Hughes Abdominal Repair Trial (HART) – Abdominal wall closure techniques to reduce the incidence of incisional hernias: study protocol for a randomised controlled trial

Background Incisional hernias are common complications of midline closure following abdominal surgery and cause significant morbidity, impaired quality of life and increased health care costs. The ‘Hughes Repair’ combines a standard mass closure with a series of horizontal and two vertical mattress sutures within a single suture. This theoretically distributes the load along the incision length as well as across it. There is evidence to suggest that this technique is as effective as mesh repair for the operative management of incisional hernias; however, no trials have compared the Hughes Repair with standard mass closure for the prevention of incisional hernia formation following a midline incision. Methods/design This is a 1:1 randomised controlled trial comparing two suture techniques for the closure of the midline abdominal wound following surgery for colorectal cancer. Full ethical approval has been gained (Wales REC 3, MREC 12/WA/0374). Eight hundred patients will be randomised from approximately 20 general surgical units within the United Kingdom. Patients undergoing open or laparoscopic (more than a 5-cm midline incision) surgery for colorectal cancer, elective or emergency, are eligible. Patients under the age of 18 years, those having mesh inserted or undergoing musculofascial flap closure of the perineal defect in abdominoperineal wound closure, and those unable to give informed consent will be excluded. Patients will be randomised intraoperatively to either the Hughes Repair or standard mass closure. The primary outcome measure is the incidence of incisional hernias at 1 year as assessed by standardised clinical examination. The secondary outcomes include quality of life patient-reported outcome measures, cost-utility analysis, incidence of complete abdominal wound dehiscence and C-POSSUM scores. The incidence of incisional hernia at 1 year, assessed by computerised tomography, will form a tertiary outcome. Discussion A feasibility phase has been completed. The results of the study will be used to inform current and future practice and potentially reduce the risk of incisional hernia formation following midline incisions

Author response to: Comment on: Cachexia index for prognostication in surgical patients with locally advanced oesophageal or gastric cancer: multicentre cohort study

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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. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection

mRNA profiling of the cancer degradome in oesophago-gastric adenocarcinoma.

BACKGROUND: Degradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago-gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis. METHODS: Comprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level). RESULTS: Gene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011). CONCLUSION: This study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers

A Decade of the Oesophageal Cancer Clinical and Molecular Stratification Consortium: OCCAMS

Multi-centre collaboration is essential to achieve the sample sizes required for robust and informative research studies for less common medical conditions. Substantial logistical and governance support is needed to ensure that the clinical and molecular data generated are high quality and can benefit the international research community and patients.The Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium was created in 2009 as a collaboration across the United Kingdom to better understand oesophageal adenocarcinoma (OAC). The aims of OCCAMS are: to develop a bioresource of samples with clinical data from oesophageal and gastro-oesophageal junction (GOJ) adenocarcinoma patients; to identify clinical, demographic, and molecular factors affecting development and progression of OAC; to promote use of these data and the OCCAMS network for clinical trials to improve management of this cancer; and to share data with internal and external academic and commercial parties for the benefit of patients.At the time of writing, OCCAMS has collected and curated a bioresource derived from 4,440 oesophageal cancer patients, representing over 44,000 individual samples with detailed clinical and epidemiological annotations, from 27 UK centres (Figure 1). OCCAMS was a key contributor to the International Cancer Genome Consortium (ICGC), ICGC 25K and ICGC ARGO projects, as well as the Pan-Cancer Analysis of Whole Genomes (PCAWG) study. OCCAMS has also contributed to the Cancer Research UK Grand Challenge Mutographs project and projects run by Genomics England.We have continued to extend the OCCAMS genomic resource and are increasingly complementing this with other -omics data including single cell technologies and 3D organoids. The OCCAMS Steering Committee was created at inception and consists of members of the core OCCAMS infrastructure team and representatives from every site that contributes to the consortium. Proposals for new research projects are formally submitted using a proforma for discussion at regular meetings of the steering committee. This structure allowed OCCAMS to control the use of finite resources, such as blood and tissue, whilst encouraging researchers to apply to use the resource. It also allowed similar projects to be combined, or aligned, to reduce academic wastage and maximise the quality of the scientific output. Bespoke cohorts can be created for a specific project via the Cambridge-based OCCAMS team, and clinical and -omics data are provided so that specific research can be conducted. Sequencing reads and methylation array data have been made available to the wider research community via the International Cancer Genome Consortium and/or the European Genome-phenome Archive (EGA), to take advantage of existing governance structures. Molecular and clinical data, as well as patient-derived organoids, from OCCAMS have been extensively exploited to understand various aspects of OAC biology within and outside the Consortium. In total, we have established 33 collaborations within OCCAMS and 14 with external groups, including European and US partners from academia and industry, resulting in 34 research publications. There are further studies still underway, which will provide further research outputs for this cancer, which has poor outcomes. Some scientific outputs of OCCAMS to date are described in table 1.Our key overall lesson drawn from OCCAMS is that multicentre consortia can collect data and tissue (including fresh frozen) from huge numbers of patients, even when studying a cancer like OAC, which has a relatively low incidence. However, care must be taken to create robust and detailed databases, with metadata, to make sure that the clinical information being recorded is accurate and relevant to the molecular questions being asked. Accurate patient outcomes should be linked to national registries. Ethical approval should encompass all the data and tissue required and include agreement from the patient to track patient outcomes across relevant national registries as well as to share data and resources with academic collaborators. During the course of OCCAMS we amended the consent to allow data sharing with commercial collaborators with a specific tick box so that patients can opt in or out. This was included to ensure maximal opportunity for clinical translation of the findings; the majority of patients have consented for commercial as well as academic collaboration.We allowed flexibility as to which samples each centre collected, for example whether samples were fresh frozen or formalin-fixed paraffin-embedded, or whether ctDNA was double spun on site or collected in Streck tubes. This allowed more centres to get involved, which often led to their infrastructure being expanded to collect a wider range of sample types. This encouraged inclusivity of OCCAMS membership, maximising buy in from the UK clinical community. Clear, standardised protocols were needed to reduce sample wastage and maximise quality. As the number of molecular analyses using OCCAMS samples increased there was careful consideration of how all the data, which included demographic, clinical, whole genome sequencing, and RNAseq, could be linked. Linkage increases the value of this data and enhances the ability to generate new insights into disease. The steering group coordinated the academic output of this resource, driving forward research. A sense of community was created by holding yearly in-person meetings to share new findings and discuss future projects, with competitions to encourage junior clinical researchers to access the data. The goal was to create a sense of ownership for the clinical researchers who contributed patient data to OCCAMS, as this encouraged use of the data for molecular projects and for understanding the clinical features of OAC. A multicentre collaboration must focus on the patient. Throughout this project we had strong patient representation to ensure that our research focus was relevant and that all materials were clear and consistent. This included discussion between patients and researchers about research priorities as well as co-production of patient facing materials and patient led sessions at our annual symposium. The exchange between patients, public and researchers, especially those new to the field, led to a heightened appreciation of why research in this disease is so important. New discoveries will lead to improved patient outcomes only when the potential clinical impact of the science is constantly borne in mind. <br/

