Impact of radiotherapy schedule on survival of patients treated with immune-checkpoint inhibitors for advanced melanoma and non-small cell lung cancer.

PURPOSE: Preclinical and clinical data suggest a potential benefit in the addition of radiotherapy (RT) to immune-checkpoint inhibitors (ICI) during the treatment of advanced cancers. Nevertheless, the ideal patients for this approach and the optimal RT regimen is still debated. MATERIAL AND METHODS: The aim of this study was to determine the effect RT schedule has on survival for advanced non-small cell lung cancer and melanoma patients (pts) treated with ICI (anti-PD1 or anti-CTLA4) and concomitant RT. RESULTS: A total of 58 pts were identified, of which 26 received RT concomitantly with ICI while the remaining 32 pts were treated with RT at the time of progression under ICI. The RT parameters associated with outcome include dose per fraction, biological effective dose, RT to all targets and lung irradiation. Independent predictors of improved progression-free survival were lung irradiation, melanoma histology, oligometastatic status (<6 metastasis), presence of liver metastasis, PNN<7000/mm3 and normal LDH. Independent predictors of improved overall survival were melanoma histology and normal LDH. Among pts who were irradiated at progression, 68.7% had an overall clinical benefit and had a median extension of ICI use by 2.3 months (range: 0-29.1), among which 2 presented with an abscopal effect. CONCLUSIONS: The irradiation of lung metastases may increase survival in patients under ICI. RT at progression could prolong the use of ICI, and neutrophilia and LDH should be considered during patient selection of this combined RT/ICI approach.

Relevance of body mass index as a predictor of systemic therapy outcomes in metastatic melanoma: analysis of the MelBase French cohort data☆.

BACKGROUND: The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy. PATIENTS AND METHODS: This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out. RESULTS: A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n = 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P = 0.88)/overall survival (P = 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI. CONCLUSION: The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution.

Association of combined PD-L1 expression and tumour-infiltrating lymphocyte features with survival and treatment outcomes in patients with metastatic melanoma.

BACKGROUND: Recent advances obtained with immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) protein have significantly improved the outcome of patients with metastatic melanoma. The PD-L1 expression in tumour cells as detected by immunohistochemistry is a predictive biomarker in some solid tumours, but appears insufficient as prognostic or predictive factor of response to ICIs in metastatic melanomas. OBJECTIVES: We investigated whether the presence and the features of pretreatment CD8+ tumour-infiltrating T lymphocytes (TILs) could be a complementary prognostic or predictive biomarker in patients with metastatic melanoma. METHODS: In this retrospective study, we evaluated the association of PD-L1 expression ≥5% of tumour cells combined with TIL features (CD8, CD28, Ki67) with the overall survival (OS) among 51 patients treated with ICIs and 54 patients treated with other treatment options (non-ICIs). RESULTS: PD-L1 positivity was observed in 33% and 39% of primary melanomas and matched metastases, respectively, with, however, poor concordance between the primary and the matched metastatic site (κ = 0.283). No significant association was noted between PD-L1 expression and CD8+ TIL profile analysed as single markers and OS or response to immunotherapy. Instead, their combined analysis in primary melanoma samples showed that the PD-L1-/CD8+ status was significantly associated with prolonged OS in the whole population (P = 0.04) and in the subgroup treated with non-ICIs (P = 0.009). Conversely, the PD-L1+/CD8+ status was a good prognostic factor in patients treated with ICIs (P = 0.022), whereas was significantly associated with poor prognosis in patients treated with non-ICIs (P = 0.014). While the expression of CD28 was not related to outcome, the Ki67 expression was significantly associated with poor OS in the subgroup CD8+ TIL+/PD-L1- (P = 0.02). CONCLUSIONS: The pretreatment combination of PD-L1 expression with the level of CD8+ TILs could better assess OS and predict therapeutic response of patients with metastatic melanoma treated by either immunotherapy or other treatment regimens.

Cancer cell-derived long pentraxin 3 (PTX3) promotes melanoma migration through a toll-like receptor 4 (TLR4)/NF-κB signaling pathway.

