Sequential combination of Sonic Hedgehog inhibitors followed by consolidation radiotherapy in locally advanced basal cell carcinoma.

BACKGROUND: Sonic Hedgehog inhibitors (SHHis) are an effective treatment in locally advanced basal cell carcinoma (laBCC), but the use of these drugs is limited by adverse events and relapse at discontinuation in around half of patients. A few cases of patients treated concomitantly by radiotherapy (RT) and SHHis have been reported in the literature, suggesting that the combination results in an improved overall response. Maintaining complete response after stopping treatment is a concern, especially since resuming treatment in the case of relapse does not guarantee a new therapeutic response. The optimal combination and sequence of treatment to improve local control of laBCCs are not yet defined. OBJECTIVE: We hypothesized that consolidation RT after complete response to SHHis could reduce the risk of relapse at discontinuation. METHODS: We present a case series of patients with laBCCs who achieved complete response (CR) after SHHi treatment and were treated with consolidation RT. Patients were evaluated by a skin cancer board. The closure RT technique and dosage were refined by a radiotherapist. RESULTS: Eleven patients were included. SHHis were prescribed for 5 months (range 4-11). Consolidation RT was performed after CR to SHHis and discontinuation. RT was delivered at a median dose of 45 Gy (range 40.5-66) in 10 fractions (range 9-33). With a median follow-up of 23 months, all patients maintained complete clinical response. This strategy was well tolerated with no grade 3 adverse events. CONCLUSION: SHHi treatment followed by RT consolidation after drug discontinuation seems effective and safe. Further studies are needed to develop a precise strategy for the management of laBCCs.

Description of supportive care and feasibility of physical exercise program to improve quality of life in advanced melanoma patients.

Physical activity is the first-line treatment of cancer-related fatigue. It has shown benefits on patient's quality of life (QoL) when practiced during and after treatment. New treatments have drastically changed the prognosis of melanoma. Still, few data are available about research program of supportive care in advanced melanoma. The primary outcome was to assess the feasibility of setting up a prospective study evaluating the benefits of Adapted Physical Activity (APA) on the QoL of patients with advanced melanoma. Feasibility was defined with a combination of five criteria including completion of questionnaire, recruitment, participant retention, patient adhesion to supportive care, and absence of adverse event. Between September 2019 and March 2021, 271 melanoma patients were questioned. Around 60% of stage IV melanoma patients were interested in support care. Patient retention at 3 months was sufficient. Only one patient could not be evaluated after 3 months of enrolment because of deterioration of the general state. Adhesion to exercise and sessions was good. Supervised APA program appeared to be safe and well tolerated as no adverse events or discontinuations were reported. Setting up a prospective research program evaluating the benefits of physical activity in advanced melanoma patients seems feasible. With melanoma becoming a chronic disease, supportive care may reduce fatigue, improve QoL and help maintain a healthy lifestyle. Data supporting its benefits on this survivor population are needed.

Impact of Extra-Intestinal Manifestations at Diagnosis on Disease Outcome in Pediatric- and Elderly-Onset Crohn's Disease: A French Population-Based Study.

Background: Extraintestinal manifestations (EIM) have been associated with more severe course of inflammatory bowel disease. The aim was to study the frequency of EIM in pediatric- and elderly-onset Crohn's disease (CD) and the factors associated with EIM and their impact on long-term disease outcome. Methods: Pediatric- (age at diagnosis younger than 17 years) and elderly-onset CD patients (age at diagnosis 60 years or older) from a prospective population-based registry (EPIMAD) were recruited. Data on EIM and clinical factors at diagnosis and at maximal follow-up were collected. Results: We included 535 pediatric- and 370 elderly-onset patients (median age 14.5 and 69.9 years; median follow-up 11.1 and 5.9 years). Extraintestinal manifestations presented in 23.5% of childhood-onset and 4.9% of elderly-onset individuals at diagnosis, while in 29.8% and 5.9% of patients, EIM developed newly during the follow-up (hazard ration [HR] 4.4, 95% CI, 2.7-7.0, P < 0.001). The most frequently involved organ in both age cohorts, either at diagnosis or during disease course, were joints (pediatric: 11.2% and 22.6%; elderly: 3.2% and 3.5%, respectively) followed by skin (pediatric: 15.9% and 13.6%; elderly: 2.7% and 2.7%, respectively). Extraintestinal manifestations at diagnosis were associated with increased risk for corticosteroids (HR 1.42, 95% CI, 1.14-1.78 and HR 3.38, 95% CI, 1.88-6.08) and immunosuppressive therapy (HR 1.30, 95% CI, 1.02-1.65 and HR 4.24, 95% CI, 1.91-9.42), in both age populations. Conclusions: Extraintestinal manifestations occurred at lower frequency in elderly-onset compared with pediatric-onset patients. In both age populations, presence of EIM at diagnosis independently increased the need for corticosteroid and immunosuppressive treatment.

Severe skin toxicity with organ damage under the combination of targeted therapy following immunotherapy in metastatic melanoma.

