Feature-specific quantile normalization and feature-specific mean-variance normalization deliver robust bi-directional classification and feature selection performance between microarray and RNAseq data.

BACKGROUND: Cross-platform normalization seeks to minimize technological bias between microarray and RNAseq whole-transcriptome data. Incorporating multiple gene expression platforms permits external validation of experimental findings, and augments training sets for machine learning models. Here, we compare the performance of Feature Specific Quantile Normalization (FSQN) to a previously used but unvalidated and uncharacterized method we label as Feature Specific Mean Variance Normalization (FSMVN). We evaluate the performance of these methods for bidirectional normalization in the context of nested feature selection. RESULTS: FSQN and FSMVN provided clinically equivalent bidirectional model performance with and without feature selection for colon CMS and breast PAM50 classification. Using principal component analysis, we determine that these methods eliminate batch effects related to technological platforms. Without feature selection, no statistical difference was identified between the performance of FSQN and FSMVN of cross-platform data compared to within-platform distributions. Under optimal feature selection conditions, balanced accuracy was FSQN and FSMVN were statistically equivalent to the within-platform distribution performance in multivariable linear regression analysis. FSQN and FSMVN also provided similar performance to within-platform distributions as the number of selected genes used to create models decreases. CONCLUSIONS: In the context of generating supervised machine learning classifiers for molecular subtypes, FSQN and FSMVN are equally effective. Under optimal modeling conditions, FSQN and FSMVN provide equivalent model accuracy performance on cross-platform normalization data compared to within-platform data. Using cross-platform data should still be approached with caution as subtle performance differences may exist depending on the classification problem, training, and testing distributions.

Individual Survival Distributions Generated by Multi-Task Logistic Regression Yield a New Perspective on Molecular and Clinical Prognostic Factors in Gastric Adenocarcinoma.

Recent advances in our understanding of gastric cancer biology have prompted a shift towards more personalized therapy. However, results are based on population-based survival analyses, which evaluate the average survival effects of entire treatment groups or single prognostic variables. This study uses a personalized survival modelling approach called individual survival distributions (ISDs) with the multi-task logistic regression (MTLR) model to provide novel insight into personalized survival in gastric adenocarcinoma. We performed a pooled analysis using 1043 patients from a previously characterized database annotated with molecular subtypes from the Cancer Genome Atlas, Asian Cancer Research Group, and tumour microenvironment (TME) score. The MTLR model achieved a 5-fold cross-validated concordance index of 72.1 ± 3.3%. This model found that the TME score and chemotherapy had similar survival effects over the entire study time. The TME score provided the greatest survival benefit beyond a 5-year follow-up. Stage III and Stage IV disease contributed the greatest negative effect on survival. The MTLR model weights were significantly correlated with the Cox model coefficients (Pearson coefficient = 0.86, p < 0.0001). We illustrate how ISDs can accurately predict the survival time for each patient, which is especially relevant in cases of molecular subtype heterogeneity. This study provides evidence that the TME score is principally associated with long-term survival in gastric adenocarcinoma. Additional external validation and investigation into the clinical utility of this ISD model in gastric cancer is an area of future research.

A prospective Canadian gastroesophageal cancer database: What have we learned?

BACKGROUND: Minimal literature exists on outcomes for Canadian patients with gastroesophageal adenocarcinoma (GEA). The objective of our study was to establish a prospective clinical database to evaluate demographic characteristics, presentation and outcomes of patients with GEA. METHODS: Patients diagnosed with GEA were recruited from Jan. 30, 2017, to Aug. 30, 2020. Data collected included demographic characteristics, presentation, treatment and survival. A multivariable model for overall survival in patients treated with curative intent was created using sex, lymph node status, resection margin status, age and tumour location as variables. RESULTS: A total of 122 patients with adenocarcinoma of the stomach or gastroesophageal junction were included. Median age was 65 years (interquartile range [IQR] 59-74), 70% of patients were male and 26% were born outside of Canada. Median follow-up time was 14.5 (IQR 8.0-31.0) months. Following staging computed tomography scanning, 88% of patients were deemed to have potentially resectable disease. Eighty-one (76%) received staging laparoscopy and 74 (61%) were treated with curativeintent surgery. Forty-six (62%) patients had nodal metastases. The median number of nodes harvested was 22 (IQR 18-30). The R0 resection margin rate was 82%. The 3-year overall survival for patients who received curative-intent treatment was 63% and 38% for all patients. On multivariable analysis, female sex (hazard ratio [HR] 3.88, p = 0.01), positive nodal status (HR 3.58, p = 0.02), positive margins (HR 3.11, p = 0.03) and tumour location (HR 3.00, p = 0.03) were associated with decreased overall survival. CONCLUSION: Many of the patients with GEA in this study presented with advanced disease, and only 61% were offered curative-intent surgery. A prospective multicentre national GEA database is now being established.

