Publications by authors named "John V Reynolds"

244 Publications

Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.

Dis Esophagus 2022 Apr 12. Epub 2022 Apr 12.

Department of Surgery, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.

Anastomotic leak (AL) is a severe complication after esophagectomy. Clinical presentation of AL is diverse and there is large practice variation regarding treatment of AL. This study aimed to explore different AL treatment strategies and their underlying rationale. This mixed-methods study consisted of an international survey among upper gastro-intestinal (GI) surgeons and focus groups with expert upper GI surgeons. The survey included 10 case vignettes and data sources were integrated after separate analysis. The survey was completed by 188 respondents (completion rate 69%) and 6 focus groups were conducted with 20 international experts. Prevention of mortality was the most important goal of primary treatment. Goals of secondary treatment were to promote tissue healing, return to oral feeding and safe hospital discharge. There was substantial variation in the preferred treatment principles (e.g. drainage or defect closure) and modalities (e.g. stent or endoVAC) within different presentations of AL. Patients with local symptoms were treated by supportive means only or by non-surgical drainage and/or defect closure. Drainage was routinely performed in patients with intrathoracic collections and often combined with defect closure. Patients with conduit necrosis were predominantly treated by resection and reconstruction of the anastomosis or by esophageal diversion. This mixed-methods study shows that overall treatment strategies for AL are determined by vitality of the conduit and presence of intrathoracic collections. There is large variation in preferred treatment principles and modalities. Future research may investigate optimal treatment for specific AL presentations and aim to develop consensus-based treatment guidelines for AL after esophagectomy.
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http://dx.doi.org/10.1093/dote/doac020DOI Listing
April 2022

Interventions targeting postoperative pulmonary complications (PPCs) in patients undergoing esophageal cancer surgery: a systematic review of randomized clinical trials and narrative discussion.

Dis Esophagus 2022 Apr 8. Epub 2022 Apr 8.

National Esophageal and Gastric Centre, St James's Hospital Dublin 8 and Trinity St. James's Cancer Institute, Dublin, Ireland.

Postoperative pulmonary complications (PPCs) represent the most common complications after esophageal cancer surgery. The lack of a uniform reporting nomenclature and a severity classification has hampered consistency of research in this area, including the study of interventions targeting prevention and treatment of PPCs. This systematic review focused on RCTs of clinical interventions used to minimize the impact of PPCs. Searches were conducted up to 08/02/2021 on MEDLINE (OVID), CINAHL, Embase, Web of Science, and the COCHRANE library for RCTs and reported in accordance with PRISMA guidelines. A total of 339 citations, with a pooled dataset of 1,369 patients and 14 RCTs, were included. Heterogeneity of study design and outcomes prevented meta-analysis. PPCs are multi-faceted and not fully understood with respect to etiology. The review highlights the paucity of high-quality evidence for best practice in the management of PPCs. Further research in the area of intraoperative interventions and early postoperative ERAS standards is required. A consistent uniform for definition of pneumonia after esophagectomy and the development of a severity scale appears warranted to inform further RCTs and guidelines.
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http://dx.doi.org/10.1093/dote/doac017DOI Listing
April 2022

Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma.

Transl Oncol 2022 Jun 30;20:101406. Epub 2022 Mar 30.

Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, Ireland. Electronic address:

Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting 'cold' tumours into 'hot' tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics. The effect of first-line chemotherapy regimens (FLOT and CROSS) on anti-tumour T cell immunity was assessed to help guide design of ICB and chemotherapy combinations in the first-line setting. The ability of ICB to enhance lymphocyte-mediated cytolysis of OAC cells in the absence and presence of post-FLOT and post-CROSS chemotherapy tumour cell secretome was assessed by a CCK-8 assay. Expression of ICs on T cells positively correlated with higher grade tumours and a subsequent poor response to neoadjuvant treatment. First-line chemotherapy regimens substantially altered IC expression profiles of T cells increasing PD-1, A2aR, KLRG-1, PD-L1, PD-L2 and CD160 and decreasing TIM-3 and LAG-3. In addition, pro-inflammatory T cell cytokine profiles were enhanced by first-line chemotherapy regimens. T cell activation status was significantly altered; both chemotherapy regimens upregulated co-stimulatory markers ICOS and CD69 yet downregulated co-stimulatory marker CD27. However, ICB attenuated chemotherapy-induced downregulation of CD27 on T cells and promoted differentiation of effector memory T cells into a terminally differentiated state. Importantly, dual nivolumab-ipilimumab treatment increased lymphocyte-mediated cytolysis of OAC cells, an effect further enhanced in the presence of post-FLOT tumour cell secretome. These findings justify a rationale to administer ICBs concurrently with first-line chemotherapies.
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http://dx.doi.org/10.1016/j.tranon.2022.101406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976141PMC
June 2022

Investigating the susceptibility of treatment-resistant oesophageal tumours to natural killer cell-mediated responses.

Clin Exp Med 2022 Apr 1. Epub 2022 Apr 1.

Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.

The majority of oesophageal adenocarcinoma (OAC) patients do not respond to multimodal treatment regimens and face dismal survival rates. Natural killer (NK) cells are crucial anti-tumour immune cells, and this study investigated the susceptibility of treatment-resistant OAC cells to these potent tumour killers. Natural killer receptor (NKR) ligand expression by OE33CisP (cisplatin-sensitive) and OE33CisR (cisplatin-resistant) cells was investigated. The immunomodulatory effects of OE33CisP and OE33CisR cells on NK cell phenotype and function were assessed. Finally, the impact of chemotherapy regimens on NKR ligand shedding was examined. Our data revealed significantly less surface expression of activating ligands B7-H6, MICA/B, ULBP-3 and activating/inhibitory ligands PVRL-1 and PVRL-4 by OE33CisR cells, compared to OE33CisP cells. Co-culture with OE33CisR cells reduced the frequencies of NKp30 and NKp46 NK cells and increased frequencies of TIGIT, FasL and TRAIL NK cells. Frequencies of IFN-γ-producing NK cells increased while frequencies of TIM-3 NK cells decreased after culture with OE33CisP and OE33CisR cells. Frequencies of circulating NKp30 NK cells were significantly lower in OAC patients with the poorest treatment response and in patients who received FLOT chemotherapy, while B7-H6 shedding by OAC tumour cells was induced by FLOT. Overall, OE33CisR cells express less activating NKR ligands than OE33CisP cells and have differential effects on NKR expression by NK cells. However, neither cell line significantly dampened NK cell cytokine production, death receptor expression or degranulation. In addition, our data indicate that FLOT chemotherapy may promote B7-H6 shedding and immune evasion with detrimental consequences in OAC patients.
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http://dx.doi.org/10.1007/s10238-022-00811-6DOI Listing
April 2022

PD-1 and TIGIT blockade differentially affect tumour cell survival under hypoxia and glucose deprived conditions in oesophageal adenocarcinoma; implications for overcoming resistance to PD-1 blockade in hypoxic tumours.

