Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib.

Background: The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better understand patterns and potential causes of genomic instability.

Patients And Methods: Homologous recombination deficiency (HRD) was assessed in 2147 tumor samples from SOLO1, PAOLA-1, Study 19, SOLO2, OPINION, and LIGHT using next-generation sequencing technology.

Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia.

Background: Obecabtagene autoleucel (obe-cel) is an autologous 41BB-ζ anti-CD19 chimeric antigen receptor (CAR) T-cell therapy which uses an intermediate-affinity CAR to reduce toxic effects and improve persistence.

Methods: We conducted a phase 1b-2 multicenter study of obe-cel in adults (≥18 years of age) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The main cohort, cohort 2A, included patients with morphologic disease; patients in cohort 2B had measurable residual disease.

TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial.

Relapsed/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment.

Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial.

Purpose: The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)-positive tumors. We explored whether mutations in non- or homologous recombination repair (non-BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1.

Methods: Eight hundred and six patients were randomly assigned (2:1).

Treatment for Barrett's oesophagus.

This review has been withdrawn because it has been split into the following reviews: 'Pharmaceutical interventions for Barrett's oesophagus' and 'Endoscopic interventions for Barrett's oesophagus'.

Lectins in Cervical Screening.

Cervical screening in low-resource settings remains an unmet need. Lectins are naturally occurring sugar-binding glycoproteins whose binding patterns change as cancer develops. Lectins discriminate between dysplasia and normal tissue in several precancerous conditions.

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma.

The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points.

A biomarker panel predicts progression of Barrett's esophagus to esophageal adenocarcinoma.

Progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is uncommon but the consequences are serious. Predictors of progression are essential to optimize resource utilization. This study assessed the utility of a promising panel of biomarkers applicable to routine paraffin embedded biopsies (FFPE) to predict progression of BE to EAC in a large population-based, nested case-control study.

Barrett's oESophagus trial 3 (BEST3): study protocol for a randomised controlled trial comparing the Cytosponge-TFF3 test with usual care to facilitate the diagnosis of oesophageal pre-cancer in primary care patients with chronic acid reflux.

Background: Early detection of oesophageal cancer improves outcomes; however, the optimal strategy for identifying patients at increased risk from the pre-cancerous lesion Barrett's oesophagus (BE) is not clear. The Cytosponge, a novel non-endoscopic sponge device, combined with the biomarker Trefoil Factor 3 (TFF3) has been tested in four clinical studies. It was found to be safe, accurate and acceptable to patients.

Selection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus.

Background & Aims: MicroRNA (miRNA) is highly stable in biospecimens and provides tissue-specific profiles, making it a useful biomarker of carcinogenesis. We aimed to discover a set of miRNAs that could accurately discriminate Barrett's esophagus (BE) from normal esophageal tissue and to test its diagnostic accuracy when applied to samples collected by a noninvasive esophageal cell sampling device.

Methods: We analyzed miRNA expression profiles of 2 independent sets of esophageal biopsy tissues collected during endoscopy from 38 patients with BE and 26 patients with normal esophagus (controls) using Agilent microarray and Nanostring nCounter assays.

Glucose transporter 1 expression as a marker of prognosis in oesophageal adenocarcinoma.

Background: The current TNM staging system for oesophageal adenocarcinoma (OAC) has limited ability to stratify patients and inform clinical management following neo-adjuvant chemotherapy and surgery.

Results: Functional genomic analysis of the gene expression data using Gene Set Enrichment Analysis (GSEA) identified GLUT1 as putative prognostic marker in OAC.In the discovery cohort GLUT1 positivity was observed in 114 patients (80.

Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study.

Background: Barrett's oesophagus predisposes to adenocarcinoma. However, most patients with Barrett's oesophagus will not progress and endoscopic surveillance is invasive, expensive, and fraught by issues of sampling bias and the subjective assessment of dysplasia. We investigated whether a non-endoscopic device, the Cytosponge, could be coupled with clinical and molecular biomarkers to identify a group of patients with low risk of progression suitable for non-endoscopic follow-up.

Range of pathologies diagnosed using a minimally invasive capsule sponge to evaluate patients with reflux symptoms.

Aims: Reflux symptoms are highly prevalent and non-specific; hence, in the absence of alarm symptoms, endoscopy referral decisions are challenging. This study evaluated whether a non-endoscopic Cytosponge could detect benign oesophageal pathologies and thus have future potential in triaging patients with persistent symptoms.

