Preliminary findings of a 'test bundle' to accelerate the diagnosis of MS and NMOSD following optic neuritis.

No study has investigated the length of time it takes to diagnose multiple sclerosis (MS) or neuromyelitis optic spectrum disorder (NMOSD, aquaporin 4 antibody disease or myelin oligodendrocyte glycoprotein antibody disease, MOGAD) following the onset of de novo optic neuritis (ON). Minimizing the time between ON and downstream diagnoses needs urgency since early diagnosis equals early treatment. The time elapsed from ON to a subsequent diagnosis of MS/NMOSD was estimated through analysis of retrospective data collected from the Axon Registry (AR) of the American Academy of Neurology (AAN) and from the University of Kentucky (UK), Lexington.

Laparoscopically assisted versus open oesophagectomy for patients with oesophageal cancer-the Randomised Oesophagectomy: Minimally Invasive or Open (ROMIO) study: protocol for a randomised controlled trial (RCT).

Introduction: Surgery (oesophagectomy), with neoadjuvant chemo(radio)therapy, is the main curative treatment for patients with oesophageal cancer. Several surgical approaches can be used to remove an oesophageal tumour. The Ivor Lewis (two-phase procedure) is usually used in the UK.

Distribution of lymph node metastases in esophageal carcinoma [TIGER study]: study protocol of a multinational observational study.

Background: An important parameter for survival in patients with esophageal carcinoma is lymph node status. The distribution of lymph node metastases depends on tumor characteristics such as tumor location, histology, invasion depth, and on neoadjuvant treatment. The exact distribution is unknown.

Wildfires Alter Forest Watersheds and Threaten Drinking Water Quality.

Wildfires are a natural part of most forest ecosystems, but due to changing climatic and environmental conditions, they have become larger, more severe, and potentially more damaging. Forested watersheds vulnerable to wildfire serve as drinking water supplies for many urban and rural communities. The highly variable nature of wildfire behavior combined with spatially complex patterns in vegetation, landscape, and hydrologic factors create uncertainty surrounding the postfire effects on water supplies.

Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer.

Objective: Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited.

Design: To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations.

Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer.

Purpose: To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition.

Experimental Design: The HR status of 12 OCCC cell lines was determined using RAD51/γH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status.

Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification.

Background: HER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically challenging scenarios. Currently, breast cancers with HER2 amplification/overexpression in just over 10% of cancer cells are considered HER2-positive for clinical purposes; however, it is unclear as to whether the HER2-negative components of such tumors would be driven by distinct genetic alterations.

Integrative genomic and transcriptomic characterization of papillary carcinomas of the breast.

Papillary carcinoma (PC) is a rare type of breast cancer, which comprises three histologic subtypes: encapsulated PC (EPC), solid PC (SPC) and invasive PC (IPC). Microarray-based gene expression and Affymetrix SNP 6.0 gene copy number profiling, and RNA-sequencing revealed that PCs are luminal breast cancers that display transcriptomic profiles distinct from those of grade- and estrogen receptor (ER)-matched invasive ductal carcinomas of no special type (IDC-NSTs), and that the papillary histologic pattern is unlikely to be underpinned by a highly recurrent expressed fusion gene or a highly recurrent expressed mutation.

Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast.

Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis.

From integrative genomics to therapeutic targets.

Combinatorial approaches that integrate conventional pathology with genomic profiling and functional genomics have begun to enhance our understanding of the genetic basis of breast cancer. These methods have identified key genotypic-phenotypic correlations in different breast cancer subtypes that have led to the discovery of genetic dependencies that drive their behavior. Moreover, this knowledge has been applied to define novel tailored therapies for these groups of patients with cancer.

Mutation profiling of adenoid cystic carcinomas from multiple anatomical sites identifies mutations in the RAS pathway, but no KIT mutations.

Aims: The majority of adenoid cystic carcinomas (AdCCs), regardless of anatomical site, harbour the MYB-NFIB fusion gene. The aim of this study was to characterize the repertoire of somatic genetic events affecting known cancer genes in AdCCs.

Methods And Results: DNA was extracted from 13 microdissected breast AdCCs, and subjected to a mutation survey using the Sequenom OncoCarta Panel v1.

The 11q13-q14 amplicon: clinicopathological correlations and potential drivers.

