Paraconduit hiatus hernia after esophageal cancer surgery: incidence, risk factors, and management.

In parallel with improved operative and oncologic outcomes for esophageal cancer, paraconduit hiatus hernia (PHH) is an increasingly recognized entity, both in the early postoperative phase and in long-term follow-up. The aim of this study was to assess the incidence of and risk factors for PHH, and to describe management approaches in a tertiary referral center. All patients undergoing surgery with curative intent for esophageal cancer from 2008 to 2022 at a single center were included. Early PHH was defined as occurring within three months of index surgery, with all other cases defined as late PHH. Surveillance computed tomography scans were undertaken among all disease-free patients to 5 years postoperatively. Kaplan Meier and Cox proportional hazards regression models were used to determine independent risk factors for PHH. Overall, 897 patients were studied. Totally, 62 patients (6.9%) developed PHH during follow-up. The 5-year survival-adjusted incidence of PHH was 9.7%. PHH was an asymptomatic radiologic finding in 45.5% of early and 84.3% of late cases (P = 0.070). Surgical intervention was required in 16 cases (25.8%), more commonly following early (63.6%) as compared with late PHH (17.6%, P < 0.01). Younger age (P < 0.039), initial transhiatal operative approach (P < 0.006) and extended resection of the crura (P < 0.001) were independently associated with increased risk of PHH on multivariable analysis. PHH was identified in almost 1 in 10 patients using surveillance imaging in long-term follow-up, independently associated with the transhiatal surgical approach and resection of crura, which raises consideration of prevention strategies. Surgical intervention is often required for patients with PHH presenting early after surgery, but many patients presenting with late PHH may be managed expectantly.

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).

Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.

BACKGROUND: Investigating the contributory role that epithelial cell metabolism plays in allergic inflammation is a key factor to understanding what influences dysfunction and the pathogenesis of the allergic disease eosinophilic esophagitis (EoE). We previously highlighted that the absence of hypoxia signaling through hypoxia-inducible factor (HIF)-1α in EoE contributes to esophageal epithelial dysfunction. However, metabolic regulation by HIF-1α has not been explored in esophageal allergy. OBJECTIVES: We sought to define the role of HIF-1α-mediated metabolic dysfunction in esophageal epithelial differentiation processes and barrier function in EoE. METHODS: In RNA sequencing of EoE patient biopsy samples, we observed the expression pattern of key genes involved in mitochondrial metabolism/oxidative phosphorylation (OXPHOS) and glycolysis. Seahorse bioenergetics analysis was performed on EPC2-hTERT cells to decipher the metabolic processes involved in epithelial differentiation processes. In addition, air-liquid interface cultures were used to delineate metabolic dependency mechanisms required for epithelial differentiation. RESULTS: Transcriptomic analysis identified an increase in genes associated with OXPHOS in patients with EoE. Epithelial origin of this signature was confirmed by complex V immunofluorescence of patient biopsy samples. Bioenergetic analysis in vitro revealed that differentiated epithelium was less reliant on OXPHOS compared with undifferentiated epithelium. Increased OXPHOS potential and reduced glycolytic capacity was mirrored in HIF1A-knockdown EPC2-hTERT cells that exhibited a significant absence of terminal markers of epithelial differentiation, including involucrin. Pharmacologic glucose transport inhibition phenocopied this, while rescue of the HIF-1α-deficient phenotype using the pan-prolyl hydroxylase inhibitor dimethyloxalylglycine resulted in restored expression of epithelial differentiation markers. CONCLUSIONS: An OXPHOS-dominated metabolic pattern in EoE patients, brought about largely by the absence of HIF-1α-mediated glycolysis, is linked with the deficit in esophageal epithelial differentiation.

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.

Computed tomography (CT) derived radiomics to predict post-operative disease recurrence in gastric cancer; a systematic review and meta-analysis.

