MicroRNA-330-5p as a putative modulator of neoadjuvant chemoradiotherapy sensitivity in oesophageal adenocarcinoma

Oesophageal adenocarcinoma (OAC) is the sixth most common cause of cancer deaths worldwide, and the 5-year survival rate for patients diagnosed with the disease is approximately 17%. The standard of care for locally advanced disease is neoadjuvant chemotherapy or, more commonly, combined neoadjuvant chemoradiation therapy (neo-CRT) prior to surgery. Unfortunately, ~60-70% of patients will fail to respond to neo-CRT. Therefore, the identification of biomarkers indicative of patient response to treatment has significant clinical implications in the stratification of patient treatment. Furthermore, understanding the molecular mechanisms underpinning tumour response and resistance to neo-CRT will contribute towards the identification of novel therapeutic targets for enhancing OAC sensitivity to CRT. MicroRNAs (miRNA/miR) function to regulate gene and protein expression and play a causal role in cancer development and progression. MiRNAs have also been identified as modulators of key cellular pathways associated with resistance to CRT. Here, to identify miRNAs associated with resistance to CRT, pre-treatment diagnostic biopsy specimens from patients with OAC were analysed using miRNA-profiling arrays. In pre-treatment biopsies miR-330-5p was the most downregulated miRNA in patients who subsequently failed to respond to neo-CRT. The role of miR-330 as a potential modulator of tumour response and sensitivity to CRT in OAC was further investigated in vitro. Through vector-based overexpression the E2F1/p-AKT survival pathway, as previously described, was confirmed as a target of miR-330 regulation. However, miR-330-mediated alterations to the E2F1/p-AKT pathway were insufficient to significantly alter cellular sensitivity to chemotherapy (cisplatin and 5-flurouracil). In contrast, silencing of miR-330-5p enhanced, albeit subtly, cellular resistance to clinically relevant doses of radiation. This study highlights the need for further investigation into the potential of miR-330-5p as a predictive biomarker of patient sensitivity to neo-CRT and as a novel therapeutic target for manipulating cellular sensitivity to neo-CRT in patients with OAC

Cancer Cachexia: Mechanisms and Clinical Implications

Cachexia is a multifactorial process of skeletal muscle and adipose tissue atrophy resulting in progressive weight loss. It is associated with poor quality of life, poor physical function, and poor prognosis in cancer patients. It involves multiple pathways: procachectic and proinflammatory signals from tumour cells, systemic inflammation in the host, and widespread metabolic changes (increased resting energy expenditure and alterations in metabolism of protein, fat, and carbohydrate). Whether it is primarily driven by the tumour or as a result of the host response to the tumour has yet to be fully elucidated. Cachexia is compounded by anorexia and the relationship between these two entities has not been clarified fully. Inconsistencies in the definition of cachexia have limited the epidemiological characterisation of the condition and there has been slow progress in identifying therapeutic agents and trialling them in the clinical setting. Understanding the complex interplay of tumour and host factors will uncover new therapeutic targets

Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma

Neoadjuvant chemoradiation therapy (CRT) is increasingly the standard of care for locally advanced oesophageal cancer. A complete pathological response to CRT is associated with a favourable outcome. Radiation therapy is important for local tumour control, however, radioresistance remains a substantial clinical problem. We hypothesise that alterations in mitochondrial function and energy metabolism are involved in the radioresistance of oesophageal adenocarcinoma (OAC). To investigate this, we used an established isogenic cell line model of radioresistant OAC. Radioresistant cells (OE33 R) demonstrated significantly increased levels of random mitochondrial mutations, which were coupled with alterations in mitochondrial function, size, morphology and gene expression, supporting a role for mitochondrial dysfunction in the radioresistance of this model. OE33 R cells also demonstrated altered bioenergetics, demonstrating significantly increased intracellular ATP levels, which was attributed to enhanced mitochondrial respiration. Radioresistant cells also demonstrated metabolic plasticity, efficiently switching between the glycolysis and oxidative phosphorylation energy metabolism pathways, which were accompanied by enhanced clonogenic survival. This data was supported in vivo, in pre-treatment OAC tumour tissue. Tumour ATP5B expression, a marker of oxidative phosphorylation, was significantly increased in patients who subsequently had a poor pathological response to neoadjuvant CRT. This suggests for the first time, a role for specific mitochondrial alterations and metabolic remodelling in the radioresistance of OAC

Identifying a Novel Role for Fractalkine (CX3CL1) in Memory CD8(+) T Cell Accumulation in the Omentum of Obesity-Associated Cancer Patients

