Optimal Treatment Strategies for cT2 Staged Adenocarcinoma of the Esophagus and the Gastroesophageal Junction: A Multinational, High-volume Center Retrospective Cohort Analysis.

OBJECTIVE: A multi-national high-volume center study was undertaken to evaluate outcomes after primary surgery (PS) or neoadjuvant treatment followed by surgery (NAT/S) in cT2 staged adenocarcinomas of the esophagus (EAC) and gastroesophageal junction (GEJ). BACKGROUND: Optimal treatment approach with either NAT/S or PS for clinically staged cT2cNany or cT2N0 EAC and GEJ remains unknown due to the lack of randomized controlled trials. METHODS: Retrospective analysis of prospectively maintained databases from ten centers was performed. Between 01/2012-08/2023 645 patients who fulfilled inclusion criteria of GEJ Siewert type I, II or EAC with cT2 status at diagnosis underwent PS or NAT/S with curative intent. Primary endpoint was overall survival (OS). RESULTS: In the cT2cNany cohort 192 patients (29.8%) underwent PS and 453 (70.2%) underwent NAT/S. In all cT2cN0 patients (n=333), NAT/s remained the more frequent treatment (56.2%). Patients undergoing PS were in both cT2 cohorts older (P<0.001) and had a higher ASA classification (P<0.05). R0 resection showed no differences between NAT/S and PS in both cT2 cohorts (P>0.4).Median OS was 51.0 months in the PS group (95% CI 31.6-70.4) versus 114.0 months (95% CI 53.9-174.1) in the NAT/S group (P=0.003) of cT2cNany patients. For cT2cN0 patients NAT/S was associated with longer OS (P=0.002) and disease-free survival (DFS) (P=0.001). After propensity score matching of cT2N0 patients, survival benefit for NAT/S remained (P=0.004). Histopathology showed that 38.1% of cT2cNany and 34.2% of cT2cN0 patients were understaged. CONCLUSIONS: Due to unreliable identification of cT2N0 disease, all patients should be offered a multimodal therapeutic approach.

Evaluating the impact of enhanced recovery after surgery protocols following emergency laparotomy - A systematic review and meta-analysis of randomised clinical trials.

INTRODUCTION: Enhanced recovery after surgery (ERAS) protocols are an evidence-based, multidisciplinary, and systematic approach to peri-operative care, which attempt to reduce the anticipated physiological strain on patients after major surgery. This meta-analysis of randomised clinical trials (RCTs) evaluated the impact of ERAS following emergency laparotomy versus standard care. METHODS: A systematic review was performed as per PRISMA guidelines. Meta-analysis was performed using RevMan v5.4. RESULTS: Six RCTs involving 509 patients were included. Patients randomised to ERAS had reduced post-operative nausea and vomiting (PONV) (odds ratio (OR): 0.32, 95 â€‹% confidence interval (CI): 0.20-0.51), time to ambulation (mean difference (MD): 1.67, 95 â€‹% CI: -2.56 to -0.78) and bowel opening (MD: -1.26, 95 â€‹% CI: -2.03 to -0.49), length of stay (LOS) (MD: -2.92 95 â€‹% CI: -3.73 - - 2.10), pulmonary complications (OR: 0.43, 95 â€‹% CI: 0.24-0.75), surgical site (OR: 0.33 95 â€‹% CI: 0.2-0.50) and urinary tract infections (OR: 0.48 95 â€‹% CI: 0.19-1.16). CONCLUSION: ERAS successfully reduced patient recovery, LOS, and complications. ERAS protocols should be deployed, where feasible, for emergency laparotomy.

Evidence for the Positive Impact of Centralization in Esophageal Cancer Surgery.

