Using neural networks to autonomously assess adequacy in intraoperative cholangiograms.

BACKGROUND: Intraoperative cholangiography (IOC) is a contrast-enhanced X-ray acquired during laparoscopic cholecystectomy. IOC images the biliary tree whereby filling defects, anatomical anomalies and duct injuries can be identified. In Australia, IOC are performed in over 81% of cholecystectomies compared with 20 to 30% internationally (Welfare AIoHa in Australian Atlas of Healthcare Variation, 2017). In this study, we aim to train artificial intelligence (AI) algorithms to interpret anatomy and recognise abnormalities in IOC images. This has potential utility in (a) intraoperative safety mechanisms to limit the risk of missed ductal injury or stone, (b) surgical training and coaching, and (c) auditing of cholangiogram quality. METHODOLOGY: Semantic segmentation masks were applied to a dataset of 1000 cholangiograms with 10 classes. Classes corresponded to anatomy, filling defects and the cholangiogram catheter instrument. Segmentation masks were applied by a surgical trainee and reviewed by a radiologist. Two convolutional neural networks (CNNs), DeeplabV3+ and U-Net, were trained and validated using 900 (90%) labelled frames. Testing was conducted on 100 (10%) hold-out frames. CNN generated segmentation class masks were compared with ground truth segmentation masks to evaluate performance according to a pixel-wise comparison. RESULTS: The trained CNNs recognised all classes.. U-Net and DeeplabV3+ achieved a mean F1 of 0.64 and 0.70 respectively in class segmentation, excluding the background class. The presence of individual classes was correctly recognised in over 80% of cases. Given the limited local dataset, these results provide proof of concept in the development of an accurate and clinically useful tool to aid in the interpretation and quality control of intraoperative cholangiograms. CONCLUSION: Our results demonstrate that a CNN can be trained to identify anatomical structures in IOC images. Future performance can be improved with the use of larger, more diverse training datasets. Implementation of this technology may provide cholangiogram quality control and improve intraoperative detection of ductal injuries or ductal injuries.

Adjunct Use of Continuous Renal Replacement Therapy with Extracorporeal Membrane Oxygenation Achieves Negative Fluid Balance and Enhances Oxygenation Which Improves Survival in Critically Ill Patients without Kidney Failure.

INTRODUCTION: Fluid overload in extracorporeal membrane oxygenation (ECMO) patients has been associated with increased mortality. Patients receiving ECMO and continuous renal replacement therapy (CRRT) who achieve a negative fluid balance have improved survival. Limited data exist on the use of CRRT solely for fluid management in ECMO patients. METHODS: We performed a single-center retrospective review of 19 adult ECMO patients without significant renal dysfunction who received CRRT for fluid management. These patients were compared to a cohort of propensity-matched controls. RESULTS: After 72 h, the treatment group had a fluid balance of -3840 mL versus + 425 mL (p ≤ 0.05). This lower fluid balance correlated with survival to discharge (odds ratio 2.54, 95% confidence interval 1.10-5.87). Improvement in the ratio of arterial oxygen content to fraction of inspired oxygen was also significantly higher in the CRRT group (102.4 vs. 0.7, p ≤ 0.05). We did not observe any significant difference in renal outcomes. CONCLUSIONS: The use of CRRT for fluid management is effective and, when resulting in negative fluid balance, improves survival in adult ECMO patients without significant renal dysfunction.

Identifying the limitations of cardiopulmonary exercise testing prior to esophagectomy using a pooled analysis of patient-level data.

