Reconciling art and science in the era of personalised medicine: the legacy of George Canguilhem.

Background: Biomedicine, i.e. the application of basic sciences to medicine, has become the cornerstone for the study of etiopathogenesis and treatment of diseases.

Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas.

Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes.

Comparison of outcomes between neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy in patients with locally advanced esophageal cancer: A network meta-analysis.

Background: Neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant chemotherapy (NCT) followed by surgery are two standard strategies in treating locally advanced esophageal cancer (EC). We aim to compare NCRT and NCT in the management of locally advanced EC patients.

Methods: MEDLINE, Embase, CENTRAL, and conferences were systematically searched for clinical trials published up to September 2021.

Identifying Cancer Drivers Using DRIVE: A Feature-Based Machine Learning Model for a Pan-Cancer Assessment of Somatic Missense Mutations.

Sporadic cancer develops from the accrual of somatic mutations. Out of all small-scale somatic aberrations in coding regions, 95% are base substitutions, with 90% being missense mutations. While multiple studies focused on the importance of this mutation type, a machine learning method based on the number of protein-protein interactions (PPIs) has not been fully explored.

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types.

The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic.

Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements.

The Evolving Genomic Landscape of Barrett's Esophagus and Esophageal Adenocarcinoma.

We have recently gained unprecedented insight into genetic factors that determine risk for Barrett's esophagus (BE) and progression to esophageal adenocarcinoma (EA). Next-generation sequencing technologies have allowed us to identify somatic mutations that initiate BE and track genetic changes during development of tumors and invasive cancer. These technologies led to identification of mechanisms of tumorigenesis that challenge the current multistep model of progression to EA.

The Medicalization of Health and Shared Responsibility.

Public, occupational and environmental health are relatively novel disciplines compared to the ancient history of medicine. Their development, together with a more insightful knowledge of the human pathophysiology (this more usual term is the one used in the article itself), have progressively expanded the field of investigation of medicine to environmental, behavioural and genetic factors that favour the development of certain medical conditions. As a result we have developed numerous additional strategies to monitor health and prevent disease, including interventions in anticipation of diseases themselves when patients are still healthy or in a grey area of increased risk.

Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance.

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro.

Whole-genome sequencing of nine esophageal adenocarcinoma cell lines.

Esophageal adenocarcinoma (EAC) is highly mutated and molecularly heterogeneous. The number of cell lines available for study is limited and their genome has been only partially characterized. The availability of an accurate annotation of their mutational landscape is crucial for accurate experimental design and correct interpretation of genotype-phenotype findings.

Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer.

Purpose: Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM).

Experimental Design: We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors.

KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs.

Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. We sought to identify epigenetic regulators driving the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human cancers. We found that KDM2B (also known as Ndy1, FBXL10, and JHDM1B), an H3K36 histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases.

Recurrence and prognostic factors in patients with aggressive fibromatosis. The role of radical surgery and its limitations.

Background: Surgery is still the standard treatment for aggressive fibromatosis (AF); however, local control remains a significant problem and the impact of R0 surgery on cumulative recurrence (CR) is objective of contradictory reports.

Methods: This is a single-institution study of 62 consecutive patients affected by extra-abdominal and intra-abdominal AF who received macroscopically radical surgery within a time period of 15 years.

Results: Definitive pathology examination confirmed an R0 situation in 49 patients and an R1 in 13 patients.

Two-year follow-up of wound complications associated with laparoendoscopic single-site adjustable gastric banding.

Background: In an effort to provide better cosmesis for patients, there has been a surge recently in the use of laparoendoscopic single-site adjustable gastric banding. Few data, however, are available on the long-term wound complications resulting from this technique. We conducted a retrospective review of patients to identify the extent of wound complications found during a minimum follow-up period of 2 years after laparoendoscopic single-site adjustable gastric banding.

TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression.

The TGF-β pathway is under active consideration as a cancer drug target based on its capacity to promote cancer cell invasion and to create a protumorigenic microenvironment. However, the clinical application of TGF-β inhibitors remains uncertain as genetic studies show a tumor suppressor function of TGF-β in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGF-β inhibition in pancreatic cancer in relation to tumor stage, genetic profile, and concurrent chemotherapy.

RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis.

Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases. Although these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing, identifying Wnt2 as a candidate gene enriched in CTCs.

Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells.

Sustained expression of the histone demethylase, KDM2B (Ndy1/FBXL10/JHDM1B), bypasses cellular senescence in primary mouse embryonic fibroblasts (MEFs). Here, we show that KDM2B is a conserved regulator of lifespan in multiple primary cell types and defines a program in which this chromatin-modifying enzyme counteracts the senescence-associated down-regulation of the EZH2 histone methyltransferase. Senescence in MEFs epigenetically silences KDM2B and induces the tumor suppressor miRNAs let-7b and miR-101, which target EZH2.

STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis.

The STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer cell survival, and inflammation. In the pancreas, STAT3 is dispensable for normal development, whereas the majority of pancreatic ductal adenocarcinomas (PDAC) show constitutive activation of STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define the mechanisms of STAT3 activation and its functional importance in PDAC pathogenesis.

Pancreatic cancers require autophagy for tumor growth.

Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy.

Aggressive treatment approach for cloacogenic carcinoma of the anorectum: report from a single cancer center.

Background/aims: The prognosis of cloacogenic carcinoma of the anorectum has rarely been investigated, and its clinical behavior is supposed to be similar to common squamous anal cancers. During the last 10 years, chemoradiation treatment (CRT) has been considered the standard of care for anal cancer.

Methods: We retrospectively investigated the treatment of cloacogenic cancers treated within the framework of a multidisciplinary cancer center team during an 8-year period.

Molecular imaging agents: impact on diagnosis and therapeutics in oncology.

Imaging has become a crucial tool in oncology throughout the course of disease detection and management, and is an integral part of clinical trials. Anatomical and functional imaging led the way, providing valuable information used in the diagnosis of disease, including data regarding the size and location of the tumour and on physiological processes such as blood flow and perfusion. As understanding of cancer pathogenesis has advanced through the identification of genetic, biochemical and cellular alterations in evolving tumours, emphasis has been put on developing methods to detect and serially monitor such alterations.

Neoadjuvant chemotherapy followed by hepatectomy for primarily resectable colorectal cancer liver metastases.

Background/aims: Hepatic resection in metastatic disease from colorectal cancer offers the best chance in selected cases for long-term survival. Neoadjuvant chemotherapy (NACT) has been advocated in some cases initially deemed irresectable with few reports of the efficacy of such a strategy and the influence of the response to chemotherapy on the outcome of radical hepatic resection.

Methodology: Between December 1995 and May 2005, 88 patients with colorectal liver metastases underwent hepatic resection with curative intent.