Cutaneous melanoma is one of the most aggressive cancers characterized by a high plasticity, a propensity for metastasis, and drug resistance. Melanomas are composed of phenotypically diverse subpopulations of tumor cells with heterogeneous molecular profiles that reflect intrinsic invasive abilities. In an attempt to identify novel factors of the melanoma invasive cell state, we previously investigated the nature of the invasive secretome by using a comparative proteomic approach. Here, we have extended this analysis to show that PTX3, an acute phase inflammatory glycoprotein, is one such factor secreted by invasive melanoma to promote tumor cell invasiveness. Elevated PTX3 production was observed in the population of MITFlow invasive cells but not in the population of MITFhigh differentiated melanoma cells. Consistently, MITF knockdown increased PTX3 expression in MITFhigh proliferative and poorly invasive cells. High levels of PTX3 were found in tissues and blood of metastatic melanoma patients, and in BRAF inhibitor-resistant melanoma cells displaying a mesenchymal invasive MITFlow phenotype. Genetic silencing of PTX3 in invasive melanoma cells dramatically impaired migration and invasion in vitro and in experimental lung extravasation assay in xenografted mice. In contrast, addition of melanoma-derived or recombinant PTX3, or expression of PTX3 enhanced motility of low migratory cells. Mechanistically, autocrine production of PTX3 by melanoma cells triggered an IKK/NFκB signaling pathway that promotes migration, invasion, and expression of the EMT factor TWIST1. Finally, we found that TLR4 and MYD88 knockdown inhibited PTX3-induced melanoma cell migration, suggesting that PTX3 functions through a TLR4-dependent pathway. Our work reveals that tumor-derived PTX3 contributes to melanoma cell invasion via targetable inflammation-related pathways. In addition to providing new insights into the biology of melanoma invasive behavior, this study underscores the notion that secreted PTX3 represents a potential biomarker and therapeutic target in a subpopulation of MITFlow invasive and/or refractory melanoma.

Efficacy and safety data for checkpoint inhibitors in advanced melanoma under real-life conditions: A monocentric study conducted in Nice from 2010 to 2016.

BACKGROUND: Immunotherapies using anti-CTLA4 and anti-PD1 antibodies have revolutionised the management of patients with advanced melanoma. The aim of our study was to analyse the efficacy and safety of immunotherapies in patients with advanced melanoma under real-life conditions. METHODS: We conducted a monocentric, retrospective, observational study that included all patients treated with immunotherapies (ipilimumab, i.e. ipi; nivolumab, i.e. niv and pembrolizumab, i.e. pbr) for advanced melanoma with exclusion of primary mucosal or ocular melanoma. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 110 patients were included. Median PFS was better in the anti-PD1 group than in the anti-CTLA4 group (3.9 months vs. 2.9 months, P=0.025). The frequency of adverse events of any grade was 53.4% with ipi, 66.7% with niv and 75% with pbr. DISCUSSION: Our study shows slightly inferior efficacy data vs. clinical trials of ipi and niv because patients were presenting more severe illness at inclusion. Nevertheless, the study argues in favour of the superiority of anti-PD1 antibodies vs. anti-CTLA4 antibodies in terms of PFS and best overall response. Moreover, our study exhibits safety data comparable to those from clinical trials except for a lower frequency with ipi. CONCLUSION: Our efficacy and safety data obtained under real-life conditions are reassuring since they are consistent with data already published.

[Lymphedema of the lower limbs: Initial manifestation of gastric linitis plastica]. / Lymphœdème des membres inférieurs révélant une linite gastrique.

BACKGROUND: Primary lymphedemas are constitutional abnormalities of the lymphatic system. Secondary lymphedemas occur after damage to the lymphatic system, mainly after cancer treatments or tumour mass compression. There are many other causes, including filariasis, which is nonetheless very rare in France. PATIENTS AND METHODS: A 52-year-old man presented with a two-month history of increased size of the left leg. He was asymptomatic and in good general condition. Clinical examination revealed non-pitting lymphedema and ipsilateral hydrocele without loco-regional compressive lymph node. Initial extensive explorations were unremarkable. Lymphoscintigraphy revealed low tracer fixation in the left leg. The symptoms continued to worsen, with exacerbation and bilateralization of the lymphedema. Two months later, axillary lymph nodes appeared corresponding to metastasis from a signet-ring cell carcinoma. Despite two lines of chemotherapy, the patient died 8 months later due to multiple metastatic disease. DISCUSSION: Our case is remarkable because the lymphedema was not related to extrinsic compression and was the first symptom of gastric cancer. In the absence of compression, endo-lymphatic micro-metastases could constitute the causative process. Acquired lymphedema of the lower limbs must be recognized as a potential early symptom of gastric carcinoma and should therefore prompt further investigations.

Pulmonary sarcoid-like granulomatosis induced by nivolumab.

