Potential of damage associated molecular patterns in synergising radiation and the immune response in oesophageal cancer.

BACKGROUND: There is an intimate crosstalk between cancer formation, dissemination, treatment response and the host immune system, with inducing tumour cell death the ultimate therapeutic goal for most anti-cancer treatments. However, inducing a purposeful synergistic response between conventional therapies and the immune system remains evasive. The release of damage associated molecular patterns (DAMPs) is indicative of immunogenic cell death and propagation of established immune responses. However, there is a gap in the literature regarding the importance of DAMP expression in oesophageal adenocarcinoma (OAC) or by immune cells themselves. AIM: To investigate the effects of conventional therapies on DAMP expression and to determine whether OAC is an immunogenic cancer. METHODS: We investigated the levels of immunogenic cell death-associated DAMPs, calreticulin (CRT) and HMGB1 using an OAC isogenic model of radioresistance. DAMP expression was also assessed directly using ex vivo cancer patient T cells (n = 10) and within tumour biopsies (n = 9) both pre and post-treatment with clinically relevant chemo(radio)therapeutics. RESULTS: Hypoxia in combination with nutrient deprivation significantly reduces DAMP expression by OAC cells in vitro. Significantly increased frequencies of T cell DAMP expression in OAC patients were observed following chemo(radio)therapy, which was significantly higher in tumour tissue compared with peripheral blood. Patients with high expression of HMGB1 had a significantly better tumour regression grade (TRG 1-2) compared to low expressors. CONCLUSION: In conclusion, OAC expresses an immunogenic phenotype with two distinct subgroups of high and low DAMP expressors, which correlated with tumour regression grade and lymphatic invasion. It also identifies DAMPs namely CRT and HMGB1 as potential promising biomarkers in predicting good pathological responses to conventional chemo(radio)therapies currently used in the multimodal management of locally advanced disease.

Metformin is a metabolic modulator and radiosensitiser in rectal cancer.

Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer.

Application of PREVENA (Surgical Incision Protection System) in reducing surgical site infections following reversal of ileostomy or colostomy: the PRIC study protocol.

AIM: There is a current lack of evidence in the literature to support the routine use of negative pressure wound therapy (NPWT) to reduce the risk of surgical site infections (SSI) in the setting of ileostomy or colostomy reversal. The aim of this study is to examine whether routine NPWT confers a lower rate of SSI than conventional dressings following reversal of ileostomy or colostomy. METHODS: The PRIC study is a randomized, controlled, open-label, multi-centre superiority trial to assess whether routine NPWT following wound closure confers a lower rate of SSI following reversal of ileostomy or colostomy when compared to conventional dressings. Participants will be consecutively identified and recruited. Eligible participants will be randomized in a 1:1 allocation ratio, to receive either the NPWT (PREVENA) dressings or conventional dressings which will be applied immediately upon completion of surgery. PREVENA dressings will remain applied for a duration of 7 days. Surgical wounds will then be examined on post-operative day seven as well as during follow-up appointments in OPD for any evidence of SSI. In the interim, public health nurses (PHN) will provide out-patient support services incorporating wound assessment and care as part of a routine basis. Study investigators will liaise with PHN to gather the relevant data in relation to the time to wound healing. Our primary endpoint is the incidence of SSI within 30 days of stoma reversal. Secondary endpoints include measuring time to wound healing, evaluating wound healing and aesthetics and assessing patient satisfaction. CONCLUSION: The PRIC study will assess whether routine NPWT following wound closure is superior to conventional dressings in the reduction of SSI following reversal of ileostomy or colostomy and ascertain whether routine NPWT should be considered the new standard of care.

Prostate radiotherapy and the risk of secondary rectal cancer-a meta-analysis.

PURPOSE: Radiotherapy is being used increasingly in the treatment of prostate cancer. However, ionising radiation may confer a small risk of a radiation-induced secondary malignancy. We aim to assess the risk of rectal cancer following pelvic radiotherapy for prostate cancer. METHODS: A search was conducted of the PubMed/MEDLINE, EMBASE and Web of Science databases identifying studies reporting on the risk of rectal cancer following prostatic radiotherapy. Studies must have included an appropriate control group of non-irradiated prostate cancer patients. A meta-analysis was performed to assess the risk of prostatic radiotherapy on subsequent rectal cancer diagnosis. RESULTS: In total, 4757 articles were screened with eight studies meeting the predetermined criteria. A total of 796,386 patients were included in this meta-analysis which showed an increased odds ratio (OR) for subsequent rectal cancer in prostate cancer patients treated with radiotherapy compared to those treated by non-radiotherapy means (OR 1.45, 1.07-1.97, p = 0.02). CONCLUSION: These findings confirm that prostate radiotherapy significantly increases the risk of subsequent rectal cancer. This risk has implications for treatment selection, surveillance and patient counselling. However, it is crucial that this information is presented in a rational and comprehensible manner that does not disproportionately frighten or deter patients from what might be their most suitable treatment modality.

