of multiple irAEs (OR 1.46, 95% CI (1.15 to 2.67)) and a shorter time to irAE onset. In contrast, there were no difference in irAE-related mortality nor in the rate of treatment discontinuation, and a landmark analysis revealed a better survival at 24 months among cases (p=0.02). Thirty per cent of cases experienced a pAID flare during follow-up, and baseline immunosuppression did not prevent irAE occurrence. Last, we report associations between the pAID clinical subsets and organ-specific irAEs. CONCLUSION: In our study, patients with pAID were at greater risk of all-grade, severe and multiple irAEs, yet had a better 24-month survival than controls. Thus, patients with pAID should be eligible for ICI therapy but benefit from a close monitoring for irAE occurrence, especially during the first months of therapy.

Effectiveness and safety of nivolumab in patients with advanced melanoma: A multicenter, observational study.

This retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real-world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric-Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second- or subsequent-line therapy. The median durations of progression-free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0-34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3-5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real-world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population.

Quality-of-life assessment in French patients with metastatic melanoma in real life.

BACKGROUND: Significant progress was recently observed in the treatment of metastatic melanoma (MM). With >50% of patients now reaching a second line of treatment and a significant improvement in the survival rate, an assessment of quality of life (QoL) during the whole course of the disease becomes necessary. The objective of this study was to describe the QoL of patients with MM in France, from their diagnosis of advanced disease to their death, in real life. METHODS: QoL data were collected through MelBase, a prospective, French, multicentric cohort dedicated to the follow-up of adults with MM. QoL was assessed using the EuroQoL-5D questionnaire and the Functional Assessment of Cancer Treatment (FACT)-Melanoma questionnaire at the time of study inclusion, every 3 months, and at the time of each treatment change until death. To assess longitudinal changes from baseline to death, mixed-effect models for repeated-measures analyses were used to control for baseline covariates. RESULTS: QoL was assessed in 1435 patients who were included in the study between 2013 and 2018. The median follow-up was 9.4 months, and 47% of patients died during follow-up. During first-line treatment, the model-based, mean utility score was 0.830 (95% CI, 0.818-0.843), the mean FACT-General score was 77.22 (95% CI, 76.23-78.22), and the mean FACT-Melanoma score was 129.46 (95% CI, 128.02-130.90). At the time of a change in treatment line, there was a decrease of -0.027 (95% CI, -0.03, -0.02) in the utility score, -1.82 (95% CI, -1.88, -1.76) in the FACT-General score, and -2.98 (95% CI, -3.05, -2.91) in the FACT-Melanoma score compared with first-line treatment. CONCLUSIONS: In the MelBase cohort, the QoL among patients with MM seems to be fairly stable over the whole disease course, although a small but significant decrease at time therapy is changed is observed.

Iatrogenic cutaneous graft versus host disease.

A 65-year-old man with acute myeloid leukemia 6 was treated by bone marrow allograft, developed a systemic classic chronic graft versus host disease with hepatic, rheumatologic, ophthalmic, and muco-cutaneous involvement. He received systemic corticosteroid, ruxolitinib and extracorporeal photopheresis which resulted in complete remission. During follow-up the patient presented with viral cutaneous warts on his neck and submandibular area. After various subsequent topical treatments, he developed localized cutaneous GVHD without any general GVHD reactivation symptoms. To the best of our knowledge, there has been no description in the literature of a graft versus host disease developing after local immunomodulatory or cytotoxic treatments. Topical therapies are commonly used by dermatologists for superficial skin cancers and some viral skin lesions, in high risk populations such as organ transplant patients with regular follow-up.Practitioners should be made aware of a possible localized cutaneous GVHD reactivation induced by Koebner phenomenon after local therapy.

Atypical Cowpox Virus Infection in Smallpox-Vaccinated Patient, France.

We report a case of atypical cowpox virus infection in France in 2016. The patient sought care for thoracic lesions after injury from the sharp end of a metallic guardrail previously stored in the ground. We isolated a cowpox virus from the lesions and sequenced its whole genome. The patient reported that he had been previously vaccinated against smallpox. We describe an alternative route of cowpox virus infection and raise questions about the immunological status of smallpox-vaccinated patients for circulating orthopoxviruses.

Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort.