Preoperative cardiopulmonary exercise testing (CPET) provides an objective assessment of aerobic fitness in patients undergoing surgery. While peak oxygen uptake during exercise (VO2peak) and anaerobic threshold have demonstrated a moderate correlation with the development of complications following esophagectomy, no clinically useful threshold values have been defined. By pooling patient level data from existing studies, we aimed to define optimal thresholds for preoperative CPET parameters to predict patients at high risk of postoperative complications. Studies reporting on the relationship between preoperative CPET variables and post-esophagectomy complications were determined from a comprehensive literature search. Patient-level data were obtained from six contributing centers for pooled-analyses. Outcomes of interest included cardiopulmonary and non-cardiopulmonary complications, unplanned intensive care unit readmission, and 90-day and 12-month all-cause mortality. Receiver operating characteristic curves and logistic regression models estimated the predictive value of CPET parameters for each individual outcome of interest. This analysis comprised of 621 patients who underwent CPET prior to esophagectomy during the period from January 2004 to March 2017. For both anaerobic threshold and VO2peak, none of the receiver operating characteristic curves achieved an area under the curve value > 0.66 for the outcomes of interest. The discriminatory ability of CPET for determining high-risk patients was found to be poor in patients undergoing an esophagectomy. CPET may only carry an adjunct role to clinical decision-making.

Robotic-assisted minimally invasive esophagectomy (RAMIE) for esophageal cancer training curriculum-a worldwide Delphi consensus study.

BACKGROUND: Structured training protocols can safely improve skills prior initiating complex surgical procedures such as robotic-assisted minimally invasive esophagectomy (RAMIE). As no consensus on a training curriculum for RAMIE has been established so far it is our aim to define a protocol for RAMIE with the Delphi consensus methodology. METHODS: Fourteen worldwide RAMIE experts were defined and were enrolled in this Delphi consensus project. An expert panel was created and three Delphi rounds were performed starting December 2019. Items required for RAMIE included, but were not limited to, virtual reality simulation, wet-lab training, proctoring, and continued monitoring and education. After rating performed by the experts, consensus was defined when a Cronbach alpha of ≥0.80 was reached. If ≥80% of the committee reached a consensus an item was seen as fundamental. RESULTS: All Delphi rounds were completed by 12-14 (86-100%) participants. After three rounds analyzing our 49-item questionnaire, 40 items reached consensus for a training curriculum of RAMIE. CONCLUSION: The core principles for RAMIE training were defined. This curriculum may lead to a wider adoption of RAMIE and a reduction in time to reach proficiency.

Worldwide Practice in Gastric Cancer Surgery: A 6-Year Update.

OBJECTIVES: The aim of the study was to evaluate the current status of gastric cancer surgery worldwide and update the changes compared to a previous survey in 2014. METHODS: A cross-sectional survey was sent to surgical members of the International Gastric Cancer Association, pilot centers of the World Organization for Specialized Studies on Diseases of the Esophagus, and the Australian and New Zealand Gastric and Oesophageal Surgeons Association in addition to participants of the 2019 International Gastric Cancer and European Society for Diseases of the Esophagus congresses. Topics addressed included hospital volume, staging, perioperative treatment, surgical approach, anastomotic techniques, lymphadenectomy, and palliative management. RESULTS: Between June 2019 and January 2020, 165 respondents from 44 countries completed the survey. In total, 80% worked in a hospital performing >20 gastrectomies annually. Staging laparoscopy and 18F-fluorodeoxyglucose positron emission tomography with computed tomography were preferred by 68 and 26% for advanced cancer, and 90% offered perioperative chemo(radio)therapy to patients. For early cancer, a minimally invasive surgical approach was preferred by 65% for distal and by 50% for total gastrectomy. For advanced cancer, this was preferred by 39% for distal and by 33% for total gastrectomy. And 84% favored a stapled anastomosis, and 14% created a jejunal pouch as reconstruction during total gastrectomy. A D2 lymphadenectomy was preferred for distal as well as for total gastrectomy, in both early (62 and 71%) and advanced (84 and 89%) cancer. CONCLUSION: This international survey demonstrates that perioperative chemotherapy and a D2 lymphadenectomy have now become the preferred treatment for gastric cancer. A minimally invasive surgical approach has gained popularity.

The Role of Cardiopulmonary Exercise Testing as a Risk Assessment Tool in Patients Undergoing Oesophagectomy: A Systematic Review and Meta-analysis.