The use of antibodies against programmed death (PD)1, such as nivolumab and pembrolizumab, has dramatically improved the prognosis of patients with advanced melanoma. Nivolumab is also approved in advanced squamous cell nonsmall-cell lung cancer. These immunotherapies are associated with a unique set of toxicities termed immune-related adverse events, which are different from toxicities observed with conventional cytotoxic chemotherapy. We report the case of a 56-year-old man who was diagnosed with metastatic melanoma and who received nivolumab. One week after the second infusion, he developed pulmonary symptoms, dry eye syndrome and a bilateral swelling of the parotid glands. Investigations were negative for infection. The bronchoalveolar lavage differential cell count showed 32% lymphocytes with an increased CD4 : CD8 ratio, and bronchial biopsies revealed noncaseating epithelioid granulomas, without malignant cells. The clinical and radiological courses were rapidly favourable with oral corticosteroid. This case illustrates that sarcoidosis can be induced by nivolumab treatment. With the increasing use of anti-PD1 inhibitors in patients with advanced melanoma and squamous cell nonsmall-cell lung cancer, clinicians should be aware of this potential associated immune-related adverse event.

Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases.

BACKGROUND: Inherited epidermolysis bullosa (EB) comprises a highly heterogeneous group of rare diseases characterized by exacerbated skin and/or mucosal fragility and blister formation after minor mechanical trauma. Level of cleavage in the skin, clinical features with immunofluorescence antigen mapping and/or electron microscopy examination of a skin biopsy and/or gene involved, type(s) of mutation present and sometimes specific mutation(s), allow to define the EB type and subtype. This family of genodermatoses exposes patients to several complications, cutaneous squamous cell carcinoma (cSCC) being the most severe of them. OBJECTIVE: The aim of this systematic review was to document patients with EB who developed cSCC. METHODS: A systematic literature search was performed, from inception to March 2014, using Medline, Embase, Cochrane and ClinicalTrials.gov databases. Only articles published in English and French were selected. The diagnosis of EB had to be confirmed by EM and/or IFM and/or mutation analysis, while cSCC had to be confirmed by histological analysis. RESULTS: Of 167 references in the original search, 69 relevant articles were identified, representing 117 cases. cSCCs were identified in all types of EB, though predominantly in recessive dystrophic EB (RDEB) forms (81 cases (69.2 %)). The median age at diagnosis was 36 years old (interquartile range (IQR), 27-48 years and range, 6-71 years) for all forms. Of those with measurements in the literature (88 cases (75.2 %)), tumor size was greater than 2 centimeters in 52 cases (59.1 %). The histopathological characteristics were specified in 88 cases (75.2 %) and well-differentiated forms predominated (73.9 %). No conclusion could be drawn on the choice of surgical treatment or the management in advanced forms. LIMITATIONS: This study was retrospective and statistical analysis was not included due to various biases. This study design did not allow to infer prevalence, nor EB subtype risk for cSCC occurrence. CONCLUSIONS: Our study correlated with historical data shows that most of the cSCCs occurred in subjects with the RDEB subtype, however reports also show that cSCCs can present in any patients with EB. The first signs of cSCC developed at a younger age in EB patients than in non-EB patients. Interestingly, the cSCC duration, before its diagnosis, was shorter in individuals with RDEB than with junctional EB (JEB) and dominant dystrophic EB (DDEB). This study further emphasizes the importance of regular monitoring of EB patients, particularly with the RDEB subtype as they developed cSCC at a younger age.

[Breast lesions of a metastatic melanoma on a radiotherapy territory: Treatment by vemurafenib and carcinologic surgery]. / Métastases cutanées d'un mélanome sur un territoire de radiothérapie au niveau du sein: traitement par vémurafénib et chirurgie d'exérèse large.

