Tumour Infiltrating Lymphocytes and Immune-Related Genes as Predictors of Outcome in Pancreatic Adenocarcinoma

Background: Pancreatic Carcinoma (PC) is a lethal disease with a poor prognosis. Pancreatic Carcinoma is characterized by a desmoplastic, highly heterogeneous and immune-suppressive microenvironment that hinders antitumour immunity. The aim of this study is to investigate the correlation between PC patient prognosis and the presence of tumour infiltrating lymphocytes and expression of 521 immune system genes. Materials and Method: Fresh PC specimens were obtained from patients (n=12) undergoing surgical resection at the Department of Medical, Surgical & Health Sciences, Cattinara Teaching Hospital, Trieste University, between 2005 and 2015. Prognosis of primary PC patients was determined using clinical data and Kaplan-Meier curves. Overall survival (OS) was measured from the time of surgery to the time of death or the last follow up visit. A more in-depth analysis of the 12 patients revealed two groups with different disease free survival (DFS) and/or OS: six patients with an OS between 25 and 66 months were classified as \u201cgood cases\u201d, while six with OS between 2 and 9 months or DFS between 1 and 2 months were classified as \u201cworse cases\u201d. Intratumoural CD3+, CD8+, and CD20+ lymphocytes were examined by immunohistochemistry. The results were correlated with gene expression profile using the digital multiplexed NanoString nCounter analysis system (NanoString Technologies, Seattle, WA, USA). Results: Our data showed that the CD3 level was statistically higher in the good prognosis group compared to the worse prognosis group (p=0.0267). Three primary PC patients with a good prognosis and three with a worse prognosis were then chosen for mRNA analysis by PanCancer Immune Profile Panel multiplex gene expression analysis. Twenty immune system genes were significantly differentially expressed in patients with a good prognosis relative to patients with a worse prognosis: TLR2 and TLR7 (Toll-like receptor superfamily); CD4, CD37, FOXP3, PTPRC (B cell and T cell signalling); IRF5, IRF8, STAT1, TFE3 (transcription factors); ANP32B, CCND3 (cell cycle); BTK (B cell development); TNF, TNFRF1A (TNF superfamily); HCK (leukocyte function); C1QA (complement system); BAX, PNMA1 (apoptosis); IKBKE (NF\uf06bB pathway). Differential expression was more than twice log 2 for TLR7, TNF, C1QA, FOXP3, and CD37. Conclusion: The key findings from this study, that longer-surviving PC patients had higher levels of intratumoural TILs and overexpressed five immune markers (TLR7, TNF, C1QA, FOXP3, CD37), could have two main uses. Together with an assessment of TIL levels, such an immune system gene panel constitutes a potential prognostic tool to permit a risk-based stratification of pancreatic tumour patients into personalized treatment protocols towards improving the current abysmal clinical outcome of these patients

Tumor-Agnostic Treatment for Cancer:When How is Better than Where

In the evolving landscape of precision oncology, genomic characterization of tumor has become crucial in order to move toward a molecular-based therapy for the vast majority of cancers. Recently, translational research has offered new perspectives in systemic cancer treatment thanks to the identification of novel oncogenic targets and the development of new targeted therapies, followed by the latest applications of genomic sequencing. Simultaneously, next-generation sequencing (NGS) has expanded its accessibility, being incorporated into clinical studies at the time of the initial screening, disease progression, and often in longitudinal monitoring of molecular changes. Consequently, new potentially targetable molecular alterations have been identified in several different types of tumors, leading to the development of tumor-agnostic treatments. Being highly selective for specific molecular alterations, these drugs are active against different subtypes of oncogene-addicted cancers. Three of these drugs-pembrolizumab [an anti-programmed death 1 (PD-1) monoclonal antibody (MAb)], larotrectinib [a pan-tropomyosin receptor tyrosine kinase (TRK) inhibitor], and entrectinib [a pan-TRK, anaplastic lymphoma kinase (ALK) and ROS-1 inhibitor]-received US FDA approval in 2017, 2018, and 2019, respectively. In this article, we critically review the clinical studies responsible for FDA approval and the most recently updated results. We then discuss the benefits and limitations of these new methodological approaches, paying particular attention to the largest precision medicine master protocol, NCI-MATCH. Among the benefits, there are the increased chances of offering targeted therapies for patients with specific alterations identified in different types of tumors. Among the limitations, we highlight that the same driver mutation may require different therapeutic strategies in different types of cancers. Additionally, the complex study design undeniably requires a dynamic strategy to enroll patients with considerable economic and managerial efforts.</p

Influence of Prior Tyrosine Kinase Inhibitor on Survival for Patients with Metastatic Renal Cell Carcinoma Treated with Nivolumab or Cabozantinib: Data from a Literature-based Meta-analysis

The aim of this letter is to focus on the survival of patients treated with nivolumab and cabozantinib according to prior first-line TKI. We used data from CheckMate 025 and METEOR for a subsequent subgroup analysi

Treating De novo metastatic castration sensitive prostate cancer with visceral metastases: an evolving issue

Visceral metastasis is widely considered a prognostic factor for overall survival of men with metastatic castration-sensitive prostate cancer (mCSPC) and has been historically managed with androgen deprivation therapy (ADT). More recently, this therapeutic scenario has been enriched by the possibility to integrate ADT with chemotherapy or novel androgen-signalling–targeted inhibitors. In order to define the effect of chemotherapy/androgen-signalling–targeted inhibitors plus ADT, we performed a pooled analysis on patients with mCSPC and visceral metastases revealing that survival was significantly improved in patients without visceral metastasis (HR=0.64 95%CI: 0.56-0.74; p&lt;0.01) compared with men with visceral metastases (HR=0.68; 95%CI: 0.51-0.91; p&lt;0.01). Although several limitations do not allow to draw definitive conclusions, our analysis confirms the efficacy of chemotherapy/androgen-signalling–targeted inhibitors in combination with ADT also in mCSPC with visceral metastases. In the absence of specific randomized controlled trials, symptoms, toxicity, cost, patients’ preference and clinical experience should guide the decision to add chemotherapy or androgen receptor-targeted therapy to ADT in patients with visceral metastases from mCSPC

MSI and EBV Positive Gastric Cancer's Subgroups and Their Link With Novel Immunotherapy

Gastric cancers have been historically classified based on histomorphologic features. The Cancer Genome Atlas network reported the comprehensive identification of genetic alterations associated with gastric cancer, identifying four distinct subtypes- Epstein-Barr virus (EBV)-positive, microsatellite-unstable/instability (MSI), genomically stable and chromosomal instability. In particular, EBV-positive and MSI gastric cancers seem responsive to novel immunotherapies drugs. The aim of this review is to describe MSI and EBV positive gastric cancer's subgroups and their relationship with novel immunotherapy.</p

Corticosteroid switch after progression on abiraterone acetate plus prednisone

Introduction: Abiraterone acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from prednisone to dexamethasone in patients who progressed whilst on abiraterone acetate plus prednisone or prednisolone. Materials and Methods: The aim of this review is to discuss the results from the clinical studies available, examining potential mechanisms of action and patient selection criteria for this treatment option. Results: A total of four studies were evaluated. Among possible eligibility criteria for steroid switch, we found: PSA progression without any radiological or clinical progression during abiraterone acetate + prednisone; no high-grade adverse events related to CYP-17 inhibition; and unfitness for chemotherapy or radium-223. Conclusion: Although large randomized prospective trials are warranted, steroid switch seems to offer a good option for certain patients treated with abiraterone acetate plus prednisone or prednisolone