Learning Individual Survival Models from PanCancer Whole Transcriptome Data.

PURPOSE: Personalized medicine attempts to predict survival time for each patient, based on their individual tumor molecular profile. We investigate whether our survival learner in combination with a dimension reduction method can produce useful survival estimates for a variety of patients with cancer. EXPERIMENTAL DESIGN: This article provides a method that learns a model for predicting the survival time for individual patients with cancer from the PanCancer Atlas: given the (16,335 dimensional) gene expression profiles from 10,173 patients, each having one of 33 cancers, this method uses unsupervised nonnegative matrix factorization (NMF) to reexpress the gene expression data for each patient in terms of 100 learned NMF factors. It then feeds these 100 factors into the Multi-Task Logistic Regression (MTLR) learner to produce cancer-specific models for each of 20 cancers (with >50 uncensored instances); this produces "individual survival distributions" (ISD), which provide survival probabilities at each future time for each individual patient, which provides a patient's risk score and estimated survival time. RESULTS: Our NMF-MTLR concordance indices outperformed the VAECox benchmark by 14.9% overall. We achieved optimal survival prediction using pan-cancer NMF in combination with cancer-specific MTLR models. We provide biological interpretation of the NMF model and clinical implications of ISDs for prognosis and therapeutic response prediction. CONCLUSIONS: NMF-MTLR provides many benefits over other models: superior model discrimination, superior calibration, meaningful survival time estimates, and accurate probabilistic estimates of survival over time for each individual patient. We advocate for the adoption of these cancer survival models in clinical and research settings.

Increased CD4/CD8 Lymphocyte ratio predicts favourable neoadjuvant treatment response in gastric cancer: A prospective pilot study.

BACKGROUND: Despite optimal neoadjuvant chemotherapy only 40% of gastric cancer tumours achieve complete or partial treatment response. In the absence of treatment response, neoadjuvant chemotherapy in gastric cancer contributes to adverse events without additional survival benefit compared to adjuvant treatment or surgery alone. Additional strategies and methods are required to optimize the allocation of existing treatment regimens such as FLOT chemotherapy (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel). Predictive biomarkers detected using immunohistochemistry (IHC) methods may provide useful data regarding treatment response. AIM: To investigate the utility of CD4, CD8, Galectin-3 and E-cadherin in predicting neoadjuvant FLOT chemotherapy tumour response in gastric adenocarcinoma. METHODS: Forty-three adult patients with gastric adenocarcinoma, of which 18 underwent neoadjuvant chemotherapy, were included in a prospective clinical cohort. Endoscopic biopsies were obtained from gastric cancer and normal adjacent gastric mucosa. Differences in expression of Galectin-3, E-cadherin, CD4+ and CD8+ molecules between tumours with and without treatment response to neoadjuvant chemotherapy were assessed with IHC. Treatment response was graded by clinical pathologists using the Tumour Regression Score according to the College of American Pathologists criteria. Treatment response was defined as complete or near complete tumour response, whereas partial or poor/no response was defined as incomplete. Digital IHC images were annotated and quantitatively assessed using QuPath 0.3.1. Biomarker expression between responsive and incomplete response tumours was assessed using a two-sided Wilcoxon test. Biomarker expression was also compared between normal and cancer tissue and between 15 paired tumour samples before and after chemotherapy. We performed a preliminary multivariate analysis and power analysis to guide future study. Statistical analyses were completed using R 4.1.2. RESULTS: The ratio between CD4+ and CD8+ lymphocytes was significantly greater in treatment responsive tumours (Wilcoxon, P = 0.03). In univariate models, CD4+/CD8+ ratio was the only biomarker that significantly predicted favourable treatment response (Accuracy 86%, P < 0.001). Using a glmnet multivariate model, high CD4+/CD8+ ratio and low Galectin-3 expression were the most influential variables in predicting a favourable treatment response. Analyses of paired samples found that FLOT chemotherapy also results in increased expression of CD4+ and CD8+ tumour infiltrating lymphocytes (Paired Wilcoxon, P = 0.002 and P = 0.008, respectively). Our power analysis suggests future study requires at least 35 patients in each treatment response group for CD8 and Galectin-3 molecules, whereas 80 patients in each treatment response group are required to assess CD4 and E-cadherin biomarkers. CONCLUSION: We demonstrate that an elevated CD4+/CD8+ Ratio is a promising IHC-based biomarker to predict favourable treatment response to FLOT neoadjuvant chemotherapy in locally advanced gastric cancer.

