Analyse histologique et moléculaire des métastases cérébrales

The first step in the diagnosis of a metastatic brain lesion is to exclude a primary central nervous sytem tumour, followed by verification or identification of the primary tumor site, in order to guide the clinician to specific therapy. In addition to morphological features, ancillary immunohistochemical study is most effective for the evaluation of a metastatic neoplasm of unknown primary. Although the main principles are same, there are slight variations in the approach to the secondary lesion in the central nervous system versus other regions. Indeed, immunohistochemical approach focuses on the most common tumor types associated with secondary brain colonization: lung cancer, breast cancer and melanoma. Several studies have reported that targeted therapies are capable of reducing brain metastases in melanoma or non-small cell lung cancer, sometimes with a high dramatic response. These results have clearly impacted routine neuropathological practice. It is likely that molecular subtyping of central nervous system metastases will play an increasing role in the future. In accordance with the recommendations of Inca (French national cancer institute), the pathologist develops appropriate strategies for molecular and immunohistochemical analysis, in order to provide results as soon as possible. This article summarizes the diagnosic approach to brain metastases, with a focus on the recent emergence of targeted therapies.     

Integration of genomic information in the clinical management of HCC

Molecular profiling of hepatocellular carcinoma (HCC) is enabling the advancement of novel approaches to disease diagnosis and management. Accurate prognosis prediction in HCC is specially critical. Clinical staging systems for HCC support clinical decision-making (e.g., BCLC algorithm) might be complemented by molecular-based information in the near future. Molecular signatures derived from tumour and non-tumour samples are associated with patient recurrence an outcome. Single nucleotide polymorphisms have been linked with HCC development. Next generation sequencing studies have brought to light the genomic diversity of this disease. Gens recurrently altered in HCC and susceptible to be targeted belong to signalling pathways including telomere maintenance, cell cycle, chromatin remodelling, Wnt/beta-catenin, RAS/RAF/MAPK and PI3K/AKT/mTOR pathways. Oncogenic loops are unknown but might include some of the already discovered aberrations. Despite the intratumoral heterogeneity observed in HCC tumours, studies including large number of samples can identify key genetic drivers and contribute to the development of novel treatments and a personalized medicine.     

Targeting BRAF in metastatic colorectal cancer: Maximizing molecular approaches

Oncogenic mutations in B-type Raf kinase (BRAF) occur in 7–10% of metastatic colorectal cancers (mCRC). Despite recent improvements in survival in the general population of patients with mCRC, patients with BRAF-mutant mCRC continue to have poor response to most systemic therapies, and prognosis remains poor. There is a substantial unmet need for novel therapeutic strategies to treat patients with BRAF-mutant mCRC. This review outlines the epidemiology, molecular pathogenesis, prognosis, and mechanisms of treatment resistance of BRAF-mutated CRC. Additionally, this review highlights novel therapeutic strategies aimed at enhancing response and improving outcomes.     

First-Line Mammalian Target of Rapamycin Inhibition in Metastatic Renal Cell Carcinoma: An Analysis of Practice Patterns From the International Metastatic Renal Cell Carcinoma Database Consortium

Introduction/BackgroundApproval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting.Patients and MethodsWe performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS).ResultsWe identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients.ConclusionPoor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made.     

The role of response evaluation criteria in solid tumour in anticancer treatment evaluation: Results of a survey in the oncology community

PurposeWith the increasing use of novel targeted agents and the development of high imaging techniques, response evaluation criteria in solid tumour (RECIST) 1.1 developed primarily for cytotoxic agents and anatomic imaging, has demonstrated limitations. A survey was conducted of RECIST users to identify concerns and their suggestions for future RECIST criteria.Methods140 key partners of the RECIST collaboration were asked to complete a questionnaire. The 49 questions concerned (a) satisfaction and concerns with RECIST 1.1; (b) use of modified RECIST criteria and (c) suggestions for the next RECIST Version.ResultsSixty-five replies were received. 52.3% responders were satisfied with RECIST 1.1, while 10.8% indicated dissatisfaction. Areas of potential weakness included: (a) lack of incorporation of potential early indicators of response such as functional imaging, (b) lack of validation in rarer tumour types and (c) lack of validation for novel (targeted) agents. Suggestions were multiple, with highest numbers on two points: developing sub-criteria for certain disease types and including advanced imaging techniques for the evaluation.ConclusionsConstructive suggestions were received for optimising the next version. Ongoing data collection will make it possible to investigate the possible utilisation of fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging in tumour assessment, to verify whether RECIST is/can still be applicable in novel targeted therapy and to consider the need for criteria for specific disease types.     

