Long term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAFV600-mutated melanoma.

BACKGROUND: BRAF inhibitors are approved in BRAFV600-mutated metastatic melanoma, non-small-cell lung cancer (NSCLC), Erdheim-Chester disease (ECD), and thyroid cancer. We report here the efficacy, safety, and long-term results of single-agent vemurafenib given in the AcSé vemurafenib basket study to patients with various BRAF-mutated advanced tumours other than BRAFV600-mutated melanoma and NSCLC. PATIENTS AND METHODS: Patients with advanced tumours other than BRAFV600E melanoma and progressing after standard treatment were eligible for inclusion in nine cohorts (including a miscellaneous cohort) and received oral vemurafenib 960 mg two times daily. The primary endpoint was the objective response rate (ORR) estimated with a Bayesian design. The secondary outcomes were disease control rate, duration of response, progression-free survival (PFS), overall survival (OS), and vemurafenib safety. RESULTS: A total of 98 advanced patients with various solid or haematological cancers, 88 with BRAFV600 mutations and 10 with BRAFnonV600 mutations, were included. The median follow-up duration was 47.7 months. The Bayesian estimate of ORR was 89.7% in hairy cell leukaemias (HCLs), 33.3% in the glioblastomas cohort, 18.2% in cholangiocarcinomas, 80.0% in ECD, 50.0% in ovarian cancers, 50.0% in xanthoastrocytomas, 66.7% in gangliogliomas, and 60.0% in sarcomas. The median PFS of the whole series was 8.8 months. The 12-, 24-, and 36-month PFS rates were 42.2%, 23.8%, and 17.9%, respectively. Overall, 54 patients died with a median OS of 25.9 months, with a projected 4-year OS of 40%. Adverse events were similar to those previously reported with vemurafenib. CONCLUSION: Responses and prolonged PFS were observed in many tumours with BRAF mutations, including HCL, ECD, ovarian carcinoma, gliomas, ganglioglioma, and sarcomas. Although not all cancer types responded, vemurafenib is an agnostic oncogene therapy of cancers.

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases.

PURPOSE: Stereotactic radiotherapy (SRT) is the standard treatment for brain metastases of non-small-cell lung cancer (NSCLC) and melanoma, mostly in combination with immunotherapy. The objective was to retrospectively evaluate the influence of the time-lapse between immunotherapy and stereotactic radiotherapy on toxicity. PATIENTS AND METHODS: From 2016 to 2019, 59 patients treated with SRT for 103 brain metastases of NSCLC (60%) and melanoma (40%) in combination with concomitant immunotherapy (≤30 days) were included. The prescribed dose was 20Gy/1f or 33Gy/3f at the isocentre and 14Gy or 23.1Gy (70%) respectively at the PTV envelope (PTV=GTV+2mm). The mean tumour diameter was 14mm (4-52mm). The immunotherapies used were anti-PD1 and anti-PDL1. The 103 metastases were classified into 3 groups according to the time-lapse between instatement of immunotherapy and instatement of SRT for the patient concerned: 7 (7%) in group A (≤7 days), 38 (37%) in group B (7 to 14 days) and 58 (56%) in group C (14 to 30 days). RESULTS: The mean follow-up was 10.1 months. The median overall survival was 11.5 months for NSCLC and 12.5 months for melanoma. The percentage of local control (LC) at one year was 65.1% (93.6% for NSCLC and 26.5% for melanoma). The time-lapse between immunotherapy and SRT was not a significant predictor of LC (P=0.86), while the histology was (P<0.001). The proportion of grade≥3 toxicities was 5.1%, and that of radionecrosis was 9.7% (among these patients, 80% were non-symptomatic): 0%, 13.1% and 8.6% for groups A, B and C respectively. The time-lapse between immunotherapy and SRT was not a significant predictor of toxicity. Only tumour volume was a significant predictive factor (P=0.03). CONCLUSION: The time lapse between immunotherapy and SRT does not influence brain toxicity. The tumour volume remains the main factor.

[Nasal cavity mucosal melanoma with skin extension mimicking a malignant lentigo with mucosal extension]. / Mélanome muqueux des fosses nasales avec extension cutanée mimant un lentigo malin cutané d'extension muqueuse.

Mucosal melanoma is a rare malignant disease developed from melanocyte. We report the case of a patient with nasal cavity mucosal melanoma with a primary clinical and histological diagnosis of malignant lentigo with mucosal spreading. The presence of a c-Kit mutation, in a second lecture and the evolving nature of the lesion, reorientated the diagnosis of malignant lentigo to mucosal melanoma with skin extension. Extensive surgical resection and foramen free flap with costal graft reconstruction may have a local control of the disease. Yet, after one year, a regional evolution involving a parapharyngeal node was treated by stereotaxic radiotherapy. After 5 years, the patient was considered in clinical and radiological remission. Malignant lentigo with mucosal extension is a very rare situation, this diagnoses must be evoqued after setting mucosal melanoma diagnosis.

Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy.

BACKGROUND: Sentinel lymph-node (LN) biopsy (SLNB) is a valuable tool to assess the regional LN status in Merkel cell carcinoma (MCC). However, its prognostic value is still debated. This study was undertaken to assess SLNB usefulness for MCC management and to determine the impact of SLNB status on disease-free survival (DFS) and overall survival (OS) by comparing SLNB-positive versus -negative patients according to demographic, clinical and treatment characteristics. PATIENTS AND METHODS: In this retrospective, multicenter observational study, SLNB was proposed to all patients referred for clinically N0 MCC. Treatment schedule consisted of wide-margin surgical resection of primary MCC followed by adjuvant radiation therapy (aRT) to the primary site and, for SLNB-positive patients, radical LN dissection followed by regional aRT. Univariate and multivariate analyses determined factors associated with DFS and OS. RESULTS: Among 87 patients with successful SLNB, 21 (24.1%) were SLNB-positive. Median follow-up for the entire series was 39 months; respective 3-year DFS and OS rates were 73% and 81.4%, respectively. Univariate analysis (all patients) identified SLNB-negativity as being associated with prolonged OS (P = 0.013) and aRT (all sites considered) was associated with longer DFS (P = 0.004) and OS (P = 0.018). Multivariate analysis (all patients) retained SLNB status and aRT (all sites considered) as being associated with improved DFS (P = 0.014 and 0.0008) and OS (P = 0.0020 and 0.0019). Moreover, for SLNB-negative patients, tumor-bed irradiation was also significantly associated with prolonged DFS (P = 0.006) and OS (P = 0.014). CONCLUSIONS: The present study demonstrates that SLNB-negativity is a strong predictor of longer DFS and OS in stage I and II MCC patients. The similar benefit for aRT on tumor bed observed in this study has to be confirmed by a prospective study. The results advocate for SLNB being considered to all MCC patients.

Is BRAF a prognostic factor in stage III skin melanoma? A retrospective study of 72 patients after positive sentinel lymph node dissection.

BACKGROUND: BRAF was identified as an oncogene in skin melanoma in 2002, and since 2011 has been a therapeutic target in the treatment of metastatic melanoma. The role of BRAF mutation in tumour initiation and the disease course remains to be elucidated. OBJECTIVES: The main objective of our study was to determine whether there is a relationship between BRAF status and overall survival in patients with a melanoma and a positive sentinel lymph node. We also sought an association between BRAF status and the clinicopathological features of the melanoma. Finally, we looked for a potential heterogeneity of BRAF status in primary and metastatic tumours. METHODS: All patients (n = 72) treated for melanoma and with a positive sentinel lymph node at the University Hospital of Clermont-Ferrand, France, between January 2000 and January 2010 were enrolled in the study. We investigated BRAF status in primary melanoma and lymph node metastatic tissue in our molecular pathology laboratory and collected the clinical and survival data. RESULTS: Of the 72 patients, 32 had at least one BRAF mutation. There was a statistically significant difference in overall survival between the BRAF-mutated and wild-type populations. The only clinical feature related to BRAF status was metastatic burden. Of the 25 patients in whom we obtained the status in both locations, five had a discordant result. CONCLUSIONS: BRAF mutation is an indicator of poor prognosis in patients with stage III melanoma with a positive sentinel lymph node. BRAF status could be used in the staging of this population. BRAF has a role not only in cellular immortalization but also in metastatic spread.

[Regression in primary cutaneous melanoma is not predictive for sentinel lymph node micrometastasis]. / Absence de valeur prédictive des signes de régression histologique sur l'envahissement du ganglion sentinelle.

BACKGROUND: The predictive value of regression in melanoma is debated. AIM OF THE STUDY: A retrospective single-centre study to evaluate the correlation between regression in primary skin tumor and the presence of micrometastases in sentinel lymph nodes. PATIENTS AND METHODS: Histological signs of regression in 84 melanomas (>1 mm) with corresponding sentinel lymph nodes were studied by two independent pathologists. RESULTS: Regression was seen in 40 skin melanoma tumors while micrometastasis was seen in 24. Of the tumors with micrometastasis, only 10 were regressive (RR: 0.47, p=0.49). Breslow value>2 mm and male sex were predictive for node micrometastasis (RR: 4.6, p=0.03 and RR: 7.6, p=0.006, respectively). On multivariate analysis, these two factors were independent. COMMENTS: These data suggest that regression in primary cutaneous melanoma is not predictive for lymph node metastasis.

[Melanoma of the penis: 6 cases]. / Mélanomes du pénis: 6 cas.