Transl Oncol 2022 May 1;19:101381. Epub 2022 Mar 1.

Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, Ireland. Electronic address:

Recent studies have demontrated that immune checkpoint receptors are expressed on the surface of oesophageal adenocarcinoma (OAC) cells and might confer a survival advantage. This study explores the role of PD-1 and TIGIT signalling in OAC cells in either promoting or inhibiting the survival of OAC cells under characteristic features of the tumour microenvironment including nutrient-deprivation and hypoxia. PD-1 and TIGIT are expressed in normal and pre-malignant oesophageal epithelial cells and this expression significantly decreases along the normal- Barrett's Oesophagus- OAC disease sequence. However, glucose-deprivation and hypoxia significantly upregulated PD-1 and TIGIT on the surface of OAC cells in vitro. PD-1 blockade decreased OAC cell proliferation under normoxia but enhanced proliferation and decreased cell death in OAC cells under hypoxia and glucose-deprivation. TIGIT blockade decreased proliferation and induced OAC cell death, an effect that was maintained under nutrient-deprivation and hypoxia. Basal respiration and glycolytic reserve were enhanced and GLUT1 was upregulated on the surface of a subpopulation of OAC cells following PD-1 blockade. In contrast, TIGIT blockade enhanced a glycolytic phenotype in OAC cells, yet decreased other metabolic parameters including oxidative phosphorylation and basal respiration. Interestingly, inhibition of oxidative phosphorylation significantly upregulated TIGIT expression and inhibition of oxidative phosphorylation and glycolysis significantly decreased PD-1 on the surface of a subpopulation of OAC cells in vitro. These findings suggest an immune-independent mechanism for PD-1 inhibitor resistance in hypoxic tumours and suggest that TIGIT might be a more effective therapeutic target in OAC compared with PD-1 for treating hypoxic tumours.
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http://dx.doi.org/10.1016/j.tranon.2022.101381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8894275PMC
May 2022

PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma.

Sci Rep 2022 02 28;12(1):3259. Epub 2022 Feb 28.

Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.

Chemotherapy upregulates immune checkpoint (IC) expression on the surface of tumour cells and IC-intrinsic signalling confers a survival advantage against chemotherapy in several cancer-types including oesophageal adenocarcinoma (OAC). However, the signalling pathways mediating chemotherapy-induced IC upregulation and the mechanisms employed by ICs to protect OAC cells against chemotherapy remain unknown. Longitudinal profiling revealed that FLOT-induced IC upregulation on OE33 OAC cells was sustained for up to 3 weeks post-treatment, returning to baseline upon complete tumour cell recovery. Pro-survival MEK signalling mediated FLOT-induced upregulation of PD-L1, TIM-3, LAG-3 and A2aR on OAC cells promoting a more immune-resistant phenotype. Single agent PD-1, PD-L1 and A2aR blockade decreased OAC cell viability, proliferation and mediated apoptosis. Mechanistic insights demonstrated that blockade of the PD-1 axis decreased stem-like marker ALDH and expression of DNA repair genes. Importantly, combining single agent PD-1, PD-L1 and A2aR blockade with FLOT enhanced cytotoxicity in OAC cells. These findings reveal novel mechanistic insights into the immune-independent functions of IC-intrinsic signalling in OAC cells with important clinical implications for boosting the efficacy of the first-line FLOT chemotherapy regimen in OAC in combination with ICB, to not only boost anti-tumour immunity but also to suppress IC-mediated promotion of key hallmarks of cancer that drive tumour progression.
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http://dx.doi.org/10.1038/s41598-022-07228-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8885636PMC
February 2022

The Impact of Esophageal Oncological Surgery on Perioperative Immune Function; Implications for Adjuvant Immune Checkpoint Inhibition.

Front Immunol 2022 27;13:823225. Epub 2022 Jan 27.

Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.

Background: Immune checkpoint inhibitors (ICIs) are being investigated for their role as an adjunct in the multimodal treatment of esophageal adenocarcinoma (EAC). The most effective time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumor immunity perioperatively to help inform the optimal timing of ICIs into current standards of care for EAC patients.

Methods: Systemic immunity in 11 EAC patients was phenotyped immediately prior to esophagectomy (POD-0) and post-operatively (POD)-1, 3, 7 and week 6. Longitudinal serological profiling was conducted by ELISA. The frequency of circulating lymphocytes, activation status, immune checkpoint expression and damage-associated molecular patterns was assessed by flow cytometry.

Results: The frequency of naïve T-cells significantly increased in circulation post-esophagectomy from POD-0 to POD-7 (p<0.01) with a significant decrease in effector memory T-cells by POD7 followed by a subsequent increase by week 6 (p<0.05). A significant increase in activated circulating CD27 T-cells was observed from POD-0 to POD-7 (p<0.05). The percentage of PD-1 and CTLA-4 T-cells peaked on POD-1 and was significantly decreased by week 6 (p<0.01). There was a significant increase in soluble PD-1, PD-L2, TIGIT and LAG-3 from POD-3 to week 6 (p<0.01). Increased checkpoint expression correlated with those who developed metastatic disease early in their postoperative course. Th1 cytokines and co-stimulatory factors decreased significantly in the immediate post-operative setting, with a reduction in IFN-γ, IL-12p40, IL-1RA, CD28, CD40L and TNF-α. A simultaneous increase was observed in Th2 cytokines in the immediate post-operative setting, with a significant increase in IL-4, IL-10, IL-16 and MCP-1 before returning to preoperative levels at week 6.