INTRODUCTION: Cardiopulmonary exercise testing (CPET) is an objective method of assessing functional capacity to meet the metabolic demands of surgery and has been adopted as a preoperative risk-stratification tool for patients undergoing major procedures. The two main measures are the peak rate of oxygen uptake during exercise ([Formula: see text]O2peak) and anaerobic threshold (AT), the point at which anaerobic metabolism exceeds aerobic metabolism during exercise. This systematic review and meta-analysis evaluates the predictive value of CPET for patients undergoing oesophagectomy. METHODS: A systematic literature search was conducted in databases of CINAHL, Cochrane Library, EMBASE, MEDLINE, PubMed, and Scopus to identify studies that examined associations between preoperative CPET variables and postoperative outcomes following oesophagectomy. Results were presented as standardised mean difference (SMD) with 95% confidence interval. RESULTS: Seven studies were included in this review. Preoperative [Formula: see text]O2peak moderately correlated with cardiopulmonary complications [SMD = - 0.43; 95% confidence interval (CI) - 0.77 to - 0.09; p = 0.013; I2 = 80.4%], unplanned ICU admissions (SMD = - 0.34; 95% CI - 0.60 to - 0.08; p = 0.011; I2 = 0.0%), and 1-year survival (SMD = 0.31; 95% CI 0.02-0.61; p = 0.045; I2 = 0.0%). Preoperative AT values moderately correlated with unplanned ICU admissions (SMD = - 0.34; 95% CI - 0.61 to - 0.07; p = 0.014; I2 = 0.0%), and 1-year survival (SMD = 0.34; 95% CI 0.00-0.68; p = 0.049; I2 = 7.4%). Neither [Formula: see text]O2peak nor AT demonstrated prognostic value for noncardiopulmonary complications. CONCLUSIONS: [Formula: see text]O2peak and AT, where measured by preoperative CPET testing, are inversely associated with postoperative cardiopulmonary complications, unplanned ICU admissions, and 1-year survival following oesophagectomy. This meta-analysis was not able to identify an absolute cutoff value for CPET variables to discriminate between patients of varying levels of operative risk.

Intramuscular Transplantation Improves Engraftment Rates for Esophageal Patient-Derived Tumor Xenografts.

BACKGROUND: Recently, there has been an increase in the availability of targeted molecular therapies for cancer treatment. The application of these approaches to esophageal cancer, however, has been hampered by the relative lack of appropriate models for preclinical testing. Patient-derived tumor xenograft (PDTX) models are gaining popularity for studying many cancers. Unfortunately, it has proven difficult to generate xenografts from esophageal cancer using these models. The purpose of this study was to improve the engraftment efficiency of esophageal PDTXs. METHODS: Fresh pieces of esophageal tumors obtained from endoscopic biopsies or resected specimens were collected from 23 patients. The tumors were then coated in Matrigel and transplanted in immunocompromised mice subcutaneously (n = 6) and/or using a novel implantation technique whereby the tumor is placed in a dorsal intramuscular pocket (n = 18). They are then monitored for engraftment. RESULTS: With the novel intramuscular technique, successful engraftment was achieved for all 18 patient tumors. Among these PDTXs, 13 recapitulated the original patient tumors with respect to degree of differentiation, molecular and genetic profiles, and chemotherapeutic response. Lymphomatous transformation was observed in the other five PDTXs. Successful engraftment was achieved for only one of six patient tumors using the classic subcutaneous approach. DISCUSSION: We achieved a much higher engraftment rate of PDTXs using our novel intramuscular transplant technique than has been reported in other published studies. It is hoped that this advancement will help expedite the development and testing of new therapies for esophageal cancer.

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma.