BACKGROUND: Melanomas of the penis are rare tumors of poor prognosis. METHODS: Six cases of melanoma of the penis, followed between 1975 and 2002, were retrospectively reviewed. We collected the data on epidemiological, clinical and pathologic factors, treatment and follow-up. RESULTS: The mean age was 44 years. The time to diagnosis was 2 years. Two patients had general predisposing factors for melanoma, and 3 patients local predisposing factors. Two patients had partial penectomy and 4 patients had conservative excision. One patient had local recurrence, and another had metastatic course resulting in death. Five patients out of 6 were alive and disease free at time of the study, with a 24 month follow-up. DISCUSSION: The identified risk factors for the development of penile melanoma are melanosis and pre-existing nevus. Delayed diagnosis explains the usually bad prognosis. Classical surgical treatment used to be radical, but recently, conservative surgery has been proposed. For an early diagnosis, genital melanosis requires surgical excision, when technically feasible, and any atypical lesion of the penis should be submitted to a biopsy.

In vivo and in situ modulation of the expression of genes involved in metastasis and angiogenesis in a patient treated with topical imiquimod for melanoma skin metastases.

There is a growing body of evidence to support the efficacy of topical imiquimod in the treatment of primary skin carcinomas. Conflicting data exist concerning the use of imiquimod for the treatment of skin melanoma metastases. To date, only the impact of imiquimod on cytokines involved in immunological processes has been studied extensively. We report a woman successfully treated with imiquimod (once daily for 8 weeks) for skin melanoma metastases in whom we investigated the expression of molecules involved in metastasis and angiogenesis. Before and after treatment, a skin lesion was biopsied and the expression of the following molecules was investigated using real-time reverse transcription-polymerase chain reaction: matrix metalloproteinase (MMP)-1, 2 and 9 and their inhibitors KiSS-1 and tissue inhibitor of metalloproteinase (TIMP)-1, vascular endothelial growth factor (VEGF), fibroblast growth factor-2, and angiogenesis inhibitors (thrombospondin-1 and 2). Interferon (IFN)-alpha was also investigated as an in vivo marker of imiquimod activity. IFN-alpha was upregulated by the treatment. Under imiquimod, the following molecules were upregulated: TIMP-1, KiSS-1 and MMP-1. MMP-2 expression was not modified. MMP-9 expression was dramatically decreased. The expression of angiogenesis inhibitors was slightly increased but VEGF expression remained at a basal level. These results suggest that imiquimod could downregulate metastasis invasion and angiogenesis. However, these data were obtained at a transcriptional level and from a single case, and further investigations should include migration assays and additional cases in order to confirm that imiquimod may be safely used for treatment of melanoma metastases.

Generalized pustular psoriasis complicated by acute respiratory distress syndrome.

Psoriasis has a chronic and relatively benign course. However, severe complications are possible. One rare complication is acute interstitial pneumonitis. This entity should be suspected when a patient presents with dyspnoea and high fever. Knowledge of this pathology is crucial, for although it is essential to rule out aetiologies requiring specific management such as microbial infection or drug-related syndromes, diagnosis should not be delayed as its severe clinical course is improved by corticosteroids. We report two patients with an acute respiratory distress syndrome arising during the course of pustular psoriasis. Repeated bacteriological testing in lungs and blood remained negative. In both cases lung involvement was severe, requiring artificial ventilation. Dramatic clinical resolution was obtained by using corticosteroids. Besides infectious causes and drug hypersensitivity to methotrexate or acitretin, acute respiratory distress syndrome, sometimes due to a pulmonary capillary leak syndrome, is a rare cause of pneumonitis in the course of psoriasis, and may be fatal. Its pathogenesis is unknown. However, animal models suggest a role for T-helper (Th) 1 lymphocytes, known to be activated in psoriasis, and a role for tumour necrosis factor-alpha, a major Th1 cytokine, in alveolar damage.

[Radiation-induced temporary hair loss after endovascular embolization of the cerebral arteries: six cases]. / Alopécie transitoire d'origine radique après embolisation artérielle cérébrale: 6 cas.

BACKGROUND: Intraoperative fluoroscopy imaging during coronaroplasty or transjugular intrahepatic portosystemic shunt may induce chronic radiodermatitis. Temporary hair loss is a peculiar form of radiodermatitis following endovascular surgery of the cerebral arteries. CASE REPORTS: Six patients (2 women, 4 men, age range: 27-47 years old) were seen for a solitary plaque of alopecia. In all of the cases, the plaque had appeared two weeks after a neuroradiologically guided embolization procedure. No other skin lesions were seen. Alopecia spontaneously and completely regressed within three to four months. However, it reappeared after a subsequent embolization (one case) but not after arteriographies (five cases). DISCUSSION: Five similar cases have been reported in the literature. Transient alopecia often occurs after neurologically guided endovascular surgery of the cerebral arteries. This side-effect is well known by neurosurgeons and thus, these patients are rarely referred to a dermatologist. Two differential diagnoses must be evoqued: alopecia aerata and anticonvulsant - induced alopecia. The role played as cofactor by carbamazepine which is a photosensitivant drug, is discussed.