Conclusion: Our study highlights the prevailing Th2-like immunophenotype post-surgery. Therefore, shifting the balance in favour of a Th1-like phenotype would offer a potent therapeutic approach to promote cancer regression and prevent recurrence in the adjuvant setting and could potentially propagate anti-tumour immune responses perioperatively if administered in the immediate neoadjuvant setting. Consequently, this body of work paves the way for further studies and appropriate trial design is needed to further interrogate and validate the use of ICI in the multimodal treatment of locally advanced disease in the neoadjuvant and adjuvant setting.
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http://dx.doi.org/10.3389/fimmu.2022.823225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8829578PMC
March 2022

An International Multicenter Study Exploring Whether Surveillance After Esophageal Cancer Surgery Impacts Oncological and Quality of Life Outcomes (ENSURE).

Ann Surg 2022 Jan 27. Epub 2022 Jan 27.

Trinity St. James's Cancer Institute, Trinity College Dublin, and St. James's Hospital, Dublin, Ireland Department of Surgery and Cancer, Imperial College London, 10th Floor, QEQM building, St. Mary's Hospital, London, W21NY, United Kingdom Karolinska Institutet, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden CLINTEC, Karolinska Institutet, Stockholm, Sweden Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Objective: To determine the impact of surveillance on recurrence pattern, treatment, survival and health-related quality-of-life (HRQL) following curative-intent resection for esophageal cancer.

Summary Background Data: Although therapies for recurrent esophageal cancer may impact survival and HRQL, surveillance protocols after primary curative treatment are varied and inconsistent, reflecting a lack of evidence.

Methods: ENSURE was an international multicenter study of consecutive patients undergoing surgery for esophageal and esophagogastric junction cancers (2009-2015) across 20 centers (NCT03461341). Intensive surveillance (IS) was defined as annual CT for three years postoperatively. The primary outcome measure was overall survival (OS), secondary outcomes included treatment, disease-specific survival, recurrence pattern, and HRQL. Multivariable linear, logistic and Cox proportional hazards regression analyses were performed.

Results: 4,682 patients were studied (72.6% adenocarcinoma, 69.1% neoadjuvant therapy, 45.5% IS). At median follow-up 60 months, 47.5% developed recurrence, oligometastatic in 39%. IS was associated with reduced symptomatic recurrence (OR0.17 [0.12-0.25]) and increased tumor-directed therapy (OR2.09 [1.58-2.77]). After adjusting for confounders, no OS benefit was observed among all patients (HR1.01 [0.89-1.13]), but OS was improved following IS for those who underwent surgery alone (HR0.60 [0.47-0.78]) and those with lower pathological (y)pT stages (Tis-2, HR0.72 [0.58-0.89]). IS was associated with greater anxiety (P = 0.016), but similar overall HRQL.

Conclusions: IS was associated with improved oncologic outcome in select cohorts, specifically patients with early-stage disease at presentation or favorable pathological stage post neoadjuvant therapy. This may inform guideline development, and enhance shared decision-making, at a time when therapeutic options for recurrence are expanding.
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http://dx.doi.org/10.1097/SLA.0000000000005378DOI Listing
January 2022

Visceral obesity with and without metabolic syndrome: incidence and clinical impact in esophageal adenocarcinoma treated with curative intent.

Dis Esophagus 2022 Jan 17. Epub 2022 Jan 17.

Visceral obesity (VO) and metabolic syndrome (MetS) are risk factors for esophageal adenocarcinoma (EAC); however, their impact on operative and oncological outcomes is unclear. The aim of this study was to determine the incidence of VO and MetS among patients with EAC, and to assess their independent impact on operative and oncological outcomes. A total of 454 consecutive patients undergoing treatment with curative intent were studied. Total, subcutaneous, visceral fat area (VFA), and lean body mass (LBM) were measured by computed tomography pretreatment, with VO defined as VFA >163.8cm2 for men and 80.1cm2 for women. MetS was defined per the ATPIII definition. Multivariable logistic and Cox proportional hazards regression were utilized to determine independent predictors of oncologic and operative outcomes. A total of 227 patients (50.0%) had VO. A total of 134 (30%) overall had MetS, 44% in the VO cohort. VO was associated with Barrett's esophagus (P = 0.002) and lower cT (P = 0.006) and cN stage (P = 0.011), and improved disease-specific (P = 0.021) and overall survival (P = 0.012). No survival benefit existed for patients with VO who also had MetS. For operative complications, neither VO nor MetS increased the severity of complications, or mortality. However, VO was significantly (P = 0.035) associated with anastomotic leak and pneumonia (P = 0.037). MetS alone did not increase complication risk. VO increases specific major operative complications with no increase in mortality. VO improved survival, mainly relating to earlier stage disease; however, co-existent MetS abrogated this benefit. These seemingly paradoxical outcomes highlight manageable and potentially targetable perioperative challenges in the context of an overall favorable oncologic vista.
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http://dx.doi.org/10.1093/dote/doab094DOI Listing
January 2022

Exercise-based dysphagia rehabilitation for adults with oesophageal cancer: a systematic review.

BMC Cancer 2022 Jan 10;22(1):53. Epub 2022 Jan 10.

Department of Clinical Speech and Language Studies, Trinity College Dublin, 7-9 South Leinster Street, Dublin 2, Ireland.

Background: Dysphagia is prevalent in oesophageal cancer with significant clinical and psychosocial complications. The purpose of this study was i) to examine the impact of exercise-based dysphagia rehabilitation on clinical and quality of life outcomes in this population and ii) to identify key rehabilitation components that may inform future research in this area.