Murine and Human Gastric Tissue Establishes Organoids after 48 Hours of Cold Ischemia Time during Shipment.

An inadequate supply of fresh tissue is a major limitation of three-dimensional patient-derived gastric organoid research. We propose that tissue procurement for organoid culture could be increased by developing a cold storage shipment protocol for fresh surgical tissues. Sixty stomach specimens from C57BL/6J mice were resected, of which forty-five were stored in Hank's Balanced Salt (HBSS), University of Wisconsin (UW), or Histidine-Tryptophan-Ketoglutarate (HTK) solutions for subsequent organoid culture. Stomachs were dissociated and processed into gastric organoids as fresh tissue or after transport at 4 °C for 24 or 48 h. All gastric organoid cultures were established and maintained for 10 passages. Cold storage for 24 or 48 h did not significantly affect organoid viability. Although cold storage was associated with decreased organoid growth rate, there were no differences in viability, cytotoxic dose response, or LGR5 and TROY stem cell gene expression compared to organoids prepared from fresh tissue. As a proof of concept, six human gastric cancer organoids were established after 24 or 48 h of storage. Patient-derived gastric organoids from mouse and human gastric tissue can be established after 48 h of cold ischemia. Our method, which only requires ice packs, standard shipping containers, and HBSS is feasible and reliable. This method does not affect the reliability of downstream dose-response assays and maintains organoid viability for at least 10 passages. The shipment of fresh tissue for organoid procurement could serve to enhance multicenter collaboration and achieve more elaborate or controlled organoid experimentation.

Normothermic Ex Vivo Machine Perfusion for Liver Grafts Recovered from Donors after Circulatory Death: A Systematic Review and Meta-Analysis.

As a result of donation after circulatory death liver grafts' poor tolerance to cold storage, there has been increasing research interest in normothermic machine perfusion. This study aims to systematically review the current literature comparing normothermic perfusion to cold storage in donation after circulatory death liver grafts and complete a meta-analysis of published large animal and human studies. A total of nine porcine studies comparing cold storage to normothermic machine perfusion for donation after circulatory death grafts were included for analysis. There was a significant reduction in AST (mean difference -2291 U/L, CI (-3019, -1563); P ≤ 0.00001) and ALT (mean difference -175 U/L, CI (-266, -85); P = 0.0001), for normothermic perfusion relative to static cold storage, with moderate (I2 = 61%) and high (I2 = 96%) heterogeneity, respectively. Total bile production was also significantly higher (mean difference = 174 ml, CI (155, 193); P ≤ 0.00001). Further research focusing on standardization, performance of this technology following periods of cold storage, economic implications, and clinical trial data focused on donation after circulatory death grafts will be helpful to advance this technology toward routine clinical utilization for these grafts.

Barriers to the Interpretation of Body Composition in Colorectal Cancer: A Review of the Methodological Inconsistency and Complexity of the CT-Defined Body Habitus.

BACKGROUND: Measurement of body composition by computed tomography (CT) is an advancing field. Sarcopenia, myosteatosis, and visceral obesity (VO) have been identified as predictive of survival in colorectal cancer (CRC). We performed a systematic review of contemporary studies to characterize this association and highlight methodological inconsistencies. METHODS: MEDLINE and PubMed were queried for articles published from January 2000 on, with populations of resectable CRC and with CT-measured body composition and survival data. The study quality was assessed by two independent reviewers using the Newcastle-Ottawa Scale. RESULTS: Twenty studies met inclusion criteria, with a total of 8895 patients. Only two of the studies scored as high quality and nine as moderate quality. The remaining nine studies scored as low quality. Ten studies considered sarcopenia and 12 considered visceral obesity (VO). Cutoff points to define sarcopenia, myosteatosis, and VO were identified by optimal stratification, quartiles, or median values. The prevalence of sarcopenia varied from 15 to 60%, which based on study population and cutoff value used. Sarcopenia was associated with worse overall and disease-free survival in eight of the included studies. Myosteatosis was considered in three studies with a prevalence of 19-78%. It was significantly predictive of worse overall and disease-free survival in all three studies. VO had a prevalence of 14-70% and was inconsistently predictive of survival outcomes. CONCLUSIONS: There is a lack of methodological consistency within the currently published literature. Despite this, sarcopenia and myosteatosis, but not VO, are consistently associated with worse survival outcomes, when population and cancer-specific cutoffs are utilized.