OBJECTIVES: p53 is a critical tumour suppressor and is mutated in 70% of oesophageal adenocarcinomas (OACs), resulting in chemoresistance and poor survival. APR-246 is a first-in-class reactivator of mutant p53 and is currently in clinical trials. In this study, we characterised the activity of APR-246 and its effect on p53 signalling in a large panel of cell line xenograft (CLX) and patient-derived xenograft (PDX) models of OAC. DESIGN: In vitro response to APR-246 was assessed using clonogenic survival, cell cycle and apoptosis assays. Ectopic expression, gene knockdown and CRISPR/Cas9-mediated knockout studies of mutant p53 were performed to investigate p53-dependent drug effects. p53 signalling was examined using quantitative RT-PCR and western blot. Synergistic interactions between APR-246 and conventional chemotherapies were evaluated in vitro and in vivo using CLX and PDX models. RESULTS: APR-246 upregulated p53 target genes, inhibited clonogenic survival and induced cell cycle arrest as well as apoptosis in OAC cells harbouring p53 mutations. Sensitivity to APR-246 correlated with cellular levels of mutant p53 protein. Ectopic expression of mutant p53 sensitised p53-null cells to APR-246, while p53 gene knockdown and knockout diminished drug activity. Importantly, APR-246 synergistically enhanced the inhibitory effects of cisplatin and 5-fluorouracil through p53 accumulation. Finally, APR-246 demonstrated potent antitumour activity in CLX and PDX models, and restored chemosensitivity to a cisplatin/5-fluorouracil-resistant xenograft model. CONCLUSIONS: APR-246 has significant antitumour activity in OAC. Given that APR-246 is safe at therapeutic levels our study strongly suggests that APR-246 can be translated into improving the clinical outcomes for OAC patients.

Synthesis of phenanthridine derivatives by microwave-mediated cyclization of o-furyl(allylamino)arenes.

A novel and efficient synthesis of phenanthridines and aza analogues is reported. The key step is a microwave-mediated intramolecular Diels-Alder cyclization of o-furyl(allylamino)arenes. In the presence of a catalytic amount of acid, the DA-adduct reacts further to give the dihydrophenanthridines, which easily can be oxidized to fully aromatic compounds by air in the presence of UV light or by DDQ.

C-reactive protein is a predictor of severe infective complications following gastrectomy-a retrospective analysis.

Background: Post-operative complications are the main contributing factor to increased length of stay, increased cost of care and short-term mortality experienced by patients following gastrectomy. The purpose of this study was to determine the diagnostic accuracy of C-reactive protein (CRP) in predicting complications following gastrectomy. This may assist clinicians to make better informed clinical decisions in the post-operative period. Methods: A retrospective analysis of a prospectively maintained database was performed. Sixty patients who underwent gastrectomy for gastric cancer were included. Demographic information, operative data and post-operative details such as complications, unplanned intensive care unit (ICU) admission and readmission to hospital were analysed. Complications were further analysed based on whether they were either infective or non-infective in nature. Receiver operator characteristic (ROC) analysis was performed to examine the association between CRP and post-operative morbidity. Optimum cut-offs were determined using the Youden's index. Results: From the second post-operative day (POD), CRP levels were able to predict subsequent severe infective (SI) complications following gastrectomy [area under the curve (AUC): 0.789, 95% CI : 0.636-0.941]. An optimum cut-off of 180 mg/L resulted in a sensitivity of 87.50%. The negative predictive value (NPV) at this point was 96.30%. Conclusions: CRP is a strong negative predicter of SI complications following gastrectomy. This suggests early CRP values may be useful in prompting early investigation or facilitating safer, earlier discharge from hospital. Health services may benefit by determining similar cut-offs based on their own unique patient populations.

Venoarterial Extracorporeal Membrane Oxygenation After Autologous Stem Cell Transplantation With Pancytopenia: JACC Patient Care Pathways.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides temporary mechanical circulatory support and simultaneous extracorporeal gas exchange for acute cardiorespiratory failure. By providing circulatory support, VA-ECMO gives treatments time to reach optimal efficacy or may be used as a bridge to a more durable mechanical solution for patients with acute cardiopulmonary failure. It is commonly used when a readily reversible etiology of decompensation is identified with very strict inclusion criteria for extracorporeal cardiopulmonary resuscitation use. We present a unique case in which VA-ECMO/extracorporeal cardiopulmonary resuscitation was used after cardiac arrest with pulseless electrical activity in a patient with recurrent lymphoma of the left thigh with recent autologous stem cell transplant.

