[Tyrosine kinase receptor gene fusion: A series of four cases of infantile-type hemispheric glioma]. / Gènes de fusion à activité tyrosine kinase : une série de quatre cas de gliome hémisphérique infantile.

INTRODUCTION: Infant-type hemispheric gliomas belong to pediatric-type diffuse high-grade gliomas according to the 2021 WHO classification of central nervous system tumors. They are characterized by tyrosine kinase gene rearrangements (NTRK1/2/3, ALK, ROS1, MET). The aim of the study was to describe the clinical, histopathologic, and molecular characteristics of such tumors, and to provide a review of the literature. PATIENTS AND METHODS: This retrospective series comprises four cases of infant-type hemispheric glioma diagnosed at Angers University Hospital between 2020 and 2022. The diagnosis was suspected based on morphology and immunohistochemistry and was confirmed by molecular biology techniques. RESULTS: The most common clinical sign was raised intracranial pressure. Imaging showed a large cerebral hemispheric tumor with contrast enhancement. Microscopic examination revealed diffuse astrocytoma with high-grade features, sometimes with neuronal or pseudo-ependymal differentiation. Identification of a gene fusion involving a tyrosine kinase gene allowed to make a definitive diagnosis of infant-type hemispheric glioma. DISCUSSION AND CONCLUSION: Infant-type hemispheric gliomas are rare and present as large cerebral hemispheric tumors in very young children. Searching for a tyrosine kinase gene fusion should be systematic when dealing with a high-grade glioma in an infant. Importantly, these gene fusions are therapeutic targets. The impact of targeted therapies on patient survival should be evaluated in future prospective studies.

Blue marine therapy: Sea as a trove of natural anticancer drugs.

The great variability of marine habitats and the species that live there allows the development of organisms with unique characteristics. These represent an excellent source of natural compounds and are therefore interesting in the search for new bioactive molecules. In recent years, many marine-based drugs have been commercialized or are currently under investigation, mainly in the treatment of cancer. This mini-review summarizes the marine-based drugs currently marketed and presents a non-exhaustive list of molecules currently in clinical trials, as monotherapy but also in combination with classical anticancer treatments.

[Radiotherapy and targeted therapy for the management of breast cancer: A review]. / Radiothérapie et thérapie ciblée pour la prise en charge du cancer du sein : mise au point.

The purpose of this study was to review the current knowledge regarding combinations of the most commonly used targeted therapies or those under development for the management of breast cancer with radiation therapy. Several studies have shown that the combination of radiation therapy and tamoxifen increased the risk of radiation-induced lung toxicity; therefore, the two modalities are generally not given concurrently. The combination of HER2 inhibitors (trastuzumab, pertuzumab) and radiation therapy appeared to be safe. However, trastuzumab emtansine (T-DM1) should not be given concomitantly with brain radiation therapy because this combination may increase the risk of brain radionecrosis. The combination of radiation therapy with other new targeted therapies such as new selective estrogen receptor modulators (SERDs), lapatinib, cell cycle inhibitors, immune checkpoint inhibitors, or molecules acting on DNA damage repair seems feasible but has been mainly evaluated on retrospective or prospective studies with small numbers of patients. Moreover, there is a great heterogeneity between these studies regarding the dose and fractionation used in radiotherapy, the dosage of systemic treatments and the sequence of treatments used. Therefore, the combination of these new molecules with radiotherapy should be proposed sparingly, under close monitoring, pending the ongoing prospective studies cited in this review.

[Targeting HER2 in colorectal cancer]. / Cibler HER2 dans le cancer colorectal.

Among the molecular subgroups of interest in metastatic colorectal cancer (mCRC), innovations are underway for tumors with overexpression of HER2 (Human Epidermal Growth Factor Receptor 2). Overexpression of the HER2 protein concerns 2 to 5% of CRC at any stage mainly located in the distal colon and rectum. Diagnosis is based on immunohistochemistry, in situ hybridization with appropriate criteria for colorectal localization, and molecular biology (NGS: next-generation sequencing). Overexpression of HER2 is a predictive factor for resistance to treatments targeting EGFR which are indicated in the case where the tumor is wild-type RAS. It seems to be associated with a poor prognosis of mCRC with a higher risk of brain metastasis. Regarding treatments targeting HER2, no randomized controlled phase III has been published to date. However, several combinations have been evaluated in phase II with clinically meaningful objective response rates: trastuzumab-deruxtecan (45%), trastuzumab-tucatinib (46%), trastuzumab-pyrotinib (45%), trastuzumab-pertuzumab (30%) ou trastuzumab-lapatinib (30%). In this literature review, we present here the current state of knowledge on the diagnostic methods of HER2 overexpression in CRC, the main clinical, molecular and prognostic characteristics, and the efficacy results of the different therapeutic combinations for the patients with HER2 overexpressed mCRC. This justifies, despite the lack of marketing authorization in France and in Europe for agents targeting HER2 in CRC, the systematic evaluation of the HER2 status, as recommended in particular by the NCCN (National Comprehensive Cancer Network).