OBJECTIVE: In this study we analyzed the impact of centralization on key metrics, outcomes and patterns of care at the Irish National Center. SUMMARY BACKGROUND DATA: Overall survival rates in esophageal cancer in the West have doubled in the last 25 years. An international trend towards centralization may be relevant, however this model remains controversial with Ireland, centralizing esophageal cancer surgery in 2011. STUDY DESIGN: All patients (n=1245) with adenocarcinoma of the esophagus or junction treated with curative intent involving surgery, including endoscopic surgery, were included (n= 461 from 2000-2011, and 784 from 2012-2022). All data entry was prospectively recorded. Overall survival was measured (i) for the entire cohort; (ii) patients with locally advanced disease (cT2-3N0-3); and (iii) patients undergoing neoadjuvant therapy. All complications were recorded as per Esophageal Complication Consensus Group (ECCG) definitions, and the Clavien Dindo (CD) severity classification. STATISTICAL ANALYSIS: Data were analyzed using GraphPad Prism (v.6.0) for Windows and SPSS (v.23.0) software (SPSS,Chicago,IL) RStudio (Rversion4.2.2). Survival times were calculated using log-rank test and a Cox-regression analysis, and Kaplan-Meier curves generated. RESULTS: Endotherapy for cT1a/IMC adenocarcinoma increased from 40 (9% total) to 245 (31% total) procedures between the pre-centralization (pre-C) and post-centralization (post-C) periods. A significantly (P<0.001) higher proportion of patients with cT2-3N0-3 disease in the post-C period underwent neoadjuvant therapy (66% vs 53%). Operative mortality was lower (P=0.02) post-C, at 2% vs 4.5%, and>IIIa CD major complications decreased from 33% to 25% (P<0.01). Recurrence rates were lower post-C (38% vs 53%, P<0.01). Median overall survival was 73.83 versus 47.23 months in the 2012-22 and 2000-11 cohorts respectively (P<0.001). For those who received neoadjuvant therapy, the median survival was 28.5 months pre-C and 42.5 months post-C (P<0.001). CONCLUSION: These data highlight improvements in both operative outcomes and survival from the time of centralization, and a major expansion of endoscopic surgery. Although not providing proof, the study suggests a positive impact of formal centralization with governance on key quality metrics, and an evolution in patterns of care.

Prophylactic negative pressure wound therapy (NPWT) in laparotomy wounds (PROPEL-2): protocol for a randomized clinical trial.

BACKGROUND: A proportion of patients undergoing midline laparotomy will develop surgical site infections after surgery. These complications place considerable financial burden on healthcare economies and have negative implications for patient health and quality of life. The prophylactic application of negative pressure wound therapy devices has been mooted as a pragmatic strategy to reduce surgical site infections. Nevertheless, further availability of multicentre randomized clinical trial data evaluating the prophylactic use of negative pressure wound therapy following midline laparotomy is warranted to definitely provide consensus in relation to these closure methods, while also deciphering potential differences among subgroups. The aim of this study is to determine whether prophylactic negative pressure wound therapy reduces postoperative wound complications in patients undergoing midline laparotomy. METHODS: PROPEL-2 is a multicentre prospective randomized clinical trial designed to compare standard surgical dressings (control arm) with negative pressure wound therapy dressings (Prevena™ and PICO™ being the most commonly utilized). Patient recruitment will include adult patients aged 18 years or over, who are indicated to undergo emergency or elective laparotomy. To achieve 90% power at the 5% significance level, 1006 patients will be required in each arm, which when allowing for losses to follow-up, 10% will be added to each arm, leaving the total projected sample size to be 2013 patients, who will be recruited across a 36-month enrolment period. CONCLUSION: The PROPEL-2 trial will be the largest independent multicentre randomized clinical trial designed to assess the role of prophylactic negative pressure wound therapy in patients indicated to undergo midline laparotomy. The comparison of standard treatment to two commercially available negative pressure wound therapy devices will help provide consensus on the routine management of laparotomy wounds. Enrolment to PROPEL-2 began in June 2023. Registration number: NCT05977816 (http://www.clinicaltrials.gov).

Differential signaling effects of blood glucose on delay discounting in individuals with and without type 1 diabetes.

Based on the signaling hypothesis of blood glucose (BG), a rise in BG levels signals a positive energy budget for healthy individuals but cellular starvation for individuals with type 1 diabetes. We examined this novel prediction and its intervention implications in the context of delay discounting, the degree to which delayed rewards are discounted, and the regulatory effects of insulin ingestion. We recruited 44 adults with type 1 diabetes (mean age 30.8 years, diabetes duration 15.4 years) and recorded their BG levels. The delay discounting rate was measured using the intertemporal choice task, where participants were required to choose between sets of smaller-and-sooner (SS) and larger-and-later (LL) rewards. In addition, 82 age-matched healthy participants were recruited to provide a baseline comparison on delay discounting. Random forest analysis showed that among many diagnostic factors, delay discounting was most dominating in differentiating the individuals with type 1 diabetes from the control participants. A hierarchical linear mixed model revealed that participants with type 1 diabetes had a stronger preference for SS rewards (p < .001) after controlling for covariates. Participants who had insulin delivered before the last meal exhibited a stronger preference for LL rewards compared to after-meal delivery. In contrast, subjective measures (e.g., self-reported hunger) failed to predict the participants' actual BG levels and delay discounting rates. In sum, individuals with type 1 diabetes tend to discount future rewards excessively compared to the control participants. Pre-meal insulin ingestion was associated with a higher LL preference for future rewards.