Inhibition of BMP2 and BMP4 Represses Barrett's Esophagus While Enhancing the Regeneration of Squamous Epithelium in Preclinical Models.

BACKGROUND & AIMS: Barrett's esophagus is considered to be a metaplastic lesion that predisposes for esophageal adenocarcinoma. Development of Barrett's esophagus is considered to be driven by sonic hedgehog mediated bone morphogenetic protein (BMP) signaling. We aimed to investigate in preclinical in vivo models whether targeting canonical BMP signaling could be an effective treatment for Barrett's esophagus. METHODS AND RESULTS: Selective inhibition of BMP2 and BMP4 within an in vivo organoid model of Barrett's esophagus inhibited development of columnar Barrett's cells, while favoring expansion of squamous cells. Silencing of noggin, a natural antagonist of BMP2, BMP4, and BMP7, in a conditional knockout mouse model induced expansion of a Barrett's-like neo-columnar epithelium from multi-lineage glands. Conversely, in this model specific inhibition of BMP2 and BMP4 led to the development of a neo-squamous lineage. In an ablation model, inhibition of BMP2 and BMP4 resulted in the regeneration of neo-squamous epithelium after the cryoablation of columnar epithelium at the squamocolumnar junction. Through lineage tracing the generation of the neo-squamous mucosa was found to originate from K5+ progenitor squamous cells. CONCLUSIONS: Here we demonstrate that specific inhibitors of BMP2 and BMP4 attenuate the development of Barrett's columnar epithelium, providing a novel potential strategy for the treatment of Barrett's esophagus and the prevention of esophageal adenocarcinoma.

Venoarterial Extracorporeal Membrane Oxygenation After Autologous Stem Cell Transplantation With Pancytopenia: JACC Patient Care Pathways.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides temporary mechanical circulatory support and simultaneous extracorporeal gas exchange for acute cardiorespiratory failure. By providing circulatory support, VA-ECMO gives treatments time to reach optimal efficacy or may be used as a bridge to a more durable mechanical solution for patients with acute cardiopulmonary failure. It is commonly used when a readily reversible etiology of decompensation is identified with very strict inclusion criteria for extracorporeal cardiopulmonary resuscitation use. We present a unique case in which VA-ECMO/extracorporeal cardiopulmonary resuscitation was used after cardiac arrest with pulseless electrical activity in a patient with recurrent lymphoma of the left thigh with recent autologous stem cell transplant.

Narrative Restrictions and Proxies.

We compare two approaches to using information about the signs of structural shocks at specific dates within a structural vector autoregression (SVAR): imposing "narrative restrictions" (NR) on the shock signs in an otherwise set-identified SVAR; and casting the information about the shock signs as a discrete-valued "narrative proxy" (NP) to point-identify the impulse responses. The NP is likely to be "weak" given that the sign of the shock is typically known in a small number of periods, in which case the weak-proxy robust confidence intervals in Montiel Olea, Stock, and Watson are the natural approach to conducting inference. However, we show both theoretically and via Monte Carlo simulations that these confidence intervals have distorted coverage-which may be higher or lower than the nominal level-unless the sign of the shock is known in a large number of periods. Regarding the NR approach, we show that the prior-robust Bayesian credible intervals from Giacomini, Kitagawa, and Read deliver coverage exceeding the nominal level, but which converges toward the nominal level as the number of NR increases.

Predicting Response to Neoadjuvant Therapy in Oesophageal Adenocarcinoma.