[Unusual association of BRAF and MEK inhibitors: Clinical response of metastatic melanoma treated with dabrafenib-cobimetinib]. / Association inhabituelle d'inhibiteurs de BRAF et de MEK : réponse clinique d'un mélanome métastatique traité par dabrafénib­cobimétinib.

Despite the efficacy of targeted therapies in melanoma, the management of adverse events with BRAFi and MEKi (inhibitors) is one of the limits of these treatments. Close monitoring is required to ensure efficacy and patient safety. In this case study, we report a patient treated for metastatic melanoma with an unusual and innovative combination of dabrafenib (BRAFi) and cobimetinib (MEKi), to manage pyrexia, and lead to complete remission for 19 months. This is the first case ever reported of metastatic melanoma treated with this off-label combination and characterized by the use of therapeutic drug monitoring.

A new prognostic model for brain metastases of specific primary tumors with stereotactic radiotherapy.

PURPOSE: Stereotactic radiotherapy (SRT) was widely used in brain metastases (BM), especially in oligometastases. It is imperative to develop a new prognostic score to predict the overall survival (OS) of brain metastases based on prognostic factors for specific primary tumors. MATERIAL AND METHOD: One hundred and ninety-seven patients were involved in the training cohort to develop a new prognostic score to predict the overall survival (OS) of brain metastases for specific primary tumors. Independent prognostic factors were confirmed using a Cox regression model. The score was developed based on clinical prognostic factors of OS with Cox proportional hazards model. The result was validated in another cohort with 56 participants to evaluate the performance of the score. RESULTS: One hundred and ninety-seven patients with 329 brain metastases received SRT. For NSCLC, the significant prognostic factors were extracranial metastases, target therapy and number of brain metastases. For gastrointestinal cancer, the significant prognostic factors were target therapy and number of brain metastases. CONCLUSION: The prognostic factors scores were varied by the histologic types which can be used to efficiently stratify for selected patients with brain-metastasis.

[Oesogastric cancer - new therapeutic targets]. / Adénocarcinome œsogastrique ­ nouvelles cibles thérapeutiques.

The median overall survival of metastatic esophagogastric adenocarcinoma is approximately twelve months. In fifteen years, major breakthrough have been the targeting of HER2 overexpression and more recently immunotherapy in patients with CPS≥5. Recent advances in molecular biology have identified some molecular alterations in esophageal adenocarcinoma, interesting to target. FGFR2 is overexpressed in one third of patients, and its targeting with a specific monoclonal antibody bemarituzumab showed a significant improvement in survival. Claudin 18.2 (CLDN 18.2) is overexpressed in at least a third of esophagogastric adenocarcinomas. The combination of zolbetuximab and chemotherapy provides a survival benefit, correlated with the intensity of CLDN 18.2 expression. The potential interest of targeting other pathways is under investigation in several trials with some encouraging preliminary data, and early trials in these indications, justifying considering large molecular screening in patients who might be candidate for early phase trial. Finally, with the recent advent of immunotherapy, one of the future challenges will be to optimize it through combination strategies with targeted therapies. The combination of anti-angiogenic and immunotherapy seems promising in gastric cancer.

[Radiation therapy and targeted therapies: Risks and opportunities]. / Radiothérapie et thérapies ciblées : risques et opportunités.