BACKGROUND: Dupilumab is the first biologic available to treat atopic dermatitis (AD). Its effectiveness and safety were demonstrated in clinical trials. OBJECTIVE: We sought to assess the effectiveness and safety of dupilumab in adults with AD in a real-life French multicenter retrospective cohort. METHODS: We included patients treated during March 2017-April 2018. Efficacy outcomes, including Scoring Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index (EASI) scores, were collected at baseline and 3 months when available. Adverse events (AEs) were recorded at follow-up. RESULTS: We included 241 patients. The median ± interquartile range (IQR) follow-up time was 3.8 ± 3.7 months. A ≥75% improvement in SCORAD was achieved in 27 of 163 (16.6%) patients, and a ≥75% improvement in EASI was achieved in 40 of 82 (48.8%) patients. The median SCORAD and EASI scores at 3 months were significantly lower than those at baseline (SCORAD ± IQR, 25 ± 21 vs 56 ± 27.4, P < 10-9 and EASI ± IQR, 4.1 ± 6.8 vs 17.9 ± 15.4, P < 10-9, respectively). Conjunctivitis was reported in 84 of 241 (38.2%) patients. The proportion with eosinophilia (>500 cells/mm3) during follow-up (57%) was higher than that at baseline (33.7%) (n = 172, P < 10-6). Dupilumab was stopped in 42 cases; 27 patients stopped because of AEs. LIMITATIONS: No control group, missing data. CONCLUSION: This real-life study demonstrated a similar dupilumab effectiveness as that seen in clinical trials, but it also revealed a higher frequency of conjunctivitis and eosinophilia.

Acrodermatitis continua of Hallopeau response to optimized biological therapy.

Acrodermatitis continua of Hallopeau, first described in 1890, is an uncommon variant of pustular psoriasis. It presents as a sterile pustular eruption of the tips of fingers and toes. The condition has a chronic, relapsing course and is often resistant to many anti-psoriatic therapies. In the following case, we present our experience of etanercept use in a 61-year-old man. Although initial therapy with high-dose etanercept achieved a rapid, sustained response and remission, the lesions relapsed a few months into a lower, maintenance dosage. This result prompted the use a second biotherapeutic agent ustekinumab, which resulted in complete remission, but required a higher dosage than recommended with reduced dosing intervals.

Ipilimumab for the treatment of advanced melanoma in six kidney transplant patients.

Immune checkpoint inhibitors are new therapeutic options for metastatic melanoma, but few data are available in organ transplant recipient populations. Six French patients, three men and three women, mean age 66 years (range 44-74), all kidney transplant recipients, received ipilimumab (CTLA-4 inhibitor) for metastatic melanoma. At diagnosis of advanced melanoma, immunosuppressive therapy had been minimized in all but one. Adverse effects included one case of grade 1 diarrhea and one of grade 1 pruritus. One patient had acute T cell-mediated rejection confirmed by histology after the first injection of ipilimumab. After a median follow-up of 4.5 (3-20) months, one patient achieved partial response, one had stable disease, and four had disease progression. All the patients died, five from melanoma, one from another cause. In this series and in the literature, ipilimumab proved to be safe and possibly active. The acute rejection we encountered was probably related to both a rapid, drastic reduction of immunosuppression and the use of ipilimumab. Our safety data on ipilimumab contrast with the organ transplant rejections already reported with PD-1 inhibitors. We consider that immunosuppression should not be minimized, as the impact on metastatic disease control is probably small.

[Tinnitus in a Patient Treated by Bleomycin for Kaposi's Sarcoma]. / Acouphènes chez un patient traité par bléomycine pour un sarcome de Kaposi.

We describe a case of tinnitus occurred during a bleomycin monotherapy for Kaposi's sarcoma.

The clinical response to vemurafenib in a patient with a rare BRAFV600DK601del mutation-positive melanoma.