Management of early oesophageal cancer: An overview.

The incidence of esophageal cancer, namely the adenocarcinoma subtype, continues to increase exponentially on an annual basis. The indolent nature of the disease renders a significant proportion inoperable at first presentation, however, with the increased utilisation of endoscopy, many early lesions are now being identified which are suitable for endotherapeutic approaches. This article details the options available for dealing with early esophageal cancer by endoscopic mean obviating the need for surgery thereby avoiding the potential morbidity and mortality of such intervention.

Analysing the Combined Effects of Radiotherapy and Chemokine Receptor 5 Antagonism: Complementary Approaches to Promote T Cell Function and Migration in Oesophageal Adenocarcinoma.

The presence of an immunosuppressive tumour microenvironment in oesophageal adenocarcinoma (OAC) is a major contributor to poor responses. Novel treatment strategies are required to supplement current regimens and improve patient survival. This study examined the immunomodulatory effects that radiation therapy and chemokine receptor antagonism impose on T cell phenotypes in OAC with a primary goal of identifying potential therapeutic targets to combine with radiation to improve anti-tumour responses. Compared with healthy controls, anti-tumour T cell function was impaired in OAC patients, demonstrated by lower IFN-γ production by CD4+ T helper cells and lower CD8+ T cell cytotoxic potential. Such diminished T cell effector functions were enhanced following treatment with clinically relevant doses of irradiation. Interestingly, CCR5+ T cells were significantly more abundant in OAC patient blood compared with healthy controls, and CCR5 surface expression by T cells was further enhanced by clinically relevant doses of irradiation. Moreover, irradiation enhanced T cell migration towards OAC patient-derived tumour-conditioned media (TCM). In vitro treatment with the CCR5 antagonist Maraviroc enhanced IFN-γ production by CD4+ T cells and increased the migration of irradiated CD8+ T cells towards irradiated TCM, suggesting its synergistic therapeutic potential in combination with irradiation. Overall, this study highlights the immunostimulatory properties of radiation in promoting anti-tumour T cell responses in OAC and increasing T cell migration towards chemotactic cues in the tumour. Importantly, the CCR5 antagonist Maraviroc holds promise to be repurposed in combination with radiotherapy to promote anti-tumour T cell responses in OAC.

The Impact of a Pandemic on a Military Oral and Maxillofacial Pathology Biopsy Service.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) and the resulting societal reaction presented new challenges to the medical community by limiting patient access to care in 2020 and 2021. The Navy Postgraduate Dental School (NPDS) oral and maxillofacial pathology biopsy service is dependent on in-office physician or dentist appointments and patient biopsies. The purpose of this study was to understand the regulatory and societal impacts of COVID-19 restrictions on biopsy service submissions by assessing NPDS biopsy submission quantities and disease distribution. MATERIALS AND METHODS: All NPDS oral and maxillofacial pathology biopsy submissions from calendar years 2015 to 2016 and 2019 to 2021 were evaluated, and patient demographics and biopsy diagnoses were recorded in a biopsy registry. Data collected included age, sex, biopsy site, and diagnosis. Data from 2015, 2016, and 2019 were defined as pre-COVID and 2020 and 2021 as COVID. Biopsy reports for each year were organized in quarters. Diagnoses were categorized as malignant, pre-malignant, or benign. Categorical and continuous data were evaluated and presented as counts with percentages and means or medians with standard deviations, respectively. Significant differences in proportions or means were assessed using chi-square analysis or Student t-test, respectively. Cases were aggregated by quarter and year and assessed for temporal trends using linear regression analysis. RESULTS: The study evaluated 9,351 biopsy submission reports. The annual pre-COVID count mean (± standard deviation) and yearly counts for 2020 and 2021 were 2,063 ± 33.3, 1,421, and 1,742, respectively. The mean (± standard deviation) percentage of diagnoses classified as malignant from pre-COVID, 2020, and 2021 were 2.46 ± 0.005%, 3.59%, and 3.04%, respectively. Case counts and representation as a percentage of all biopsy diagnoses for Human Papillomavirus (HPV)-associated squamous cell carcinoma increased significantly during COVID compared to pre-COVID years (P < .05). CONCLUSIONS: Overall, preventative COVID-19 health measures and protocols resulted in a reduction in biopsy submission frequency, particularly during the second quarter (April to June) of 2020. However, case counts for malignant biopsies remained consistent between pre-COVID and COVID time intervals, suggesting that the identification and analysis of cases requiring follow-on care were unaffected by COVID-19 protocols.