PURPOSE: Radiotherapy and targeted therapies play a major role in the management of cancers. Unfortunately, the toxicity and efficacy data regarding their association are tenuous and not centralized. Thus, we propose a literature review about the risks and opportunities of combining radiotherapy with targeted therapies. METHODS: We searched databases EMBASE, ClinicalTrial.gov, Medline and Web of Science for the terms « radiotherapy ¼, « radiation therapy ¼, « radiosurgery ¼, « local ablative therapy ¼, « gamma knife ¼ et « stereotactic ¼, combinés avec « cetuximab ¼, « crizotinib ¼, « erlotinib ¼, « gefitinib ¼, « lapatinib ¼ « trastuzumab ¼, "vemurafenib", « panitumumab ¼, « alectinib ¼, « ceritinib ¼, « dabrafenib ¼, « trametinib ¼, « BRAF ¼, « TKI ¼, « MEK ¼, « EGFR ¼, « ALK ¼, « ADC ¼, « trastuzumab ¼, « pertuzumab ¼, « TDM-1 ¼, « trastuzumab emtansine ¼, « TDxd ¼, « trastuzumab deruxtecan ¼, « lorlatinib ¼, « targeted therapy ¼. RESULTS: A few trials have showed a synergistic effect of radiotherapy associated with targeted therapies. MAPK inhibitors provide proven and well-known toxicity, for which clinical practice guidelines exist. CONCLUSION: This review provides a point of view in the current state of knowledge, and its limitations highlight the need for more solid data in a field full of promise.

Clinical activity of immunotherapy-based combination first-line therapies for metastatic renal cell carcinoma: the right treatment for the right patient.

Immunotherapy (IO) with checkpoint inhibitors with or without anti-angiogenic tyrosine kinase inhibitor (TKI)-based combinations have demonstrated superior efficacy over sunitinib for treatment-naive patients with metastatic clear-cell renal cell carcinoma (mRCC). Four of these combinations (nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib and pembrolizumab plus lenvatinib) represent new front-line standard-of-care options for mRCC patients, according to the International Metastatic RCC Database Consortium (IMDC) subgroups. Questions over the optimal treatment between IO-IO or IO-TKI combinations for mRCC patients in intermediate/poor IMDC risk groups and the optimal IO-TKI regimen for all IMDC risk groups remain unanswered. This review will focus on the biological pathways that have driven the hypothesis of a synergistic combination of such agents and their efficacy results, with consideration of response and survival outcomes in the overall population of phase three pivotal trials as well as in specific subgroups of interest.

[Current management and perspectives for locally advanced nasopharyngeal carcinoma]. / État des lieux et perspectives thérapeutiques pour les carcinomes nasopharyngés localement évolués.

Nasopharyngeal carcinoma diagnosis is often made at a locally advanced stage (75 to 90% of cases) due to its deep localization. Concomitant radio-chemotherapy is the cornerstone of the treatment of locally advanced forms. The advent of intensity-modulated radiotherapy has improved oncological outcomes and reduced toxicity and is currently the gold standard for irradiation technique. For the locally advanced stage, the addition of induction chemotherapy has become the new standard care according to the latest international recommendations to reduce tumor volumes and act early on micro-metastases. Despite these therapeutic advances, the local and especially distant failure rate remains high. This article reviews current treatment strategies and discuss new approaches and perspectives of locoregional and systemic treatment to reduce treatment failures.

[New data on the molecular biology of soft tissue sarcoma]. / Nouveautés sur la caractérisation moléculaire des sarcomes des tissus mous.

Sarcoma consists in a group of rare malignant tumours of mesenchymal origin characterized by their vast clinical, pathological and biological heterogeneity. The pathological diagnosis of sarcoma relies classically of the differentiation features of tumour cells, with dozens of different tumour subtypes described in the last international classifications. Over the last decades, the advances in the development of new techniques of molecular biology have led to a major complexification of sarcoma classification, with the identification of multiple and specific molecular alterations that have led to significant changes for patients diagnostic, prognostic and therapeutic management. This review aims at giving an overview on the current knowledge of the molecular biology of soft tissue sarcoma, and emphasizes on their consequences for the daily management of patients.

[The CD40-CD40L axis: Current and future implications in clinical immunology]. / L'axe CD40-CD40L : implications actuelles et futures en immunologie clinique.

The CD40-CD40 ligand (CD40L) pathway is a backbone of communication between cells of the immune system. It makes it possible to generate a proinflammatory signal and thus participates in the pathogenesis of dysimmune diseases, transplant rejection and atherosclerosis. Because of this therapeutic target of choice, several generations of anti-CD40L monoclonal antibodies have emerged since the 1990s. The first generation of antibodies was responsible for thromboembolic toxicity for which the mechanisms are starting to be defined. New generations of antibodies were designed to overcome this toxicity and are still being developed in lupus, rheumatoid arthritis, Sjogren's syndrome or immunologic thrombocytopenia. In addition to these targeted therapies, there are data suggesting the impact of several drugs among molecules used in cardiology and clinical immunology on the level of CD40L. The objective of this review is to recall the clinical issues related to the CD40-CD40L axis and to present current or future treatments that block CD40L which would allow clinicians to diversify their options for managing dysimmune diseases.