Clinical and biological characterization of skeletal muscle tissue biopsies of surgical cancer patients

BACKGROUND: Researchers increasingly use intraoperative muscle biopsy to investigate mechanisms of skeletal muscle atrophy in patients with cancer. Muscles have been assessed for morphological, cellular, and biochemical features. The aim of this study was to conduct a state‐of‐the‐science review of this literature and, secondly, to evaluate clinical and biological variation in biopsies of rectus abdominis (RA) muscle from a cohort of patients with malignancies. METHODS: Literature was searched for reports on muscle biopsies from patients with a cancer diagnosis. Quality of reports and risk of bias were assessed. Data abstracted included patient characteristics and diagnoses, sample size, tissue collection and biobanking procedures, and results. A cohort of cancer patients (n = 190, 88% gastrointestinal malignancies), who underwent open abdominal surgery as part of their clinical care, consented to RA biopsy from the site of incision. Computed tomography (CT) scans were used to quantify total abdominal muscle and RA cross‐sectional areas and radiodensity. Biopsies were assessed for muscle fibre area (μm(2)), fibre types, myosin heavy chain isoforms, and expression of genes selected for their involvement in catabolic pathways of muscle. RESULTS: Muscle biopsy occurred in 59 studies (total N = 1585 participants). RA was biopsied intraoperatively in 40 studies (67%), followed by quadriceps (26%; percutaneous biopsy) and other muscles (7%). Cancer site and stage, % of male participants, and age were highly variable between studies. Details regarding patient medical history and biopsy procedures were frequently absent. Lack of description of the population(s) sampled and low sample size contributed to low quality and risk of bias. Weight‐losing cases were compared with weight stable cancer or healthy controls without considering a measure of muscle mass in 21 out of 44 studies. In the cohort of patients providing biopsy for this study, 78% of patients had preoperative CT scans and a high proportion (64%) met published criteria for sarcopenia. Fibre type distribution in RA was type I (46% ± 13), hybrid type I/IIA (1% ± 1), type IIA (36% ± 10), hybrid type IIA/D (15% ± 14), and type IID (2% ± 5). Sexual dimorphism was prominent in RA CT cross‐sectional area, mean fibre cross‐sectional area, and in expression of genes associated with muscle growth, apoptosis, and inflammation (P < 0.05). Medical history revealed multiple co‐morbid conditions and medications. CONCLUSIONS: Continued collaboration between researchers and cancer surgeons enables a more complete understanding of mechanisms of cancer‐associated muscle atrophy. Standardization of biobanking practices, tissue manipulation, patient characterization, and classification will enhance the consistency, reliability, and comparability of future studies

Appetite and dietary intake endpoints in cancer cachexia clinical trials: Systematic Review 2 of the cachexia endpoints series

There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when compar ing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary in take as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guid ance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40–628). Forty-nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most fre quently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appe tite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24-h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge’s g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as rimary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not val idated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials

Variation in dermcidin expression in a range of primary human tumours and in hypoxic/oxidatively stressed human cell lines.

Dermcidin acts as a survival factor in a variety of cancer cell lines under hypoxia or oxidative stress. The aim of this study was to evaluate dermcidin expression in cell lines following simulation of tumour microenvironmental conditions and in a range of primary tumours. Tumour tissues were collected from patients with oesophageal (28 samples), gastric (20), pancreatic (five), bile duct (one) and prostatic (52) carcinomas as well as 30 benign tissue samples, for assessment of dermcidin mRNA levels using real-time PCR. Dermcidin expression was assessed in prostatic and pancreatic cancer cell lines, with and without induction of hypoxia or oxidative stress. Dermcidin mRNA expression was very low or absent in both unstressed and stressed prostate cell lines. None of the primary prostate tissue, benign or malignant, expressed dermcidin mRNA. Only two (4%) of the gastro-oesophageal cancer samples expressed moderate quantities of dermcidin mRNA. However, three (60%) of the pancreatic cancer samples and the single cholangiocarcinoma specimen had moderate/high levels of dermcidin expression. Of the two pancreatic cancer cell lines, one expressed dermcidin moderately but neither showed a response to hypoxia or oxidative stress. Expression of dermcidin in human primary tumours appears highly variable and is not induced substantially by hypoxia/oxidative stress in cell line model systems. The relationship of these findings to dermcidin protein levels and cell survival remains to be determined