INTRODUCTION: Radiomics offers the potential to predict oncological outcomes from pre-operative imaging in order to identify 'high risk' patients at increased risk of recurrence. The application of radiomics in predicting disease recurrence provides tailoring of therapeutic strategies. We aim to comprehensively assess the existing literature regarding the current role of radiomics as a predictor of disease recurrence in gastric cancer. METHODS: A systematic search was conducted in Medline, EMBASE, and Web of Science databases. Inclusion criteria encompassed retrospective and prospective studies investigating the use of radiomics to predict post-operative recurrence in ovarian cancer. Study quality was assessed using the QUADAS-2 and Radiomics Quality Score tools. RESULTS: Nine studies met the inclusion criteria, involving a total of 6,662 participants. Radiomic-based nomograms demonstrated consistent performance in predicting disease recurrence, as evidenced by satisfactory area under the receiver operating characteristic curve values (AUC range 0.72 - 1). The pooled AUCs calculated using the inverse-variance method for both the training and validation datasets were 0.819 and 0.789 respectively CONCLUSION: Our review provides good evidence supporting the role of radiomics as a predictor of post-operative disease recurrence in gastric cancer. Included studies noted good performance in predicting their primary outcome. Radiomics may enhance personalised medicine by tailoring treatment decision based on predicted prognosis.

Reducing recurrence rates in hiatal hernia repair: Results of a quality improvement study.

BACKGROUND: Patient and procedure factors are considered in the decision-making process for surgical repair of hiatal hernias. Recurrence is multi-factorial and has been shown to be related to size, type, BMI and age. AIMS: This study examined recurrence rates in a single institution, identified areas for improved surgical technique, and re-assessed recurrence following implantation of a quality improvement initiative. METHODS: A retrospective review of patients undergoing hiatal hernia repair surgery between 2018 and 2022 was conducted. Demographics, pre-operative characteristics, intra-operative procedures and recurrence rates were reviewed. RESULTS: Seventy-five patients from 2018 to 2020 and 34 patients from 2021 to 2022 were identified. The recurrence rate was 21% in 2018-2020, with 14% requiring a revisional procedure. Recurrence and re-operation were subsequently reduced to 6% in 2021 and 2022, which was statistically significant (p = 0.043). There was an increase in gastropexy from 21% to 41% following the review (p = 0.032), which was mainly reserved for large and giant hernias. Procedural and literature review, alongside gastropexy, can be attributed to recurrence rate reduction. CONCLUSIONS: It is important to educate patients on the likelihood and risk factors of recurrence. A comprehensive review of procedures and a quality improvement program in our facility for hiatal hernia repair is shown to reduce recurrence.

Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis.

Porphyrin atropisomerism, which arises from restricted σ-bond rotation between the macrocycle and a sufficiently bulky substituent, was identified in 1969 by Gottwald and Ullman in 5,10,15,20-tetrakis(o-hydroxyphenyl)porphyrins. Henceforth, an entirely new field has emerged utilizing this transformative tool. This review strives to explain the consequences of atropisomerism in porphyrins, the methods which have been developed for their separation and analysis and present the diverse array of applications. Porphyrins alone possess intriguing properties and a structure which can be easily decorated and molded for a specific function. Therefore, atropisomerism serves as a transformative tool, making it possible to obtain even a specific molecular shape. Atropisomerism has been thoroughly exploited in catalysis and molecular recognition yet presents both challenges and opportunities in medicinal chemistry.

Valid consent in the acute hospital setting: perspectives of patients and members of the public.

BACKGROUND: People who interact with healthcare services have an ethical and legal right to control their own lives, to make informed decisions, and to consent to what happens to them. For consent to be considered ethically and legally valid, three key criteria must be met: consent must be given voluntarily; people must be sufficiently informed of all options; and people should have capacity to make the decision to give or withhold their consent. AIM: This study set out to explore, through the use of surveys, the perspectives of patients and public in relation to consent. METHOD: Surveys were developed for patients and the public and administered paper based (patients) and through social media (public). RESULTS: One hundred and forty surveys were posted to patients, with a 38% response rate; 104 responses were received from the public. Ninety-six percent of patients were satisfied that the decision they made was informed; 100% felt they had made a voluntary decision; 98% felt the clinician seemed knowledgeable about the procedure. What matters most to the public were being informed about the risks associated with the proposed procedure and being assured that whatever choice they make they will receive the best care possible. CONCLUSIONS: The results highlight interesting similarities and differences in relation to consent between members of the public thinking about a possible treatment, surgery, or procedure and those patients who have actually been through the process in the past 12 months. Recommendations have been developed on the basis of these findings to co-design improvements in consent practices.