INTRODUCTION: This article describes the unique case of a female patient who presented distant melanoma metastasis on the breast while having irradiation therapy for breast cancer. This happened eight months after the initial treatment for a melanoma of the back (under the right scapula). Furthermore, this case report demonstrates the efficiency of Vemurafenib® as a treatment for late stage melanomas. CASE REPORT: The patient was a 47-year-old female that had a superficial spreading melanoma under the right scapula (Breslow 1.02mm) that was treated with 2cm skin excision and sentinel lymph node sampling that was negative. The melanoma was positive for the BRAF600E mutation. One month after this incident, the patient developed breast cancer that was treated with conservative surgery and radiotherapy. Three months after the end of the irradiation treatment, she developed multiple melanoma metastasis on the skin of the breast. Our multidisciplinary team decided to initiate a treatment with vemurafenib. The patient showed an excellent response, so the surgical team completed the treatment with a radical mastectomy and immediate reconstruction with a pedicled latissimus dorsi flap. The histologic report of the mastectomy specimen showed no sign of melanocytic proliferation, that demonstrates the efficacy of vemurafenib. The patient showed no relapse after two years of follow-up. DISCUSSION: The speed of development and location of cutaneous metastases in this case brought us to think about the effects of radiation therapy on the skin. Radiation therapy causes acute complications (radiodermatitis) by cellular and molecular mechanisms. Moreover, depressed immunity is found after irradiation. Association of these mecanisms could explain the appearance of these metastases in irradiation field. The efficiency of vemurafenib found in our case is consistent with what is described in literature, especially with the improvement in median overall survival. CONCLUSION: This case demonstrates a unique case of distant melanoma metastasis on the irradiation field of a breast cancer. It also demonstrates the efficacy of vemurafenib as well as the efficacy of a radical complementary surgical treatment in these patients.

Impact of systemic treatment of psoriasis on inflammatory parameters and markers of comorbidities and cardiovascular risk: results of a prospective longitudinal observational study.

BACKGROUND: Several markers of comorbidities and cardiovascular (CV) risk are disturbed in moderate to severe psoriasis (PsO). The effect of systemic treatments of psoriasis on these markers remains poorly understood. OBJECTIVES: To study the frequency of disturbance of inflammatory parameters and markers of comorbidities and CV risk associated with moderate to severe PsO and psoriatic arthritis (PsA), and to assess their evolution under systemic treatments. METHODS: Monocentric prospective study on patients with PsO and PsA starting a systemic treatment for their psoriasis. The following markers were evaluated at baseline (M0), 3 months (M3) and 6 months (M6); weight, fasting blood glucose, blood pressure, uric acid, hepatic steatosis, smoking, lipid, metabolic and inflammatory parameters. RESULTS: Forty-three patients, 31 PsO and 12 PsA, were included. Forty completed the study. Response to treatment was good, with 71% of the population obtaining a Psoriasis Area and Severity Index (PASI) of 75. All patients had at least one comorbidity, and 45% had two or more. A statistically significant decrease was observed only for inflammatory parameters (C-reactive protein [CRP], P = 0.004) and erythrocyte sedimentation rate (ESR, P = 0.002). We did not observe any correlation between the PASI and CRP (correlation coefficient 0.128, P = 0.438) or ESR (correlation coefficient 0.294, P = 0.069) for responding patients. CONCLUSIONS: We observed a high frequency of disturbance of inflammatory parameters and markers of comorbidities and CV risk in a population with moderate to severe PsO and PsA, most of which were not detected before. A significant decrease in inflammatory parameters was noted after the introduction of systemic therapy, while other parameters remained unaffected by the treatment, except the weight that increased under biologics therapies.

Drug rash with eosinophilia and systemic symptoms due to telaprevir.

We report a case of drug rash with eosinophilia and systemic symptoms (DRESS) due to telaprevir (VX-950), a specific inhibitor of the hepatitis C virus (HCV) serine protease. A 57-year-old woman with chronic hepatitis C was included in a phase 2 rollover study of VX-950. She received VX-950 in combination with pegylated interferon alfa-2a and ribavirin. Six weeks later, she developed a generalized pruritic maculopapular exanthema with malaise, fever, dyspnoea and lymph node swelling. She had an eosinophilia (up to 2.7 × 109 cells/l), large activated lymphocytes and increased concentrations of aminotransferases. Histological examination of a cutaneous biopsy was consistent with a drug rash reaction. The HCV treatment was stopped, and she was treated with topical and oral steroids. Cutaneous and systemic symptoms disappeared within 1 month. Telaprevir was considered the culprit drug. We report to our knowledge the first case of DRESS syndrome due to telaprevir. The safety data of telaprevir is derived mainly from the PROVE1, PROVE2 and PROVE3 studies. They showed a high frequency of cutaneous side effects reported under the imprecise terms of pruritus and rash, leading to an increased rate of treatment discontinuation. Telaprevir, due to its efficacy, is probably on the way to obtaining regulatory approval in the near future. It is therefore important to be aware of the high incidence of cutaneous side effects and better describe them. Our observation suggests that potentially severe hypersensitivity reactions may belong to the spectrum of rashes induced by this drug.