Diagnostic evaluation of sentinel lymph node biopsy using indocyanine green and infrared or fluorescent imaging in gastric cancer: a systematic review and meta-analysis.

BACKGROUND: Sentinel node navigation surgery (SNNS) for gastric cancer using infrared visualization of indocyanine green (ICG) is intriguing because it may limit operative morbidity. We are the first to systematically review and perform meta-analysis on the diagnostic utility of ICG and infrared electronic endoscopy (IREE) or near infrared fluorescent imaging (NIFI) for SNNS exclusively in gastric cancer. METHODS: A search of electronic databases MEDLINE, EMBASE, SCOPUS, Web of Science, and the Cochrane Library using search terms "gastric/stomach" AND "tumor/carcinoma/cancer/neoplasm/adenocarcinoma/malignancy" AND "indocyanine green" was completed in May 2017. Articles were selected by two independent reviewers based on the following major inclusion criteria: (1) diagnostic accuracy study design; (2) indocyanine green was injected at tumor site; (3) IREE or NIFI was used for intraoperative visualization. 327 titles or abstracts were screened. The quality of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. RESULTS: Ten full text studies were selected. 643 patients were identified with the majority of patients possessing T1 tumors (79.8%). Pooled identification rate, diagnostic odds ratio, sensitivity, and specificity were 0.99 (0.97-1.0), 380.0 (68.71-2101), 0.87 (0.80-0.93), and 1.00 (0.99-1.00), respectively. The summary receiver operator characteristic for ICG + IREE/NIFI demonstrated a test accuracy of 98.3%. Subgroup analysis found improved test performance for studies with low-risk QUADAS-2 scores, studies published after 2010 and submucosal ICG injection. IREE had improved diagnostic odds ratio, sensitivity, and identification rate compared to NIFI. Heterogeneity among studies ranged from low (I2 < 25%) to high (I2 > 75%). CONCLUSIONS: We found encouraging results regarding the accuracy, diagnostic odds ratio, and specificity of the test. The sensitivity was not optimal but may be improved by a strict protocol to augment the technique. Given the number and heterogeneity of studies, our results must be viewed with caution.

The Effect of Helicobacter pylori on Postoperative Outcomes in Patients Undergoing Bariatric Surgery: a Systematic Review and Meta-analysis.

Helicobacter pylori (HP) occurs in 50% of people worldwide with higher rates reported in the bariatric population. HP has been associated with adverse outcomes following bariatric surgery; however, its true impact has not yet been defined. We aimed to systematically review the effect of HP on bariatric surgery outcomes. A comprehensive literature review was conducted yielding seven studies with 255,435 patients. Meta-analysis found comparable rates of bleeding, leak, hospital length of stay, and weight loss between HP-positive and HP-negative patients. HP was, however, found to be the largest independent predictor of marginal ulceration in those undergoing RYGB, with a tenfold increase versus HP-negative patients. Overall, HP is associated with increased marginal ulceration rates, but has little impact on other bariatric surgery outcomes.

LINX® magnetic esophageal sphincter augmentation versus Nissen fundoplication for gastroesophageal reflux disease: a systematic review and meta-analysis.