Management of esophageal anastomotic leaks, a systematic review and network meta-analysis.

There is currently no consensus as to how to manage esophageal anastomotic leaks. Intervention with endoscopic vacuum-assisted closure (EVAC), stenting, reoperation, and conservative management have all been mooted as potential options. To conduct a systematic review and network meta-analysis (NMA) to evaluate the optimal management strategy for esophageal anastomotic leaks. A systematic review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines with extension for NMA. NMA was performed using R packages and Shiny. In total, 12 retrospective studies were included, which included 511 patients. Of the 449 patients for whom data regarding sex was available, 371 (82.6%) were male, 78 (17.4%) were female. The average age of patients was 62.6 years (standard deviation 10.2). The stenting cohort included 245 (47.9%) patients. The EVAC cohort included 123 (24.1%) patients. The conservative cohort included 87 (17.0%) patients. The reoperation cohort included 56 (10.9%) patients. EVAC had a significantly decreased complication rate compared to stenting (odds ratio 0.23 95%, confidence interval [CI] 0.09;0.58). EVAC had a significantly lower mortality rate than stenting (odds ratio 0.43, 95% CI 0.21; 0.87). Reoperation was used in significantly larger leaks than stenting (mean difference 14.66, 95% CI 4.61;24.70). The growing use of EVAC as a first-line intervention in esophageal anastomotic leaks should continue given its proven effectiveness and significant reduction in both complication and mortality rates. Surgical management is often necessary for significantly larger leaks and will likely remain an effective option in uncontained leaks with systemic features.

Real-time ex vivo monitoring of NK cell migration toward obesity-associated oesophageal adenocarcinoma following modulation of CX3CR1.

Oesophagogastric adenocarcinomas (OAC) are poor prognosis, obesity-associated cancers which may benefit from natural killer (NK) cell-based immunotherapies. Cellular immunotherapies encounter two key challenges to their success in OAC, namely recruitment to extratumoural tissues such as the omentum at the expense of the tumour and an immunosuppressive tumour microenvironment (TME) which can hamper NK cell function. Herein, we examined approaches to overcome the detrimental impact of obesity on NK cells and NK cell-based immunotherapies. We have demonstrated that NK cells migrate preferentially to the chemotactic signals of OAC patient-derived omentum over tumour in an ex vivo model of immune cell migration. We have identified CX3CR1 modulation and/or tumour chemokine profile remodelling as approaches to skew NK cell migration towards tumour. We also report targetable immunosuppressive facets of the obese OAC TME which dampen NK cell function, in particular cytotoxic capabilities. These data provide insights into approaches to therapeutically overcome key challenges presented by obesity and will inform superior design of NK cell-based immunotherapies for OAC.

Evaluating the Impact of Enhanced Recovery After Surgery Protocols on Surgical Outcomes Following Bariatric Surgery-A Systematic Review and Meta-analysis of Randomised Clinical Trials.