Methods: Randomised control trials (RCT), non-RCTs, cohort studies and case series were included. 10 databases (CINAHL Complete, MEDLINE, EMBASE, Web of Science, CENTRAL, and ProQuest Dissertations and Theses, OpenGrey, PROSPERO, RIAN and SpeechBITE), 3 clinical trial registries, and relevant conference abstracts were searched in November 2020. Two independent authors assessed articles for eligibility before completing data extraction, quality assessment using ROBINS-I and Downs and Black Checklist, followed by descriptive data analysis. The primary outcomes included oral intake, respiratory status and quality of life. All comparable outcomes were combined and discussed throughout the manuscript as primary and secondary outcomes.

Results: Three single centre non-randomised control studies involving 311 participants were included. A meta-analysis could not be completed due to study heterogeneity. SLT-led post-operative dysphagia intervention led to significantly earlier start to oral intake and reduced length of post-operative hospital stay. No studies found a reduction in aspiration pneumonia rates, and no studies included patient reported or quality of life outcomes. Of the reported secondary outcomes, swallow prehabilitation resulted in significantly improved swallow efficiency following oesophageal surgery compared to the control group, and rehabilitation following surgery resulted in significantly reduced vallecular and pyriform sinus residue. The three studies were found to have 'serious' to 'critical' risk of bias.

Conclusions: This systematic review highlights a low-volume of low-quality evidence to support exercise-based dysphagia rehabilitation in adults undergoing surgery for oesophageal cancer. As dysphagia is a common symptom impacting quality of life throughout survivorship, findings will guide future research to determine if swallowing rehabilitation should be included in enhanced recovery after surgery (ERAS) programmes. This review is limited by the inclusion of non-randomised control trials and the reliance on Japanese interpretation which may have resulted in bias. The reviewed studies were all of weak design with limited data reported.
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http://dx.doi.org/10.1186/s12885-021-09155-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751332PMC
January 2022

The Omentum in Obesity-Associated Cancer: A Hindrance to Effective Natural Killer Cell Migration towards Tumour Which Can Be Overcome by CX3CR1 Antagonism.

Cancers (Basel) 2021 Dec 23;14(1). Epub 2021 Dec 23.

Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.

Oesophagogastric adenocarcinomas (OAC) are obesity-associated malignancies, underpinned by severe immune dysregulation. We have previously shown that natural killer (NK) cells preferentially migrate to OAC omentum, where they undergo phenotypic and functional alterations and apoptosis. Furthermore, we have identified the CX3CR1:fractalkine (CX3CL1) pathway as pivotal in their recruitment to omentum. Here, we elucidate whether exposure to the soluble microenvironment of OAC omentum, and in particular fractalkine and IL-15 affects NK cell homing capacity towards oesophageal tumour. Our data uncover diminished NK cell migration towards OAC tumour tissue conditioned media (TCM) following exposure to omental adipose tissue conditioned media (ACM) and reveal that this migration can be rescued with CX3CR1 antagonist E6130. Furthermore, we show that fractalkine has opposing effects on NK cell migration towards TCM, when used alone or in combination with IL-15 and uncover its inhibitory effects on IL-15-mediated stimulation of death receptor ligand expression. Interestingly, treatment with fractalkine and/or IL-15 do not significantly affect NK cell adhesion to MAdCAM-1, despite changes they elicit to the expression of integrin α4β7. This study provides further evidence that CX3CR1 antagonism has therapeutic utility in rescuing NK cells from the deleterious effects of the omentum and fractalkine in OAC, thus limiting their dysfunction.
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http://dx.doi.org/10.3390/cancers14010064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750072PMC
December 2021

Alkaptonuria: clinical manifestations and an updated approach to treatment of a rare disease.

BMJ Case Rep 2021 Dec 7;14(12). Epub 2021 Dec 7.

Department of Upper GI Surgery, St.James Hospital, Dublin, Ireland.

Alkaptonuria (AKU) is a rare autosomal recessive disorder with a global incidence of 1 in 250 000 to 1 million people worldwide. It results from a deficiency of the enzyme homogentisic acid (HGA) oxidase which when absent, leads to an accumulation of HGA. Without this enzymatic degradation, HGA deposits in connective tissues resulting in pigmentation (ochronosis), plaque formation and accelerated cartilage destruction. With this, many patients who suffer from AKU develop ochronotic arthropathies, tendon ruptures, fractures, and chronic joint pain. Similarly, patients can develop cardiac valvular dysfunction and interstitial renal disease. Our two cases highlight the array of pathologies seen in AKU and, in light of newly published research, give us a platform from which we can discuss the developments in management of this rare disease.
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http://dx.doi.org/10.1136/bcr-2021-244240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655580PMC
December 2021

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

Metabolites 2021 Nov 10;11(11). Epub 2021 Nov 10.

Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James's Hospital, D08 W9RT Dublin, Ireland.

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-1β 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.
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http://dx.doi.org/10.3390/metabo11110768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624269PMC
November 2021

ASO Author Reflections: Can CRP and CRP-Based Scores Predict Survival in Operable Adenocarcinomas of the Esophagus and Esophago-Gastric Junction?

Ann Surg Oncol 2021 Nov 16. Epub 2021 Nov 16.

Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity St. James's Cancer Institute, Trinity College Dublin and St. James's Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1245/s10434-021-11069-9DOI Listing
November 2021

C-Reactive Protein and C-Reactive Protein-Based Scores to Predict Survival in Esophageal and Junctional Adenocarcinoma: Systematic Review and Meta-Analysis.

Ann Surg Oncol 2022 Mar 12;29(3):1853-1865. Epub 2021 Nov 12.

School of Medicine, Trinity College Dublin, Dublin, Ireland.

Background: Esophageal adenocarcinoma (EAC) has a poor prognosis; predictive markers of prognosis would facilitate advances in personalized therapy. C-reactive protein (CRP) and CRP-based scores are increasingly recommended across oncology; however, their role and value in EAC is unclear. This systematic review and meta-analysis examined CRP cut-point and scores and how they may best be applied in predicting survival in EAC.

Methods: A systematic literature search was conducted in EMBASE, Medline, Web of Science, Cochrane, Scopus and CINAHL databases, from inception to 1st October 2020. Studies reporting data from adults with EAC including adenocarcinoma of the gastro-esophageal junction (AEG), pre-treatment CRP or CRP-based score and Hazard Ratio (HR) for survival were included. QUIPS tool assessed risk of bias. Meta-analysis was undertaken.