International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape : Bertinoro Workshop, November 2022.

BACKGROUND: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy. Innovative treatments, like targeted therapy or immunotherapy, have recently proved to ameliorate prognosis, but a general agreement on managing oligometastatic disease has yet to be achieved. An international multi-disciplinary workshop was held in Bertinoro, Italy, in November 2022 to verify whether achieving a consensus on at least some topics was possible. METHODS: A two-round Delphi process was carried out, where participants were asked to answer 32 multiple-choice questions about CT, laparoscopic staging and biomarkers, systemic treatment for different localization, role and indication of palliative care. Consensus was established with at least a 67% agreement. RESULTS: The assembly agreed to define oligometastases as a "dynamic" disease which either regresses or remains stable in response to systemic treatment. In addition, the definition of oligometastases was restricted to the following sites: para-aortic nodal stations, liver, lung, and peritoneum, excluding bones. In detail, the following conditions should be considered as oligometastases: involvement of para-aortic stations, in particular 16a2 or 16b1; up to three technically resectable liver metastases; three unilateral or two bilateral lung metastases; peritoneal carcinomatosis with PCI ≤ 6. No consensus was achieved on how to classify positive cytology, which was considered as oligometastatic by 55% of participants only if converted to negative after chemotherapy. CONCLUSION: As assessed at the time of diagnosis, surgical treatment of oligometastases should aim at R0 curativity on the entire disease volume, including both the primary tumor and its metastases. Conversion surgery was defined as surgery on the residual volume of disease, which was initially not resectable for technical and/or oncological reasons but nevertheless responded to first-line treatment.

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.

Personalised exercise rehabilitation in cancer survivorship: the percs triage and referral system study protocol.

BACKGROUND: To effectively embed exercise rehabilitation in cancer survivorship care, a co-ordinated system of acute and community exercise rehabilitation services, forming a stepped model of care, is recommended. Patients can be directed to the exercise rehabilitation service which best meets their needs through a system of assessment, triage and referral. Triage and referral systems are not yet widely applied in cancer survivorship practice and need to be evaluated in real-world contexts. The PERCS (Personalised Exercise Rehabilitation in Cancer Survivorship) study aims to evaluate the real-world application of an exercise rehabilitation triage and referral system in cancer survivors treated during the COVID-19 pandemic. Secondary aims are to evaluate change in physical and psychosocial outcomes, and to qualitatively evaluate the impact of the system and patient experiences, at three months after application of the triage and referral system. METHODS: This study will assess the implementation of an exercise rehabilitation triage and referral system within the context of a physiotherapy-led cancer rehabilitation clinic for cancer survivors who received cancer treatment during the COVID-19 pandemic. The PERCS triage and referral system supports decision making in exercise rehabilitation referral by recommending one of three pathways: independent exercise; fitness professional referral; or health professional referral. Up to 100 adult cancer survivors treated during the COVID-19 pandemic who have completed treatment and have no signs of active disease will be recruited. We will assess participants' physical and psychosocial wellbeing and evaluate whether medical clearance for exercise is needed. Participants will then be triaged to a referral pathway and an exercise recommendation will be collaboratively decided. Reassessment will be after 12 weeks. Primary outcomes are implementation-related, guided by the RE-AIM framework. Secondary outcomes include physical function, psychosocial wellbeing and exercise levels. Qualitative analysis of semi-structured interviews guided by the Consolidated Framework for Implementation Research (CFIR) will provide insights on implementation and system impact. DISCUSSION: The PERCS study will investigate the real-world application of a cancer rehabilitation triage and referral system. This will provide proof of concept evidence for this triage approach and important insights on the implementation of a triage system in a specialist cancer centre. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov, registration number: NCT05615285, date registered: 21st October 2022.

Antitumor Immunity Mediated by Photodynamic Therapy Using Injectable Chitosan Hydrogels for Intratumoral and Sustained Drug Delivery.