Opposing Immune-Metabolic Signature in Visceral Versus Subcutaneous Adipose Tissue in Patients with Adenocarcinoma of the Oesophagus and the Oesophagogastric Junction.

Oesophageal adenocarcinoma (OAC) is an exemplar model of obesity-associated cancer. Previous work in our group has demonstrated that overweight/obese OAC patients have better responses to neoadjuvant therapy, but the underlying mechanisms are unknown. Unravelling the immune-metabolic signatures of adipose tissue may provide insight for this observation. We hypothesised that different metabolic pathways predominate in visceral (VAT) and subcutaneous adipose tissue (SAT) and inflammatory secretions will differ between the fat depots. Real-time ex vivo metabolic profiles of VAT and SAT from 12 OAC patients were analysed. These samples were screened for the secretion of 54 inflammatory mediators, and data were correlated with patient body composition. Oxidative phosphorylation (OXPHOS) was significantly higher in VAT when compared to SAT. OXPHOS was significantly higher in the SAT of patients receiving neoadjuvant treatment. VEGF-A, VEGF-C, P1GF, Flt-1, bFGF, IL-15, IL-16, IL-17A, CRP, SAA, ICAM-1, VCAM-1, IL-2, IL-13, IFN-γ, and MIP-1ß secretions were significantly higher from VAT than SAT. Higher levels of bFGF, Eotaxin-3, and TNF-α were secreted from the VAT of obese patients, while higher levels of IL-23 and TARC were secreted from the SAT of obese patients. The angiogenic factors, bFGF and VEGF-C, correlated with visceral fat area. Levels of OXPHOS are higher in VAT than SAT. Angiogenic, vascular injury and inflammatory cytokines are elevated in VAT versus SAT, indicating that VAT may promote inflammation, linked to regulating treatment response.

Life-Threatening Intraparenchymal Hemorrhage of Steroid-Induced Hepatic Adenomas in a Healthy Man.

Hepatocellular adenomas are uncommon benign epithelial tumors of the liver that are associated with several risk factors such as anabolic androgens and oral contraceptive pills. They may present as incidental findings, with abdominal pain or hemorrhage. This case report details the presentation and management of a life-threatening hepatocellular adenomas hemorrhage in a seemingly healthy 28-year-old man. After initial conservative management, a clinical deterioration prompted urgent reevaluation and successful embolization of the liver through transarterial embolization. As oral contraceptive pills use and anabolic steroid abuse have become more prevalent in recent decades, we may begin to see more of these presentations.

The role of intraoperative radiotherapy in advanced rectal cancer: a meta-analysis.

AIM: Patients with locally advanced and locally recurrent rectal cancer (LARC/LRRC) experience higher rates of local recurrence (LR) and poorer overall survival than patients with primary rectal cancer restricted to the mesorectum despite improved neoadjuvant treatment regimens and radical surgical procedures. Intraoperative radiotherapy (IORT) has been suggested as an adjunctive tool in the surgical management of these challenging cases. However, clear evidence regarding the oncological benefit of IORT is sparse. The aim of this review was to update this evidence in the era of standardized neoadjuvant radiotherapy administration. METHOD: A systematic review of patients who received IORT as part of multimodal treatment for advanced rectal cancer from 2000 to 2020 and an analysis of IORT and surgery/external beam radiotherapy (EBRT) groups was performed. The primary endpoint was the rate of LR between the two groups. RESULTS: Seven papers met the predefined criteria. LR was reduced by the addition of IORT when compared with the surgery/EBRT alone group (14.7% vs. 21.4%; OR 0.55, 95% CI 0.27-1.14; p = 0.11). There was no increase in reported genitourinary morbidity, wound issues, pelvic collections or anastomotic leak in those patients who received IORT. Notably, there was no survival difference between the two groups. CONCLUSION: The addition of IORT to current treatment strategies in the management of patients with LARC/LRRC is associated with a lower rate of locoregional recurrence without increased morbidity. However, this marks a highly selective group of patients, with heterogeneity regarding indications, prior neoadjuvant treatments and/or IORT dosing.

Obesity and anastomotic leak rates in colorectal cancer: a meta-analysis.