Results: A total of 819 records were screened. Eight papers were included, with data for 1475 people. CRP cut-points ranged from 2.8 to 10 mg/L. The Glasgow Prognostic Score (GPS) and modified GPS were the most commonly reported scores. On meta-analysis, elevated preoperative GPS/mGPS was significantly associated with worse overall survival (hazards ratio [HR] 1.81, 95% confidence interval [CI] 1.25-2.62, p = 0.002); results were similar in subgroup analyses of multimodal treatment, M0 disease, and R0 resection.

Conclusions: This is the first review to evaluate comprehensively the evidence for CRP and CRP-based scores in EAC. Meta-analysis demonstrated that elevated preoperative GPS or mGPS was significantly associated with reduced overall survival in EAC, including AEG. There is insufficient evidence to support use of CRP alone. Future studies should examine GPS/mGPS in EAC prospectively, alone and combined with other prognostic markers.
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http://dx.doi.org/10.1245/s10434-021-10988-xDOI Listing
March 2022

Advances in the curative management of oesophageal cancer.

Br J Cancer 2022 03 21;126(5):706-717. Epub 2021 Oct 21.

Trinity St. James's Cancer Institute, Dublin 8, Ireland.

The incidence of oesophageal cancer, in particular adenocarcinoma, has markedly increased over the last four decades with adenocarcinoma becoming the dominant subtype in the West, and mortality rates are high. Nevertheless, overall survival of patients with oesophageal cancer has doubled in the past 20 years, with earlier diagnosis and improved treatments benefiting those patients who can be treated with curative intent. Advances in endotherapy, surgical approaches, and multimodal and other combination therapies have been reported. New vistas have emerged in targeted therapies and immunotherapy, informed by new knowledge in genomics and molecular biology, which present opportunities for personalised cancer therapy and novel clinical trials. This review focuses exclusively on the curative intent treatment pathway, and highlights emerging advances.
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http://dx.doi.org/10.1038/s41416-021-01485-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528946PMC
March 2022

Effect of the Rehabilitation Program, ReStOre, on Serum Biomarkers in a Randomized Control Trial of Esophagogastric Cancer Survivors.

Front Oncol 2021 15;11:669078. Epub 2021 Sep 15.

Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, St. James's Hospital, Trinity College Dublin, Dublin, Ireland.

Background: The Rehabilitation Strategies Following Esophagogastric cancer (ReStOre) randomized control trial demonstrated a significant improvement in cardiorespiratory fitness of esophagogastric cancer survivors. This follow-up, exploratory study analyzed the biological effect of exercise intervention on levels of 55 serum proteins, encompassing mediators of angiogenesis, inflammation, and vascular injury, from participants on the ReStOre trial.

Methods: Patients >6 months disease free from esophagogastric cancer were randomized to usual care or the 12-week ReStOre program (exercise training, dietary counselling, and multidisciplinary education). Serum was collected at baseline (T0), post-intervention (T1), and at 3-month follow up (T2). Serum biomarkers were quantified by enzyme-linked immunosorbent assay (ELISA).

Results: Thirty-seven patients participated in this study; 17 in the control arm and 20 in the intervention arm. Exercise intervention resulted in significant alterations in the level of expression of serum IP-10 (mean difference (MD): 38.02 (95% CI: 0.69 to 75.35)), IL-27 (MD: 249.48 (95% CI: 22.43 to 476.53)), and the vascular injury biomarkers, ICAM-1 (MD: 1.05 (95% CI: 1.07 to 1.66)), and VCAM-1 (MD: 1.51 (95% CI: 1.04 to 2.14)) at T1. A significant increase in eotaxin-3 (MD: 2.59 (95% CI: 0.23 to 4.96)), IL-15 (MD: 0.27 (95% CI: 0 to 0.54)) and decrease in bFGF (MD: 1.62 (95% CI: -2.99 to 0.26)) expression was observed between control and intervention cohorts at T2 (p<0.05).

Conclusions: Exercise intervention significantly altered the expression of a number of serum biomarkers in disease-free patients who had prior treatment for esophagogastric cancer.

Impact: Exercise rehabilitation causes a significant biological effect on serum biomarkers in esophagogastric cancer survivors.

Clinical Trial Registration: ClinicalTrials.gov (NCT03314311).
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http://dx.doi.org/10.3389/fonc.2021.669078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479183PMC
September 2021

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers.

Biomedicines 2021 Aug 16;9(8). Epub 2021 Aug 16.

Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, D08 W9RT Dublin 8, Ireland.

Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours ( = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.
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http://dx.doi.org/10.3390/biomedicines9081024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392860PMC
August 2021

The Prognostic Value of the Lymph Node in Oesophageal Adenocarcinoma; Incorporating Clinicopathological and Immunological Profiling.

Cancers (Basel) 2021 Aug 9;13(16). Epub 2021 Aug 9.

Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James's Hospital, D08 W9RT Dublin, Ireland.

Response rates to the current gold standards of care for treating oesophageal adenocarcinoma (OAC) remain modest with 15-25% of patients achieving meaningful pathological responses, highlighting the need for novel therapeutic strategies. This study consists of immune, angiogenic, and inflammatory profiling of the tumour microenvironment (TME) and lymph node microenvironment (LNME) in OAC. The prognostic value of nodal involvement and clinicopathological features was compared using a retrospective cohort of OAC patients ( = 702). The expression of inhibitory immune checkpoints by T cells infiltrating tumour-draining lymph nodes (TDLNs) and tumour tissue post-chemo(radio)therapy at surgical resection was assessed by flow cytometry. Nodal metastases is of equal prognostic importance to clinical tumour stage and tumour regression grade (TRG) in OAC. The TME exhibited a greater immuno-suppressive phenotype than the LNME. Our data suggests that blockade of these checkpoints may have a therapeutic rationale for boosting response rates in OAC.
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http://dx.doi.org/10.3390/cancers13164005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391676PMC
August 2021

Fractalkine Elicits Chemotactic, Phenotypic, and Functional Effects on CX3CR1CD27 NK Cells in Obesity-Associated Cancer.

