Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries.

In the past two decades, the treatment of metastatic non-small cell lung cancer (NSCLC), has undergone significant changes due to the introduction of targeted therapies and immunotherapy. These advancements have led to the need for predictive molecular tests to identify patients eligible for targeted therapy. This review provides an overview of the development and current application of targeted therapies and predictive biomarker testing in European patients with advanced stage NSCLC.

Landscape of cancer biomarker testing in England following genomic services reconfiguration: insights from a nationwide pathologist survey.

Aims: Cancer diagnostics have been evolving rapidly. In England, the new National Health Service Genomic Medicine Service (GMS) provides centralised access to genomic testing via seven regional Genomic Laboratory Hubs. The PATHways survey aimed to capture pathologists' experience with current diagnostic pathways and opportunities for optimisation to ensure equitable and timely access to biomarker testing.

Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists.

Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies.

The molecular landscape of well differentiated retroperitoneal liposarcoma.

Well differentiated liposarcoma (WD-LPS) is a relatively rare tumour, with fewer than 50 cases occurring per year in the UK. These tumours are both chemotherapy- and radiotherapy-resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist.

Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2.

Gastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm arising in the gastrointestinal tract. A rare subset of GISTs are classified as wild-type GIST (wtGIST) and these are frequently associated with germline variants that affect the function of cancer predisposition genes such as the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD) or NF1. However, despite this high heritability, familial clustering of wtGIST is extremely rare.

Tumor necrosis is significantly associated with reduced recurrence-free survival after curative resection of gastrointestinal stromal tumors.

Background Objectives: The impact of tumor necrosis as a prognostic factor in gastrointestinal stromal tumor (GISTs) is still debated. The objective was to determine whether tumor necrosis is an independent risk factor for survival in patients with GISTs.

Methods: Patients undergoing surgery for primary GIST from March 2003 to October 2018 at two sarcoma referral centers were retrospectively identified.

Correction to: Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants.

This article was originally published under a [CC BY NC 4.0] license.

The effects of resection margin and KRAS status on outcomes after resection of colorectal liver metastases.

Background: The aim of this study was to investigate the influence of resection margin status in patients with KRAS mutations (mt-KRAS) when compared to those with wild-type KRAS (wt-KRAS) on long-term outcomes in patients with resected CRLM.

Methods: All patients who underwent resection of CRLM with curative intent between January 2011 and December 2016 and had a KRAS type recorded were included in the study. Overall survival (OS), as well as death-censored overall (RFS) and liver-specific (LS-RFS) recurrence-free survival between KRAS types and the margin status within KRAS subgroups were compared using Cox regression models.

Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants.

Introduction: The identification of tumour mutational burden (TMB) as a biomarker of response to programmed cell death protein 1 (PD-1) immunotherapy has necessitated the development of genomic assays to measure this. We carried out comprehensive molecular profiling of cancers using the Illumina TruSight Oncology 500 (TSO500) panel and compared these to whole-genome sequencing (WGS).

Methods: Cancer samples derived from formalin-fixed material were profiled on the TSO500 panel, sequenced on an Illumina NextSeq 500 instrument and processed through the TSO500 Docker pipeline.

In situ growth in early lung adenocarcinoma may represent precursor growth or invasive clone outgrowth-a clinically relevant distinction.

The switch from in situ to invasive tumor growth represents a crucial stage in the evolution of lung adenocarcinoma. However, the biological understanding of this shift is limited, and 'Noguchi Type C' tumors, being early lung adenocarcinomas with mixed in situ and invasive growth, represent those that are highly valuable in advancing our understanding of this process. All Noguchi Type C adenocarcinomas (n = 110) from the LATTICE-A cohort were reviewed and two patterns of in situ tumor growth were identified: those deemed likely to represent a true shift from precursor in situ to invasive disease ('Noguchi C1') and those in which the lepidic component appeared to represent outgrowth of the invasive tumor along existing airspaces ('Noguchi C2').

Autotransplantation of the Liver for Ex Vivo Resection of Intrahepatic Caval Leiomyosarcoma: A Case Report.

Intrahepatic caval leiomyosarcomas are rare tumors with limited therapeutic options as patients with the disease are not eligible for liver transplantation from the deceased-donor pool. Advances in surgical techniques gained in split and domino liver transplant procedures can be applied to resection of advanced tumors involving the hepatocaval confluence. Here, we describe the case of a 58-year-old white female who presented with visible abdominal wall collaterals and a palpable right subcostal tumor.

Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study.