BACKGROUND: Enhanced recovery after surgery (ERAS) programmes are evidence-based care improvement processes for surgical patients, which are designed to decrease the impact the anticipated negative physiological cascades following surgery. AIM: To perform a systematic review and meta-analysis of randomised clinical trials (RCTs) to evaluate the impact of ERAS protocols on outcomes following bariatric surgery compared to standard care (SC). METHODS: A systematic review was performed in accordance with PRISMA guidelines. Meta-analysis was performed using Review Manager version 5.4 RESULTS: Six RCTs including 740 patients were included. The mean age was 40.2 years, and mean body mass index was 44.1 kg/m2. Overall, 54.1% underwent Roux-en-Y gastric bypass surgery (400/740) and 45.9% sleeve gastrectomy (340/700). Overall, patients randomised to ERAS programmes had a significant reduction in nausea and vomiting (odds ratio (OR): 0.42, 95% confidence interval (CI): 0.19-0.95, P = 0.040), intraoperative time (mean difference (MD): 5.40, 95% CI: 3.05-7.77, P < 0.001), time to mobilisation (MD: - 7.78, 95% CI: - 5.46 to - 2.10, P < 0.001), intensive care unit stay (ICUS) (MD: 0.70, 95% CI: 0.13-1.27, P = 0.020), total hospital stay (THS) (MD: - 0.42, 95% CI: - 0.69 to - 0.16, P = 0.002), and functional hospital stay (FHS) (MD: - 0.60, 95% CI: - 0.98 to - 0.22, P = 0.002) compared to those who received SC. CONCLUSION: ERAS programmes reduce postoperative nausea and vomiting, intraoperative time, time to mobilisation, ICUS, THS, and FHS compared to those who received SC. Accordingly, ERAS should be implemented, where feasible, for patients indicated to undergo bariatric surgery. Trial registration International Prospective Register of Systematic Reviews (PROSPERO - CRD42023434492.

Evaluating analgesia strategies in patients who have undergone oesophagectomy-a systematic review and network meta-analysis of randomised clinical trials.

Optimal pain control following esophagectomy remains a topic of contention. The aim was to perform a systematic review and network meta-analysis (NMA) of randomized clinical trials (RCTs) evaluating the analgesia strategies post-esophagectomy. A NMA was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-NMA guidelines. Statistical analysis was performed using Shiny and R. Fourteen RCTs which included 565 patients and assessed nine analgesia techniques were included. Relative to systemic opioids, thoracic epidural analgesia (TEA) significantly reduced static pain scores at 24 hours post-operatively (mean difference (MD): -13.73, 95% Confidence Interval (CI): -27.01-0.45) (n = 424, 12 RCTs). Intrapleural analgesia (IPA) demonstrated the best efficacy for static (MD: -36.2, 95% CI: -61.44-10.96) (n = 569, 15 RCTs) and dynamic (MD: -42.90, 95% CI: -68.42-17.38) (n = 444, 11 RCTs) pain scores at 48 hours. TEA also significantly reduced static (MD: -13.05, 95% CI: -22.74-3.36) and dynamic (MD: -18.08, 95% CI: -31.70-4.40) pain scores at 48 hours post-operatively, as well as reducing opioid consumption at 24 hours (MD: -33.20, 95% CI: -60.57-5.83) and 48 hours (MD: -42.66, 95% CI: -59.45-25.88). Moreover, TEA significantly shortened intensive care unit (ICU) stays (MD: -5.00, 95% CI: -6.82-3.18) and time to extubation (MD: -4.40, 95% CI: -5.91-2.89) while increased post-operative forced vital capacity (MD: 9.89, 95% CI: 0.91-18.87) and forced expiratory volume (MD: 13.87, 95% CI: 0.87-26.87). TEA provides optimal pain control and improved post-operative respiratory function in patients post-esophagectomy, reducing ICU stays, one of the benchmarks of improved post-operative recovery. IPA demonstrates promising results for potential implementation in the future following esophagectomy.

Evaluating mesh fixation techniques for ventral hernia repair: A systematic review and network meta-analysis of randomised control trials.

INTRODUCTION: There is uncertainty regarding the optimal mesh fixation techniques for laparoscopic ventral and incisional hernia repair. AIM: To perform a systematic review and network meta-analysis of randomised control trials (RCTs) to investigate the advantages and disadvantages associated with absorbable tacks, non-absorbable tacks, non-absorbable sutures, non-absorbable staples, absorbable synthetic glue, absorbable sutures and non-absorbable tacks, and non-absorbable sutures and non-absorbable tacks. METHODS: A systematic review was performed as per PRISMA-NMA guidelines. Odds ratios (ORs) and mean differences (MDs) were extracted to compare the efficacy of the surgical approaches. RESULTS: Nine RCTs were included with 707 patients. Short-term pain was significantly reduced in non-absorbable staples (MD; -1.56, confidence interval (CI); -2.93 to -0.19) and non-absorbable sutures (MD; -1.00, CI; -1.60 to -0.40) relative to absorbable tacks. Recurrence, length of stay, operative time, conversion to open surgery, seroma and haematoma formation were unaffected by mesh fixation technique. CONCLUSION: Short-term post-operative pain maybe reduced by the use of non-absorbable sutures and non-absorbable staples. There is clinical equipoise between each modality in relation to recurrence, length of stay, and operative time.