Amplification at 11q13-q14 is a common event in cancers from multiple anatomical sites. This complex amplicon has multiple cores and several genes have been put forward as potential "drivers." In this review, based on the technical advancements of the last decade, which resulted in methods allowing for a deeper genomic and functional genomic characterization of amplicons and their drivers, we discuss the current definitions of amplicons and driver genes, the clinical and biological significance of the 11q13-q14 amplicon in distinct types of human cancer, its coamplification partners, and the roles of various genes located within the amplicon as potential "drivers.

Functional characterization of the 19q12 amplicon in grade III breast cancers.

Introduction: The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification.

A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers.

BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive.

Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection.

The mechanisms underlying the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast are yet to be fully elucidated. Several hypotheses have been put forward to explain the progression from DCIS to IDC, including the selection of a subpopulation of cancer cells with specific genetic aberrations, and the acquisition of new genetic aberrations or non-genetic mechanisms mediated by the tumour microenvironment. To determine whether synchronously diagnosed ipsilateral DCI and IDCs have modal populations with distinct repertoires of gene copy number aberrations and mutations in common oncogenes, matched frozen samples of DCIS and IDC were retrieved from 13 patients and subjected to microarray-based comparative genomic hybridization (aCGH) and Sequenom MassARRAY (Oncocarta v 1.

Immunophenotypic and genomic characterization of papillary carcinomas of the breast.

Papillary carcinomas are a special histological type of breast cancer and have a relatively good outcome. We characterized the genomic and phenotypic characteristics of papillary carcinomas to determine whether they would constitute an entity distinct from grade- and oestrogen receptor (ER)-matched invasive ductal carcinomas of no special type (IDC-NSTs). The phenotype of 63 papillary carcinomas of the breast and grade- and ER-matched IDC-NSTs was determined by immunohistochemistry.

High-throughput detection of fusion genes in cancer using the Sequenom MassARRAY platform.

Fusion genes have pivotal roles in the development and progression of human cancer and offer potential for rational drug design. Massively parallel sequencing has identified a panoply of in-frame expressed fusion genes, but early reports suggest that the majority of these are present at very low prevalence or are private events. Conventional methods for the identification of recurrent expressed fusion genes in large cohorts of cancers (eg fluorescence in situ hybridization (FISH) and reverse transcriptase PCR (RT-PCR)) are time consuming and prone to artifacts.

Functional characterization of EMSY gene amplification in human cancers.

The 11q13-q14 locus is frequently amplified in human cancers, with a complex structure harbouring multiple potential oncogenic drivers. The EMSY gene has been proposed as a driver of the third core of the 11q13-q14 amplicon. This gene encodes a protein reported to be a BRCA2-binding partner, which when over-expressed would lead to impairment of BRCA2 functions and could constitute a mechanism for BRCA2 inactivation in non-hereditary breast and ovarian cancers.

Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations.

Utilizing the concept of synthetic lethality has provided new opportunities for the development of targeted therapies, by allowing the targeting of loss of function genetic aberrations. In cancer cells with BRCA1 or BRCA2 loss of function, which harbor deficiency of DNA repair by homologous recombination, inhibition of PARP1 enzymatic activity leads to an accumulation of single strand breaks that are converted to double strand breaks but cannot be repaired by homologous recombination. Inhibition of PARP has therefore been advanced as a novel targeted therapy for cancers harboring BRCA1/2 mutations.

Thoracobilia: a rare complication of gallstone disease.

Thoracobilia and pleurobiliary fistulae secondary to obstructed choledocholithiasis are rare complications of gallstone disease. We present the case of a 64-year-old man with gallstone pancreatitis who developed a pleurobiliary fistula secondary to an obstructing ductal calculus, and was successfully managed non-operatively.

Cortactin gene amplification and expression in breast cancer: a chromogenic in situ hybridisation and immunohistochemical study.

Amplification of 11q13 is found in approximately 15% of breast cancers. Cyclin D1 (CCND1) has been reported to be the 'driver' of this amplicon, however, multiple genes map to the smallest region of amplification of 11q13. Out of these genes, cortactin (CTTN) has been shown to be consistently overexpressed at the mRNA level in tumours harbouring 11q13 amplification.