Targeted therapy combination (TTC: antiRAF+antiMEK) is known to improve metastatic melanoma survival. Few severe skin toxicities (grade ≥3) are described with first-line TTC (17% for vemurafenib+cobimetinib and none for dabrafenib+trametinib) in a phase III trial. Among our 42 patients treated by TTC between January 2014 and March 2017, 4.8% (2/42) of those treated in the first line presented severe skin rash versus 19% (8/42) of patients treated in the second line after previous immunotherapy. In particular, we observed one case of Stevens-Johnson syndrome and four cases of severe drug reaction with eosinophilia and systemic symptoms syndrome under TTC in patients who had received immunotherapy previously. Thus, previous immunotherapy appears to play an important role in the skin rash onset and severity induced by TTC.

Pembrolizumab-induced pneumonitis.

Three cases of pembrolizumab-induced pneumonitis are described, two being consistent with organising pneumonia http://ow.ly/Dvhc308QI39.

BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response.

BRAF inhibitors (BRAFi), a targeted therapy, are used to treat metastatic late-stage melanomas harbouring the BRAF-V600 mutation (found in about 50% of melanomas). The targeted therapy is generally maintained until tumour progression or major toxicity occurs, although responses are often limited in time. It is unknown whether melanoma patients achieving a complete response with targeted therapy can safely discontinue treatment. We retrospectively observed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving a complete response and those with an incomplete response combined with surgical removal of the remaining tumours. We also evaluated the effectiveness of BRAFi in these patients after recurrence. In 11 patients, the best response was diagnosed after a median BRAFi treatment duration of 105 (29-341) days. The median follow-up after BRAFi initiation was 769 (435-1765) days. Recurrence was observed in all 11 patients (100%), median: 82 (27-322) days. Five patients achieved a complete response, with a median progression-free survival after cessation of 136.5 (34-322) days versus 82 (27-144) days for six patients with an incomplete response combined with surgical removal of remaining tumours. Baseline characteristics and time to best response and to discontinuation did not influence the rate of relapse. Subsequently, eight patients were rechallenged with a BRAFi. The median progression-free survival time after BRAFi rechallenge was 222.5 (15-425) days. The three remaining patients received treatments other than BRAFi. Our findings may be valuable with respect to ongoing clinical trials of combinations of targeted therapies and immunomodulatory antibodies.

Ipilimumab in anti-PD1 refractory metastatic melanoma: a report of eight cases.

Targeted therapy and immunotherapy in metastatic melanoma have led to a marked improvement in patients' survival and their quality of life. Although there are data on anti-programmed-death-receptor-1 (anti-PD1) after ipilimumab, only few data are available on ipilimumab following anti-PD1 as the first-line treatment. The aim of our study was to evaluate tolerance and survival of patients treated with ipilimumab as the second-line immunotherapy among metastatic melanoma patients following anti-PD1 treatment. Retrospective and descriptive epidemiological studies were carried out at the Dermatology Department of the University Hospital of Lille. We describe a case series of patients treated with ipilimumab after anti-PD1 failure for metastatic melanomas. For each patient, we assessed disease extension since ipilimumab introduction using RECIST 1.1. The time between ipilimumab introduction and other systemic treatment and overall survival (between ipilimumab introduction and last patient visit) was assessed. The effect of ipilimumab after anti-PD1 treatment was evaluated in eight patients. Four patients responded to ipilimumab: three showed a complete response and one showed a partial response. For these patients, the time period between the first ipilimumab injection and another systemic treatment ranged from 209 to 391 days and the overall survival ranged from 314 to 581 days. One patient showed grade 3 chorioretinitis, an unusual toxicity with ipilimumab or anti-PD1 to our knowledge. We have described the efficacy of ipilimumab following anti-PD1 in metastatic melanoma in eight patients. Several comparative studies are still in progress, and their results will be important to develop an optimal therapeutic strategy for our patients.

Cerebrospinal fluid concentrations of vemurafenib in patients treated for brain metastatic BRAF-V600 mutated melanoma.

Anti-BRAF agents, including vemurafenib, have modified the prognosis for patients with melanoma. However, a difference can still be observed between extracerebral and cerebral responses. The aim of this study was to investigate the diffusion of vemurafenib in cerebrospinal fluid (CSF) from patients treated for brain metastatic BRAF-V600 mutated melanoma. Six patients treated with vemurafenib 960 mg twice daily were included. These patients had undergone a lumbar puncture because of suspicions of leptomeningeal metastasis, along with simultaneous blood sampling to measure vemurafenib level. The concentrations of vemurafenib in the CSF and the plasma were measured by high-performance liquid chromatography. The mean plasma and CSF concentrations of vemurafenib were 53.4±26.2 and 0.47±0.37 mg/l, respectively. The mean ratio of the CSF : plasma concentration was 0.98±0.84%. No relationship was found between plasma and CSF concentrations (P=0.8). In conclusion, our preliminary results highlight for the first time a low CSF vemurafenib penetration rate associated with a large interindividual variability in patients treated for metastatic BRAF-V600 mutated melanoma and brain metastases. Further investigations with larger cohorts are required to study the relationship between CSF vemurafenib concentrations and cerebral response.