J Immunol 2021 08 28;207(4):1200-1210. Epub 2021 Jul 28.

Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and the Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland;

Esophagogastric adenocarcinomas (EAC) are obesity-associated malignancies underpinned by severe immune dysregulation and inflammation. Our previous work indicates that NK cells migrate to EAC omentum, where they undergo phenotypic and functional alterations and apoptosis. In this study, we investigate whether such erroneous chemotaxis to omentum is paralleled by compromised NK cell infiltration of EAC patient tumor and examine the role of the inflammatory chemokine fractalkine in shaping the NK cell-mediated response. Our data show diminished NK cell frequencies in EAC tumor compared with those in the circulation and reveal that intratumoral NK cell frequencies decline as visceral obesity increases in EAC patients. Our in vitro findings demonstrate that antagonism of fractalkine receptor CX3CR1 significantly reduces NK cell migration to EAC patient-derived, omental adipose tissue-conditioned media, but not toward tumor-conditioned media. These data suggest fractalkine is a key driver of NK cell chemotaxis to omentum but has a lesser role in NK cell homing to tumor in EAC. We propose that this may offer a novel therapeutic strategy to limit NK cell depletion in the omentum of obese EAC patients, and our data suggest the optimal timing for CX3CR1 antagonism is after neoadjuvant chemoradiotherapy. Our functional studies demonstrate that fractalkine induces the conversion from CX3CR1CD27 to CX3CR1CD27 NK cells and increases their IFN-γ and TNF-α production, indicative of its role in shaping the dominant NK cell phenotype in EAC omentum. This study uncovers crucial and potentially druggable pathways underpinning NK cell dysfunction in obesity-associated cancer and provides compelling insights into fractalkine's diverse biological functions.
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http://dx.doi.org/10.4049/jimmunol.2000987DOI Listing
August 2021

FLOT-regimen Chemotherapy and Transthoracic en bloc Resection for Esophageal and Junctional Adenocarcinoma.

Ann Surg 2021 11;274(5):814-820

Department of Surgery, Trinity St. James's Cancer Institute, Dublin, Ireland.

Background And Aims: The FLOT4-AIO trial established the FLOT regimen as a compelling option for gastric, junctional and esophageal adenocarcinoma. Data on FLOT with en-bloc transthoracic esophagectomy (TTE) are limited. This study explored operative complications, tolerance, toxicity, physiological impact, and oncologic outcomes.

Study Design: An observational cohort study on consecutive patients at 3 tertiary centers undergoing FLOT and TTE. Toxicity, operative complications (per ECCG definitions), tumor regression grade (TRG), recurrences and survival were documented, as well as pre and post FLOT assessment of sarcopenia and pulmonary physiology.

Results: 175 patients (cT2-4a, Nany) commenced treatment, 84% male, median age 65, 94% cT3/T4a, 73% cN+. 89% completed 4 preoperative cycles, and 35% all cycles. Grade 3/4 toxicities included neutropenia (12%), diarrhoea (13%), and infection (15%). Sarcopenia increased from 18% to 37% (P = 0.020), and diffusion capacity (DLCO) decreased by 8% (-34% + 25%; P < 0.010). On pathology, ypT3/4 was 59%, and ypN+54%, with 10% TRG 1, 14% TRG 2, and 76% TRG3-5, and R0 95%. 161 underwent TTE, with an in-hospital mortality of 0.6%, 24%-pneumonia, 11%-anastomotic leak, and Clavien Dindo ≥III in 27%. At a median follow up of 12 months (1-85), 33 relapsed, 8 (5%) locally, and 3yr survival was 60%.

Conclusion: FLOT and en bloc TTE was safe, with no discernible impact on operative complications, with 24% having a major pathologic response. Caveats include a limited pathologic response in the majority, and negative impact on muscle mass and lung physiology, and low use of adjuvant cycles. These data may provide a real-world benchmark for this complex care pathway.
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http://dx.doi.org/10.1097/SLA.0000000000005097DOI Listing
November 2021

Tissue distribution of γδ T cell subsets in oesophageal adenocarcinoma.

Clin Immunol 2021 08 15;229:108797. Epub 2021 Jul 15.

Cancer Immunology and Immunotherapy Group, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland. Electronic address:

The global obesity epidemic is contributing to increased prevalence of diseases fuelled by chronic inflammation, including cancer. Oesophageal adenocarcinoma (OAC) is an obesity-associated malignancy with increasing prevalence, dismal prognosis, and severely dysregulated immune processes. We previously reported that αβ T cells migrate to omentum and liver in OAC and contribute to inflammation in these tissues. Here, we assessed the tissue distribution and phenotype of gamma/delta (γδ) T cells in the blood, omentum, liver and tumour of OAC patients. Our data show that the Vδ1 and Vδ3 subsets of γδ T cells are most prevalent in omentum and liver of OAC patients. Furthermore, γδ T cells are predominantly pro-inflammatory in these tissues, and co-express IFN-γ and IL-17. Moreover, γδ T cells exhibit cytotoxic capabilities in OAC omentum and liver. This study provides the first indication that γδ T cells contribute to obesity-associated inflammation in OAC and might be exploited therapeutically.
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http://dx.doi.org/10.1016/j.clim.2021.108797DOI Listing
August 2021

Preoperative high intensity interval training for oncological resections: A systematic review and meta-analysis.

Surg Oncol 2021 Sep 12;38:101620. Epub 2021 Jun 12.