[Panniculitis during BRAF inhibitor and/or MEK inhibitor therapy: A new case report and literature review]. / Hypodermite sous inhibiteur de BRAF et/ou inhibiteur de MEK : revue de la littérature à partir d'une nouvelle observation.

INTRODUCTION: BRAF inhibitors±MEK inhibitors can cause panniculitis. Since the initial case described in 2012 by Zimmer et al., some sixty further cases have been reported. Based on a clinical study and a recent and complete review of the literature, we set out in detail the characteristics of panniculitis occurring during BRAF and MEK inhibition therapy as well as the treatment thereof. PATIENTS AND METHODS: A 25-year-old-patient followed for multi-metastatic melanoma and taking dabrafenib and trametinib consulted for the appearance, twenty-two days after the start of targeted therapy (TT), of panniculitis of the legs and forearms possibly induced by the TT after other causes had been ruled out. The TT had been continued following dose reduction and corticoid therapy for ten days, and complete resolution occurred after fifteen days. RESULTS: Fifty-three cases of panniculitis during BRAF±MEK inhibition therapy were analysed. The condition occurred mainly with BRAF inhibitors alone (especially vemurafenib), but it was also described with three combinations of BRAF and MEK inhibitors, regardless of age (median: 45 years), with a M/F ratio of 0.51, and in 50 % of cases, it occurred within the first month (time to onset: between 1 and 480 days). Non-specific biopsy is useful to rule out differential diagnoses. Symptomatic anti-inflammatory treatment, whether systemic or topical, may be given. In the absence of signs of severity, the TT may be continued. CONCLUSION: When panniculitis occurs during BRAF±MEK inhibitor therapy, the causal role of the TT must be considered after full etiological investigation. It is essential to determine whether a causal relationship exists in order to avoid unwarranted cessation of treatment.

[What is the place of surgery in the management of brain metastases in 2020?] / Quelle est la place de la chirurgie dans la prise en charge des métastases cérébrales en 2020 ?

Brain metastases are the most common intracranial tumors and are associated with a dismal prognosis. The management of patients with brain metastases has become more important because of the increased incidence of these tumours, the better treatment of the systemic disease and the improvement of surgical techniques. The treatment requires multidisciplinary approaches and become complex because of new emerging systemic therapy and advancements in neurosurgery and radiation oncology. The surgical treatment has an indispensable role to obtain a tissue diagnosis, in relieving intracranial effect mass and improving neurological status by improving induced encephalopathy. An understanding of the role and indications of the surgery in patients with metastatic brain lesions is essential for the effective management of this growing population.

[Systemic treatment of locally advanced or metastatic penile cancer]. / Traitement systémique du cancer du pénis localement avancé ou métastatique.

Penile cancers are rare, the vast majority is represented by squamous cell carcinoma, with HPV virus being found in 30 to 40% of cases. At a locally advanced or metastatic stage, first-line treatment relies on platinum and taxane based polychemotherapy. The prognosis for advanced or metastatic penile cancer remains poor, with overall survival ranging from 13.9 to 17.1 months. After the first line, guidelines recommend various chemotherapy treatments or targeted anti-EGFR therapies whose results as well as the level of evidence are limited. A better understanding of the oncogenic pathways involved in penile cancer and a frequent expression of PD-L1 are the rationale for the elaboration of new strategies. This review article presents the data, guidelines and ongoing studies in locally advanced or metastatic penile cancer.

[Management of a patient with a double EGFR and MET anomaly by combined treatment]. / Prise en charge d'un patient par traitement combiné d'une double anomalie EGFR et MET.

INTRODUCTION: Lung cancer displays molecular anomalies for which targeted therapies are the standard first line treatment. The EGFR mutation is present in 10% of cases of non-small cell lung cancer in Caucasians. MET amplification associated with an exon 19 EGFR mutation has been identified though it is usually regarded as a mechanism of resistance. CASE REPORT: We report the case of a 74-year-old never-smoking woman who was diagnosed with stage IV bronchial adenocarcinoma showing both EGFR mutation and MET amplification. Initial treatment with gefitinib did not control the disease. Platinum-based chemotherapy with pemetrexed maintenance allowed a temporary response. Treatment with durvalumab for 27 months was associated with disease stability. Single agent crizotinib was associated with a slight response followed by progression. The concomitant introduction of crizotinib and gefitinib led to a spectacular and durable response with no safety issues. CONCLUSIONS: This case highlights the efficacy of concomitant treatment in a patient with two oncogenic drivers.