BACKGROUND: Mutations in the activation segment of the v-raf murine sarcoma viral oncogene homolog B (BRAF) gene are present in approximately 50% of melanomas. The selective BRAF inhibitor vemurafenib has demonstrated significant clinical benefits in patients with melanomas harboring the most common mutations (V600E, V600K and V600R). However, the clinical activity of BRAF inhibitors in patients with rare mutations of codon 600 and the surrounding codons has not been documented. CASE PRESENTATION: We used the BRAF inhibitor vemurafenib to treat a patient presenting a rare p.V600_K601delinsD-mutated melanoma. An objective response was evidenced by two months of progression-free survival. By cloning and sequencing BRAF exon 15, we confirmed that a dual mutation was present on a single allele and thus resulted in a BRAFV(600DK601del) mutant protein. We also performed an in silico crystal structure analysis of the mutated protein, in order to characterize the nature of the putative interaction between vemurafenib and the mutant protein. CONCLUSION: This clinical experience suggests that (i) patients with BRAFV(600DK601del)-mutation-positive melanoma can be treated successfully with the oral BRAF inhibitor vemurafenib and (ii) molecular screening in this context should encompass rare and complex mutations.

Clostridium difficile infection and immune checkpoint inhibitor-induced colitis in melanoma: 18 cases and a review of the literature.

Immunotherapy has become the standard of care for several types of cancer, such as melanoma. However, it can induce toxicity, including immune checkpoint inhibitor-induced colitis (CIC). CIC shares several clinical, histological, biological, and therapeutic features with inflammatory bowel disease (IBD). Clostridium difficile infection (CDI) can complicate the evolution of IBD. We aimed to characterize the association between CDI and CIC in patients treated with anti-CTLA-4 and anti-PD-1 for melanoma. Patients from nine centers treated with anti-CTLA-4 and anti-PD-1 for melanoma and presenting with CDI from 2010 to 2021 were included in this retrospective cohort. The primary endpoint was the occurrence of CIC. The secondary endpoints were findings allowing us to characterize CDI. Eighteen patients were included. Eleven were treated with anti-PD-1, four with anti-CTLA-4, and three with anti-PD-1 in combination with anti-CTLA-4. Among the 18 patients, six had isolated CDI and 12 had CIC and CDI. Among these 12 patients, eight had CIC complicated by CDI, three had concurrent CIC and CDI, and one had CDI followed by CIC. CDI was fulminant in three patients. Endoscopic and histological features did not specifically differentiate CDI from CIC. Nine of 11 patients required immunosuppressive therapy when CDI was associated with CIC. In nine cases, immunotherapy was discontinued due to digestive toxicity. CDI can be isolated or can complicate or reveal CIC. CDI in patients treated with immunotherapy shares many characteristics with CDI complicating IBD. Stool tests for Clostridium difficile should be carried out for all patients with diarrhea who are being treated with immunotherapy.

Efficacy and Safety of Botulinum Toxin in Adults with Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To determine whether a single session of botulinum toxin type A (BTA) injections into both hands more effectively decreases the frequency of systemic sclerosis-associated Raynaud's phenomenon (SSc-RP) episodes than placebo. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group phase III trial in patients with SSc-RP assessed the effect of 50-unit BTA or placebo injections into the palms of both hands around each neurovascular bundle during 1 session in winter. The primary end point was the between-group difference in the median change in the number of RP episodes from baseline (day 0) to 4 weeks postinjection. Values between the groups were compared with the Wilcoxon rank-sum test. RESULTS: The intent-to-treat analysis included 46 BTA-treated patients and 44 placebo recipients. At 4 weeks after assigned treatment injections, the median number of daily RP episodes decreased comparably in the BTA and placebo groups (median change -1 episode/day [interquartile range (IQR) -1.5, 0 episodes/day] and -1 episode/day [IQR -2.5, 0 episodes/day], respectively) (P = 0.77 versus placebo). Moreover, change in Raynaud's Condition Score, quality of life assessed by Health Assessment Questionnaire disability index, and hand function assessed by shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) and Cochin Hand Function Scale from baseline to follow-up weeks 4, 12, and 24 did not differ significantly between groups. The BTA group experienced transient hand muscle weakness significantly more frequently (P = 0.003). CONCLUSION: Neither the primary nor secondary end points were reached, and our results do not support any beneficial effect of palmar BTA injections to treat SSc-RP.

Differential gradients of immunotherapy vs targeted therapy efficacy according to the sun-exposure pattern of the site of occurrence of primary melanoma: a multicenter prospective cohort study (MelBase).