School of Medicine, Trinity College Dublin, Dublin, Ireland. Electronic address:

Exercise prehabilitation prior to major surgery targets a reduction in postoperative complications through improved conditioning and respiratory function. However its effectiveness in cancer surgery is unclear. The objective of this review was to determine if preoperative high-intensity interval training (HIIT) improves preoperative fitness in patients scheduled for oncologic resection, and whether postoperative complications are impacted. METHODS: CINAHL, AMED, PEDro, EMBASE, The Cochrane Library and PubMed/MEDLINE were searched until April 2021 using predefined search strategy and accompanied by manual forward and backwards citation review. Screening of titles, abstracts, full-texts, data extraction, risk of bias assessment and methodologic quality was performed independently by two reviewers. Mean difference (MD) with 95% confidence intervals (CI) was compared and heterogeneity assessed using Chi Squared Test and I statistic. Six randomised controlled trials (RCTs) were included in the systematic review. Interventions prescribed bouts of high-intensity exercise [80-115% peak work rate (WRp)] interspaced with low-intensity (rest-50% WRp) exercise. The meta-analysis included five RCTs reporting peak oxygen consumption (VO). Preoperative HIIT did not result in significantly higher VO in comparison to usual care or moderate intensity exercise (MD 0.83, 95%CI-0.51-2.17) kg/ml/min, p = 0.12). Studies were insufficiently powered with respect to postoperative complications, but there is no evidence of significant impact. No adverse events occurred and high adherence rates were reported. Results of this systematic review and meta-analysis demonstrate there is insufficient evidence to support HIIT as a method of improving preoperative fitness prior to oncologic resection. Further work is needed to determine if specific HIIT parameters can be adapted to improve efficacy over short time-frames.
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http://dx.doi.org/10.1016/j.suronc.2021.101620DOI Listing
September 2021

Risk Prediction Model of 90-Day Mortality After Esophagectomy for Cancer.

JAMA Surg 2021 09;156(9):836-845

Department of Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham Foundation Trust, Birmingham, United Kingdom.

Importance: Ninety-day mortality rates after esophagectomy are an indicator of the quality of surgical oncologic management. Accurate risk prediction based on large data sets may aid patients and surgeons in making informed decisions.

Objective: To develop and validate a risk prediction model of death within 90 days after esophagectomy for cancer using the International Esodata Study Group (IESG) database, the largest existing prospective, multicenter cohort reporting standardized postoperative outcomes.

Design, Setting, And Participants: In this diagnostic/prognostic study, we performed a retrospective analysis of patients from 39 institutions in 19 countries between January 1, 2015, and December 31, 2019. Patients with esophageal cancer were randomly assigned to development and validation cohorts. A scoring system that predicted death within 90 days based on logistic regression β coefficients was conducted. A final prognostic score was determined and categorized into homogeneous risk groups that predicted death within 90 days. Calibration and discrimination tests were assessed between cohorts.

Exposures: Esophageal resection for cancer of the esophagus and gastroesophageal junction.

Main Outcomes And Measures: All-cause postoperative 90-day mortality.

Results: A total of 8403 patients (mean [SD] age, 63.6 [9.0] years; 6641 [79.0%] male) were included. The 30-day mortality rate was 2.0% (n = 164), and the 90-day mortality rate was 4.2% (n = 353). Development (n = 4172) and validation (n = 4231) cohorts were randomly assigned. The multiple logistic regression model identified 10 weighted point variables factored into the prognostic score: age, sex, body mass index, performance status, myocardial infarction, connective tissue disease, peripheral vascular disease, liver disease, neoadjuvant treatment, and hospital volume. The prognostic scores were categorized into 5 risk groups: very low risk (score, ≥1; 90-day mortality, 1.8%), low risk (score, 0; 90-day mortality, 3.0%), medium risk (score, -1 to -2; 90-day mortality, 5.8%), high risk (score, -3 to -4: 90-day mortality, 8.9%), and very high risk (score, ≤-5; 90-day mortality, 18.2%). The model was supported by nonsignificance in the Hosmer-Lemeshow test. The discrimination (area under the receiver operating characteristic curve) was 0.68 (95% CI, 0.64-0.72) in the development cohort and 0.64 (95% CI, 0.60-0.69) in the validation cohort.

Conclusions And Relevance: In this study, on the basis of preoperative variables, the IESG risk prediction model allowed stratification of an individual patient's risk of death within 90 days after esophagectomy. These data suggest that this model can help in the decision-making process when esophageal cancer surgery is being considered and in informed consent.
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http://dx.doi.org/10.1001/jamasurg.2021.2376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223144PMC
September 2021

Methods for conducting international Delphi surveys to optimise global participation in core outcome set development: a case study in gastric cancer informed by a comprehensive literature review.

Trials 2021 Jun 21;22(1):410. Epub 2021 Jun 21.

Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Background: Core outcome sets (COS) should be relevant to key stakeholders and widely applicable and usable. Ideally, they are developed for international use to allow optimal data synthesis from trials. Electronic Delphi surveys are commonly used to facilitate global participation; however, this has limitations. It is common for these surveys to be conducted in a single language potentially excluding those not fluent in that tongue. The aim of this study is to summarise current approaches for optimising international participation in Delphi studies and make recommendations for future practice.

Methods: A comprehensive literature review of current approaches to translating Delphi surveys for COS development was undertaken. A standardised methodology adapted from international guidance derived from 12 major sets of translation guidelines in the field of outcome reporting was developed. As a case study, this was applied to a COS project for surgical trials in gastric cancer to translate a Delphi survey into 7 target languages from regions active in gastric cancer research.

Results: Three hundred thirty-two abstracts were screened and four studies addressing COS development in rheumatoid and osteoarthritis, vascular malformations and polypharmacy were eligible for inclusion. There was wide variation in methodological approaches to translation, including the number of forward translations, the inclusion of back translation, the employment of cognitive debriefing and how discrepancies and disagreements were handled. Important considerations were identified during the development of the gastric cancer survey including establishing translation groups, timelines, understanding financial implications, strategies to maximise recruitment and regulatory approvals. The methodological approach to translating the Delphi surveys was easily reproducible by local collaborators and resulted in an additional 637 participants to the 315 recruited to complete the source language survey. Ninety-nine per cent of patients and 97% of healthcare professionals from non-English-speaking regions used translated surveys.

Conclusion: Consideration of the issues described will improve planning by other COS developers and can be used to widen international participation from both patients and healthcare professionals.
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http://dx.doi.org/10.1186/s13063-021-05338-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218463PMC
June 2021

[email protected]: Feasibility study of a virtually delivered 12-week multidisciplinary rehabilitation programme for survivors of upper gastrointestinal (UGI) cancer - study protocol.