Nanoformulation of natural products for prevention and therapy of prostate cancer

There is a need for developing improved therapeutic options for the management of prostate cancer, able to inhibit proliferation of precancerous and malignant lesions and/or to improve the effectiveness of conventional chemopreventive and chemotherapeutic agents. In this perspective, application of nanotechnology based strategies for the delivery of natural compounds for effective management of the disease is being actively researched. Here, after highlighting the most promising natural compounds for chemoprevention and chemotherapy of prostate cancer, the state of the art nanotherapeutics and the recent proof-of-concept of “nanochemoprevention”, as well as the clinical development of promising targeted nanoprototypes for use in the prostate cancer treatment are being discussed.     

Targeted eco-pharmacovigilance as an optimized management strategy for adverse effects of pharmaceuticals in the environment

From a perspective of drug administration, eco-pharmacovigilance (EPV) has been proposed as a new approach to prevent the environmental risks posed by pharmaceutical emerging contaminants. However, it is impracticable to practice unitary and rigor EPV process for all the pharmaceutical substances with complex and diversified chemical, biological or toxicological properties. We proposed the “targeted EPV” that is the science and activities associated with the targeted detection, evaluation, understanding, and prevention of adverse effects of high-priority hazardous pharmaceuticals in the environment, especially focusing on the control of main anthropogenic sources of pharmaceutical emission among key stakeholders in high-risk areas could be used as an optimized management strategy for pharmaceutical pollution. “Targeted EPV” implementation should focus on the targeted monitoring of the occurrence of high-priority pharmaceuticals in environmental samples, the targeted reporting of over-standard discharge, the targeted management for main emission sources, the targeted legislation and researches on high-priority pharmaceutical pollutants, as well as the targeted educational strategies for specific key populations.     

Genomic Alterations in Advanced Esophageal Cancer May Lead to Subtype‐Specific Therapies

The development of targeted agents for metastatic esophageal or gastroesophageal junction (GEJ) tumors has been limited when compared with that for other common tumors. To date, the anti‐human epidermal growth factor receptor‐2 (HER‐2) antibody, trastuzumab, in combination with chemotherapy, is the only approved novel agent for these cancers, and its use is limited to the small population of patients whose tumors overexpress HER‐2. Despite recent progress in the field, median overall survival remains only 8–12 months for patients with stage IV esophageal or GEJ cancer. In this article, we examine the molecular aberrations thought to drive the development and spread of esophageal cancer and identify promising targets for specific tumor inhibition. Data from clinical studies of targeted agents are reviewed, including epidermal growth factor receptor antibodies, tyrosine kinase inhibitors, HER‐2, and vascular endothelial growth factor‐directed therapy. Current and future targets include MET, fibroblast growth factor receptor, and immune‐based therapies. Evidence from trials to date suggests that molecularly unselected patient cohorts derive minimal benefit from most target‐specific agents, suggesting that future collaborative investigation should focus on preselected molecular subgroups of patients with this challenging heterogeneous disease.     

Potential impact of PD-L1 (SP-142) immunohistochemical heterogeneity in clear cell renal cell carcinoma immunotherapy

Intratumor heterogeneity (ITH) detection remains a challenge in modern oncology because it can have a direct impact on the success of new therapies. Anti-PD-1/PD-L1 immunotherapy is an emerging treatment modality that is showing great promise for clear cell renal cell carcinoma (CCRCC) patients with advanced disease. Patient selection for such therapy relies upon the immunohistochemical detection of PD-1/PD-L1, however the degree of ITH for these markers among tumor cells and/or inflammatory mononuclear infiltrates remains unknown. Therefore, we analyzed PD-L1 (SP-142) expression in the tumor inflammatory cells of 22 CCRCC cases with the aim to define the pattern of PD-L1 expression, and to compare the reliability of current tumor sampling protocols (RS) with a multisite tumor sampling strategy (MSTS). While the RS protocol identified 5/22 (22.7%) of cases that were positive for PD-L1 expression, MSTS identified 10/22 (45.45%) of cases. This suggests that RS may miss a proportion of CCRCC patients that might benefit from immunotherapy. In addition, MSTS demonstrated that positive and negative regions of PD-L1 expression are very variable within each tumor.