Background: Chronic inflammation caused by ulcerative colitis (UC) causes a pro-neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasive malignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia.

Somatic cancer genetics in the UK: real-world data from phase I of the Cancer Research UK Stratified Medicine Programme.

Introduction: Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context.

Methods: A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013.

Discovery and Validation of Methylation Biomarkers for Ulcerative Colitis Associated Neoplasia.

Background And Aims: Ulcerative colitis (UC) is associated with a higher background risk of dysplasia and/or neoplasia due to chronic inflammation. There exist few biomarkers for identification of patients with dysplasia, and targeted biopsies in this group of patients are inaccurate in reliably identifying dysplasia. We aimed to examine the epigenome of UC dysplasia and to identify and validate potential biomarkers.

Detection of EGFR Variants in Plasma: A Multilaboratory Comparison of a Real-Time PCR EGFR Mutation Test in Europe.

Molecular testing of EGFR is required to predict the response likelihood to targeted therapy in non-small cell lung cancer. Analysis of circulating tumor DNA in plasma may complement limitations of tumor tissue. This study evaluated the interlaboratory performance and reproducibility of a real-time PCR EGFR mutation test (cobas EGFR Mutation Test v2) to detect EGFR variants in plasma.

Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors and Non-Small Cell Lung Cancer (NSCLC) - Advances in Molecular Diagnostic Techniques to Facilitate Targeted Therapy.

A subset of patients with non-small cell lung cancer (NSCLC) respond well to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), due to the presence of sensitising mutations in the gene encoding EGFR. Mutations associated with resistance to first generation EGFR TKIs have also been identified, which lead to therapeutic failure and the requirement for new drugs. Three generations of EGFR TKIs have been developed and either have been, or are being, evaluated as first and/or second line therapeutic agents.

SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity.

Purpose: To evaluate the role of germline mutation analysis by (1) comprehensive literature review, (2) description of novel germline mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA.

Patients And Methods: A systematic literature review and a retrospective review of the molecular and clinical features of patients identified with putative germline variants in UK molecular genetic laboratories was performed. To evaluate the molecular consequences of missense variants, a novel model of the SDHA/B/C/D complex was generated and the structural effects of missense substitutions identified in the literature, our UK novel cohort and a further 32 "control missense variants" were predicted by the mCSM computational platform.

Metabolomic Evidence for a Field Effect in Histologically Normal and Metaplastic Tissues in Patients with Esophageal Adenocarcinoma.

Patients with Barrett's esophagus (BO) are at increased risk of developing esophageal adenocarcinoma (EAC). Most Barrett's patients, however, do not develop EAC, and there is a need for markers that can identify those most at risk. This study aimed to see if a metabolic signature associated with the development of EAC existed.

Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.

Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.

The incremental benefit of two quadrant lavage for peritoneal cytology at staging laparoscopy for oesophagogastric adenocarcinoma.

Background: Patients with positive peritoneal cytology from oesophagogastric cancer have a poor prognosis. The purpose of this study was to compare lavage cytology from the pelvis alone with the pelvis and subphrenic areas at staging laparoscopy in patients with potentially resectable oesophagogastric adenocarcinoma.

Methods: Between November 2006 and November 2010, all patients with operable oesophagogastric adenocarcinoma on spiral CT considered fit for surgical resection underwent staging laparoscopy.

MALDI profiles of proteins and lipids for the rapid characterisation of upper GI-tract cancers.

Aim: To identify a reliable MALDI 'cancer fingerprint' to aid in the rapid detection and characterisation of malignant upper GI-tract disease from endoscopic biopsies.

Methods: A total of 183 tissue biopsies were collected from 126 patients with or without oesophago-gastric malignancy and proteins and lipids separated by methanol/chloroform extraction. Peak intensities in the lipid and protein MALDI spectra from five types of samples (normal oesophageal mucosa from controls, normal oesophageal mucosa from patients with oesophageal adenocarcinoma, nondysplastic Barrett's oesophagus, oesophageal adenocarcinoma, normal gastric mucosa and gastric adenocarcinoma) were compared using non-parametric statistical tests and ROC analyses.

Young man presenting with recurrent food bolus impaction.

A young man with recurrent food bolus obstruction presented to the gastroenterology clinic and, after investigation, was found to have eosinophilic oesophagitis. This unusual condition is closely linked to atopy and, in parallel with other atopic conditions, is increasing in incidence. Diagnosis is confirmed on oesophageal biopsy and treatment includes topical steroids and exclusion diet.