(1) Background: Oesophageal cancers are often late-presenting and have a poor 5-year survival rate. The standard treatment of oesophageal adenocarcinomas involves neoadjuvant chemotherapy with or without radiotherapy followed by surgery. However, less than one third of patients respond to neoadjuvant therapy, thereby unnecessarily exposing patients to toxicity and deconditioning. Hence, there is an urgent need for biomarkers to predict response to neoadjuvant therapy. This review explores the current biomarker landscape. (2) Methods: MEDLINE, EMBASE and ClinicalTrial databases were searched with key words relating to "predictive biomarker", "neoadjuvant therapy" and "oesophageal adenocarcinoma" and screened as per the inclusion and exclusion criteria. All peer-reviewed full-text articles and conference abstracts were included. (3) Results: The search yielded 548 results of which 71 full-texts, conference abstracts and clinical trials were eligible for review. A total of 242 duplicates were removed, 191 articles were screened out, and 44 articles were excluded. (4) Discussion: Biomarkers were discussed in seven categories including imaging, epigenetic, genetic, protein, immunologic, blood and serum-based with remaining studies grouped in a miscellaneous category. (5) Conclusion: Although promising markers and novel methods have emerged, current biomarkers lack sufficient evidence to support clinical application. Novel approaches have been recommended to assess predictive potential more efficiently.

Economic burden of complications and readmission following oesophageal cancer surgery.

BACKGROUND: Oesophageal cancer is the seventh most prevalent malignancy globally, and the sixth most common cause of cancer-related death. Oesophageal cancer is also one of the most costly cancers to treat. The aim of this study was to assess the financial impact of post-operative morbidity and hospital readmissions following oesophagectomy for oesophageal cancer. METHODS: A retrospective analysis was performed on a prospectively maintained database of patients with oesophageal cancer who underwent an oesophagectomy at a single centre between July 2014 and June 2019 (N = 56). Readmission costs were also assessed in this cohort for 12 months post-operatively. RESULTS: The total median cost for oesophagectomy in this cohort was AU$57 250. Major complications occurred in 40% of patients, with a median total admission cost of AU$74 606, significantly higher than patients with either minor or no complications (median admission cost of AU$52 713, P < 0.001). Patients whose operation was complicated by an anastomotic leak had a higher median admission cost than those without a leak (AU$104 328 and AU$54 972 respectively, P < 0.001). Cost centres representing the greatest proportion of costs were theatre resources and surgical ward care (medical and nursing). A total of 110 readmissions in 25 patients were recorded in the 12 months post-operatively, the majority for gastroscopy and dilatation of anastomotic stricture. CONCLUSION: Post-oesophagectomy morbidity greatly increases cost of care. In addition to the clinical benefits, interventions to minimize post-operative complications are likely to result in substantial cost savings.

Body Composition Differences Between Excess Weight Loss ≥ 50% and < 50% at 12 Months Following Bariatric Surgery.

BACKGROUND: The relationship between weight loss and body composition is undefined after bariatric surgery. The objective of this study was to compare body composition changes in patients with excess weight loss ≥ 50% (EWL ≥ 50) and < 50% at 12 months post-operatively (EWL < 50). METHODS: A prospective cohort study was completed on patients undergoing bariatric surgery at two tertiary hospitals between 2017 and 2021. Body composition was measured with dual-energy X-ray absorptiometry immediately before surgery, and at 1, 6, and 12 months post-operatively. Body mass index (BMI), fat mass (FM), lean body mass (LBM), and skeletal muscle index (SMI) trajectories were analysed between patients with EWL ≥ 50% and EWL < 50%. RESULTS: Thirty-seven patients were included in this series (EWL ≥ 50% n = 25, EWL < 50% n = 12), comprising of both primary and revisional bariatric surgery cases, undergoing a sleeve gastrectomy (62.2%), Roux-en-Y gastric bypass (32.4%), or one anastomosis gastric bypass (5.4%). The EWL ≥ 50% group demonstrated a more optimal mean FM-to-LBM loss ratio than the EWL < 50% group. EWL ≥ 50% patients lost 2.0 kg more FM than EWL < 50% patients for each 1 kg of LBM lost. EWL ≥ 50% was also associated with an increase in mean SMI% over 12 months (5.5 vs. 2.4%; p < 0.0009). Across the whole cohort, the first month after surgery accounted for 67.4% of the total LBM reduction that occurred during the 12-month post-operative period. CONCLUSION: This data suggests EWL ≥ 50% is associated with a more optimal body composition outcome than EWL < 50%. LBM reduction occurs predominantly in the early post-operative period.