HRB Open Res 2020 4;3:86. Epub 2021 May 4.

Discipline of Physiotherapy, Trinity College Dublin, the University of Dublin, Dublin, Ireland.

Exercise rehabilitation programmes, traditionally involving supervised exercise sessions, have had to rapidly adapt to virtual delivery in response to the coronavirus disease 2019 (COVID-19) pandemic to minimise patient contacts. In the absence of an effective vaccine, the pandemic is likely to persist in the medium term and during this time it is important that the feasibility and effectiveness of remote solutions is considered.  We have previously established the feasibility of the Rehabilitation Strategies following Oesophago-gastric Cancer (ReStOre) intervention - a face to face multidisciplinary rehabilitation programme for upper gastrointestinal (UGI) cancer survivors. This study will examine the feasibility of a virtually delivered 12-week multi-component [email protected] programme. This single arm feasibility study will recruit 12 patients who have completed curative treatment for oesophago-gastric cancer. Participants will complete the 12-week [email protected] programme consisting of exercise (aerobic and resistance training), 1:1 dietary counselling and group education sessions through virtual delivery. Underpinned by the Medical Research Council (MRC) Framework, feasibility will be determined by recruitment rates, adherence, retention, incidents, and acceptability. Acceptability will be assessed qualitatively through post-intervention interview and the Telehealth Usability Questionnaire. Secondary outcomes will be assessed pre and post-intervention and will include measures of physical performance (cardiopulmonary exercise test, short physical performance battery, hand grip strength, Godin Leisure Time Questionnaire, and body composition), health related quality of life (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) and oesophago-gastric cancer specific subscale (EORTC-QLQ-OG25), fatigue (Multidimensional Fatigue Inventory (MFI-20), and venous blood samples will be collected for the UGI Cancer Survivorship Biobank. The [email protected] feasibility study will provide important data regarding the amenability of a multidisciplinary programme designed for UGI cancer survivors to virtual delivery. ClinicalTrials.gov NCT04603339 (26/10/2020).
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http://dx.doi.org/10.12688/hrbopenres.13185.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127012PMC
May 2021

Descending necrotising mediastinitis: how a sore throat can result in purulent peritonitis.

BMJ Case Rep 2021 May 24;14(5). Epub 2021 May 24.

Department of General and Upper GI Surgery, St James Hospital, Dublin, Ireland.

This is a rare case of descending necrotising mediastinitis (DNM) that originated as an oropharyngeal infection, before spreading caudally to include all compartments of the mediastinum and the peritoneum beyond. The mediastinitis was treated early and aggressively with drainage, lavage and debridement in conjunction with broad-spectrum antimicrobial treatment. This case includes a right cervical incision, and a seldom needed surgical laparotomy approach to address the intra-abdominal involvement, and necessity of peritoneal washout. Following a prolonged Intesive Care Unit (ICU) stay and antibiotic course as well as other interventions detailed, the patient made a remarkable recovery and was discharged 101 days post presentation. This report goes on to discuss the rapidly evolving, life-threatening nature of DNM as well as providing an overview of possible management options, outlining how we think such cases should be approached and the clinical suspicion required in a deteriorating patient.
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http://dx.doi.org/10.1136/bcr-2021-242145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149320PMC
May 2021

Identifying outcomes reported in exercise interventions in oesophagogastric cancer survivors: a systematic review.

BMC Cancer 2021 May 22;21(1):586. Epub 2021 May 22.

School of Medicine, Trinity College Dublin, Dublin, Ireland.

Background: Research investigating exercise interventions in oesophagogastric cancer survivors is sparse, and the outcomes are varied. The aim of this systematic review is to identify the domains and outcomes reported in exercise interventions in oesophagogastric cancer survivors to be included in a Delphi study, with a view to informing the development of a core outcome set (COS).

Methods: EMBASE, PubMed, CINHAL, Cochrane Library, SCOPUS, and PEDro were searched up to March 2020 using a predefined search strategy. The outcomes identified during data extraction were categorised using the core areas outlined in the OMERACT Filter 2.0.

Results: Fourteen domains and 63 outcomes were identified. The most frequently reported outcomes were in the domains of quality of life using the EORTC-QLQ-C30 questionnaire and the relevant disease-specific modules (100%), exercise capacity/fitness/physical function (100%), anthropometrics (83.33%), physical activity (66.67%), and biomarker analysis (50%).

Conclusion: This systematic review quantifies and describes the domains and outcomes examined in exercise interventions in oesophagogastric cancer survivors. Some inconsistency exists within the domains and outcomes used, and little attention was given to nutritional or economic endpoints. In order to develop a COS, a Delphi consensus process with key stakeholders is needed to identify the relevant domains and outcomes for inclusion.
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http://dx.doi.org/10.1186/s12885-021-08290-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141124PMC
May 2021

Thinking through the multimodal treatment of localized oesophageal cancer: the point of view of the surgeon.

Curr Opin Oncol 2021 07;33(4):353-361

Department of Surgery, Guy's and St Thomas' NHS Foundation Trust, London.

Purpose Of Review: This review examines current developments and controversies in the multimodal management of oesophageal cancer, with an emphasis on surgical dilemmas and outcomes from the surgeon's perspective.

Recent Findings: Despite the advancement of oncological neoadjuvant treatments, there is still no consensus on what regimen is superior. The majority of patients may still fail to respond to neoadjuvant therapy and suffer potential harm without any survival advantage as a result. In patients who do not respond, adjuvant therapy is still often recommended after surgery despite any evidence for its benefit. We examine the implications of different regimens and treatment approaches for both squamous cell cancer and adenocarcinoma of the oesophagus.

Summary: The efficacy of neoadjuvant treatment is highly variable and likely relates to variability of tumour biology. Ongoing work to identify responders, or optimize treatment on an individual patient, should increase the efficacy of multimodal therapy and improve patient outcomes.
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http://dx.doi.org/10.1097/CCO.0000000000000751DOI Listing
July 2021
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