Self-regulatory processes in goal striving during excellent distance-running performances: A qualitative study.

OBJECTIVE: Goal setting can improve endurance performance, yet how endurance performers maintain goal striving and bring it to a successful close has received limited attention. In this study, we investigated the self-regulatory processes employed by long-distance runners during goal striving in excellent competitive performances. METHOD: Through in-depth, event-focused interviews, we explored 21 long-distance runners' experiences of goal striving in excellent competitive performances (M = 77.43 h post-race). Furthermore, we recruited 10 additional participants with relevant experiences (runner n = 7, coach n = 2; sport psychologist n = 1) for external member-reflection interviews. FINDINGS: Through our matrix analysis, we interpreted that by contrasting their current and future goal status periodically throughout their excellent performances, using a process called mental contrasting with implementation intentions (MCII), this helped the runners to make decisions about whether to persist with a goal, or disengage from a goal and reengage with an alternative. Furthermore, our findings depict how these goal decisions unfolded when runners perceived they were behind, equalling, or exceeding their goal(s). We also illustrate how goal revision was used as an adaptive process to maximise performance, and to avert or manage action crises. CONCLUSIONS: Our findings extend theoretical understandings of goal striving and the self-regulatory processes endurance performers employ to attain and/or adapt their goals. Psychological support provided for athletes should go beyond simply setting goals, but also include training on mental frameworks such as MCII to manage goal-striving challenges and decisional conflict encountered during performances.

The Perceived Intersection of Parenting and Physician Assistant Training Among Current Physician Assistant Students.

PURPOSE: Despite recent advancements in policies supporting pregnancy and parenting-related resources for physician assistant (PA) students, there remains a paucity of data on the perceptions of family planning or available resources during training. The purpose of this study was to explore the perceptions of support for, and impact on, family planning and parenting, including lactation, among PA students. METHODS: This cross-sectional study used data collected from the American Academy of Physician Associates Student Survey between January and March 2023. Descriptive and inferential statistics were performed. RESULTS: A total of 557 students (557/1353; 41.2%) completed the survey. Less than 15% of students (14.4%) believed their program provides resources to support parental leave, and many students (52.1%) remained unsure whether resources exist(ed). There was a significant difference for PA students (P = .005) by gender in whether family planning affected the decision to pursue PA training over another profession, with female students proportionately affected more than male students. Medical school was the most often considered aside from PA training. Most PA students (311/548; 56.8%) also felt pressure to wait until after training to have children. In addition, multiple students (26/554; 4.7%) admitted to being asked questions they believed were biased or inappropriate regarding pregnancy or parenting during the interview process for, or after beginning, PA school. CONCLUSION: Programs should seek opportunities to support students through all stages of family planning. Support will require both cultural and structural shifts beginning with peer stigma and extending through admissions interview question audits, faculty training, university policies, and accreditation requirements.

External validation of a nomogram predicting conditional survival after tri-modality treatment of esophageal cancer.

BACKGROUND: A conditional survival nomogram was developed at a single high-volume center to predict 5-year overall survival for esophageal cancer patients after neoadjuvant chemoradiation and esophagectomy. The aim of this study was to externally validate the nomogram in a cohort of patients with esophageal adeno- or squamous cell carcinoma from another high-volume center. METHODS: Consecutive patients with an esophageal adeno- or squamous cell carcinoma who had undergone esophagectomy after being treated with preoperative chemoradiation between 2004 and 2016 were selected from a prospectively maintained institutional database. The level of discrimination for prediction of 5-year overall survival was quantified by Harrell's C statistic. Calibration of the conditional survival nomogram was visualized by plotting predicted 5-year survival and observed 5-year survival for comparison. RESULTS: Of the 296 patients examined, the probability of 5-year overall survival directly after surgery was 45% and increased to 51%, 68%, 78%, and 89% for each additional year survived. The predicted 5-year overall survival differed from the observed survival, with a calibration slope of 0.54, 0.55, 0.59, 0.73, and 1.09 directly after surgery and 1, 2, 3, and 4 years of survival after surgery, respectively. The nomogram's discrimination level for 5-year survival was moderate, with a C statistic of 0.65 compared to the 0.70 reported in the original study. CONCLUSION: The nomogram model has moderate predictive discrimination and accuracy, supporting its applicability to external cohorts to predict conditional survival. Further validation studies should empirically assess the model for predictive performance.

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.