PURPOSE: Anastomotic leak (AL) following colorectal cancer resection is associated with considerable morbidity and mortality with an impact on recurrence rates and survival. The impact of obesity on AL rates is debated. This meta-analysis aims to investigate the relationship between obesity and AL. METHODS: A search was conducted of the PubMed/MEDLINE, and Web of Science databases and included studies were split into Western and Asian groups based on population-specific body mass index (BMI) ranges for obesity. A meta-analysis was performed to assess the impact of obesity on AL rate following colorectal cancer resection. RESULTS: Two thousand three hundred and four articles were initially screened. Thirty-one studies totaling 32,953 patients were included. Patients with obesity had a statistically significant increase in AL rate in all Western and Asian study groups. However, this increase was only clinically significant in the rectal anastomotic subgroups-Western: 10.8% vs 8.4%, OR 1.57 (1.01-2.44) and Asian: 9.4% vs 7.4%, OR 1.58 (1.07-2.32). CONCLUSIONS: The findings of this analysis confirm that obesity is a significant risk factor for anastomotic leak, particularly in rectal anastomoses. This effect is thought to be primarily mediated via technical difficulties of surgery although metabolic and immunological factors may also play a role. Obesity in patients undergoing restorative CRC resection should be discussed and considered as part of the pre-operative counselling.

The Protein Secretome Is Altered in Rectal Cancer Tissue Compared to Normal Rectal Tissue, and Alterations in the Secretome Induce Enhanced Innate Immune Responses.

Locally advanced rectal cancer is treated with neoadjuvant-chemoradiotherapy; however, only ~22% of patients achieve a complete response, and resistance mechanisms are poorly understood. The role of inflammation and immune cell biology in this setting is under-investigated. In this study, we profiled the inflammatory protein secretome of normal (non-cancer) (n = 8) and malignant rectal tissue (n = 12) pre- and post-radiation in human ex vivo explant models and examined the influence of these untreated and treated secretomes on dendritic cell biology (n = 8 for cancer and normal). These resultant profiles were correlated with patient clinical characteristics. Nineteen factors were secreted at significantly higher levels from the rectal cancer secretome when compared to the normal rectal secretome; Flt-1, P1GF, IFN-γ, IL-6, IL-10, CCL20, CCL26, CCL22, CCL3, CCL4, CCL17, GM-CSF, IL-12/IL-23p40, IL-17A, IL-1α, IL-17A/F, IL-1RA, TSLP and CXCL10 (p < 0.05). Radiation was found to have differential effects on normal rectal tissue and rectal cancer tissue with increased IL-15 and CCL22 secretion following radiation from normal rectal tissue explants (p < 0.05), while no significant alterations were observed in the irradiated rectal cancer tissue. Interestingly, however, the irradiated rectal cancer secretome induced the most potent effect on dendritic cell maturation via upregulation of CD80 and PD-L1. Patient's visceral fat area correlated with secreted factors including CCL20, suggesting that obesity status may alter the tumour microenvironment (TME). These results suggest that radiation does not have a negative effect on the ability of the rectal cancer TME to induce an immune response. Understanding these responses may unveil potential therapeutic targets to enhance radiation response and mitigate normal tissue injury. Tumour irradiation in this cohort enhances innate immune responses, which may be harnessed to improve patient treatment outcome.

Radiation-induced Bystander Effect (RIBE) alters mitochondrial metabolism using a human rectal cancer ex vivo explant model.

Locally advanced rectal cancer is treated with neoadjuvant-chemoradiotherapy, however only 22% of patients achieve a complete response. Resistance mechanisms are poorly understood. Radiation-induced Bystander Effect (RIBE) describes the effect of radiation on neighbouring unirradiated cells. We investigated the effects of ex vivo RIBE-induction from normal and rectal cancer tissue on bystander cell metabolism, mitochondrial function and metabolomic profiling. We correlated bystander events to patient clinical characteristics. Ex vivo RIBE-induction caused metabolic alterations in bystander cells, specifically reductions in OXPHOS following RIBE-induction in normal (p = 0.01) and cancer tissue (p = 0.03) and reduced glycolysis following RIBE-induction in cancer tissue (p = 0.01). Visceral fat area correlated with glycolysis (p = 0.02) and ATP production (p = 0.03) following exposure of cells to TCM from irradiated cancer biopsies. Leucine levels were reduced in the irradiated cancer compared to the irradiated normal secretome (p = 0.04). ROS levels were higher in cells exposed to the cancer compared to the normal secretome (p = 0.04). RIBE-induction ex vivo causes alterations in the metabolome in normal and malignant rectal tissue along with metabolic alterations in bystander cellular metabolism. This may offer greater understanding of the effects of RIBE on metabolism, mitochondrial function and the secreted metabolome.