Photodynamic therapy (PDT) is an anticancer therapy with proven efficacy; however, its application is often limited by prolonged skin photosensitivity and solubility issues associated with the phototherapeutic agents. Injectable hydrogels which can effectively provide intratumoral delivery of photosensitizers with sustained release are attracting increased interest for photodynamic cancer therapies. However, most of the hydrogels for PDT applications are based on systems with high complexity, and often, preclinical validation is not provided. Herein, we provide a simple and reliable pH-sensitive hydrogel formulation that presents appropriate rheological properties for intratumoral injection. For this, Temoporfin (m-THPC), which is one of the most potent clinical photosensitizers, was chemically modified to introduce functional groups that act as cross-linkers in the formation of chitosan-based hydrogels. The introduction of -COOH groups resulted in a water-soluble derivative, named PS2, that was the most promising candidate. Although PS2 was not internalized by the target cells, its extracellular activation caused effective damage to the cancer cells, which was likely mediated by lipid peroxidation. The injection of the hydrogel containing PS2 in the tumors was monitored by high-frequency ultrasounds and in vivo fluorescence imaging which confirmed the sustained release of PS2 for at least 72 h. Following local administration, light exposure was conducted one (single irradiation protocol) or three (multiple irradiation protocols) times. The latter delivered the best therapeutic outcomes, which included complete tumor regression and systemic anticancer immune responses. Immunological memory was induced as ∼75% of the mice cured with our strategy rejected a second rechallenge with live cancer cells. Additionally, the failure of PDT to treat immunocompromised mice bearing tumors reinforces the relevance of the host immune system. Finally, our strategy promotes anticancer immune responses that lead to the abscopal protection against distant metastases.

'SurgTalk': The Educational Outcomes Associated With Development of a Surgical Podcast for Undergraduate Medical Students.

OBJECTIVE: Educational podcast series are becoming increasingly popular as free open access medical education (FOAMed) resources, however, the educational benefit associated with their use is unclear. The aim of this study was to assess the educational outcomes associated with the implementation of a surgical podcast series for undergraduate medical students. METHODS: Two conversational case-based podcast episodes were recorded covering 2 common surgical presentations. Final-year medical students were recruited prospectively in January 2023 and underwent a baseline multiple choice question (MCQ) test covering the material within the podcast episodes. Participants were then provided with the episode files through encrypted Google Drive links. Two weeks following baseline assessment, students repeated the initial MCQ test and completed a postpodcast reaction survey. Data were analyzed using a paired t-test, multivariable regression analyses, and simple descriptive statistics. RESULTS: Fifty students were enrolled in the study. All participants undertook the baseline assessment. About 98% completed the postpodcast MCQ, while 94% completed the postpodcast reaction survey. All participants who undertook the reaction survey (n = 47) found the podcast helpful in explaining surgical concepts, 92% of participants found the podcast enjoyable to listen to. The most commonly reported activity undertaken while listening was "commuting/driving" (n = 24, 48%). The mean baseline MCQ score was 44.6%. The mean postpodcast MCQ score was 65.51%. There was a mean absolute increase in test score of 20.2% from baseline which was statistically significant (95%CI 14.67-25.6, p < 0.001). CONCLUSION: Implementation of this podcast series was associated with a statistically significant improvement in mean test score from baseline, reflecting knowledge acquisition. There was a positive user reaction and students were able to listen while performing other activities. Further evaluation of the educational outcomes associated with podcast use, particularly the effects on knowledge retention and clinical competence, is required.

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.

Management Experiences of Post-Gastrectomy Severe Alkaline Reflux Esophagitis.

Alkaline reflux esophagitis is a recognized complication of procedures that compromise the lower esophageal sphincter (LES), including gastrectomy. Incidence of reflux is dependent on the reconstructive procedure, with Roux-en-Y (RY) esophagojejunostomy commonly accepted as the optimal method. The authors report their experience of 5 patients who underwent remedial intervention for severe alkaline reflux esophagitis following gastric cancer surgery, over a 6-year period (2014-2020). Primary diagnoses encompassed 4 gastric adenocarcinomas and 1 gastric neuroendocrine tumor. Four patients previously underwent total gastrectomy and 1 subtotal gastrectomy with RY reconstruction. Onset of postoperative reflux symptoms ranged from 2 weeks to 3 years. Failing medical management, all patients underwent jejunojejunal anastomosis and Roux limb length revision with surgical jejunostomy. At follow-up, 4 out of 5 patients had some degree of symptom resolution and one with unresolved symptoms. The authors report our experience of managing this complication following gastrectomy with jejunojejunal anastomosis and Roux limb length revision.