Methods And Results: Two complementary cohorts were recruited: (i) patients with reflux symptoms and no prior endoscopy (n = 409), and (ii) patients with reflux symptoms referred for endoscopy (n = 411).

The Discovery and Validation of Biomarkers for the Diagnosis of Esophageal Squamous Dysplasia and Squamous Cell Carcinoma.

The 5-year survival rate of esophageal cancer is less than 10% in developing countries, where more than 90% of these cancers are esophageal squamous cell carcinomas (ESCC). Endoscopic screening is undertaken in high incidence areas. Biomarker analysis could reduce the subjectivity associated with histologic assessment of dysplasia and thus improve diagnostic accuracy.

Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.

Background: Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo.

Methods: Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery.

Analysis of dysplasia in patients with Barrett's esophagus based on expression pattern of 90 genes.

Background & Aims: Diagnoses of dysplasia, based on histologic analyses, dictate management decisions for patients with Barrett's esophagus (BE). However, there is much intra- and inter-observer variation in identification of dysplasia-particularly low-grade dysplasia. We aimed to identify a biomarker that could be used to assign patients with low-grade dysplasia to a low- or high-risk group.

Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study.

Background: Barrett's esophagus (BE) is a commonly undiagnosed condition that predisposes to esophageal adenocarcinoma. Routine endoscopic screening for BE is not recommended because of the burden this would impose on the health care system. The objective of this study was to determine whether a novel approach using a minimally invasive cell sampling device, the Cytosponge, coupled with immunohistochemical staining for the biomarker Trefoil Factor 3 (TFF3), could be used to identify patients who warrant endoscopy to diagnose BE.

Pilot study of cytological testing for oesophageal squamous cell dysplasia in a high-risk area in Northern Iran.

Background: Oesophageal squamous cell carcinoma (ESCC) is a fatal disease with 5-year survival rates of <5% in Northern Iran. Oesophageal squamous dysplasia (ESD) is the precursor histologic lesion of ESCC. This pilot study was conducted to assess the feasibility, safety, and acceptability of non-endoscopic cytological examination of the oesophagus and to provide initial data on the accuracy of cytological atypia for identifying patients with ESD in this very-high-risk area.

Accuracy, safety, and tolerability of tissue collection by Cytosponge vs endoscopy for evaluation of eosinophilic esophagitis.

Background & Aims: Management of eosinophilic esophagitis (EoE) requires repeated endoscopic collection of mucosal samples to assess disease activity and response to therapy. An easier and less expensive means of monitoring of EoE is required. We compared the accuracy, safety, and tolerability of sample collection via Cytosponge (an ingestible gelatin capsule comprising compressed mesh attached to a string) with those of endoscopy for assessment of EoE.

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs.

Gastro-esophageal reflux disease symptoms and demographic factors as a pre-screening tool for Barrett's esophagus.

Background: Barrett's esophagus (BE) occurs as consequence of reflux and is a risk factor for esophageal adenocarcinoma. The current "gold-standard" for diagnosing BE is endoscopy which remains prohibitively expensive and impractical as a population screening tool. We aimed to develop a pre-screening tool to aid decision making for diagnostic referrals.

The combination of autofluorescence endoscopy and molecular biomarkers is a novel diagnostic tool for dysplasia in Barrett's oesophagus.

Objective: Endoscopic surveillance for Barrett's oesophagus (BO) is limited by sampling error and the subjectivity of diagnosing dysplasia. We aimed to compare a biomarker panel on minimal biopsies directed by autofluorescence imaging (AFI) with the standard surveillance protocol to derive an objective tool for dysplasia assessment.

Design: We performed a cross-sectional prospective study in three tertiary referral centres.

A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases.

Endoscopic TriModal imaging and biomarkers for neoplasia conjoined: a feasibility study in Barrett's esophagus.

In Barrett's esophagus (BE), the normal squamous lining of the esophagus is replaced by specialized columnar epithelium. Endoscopic surveillance with autofluorescence imaging (AFI) and molecular biomarkers have been studied separately to detect early neoplasia (EN) in BE. The combination of advanced-imaging modalities and biomarkers has not been investigated; AFI may help detecting biomarkers as a risk-stratification tool.