The omentum is enriched with pro-inflammatory effector memory CD8+ T cells in patients with the obesity-associated malignancy, esophagogastric adenocarcinoma (EAC) and we have identified the chemokine macrophage inflammatory protein-1alpha as a key player in their active migration to this inflamed tissue. More recently, others have established that subsets of memory CD8+ T cells can be classified based on their surface expression of CX3CR1; the specific receptor for the inflammatory chemokine fractalkine. CD8+ T cells expressing intermediate levels (CX3CR1INT) are defined as peripheral memory, those expressing the highest levels (CX3CR1HI) are effector memory/terminally differentiated and those lacking CX3CR1 (CX3CR1NEG) are classified as central memory. To date, the fractalkine:CX3CR1 axis has not been examined in the context of CD8+ T cell enrichment in the omentum and here we examine this chemokines involvement in the accumulation of memory CD8+ T cells in the omentum of EAC patients. Our data show that fractalkine is significantly enriched in the omentum of EAC patients and drives migration of T cells derived from EAC patient blood. Furthermore, CX3CR1 is endocytosed specifically by CD8+ T cells upon encountering fractalkine, which is consistent with the significantly diminished frequencies of CX3CR1INT and CX3CR1HI CD8+ T cells in the fractalkine-rich environment of omentum in EAC, relative to matched blood. Fractalkine-mediated endocytosis of CX3CR1 by CD8+ T cells is sustained and is followed by enhanced surface expression of L-selectin (CD62L). These novel data align with our findings that circulating CX3CR1NEG CD8+ T cells express higher levels of L-selectin than CX3CR1INT CD8+ T cells. This is consistent with previous reports and implicates fractalkine in the conversion of CX3CR1INT CD8+ T cells to a CX3CR1NEG phenotype characterized by alterations in the migratory capacity of these T cells. For the first time, these findings identify fractalkine as a driver of T cell migration to the omentum in EAC and indicate that CD8+ T cells undergo sequenced fractalkine-mediated alterations in CX3CR1 and L-selectin expression. These data implicate fractalkine as more than a chemotactic cytokine in obesity-associated meta-inflammation and reveal a role for this chemokine in the maintenance of the CX3CR1NEG CD8+ T cell populations

The value of double balloon enteroscopy in diagnosing blue rubber bleb naevus syndrome: a case report

Blue rubber bleb naevus syndrome is a rare vascular disorder associated with multiple gastrointestinal haemangiomas that have the potential for life-threatening haemorrhage. These may be difficult to diagnose, and have classically been described using computed tomographic studies and/or mesenteric angiography. Resected surgical specimens of these lesions, especially in the small bowel, have often been extensive and poorly localized. The recent advent and progressive development of double balloon enteroscopy has allowed the direct visualization and marking of these enteric lesions and serves as a valuable adjunct not only in diagnosis but also planning prior to surgery to allow accurate estimate of the extent of resection

The impact of Nutrition and Gastrointestinal Symptoms on Health-related Quality of Life in Survivorship after Oesophageal Cancer Surgery

Summary Background and Aims Oesophagectomy is the primary curative treatment for oesophageal cancer but is associated with considerable postoperative morbidity and mortality. To better understand the aetiology of impaired health-related quality of life (HRQL) in oesophageal cancer survivors (OCS), this study sought to determine the longitudinal changes in nutritional status, nutrition-impact symptoms (NIS), and HRQL in this cohort, and to determine which variables have the greatest impact on postoperative HRQL decline. Methods Data, derived from St. James\u27 Hospital, Dublin, included patients who underwent oesophagectomy from October 2017 to May 2019 and attended clinic preoperatively and 6 months postoperatively. A subset attended a further 12-month appointment. HRQL and symptom data were collected using validated questionnaires and anthropometric measures were completed by clinicians. Data were analysed using SPSS. Results A total of 66 patients were studied preoperatively and 6 months postoperatively, of whom 37 were studied at 12 months postoperatively. Malnutrition remained prevalent at each time-point, although rates did not significantly change longitudinally. Conversely, the prevalence of malabsorption (7.6%–14.3%, P\u3c0.001) and dumping syndrome (67.7%–74.3%, P=0.003) significantly increased with increasing time postoperatively. NIS were significantly associated with impaired HRQL function scores and were independent predictors of global quality of life (gQOL) score postoperatively (P=0.004). A diagnostic threshold of gastrointestinal symptom severity (11.5) that identifies patients at risk of impaired gQOL was therefore reported. Conclusion Malnutrition and NIS are prevalent post-oesophagectomy, the latter significantly associated with reduced HRQL. Targeted intervention in those with severe NIS could be highly beneficial, highlighting the need for dietetic input in OCS

In vitro ecotoxicological assessment of pelagic ecosystems

The ICES biological effects monitoring in pelagic ecosystems (BECPELAG) workshop is a multi-national, multi-disciplinary workshop aimed at establishing suitable techniques for monitoring the effects of contaminants on pelagic ecosystems. One of the many activities that have been performed concurrently is the extraction of water samples using semi-permeable membrane devices (SPMDs) and large volume solid phase extraction (SPE) followed by in vitro testing and targeted chemical analysis of the concentrated extracts. The following in vitro assays were used: DR-CALUX, yeast oestrogen and androgen screen (YES & YAS), blue mussel (Mytilus edulis) embryo, Tisbe battagliai, and Skeletonema costatum. Data from the study are presented along with recommendations on procedures for the use of in vitro in the monitoring of the pelagic environment

Preoperative Exercise to Improve Fitness in Patients Undergoing Complex Surgery for Cancer of the Lung or Oesophagus (PRE-HIIT): Protocol for a Randomized Controlled Trial

Patients with cancer of the lung or oesophagus, undergoing curative treatment, usually require a thoracotomy and a complex oncological resection. These surgeries carry a risk of major morbidity and mortality, and risk assessment, preoperative optimisation, and enhanced recovery after surgery (ERAS) pathways are modern approaches to optimise outcomes. Pre-operative fitness is an established predictor of postoperative outcome, accordingly, targeting pre-operative fitness through exercise prehabilitation has logical appeal. Exercise prehabilitation is challenging to implement however due to the short opportunity for intervention between diagnosis and surgery. Therefore, individually prescribed, intensive exercise training protocols which convey clinically meaningful improvements in cardiopulmonary fitness over a short period need to be investigated. This project will examine the influence of exercise prehabilitation on physiological outcomes and postoperative recovery and, through evaluation of health economics, the impact of the programme on hospital costs