PD-1 blockade attenuates surgery-mediated immunosuppression and boosts Th1 immunity perioperatively in oesophagogastric junctional adenocarcinoma.

Introduction: This timely study assesses the immunosuppressive effects of surgery on cytotoxic Th1-like immunity and investigates if immune checkpoint blockade (ICB) can boost Th1-like immunity in the perioperative window in upper gastrointestinal cancer (UGI) patients. Methods: PBMCs were isolated from 11 UGI patients undergoing tumour resection on post-operative days (POD) 0, 1, 7 and 42 and expanded ex vivo using anti-CD3/28 and IL-2 for 5 days in the absence/presence of nivolumab or ipilimumab. T cells were subsequently immunophenotyped via flow cytometry to determine the frequency of T helper (Th)1-like, Th1/17-like, Th17-like and regulatory T cell (Tregs) subsets and their immune checkpoint expression profile. Lymphocyte secretions were also assessed via multiplex ELISA (IFN-γ, granzyme B, IL-17 and IL-10). The 48h cytotoxic ability of vehicle-, nivolumab- and ipilimumab-expanded PBMCs isolated on POD 0, 1, 7 and 42 against radiosensitive and radioresistant oesophageal adenocarcinoma tumour cells (OE33 P and OE33 R) was also examined using a cell counting kit-8 (CCK-8) assay to determine if surgery affected the killing ability of lymphocytes and whether the use of ICB could enhance cytotoxicity. Results: Th1-like immunity was suppressed in expanded PBMCs in the immediate post-operative setting. The frequency of expanded circulating Th1-like cells was significantly decreased post-operatively accompanied by a decrease in IFN-γ production and a concomitant increase in the frequency of expanded regulatory T cells with an increase in circulating levels of IL-10. Interestingly, PD-L1 and CTLA-4 immune checkpoint proteins were also upregulated on expanded Th1-like cells post-operatively. Additionally, the cytotoxic ability of expanded lymphocytes against oesophageal adenocarcinoma tumour cells was abrogated post-surgery. Of note, the addition of nivolumab or ipilimumab attenuated the surgery-mediated suppression of lymphocyte cytotoxicity, demonstrated by a significant increase in tumour cell killing and an increase in the frequency of Th1-like cells and Th1 cytokine production. Conclusion: These findings support the hypothesis of a surgery-mediated suppression in Th1-like cytotoxic immunity and highlights a rationale for the use of ICB within the perioperative setting to abrogate tumour-promoting effects of surgery and ameliorate the risk of recurrence.

MicroRNA dysregulation and therapeutic opportunities in esophageal diseases.

MicroRNAs (miRNAs) are a class of small endogenous RNA molecules between 18 and 25 nucleotides long. The primary function of miRNAs is in the posttranscriptional regulation of mRNA targets through RNA interference culminating in mRNA degradation or translational repression. MiRNAs are fundamental in physiological and pathological processes such as cell proliferation, differentiation, apoptosis, and inflammation. Among this includes the uncovered potential of miRNAs in overall esophageal disease with a focus on the clinicopathologic allergic disease eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD), and the tumorigenic continuum from Barrett's esophagus (BE) toward esophageal adenocarcinoma (EAC). Although these pathologies are distinct from one another, they share pathophysiological elements such as an intense inflammatory milieu, esophageal dysfunction, and as presented in this review, an overlap in miRNA expression which contributes to overall esophageal disease. The overlap in the dysregulated miRNA transcriptome of these pathologies highlights the key role miRNAs play in contributing to esophageal disease progression. Owing to this notable dysregulation, there is an attractive utility for miRNAs as diagnostic and prognostic biomarkers in esophageal diseases that already require invasive endoscopies and biopsy retrieval. In this review miRNAs within EoE, GERD, BE, EAC, and esophageal achalasia are discussed, as well as reviewing a core set of miRNAs shared in the disease progression among some of these pathologies, along with the potential utility of targeting miRNAs as therapeutic options in overall esophageal disease.