Background: The tumor mutational burden (TMB) is high in melanomas owing to UV-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment. Patients and methods: Patients were screened from MelBase, a multicenter biobank dedicated to the prospective follow-up of stage III/IV melanoma. All patients with a known cutaneous primary melanoma who received a 1st-line systemic treatment by immunotherapy or targeted therapy were included (2013-2019). Outcomes were progression-free survival (PFS) and overall survival (OS). Results: 973 patients received either anti PD-1(n=466), anti CTLA-4(n=143), a combination of both (n=118), or targeted therapies (n=246). Patients' characteristics at treatment initiation were: male (62%), median age of 62, AJCC stage IV (84%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 202 patients (G1: head neck), on intermittently sun-exposed skin in 699 patients (G2: trunk, arms, legs), and on sun-protected areas in 72 patients (G3: palms, soles). Median PFS was significantly higher in G1 under anti PD-1 treatment (8.7 months vs 3.3 and 3.4 months for G2 and G3, respectively) (p=0.011). PFS did not significantly differ in other groups. Similarly, median OS was significantly higher in G1 receiving 1st line anti PD-1 treatment (45.6 months vs 31.6 and 21.4 months for G2 and G3) (p=0.04), as opposed to 1st line targeted therapy (19.5 months vs 16.3 and 21.1 months for G1, G2 and G3 respectively). Conclusion: Our study confirms that immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas, but this finding needs to be confirmed by further research.

Non-V600E/K BRAF Mutations in Metastatic Melanoma: Molecular Description, Frequency, and Effectiveness of Targeted Therapy in a Large National Cohort.

PURPOSE: Mitogen-activating protein kinase inhibitors (MAPKis) are largely used in V600E/K BRAF-mutated metastatic melanomas, but data regarding effectiveness of targeted therapy in patients with rare BRAF mutations and molecular description of these infrequent mutations are scarce. PATIENTS AND METHODS: A multicenter study was conducted on patients with metastatic melanoma harboring a well-identified mutation of BRAF and enrolled from March 2013 to June 2021 in the French nationwide prospective cohort MelBase. The molecular BRAF mutation pattern, response to MAPKis when applicable, and survival data were analyzed. RESULTS: Of 856 selected patients, 51 (6%) harbored a non-V600E/K BRAF mutation involving codons V600 (24 of 51, 47%; V600G 27.4%, V600R 15.6%), K601 (6 of 51, 11.7%), and L597 (4 of 51, 7.8%). An objective response to MAPKis either BRAF inhibitor (BRAFi) alone or combined with MEK inhibitor was achieved in 56% (353 of 631) of V600E/K, 58% (11 of 19) of non-E/K V600, and 22% (2 of 9) of non-V600 BRAF-mutated patients, with a median progression-free survival of 7.7, 7.8, and 2.8 months, respectively. Overall, objective response rate was higher with BRAFi + MEK inhibitor combination than with BRAFi in monotherapy for each subset. CONCLUSION: Rare BRAF mutations are not anecdotal in the metastatic melanoma population. Although data interpretation must remain careful owing to the limited size of some subsets of patients, non-E/K V600 BRAF mutations seem to confer a high sensitivity to targeted therapy, whereas MAPKis seem less effective in patients with non-V600 BRAF mutations. However, this strategy may be used as an alternative option in the case of immunotherapy failure in the latter population.

Cost-Effectiveness Analysis of Sequential Treatment Strategies for Advanced Melanoma in Real Life in France.

Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients' characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained.

RAF inhibition and induction of cutaneous squamous cell carcinoma.

PURPOSE OF REVIEW: Targeted anticancer agents are associated with frequent skin side-effects. Several kinase inhibitors have been implicated in the appearance of borderline and malignant skin tumors such as keratoacanthomas and squamous cell carcinomas. The purpose of this review is to discuss the mechanisms as well as the management and implications of this unexpected side-effect. RECENT FINDINGS: Recent findings suggest that these skin neoplasms are due to RAF inhibition and that they are more frequent and arise earlier after treatment initiation with the more specific and potent RAF inhibitors than with the multikinase and pan-RAF inhibitor sorafenib. Biological results show that RAF inhibition induces paradoxical activation of the MAPK (mitogen-activated protein kinase) signaling pathway in cells that do not carry BRAF mutation. SUMMARY: This review discusses the various mechanisms that could be implicated in the appearance of skin tumors during the course of anti-RAF treatments as well as the implications of these findings for clinical practice and future drug development. The unexpected emergence of tumors during the course of anticancer therapies is a concern that stimulates an active field of research in the aim of understanding the underlying mechanisms and preventing if possible skin tumor initiation.