BACKGROUND: The LINX® magnetic sphincter augmentation system (MSA) is a surgical technique with short-term evidence demonstrating efficacy in the treatment of medically refractory or chronic gastroesophageal reflux disease (GERD). Currently, the Nissen fundoplication is the gold-standard surgical treatment for GERD. We are the first to systematically review the literature and perform a meta-analysis comparing MSA to the Nissen fundoplication. METHODS: A comprehensive search of electronic databases (e.g., MEDLINE, EMBASE, SCOPUS, Web of Science and the Cochrane Library) using search terms "Gastroesophageal reflux or heartburn" and "LINX or endoluminal or magnetic" and "fundoplication or Nissen" was completed. All randomized controlled trials, non-randomized comparison study and case series with greater than 5 patients were included. Five hundred and forty-seven titles were identified through primary search, and 197 titles or abstracts were screened after removing duplicates. Meta-analysis was performed on postoperative quality of life outcomes, procedural efficacy and patient procedural satisfaction. RESULTS: Three primary studies identified a total of 688 patients, of whom 273 and 415 underwent Nissen fundoplication and MSA, respectively. MSA was statistically superior to LNF in preserving patient's ability to belch (95.2 vs 65.9%, p < 0.00001) and ability to emesis (93.5 vs 49.5%, p < 0.0001). There was no statistically significant difference between MSA and LNF in gas/bloating (26.7 vs 53.4%, p = 0.06), postoperative dysphagia (33.9 vs 47.1%, p = 0.43) and proton pump inhibitor (PPI) elimination (81.4 vs 81.5%, p = 0.68). CONCLUSION: Magnetic sphincter augmentation appears to be an effective treatment for GERD with short-term outcomes comparable to the more technically challenging and time-consuming Nissen fundoplication. Long-term comparative outcome data past 1 year are needed in order to further understand the efficacy of magnetic sphincter augmentation.

The Impact of Bariatric Surgery on Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis.

Bariatric surgery has been proven to be a successful management strategy for morbid obesity, but limited studies exist on its effect on polycystic ovary syndrome (PCOS). A comprehensive search of electronic databases was completed. Meta-analysis was performed on PCOS, hirsutism, and menstrual irregularity outcomes following bariatric surgery. Thirteen primary studies involving a total of 2130 female patients were identified. The incidence of PCOS preoperatively was 45.6 %, which significantly decreased to 6.8 % (P < 0.001) and 7.1 % (P < 0.0002) at 12-month follow-up and study endpoint, respectively. The incidences of preoperative menstrual irregularity and hirsutism both significantly decreased at 12-month and at study end follow-up. Bariatric surgery effectively attenuates PCOS and its clinical symptomatology including hirsutism and menstrual irregularity in severely obese women.

Quality of Follow-up: Systematic Review of the Research in Bariatric Surgery.

OBJECTIVE: We aim to systematically review the bariatric surgery literature with regards to adequacy of patient follow-up, meeting the McMaster criteria of ≥80% follow-up. BACKGROUND: Loss to follow-up is a major concern and can potentially bias the outcome and interpretation of a study. The quality of follow-up in bariatric surgery is quite variable with recent systematic reviews criticizing the field for its lack of overall follow-up. METHODS: A complete search of PubMed was performed. Literature was restricted to a range of 5 years (2007-2012), English language, and publications listed in PubMed. The McMaster Evidence-based Criteria for High Quality Studies was used to assess the follow-up data adequacy and a logistic meta-regression was performed to identify factors associated with high quality follow-up studies. RESULTS: Ninety-nine published manuscripts were included. For follow-up at study end, only 40/99 (40.4%) of papers had adequate patient follow-up, 42/99 (42.4%) failed to meet the McMaster criteria and 17/99 (17.2%) failed to report any follow-up results. On average, 31% were lost to follow-up at the study's end. Only shorter study duration, and if the study was performed in the US, were associated with studies meeting the McMaster criteria. CONCLUSIONS: Only 40% of studies in the bariatric surgery literature meet criteria for adequate follow-up. On average, studies have 30% of patients lost to follow-up at the stated end-point. Identified study characteristics associated with high quality follow-up included shorter study duration and studies performed in the US.

Endoscopy services and training: a national survey of general surgeons.

BACKGROUND: Delivering high-quality endoscopy services depends largely on the competence of endoscopists. General surgery residency training in endoscopy and the associated quality of endoscopy services being delivered by general surgeons have been the subject of considerable controversy. In conjunction with the Canadian Association of General Surgeons (CAGS) executive board, we formulated a survey to evaluate the general state of endoscopy practice and training among general surgeons in Canada. METHODS: The study was designed as a cross-sectional survey. General surgeons who are members of CAGS were selected to participate in the study and were emailed a link to the online questionnaire regarding the importance of endoscopy. They were asked to compare their training to resident training today. RESULTS: Sixty-nine surveys were completed. The majority of general surgeons (95.7%) indicated that endoscopy was an important skill to possess, and more than 85.5% used endoscopy in their own practices. However, nearly half (46.4%) felt that general surgery endoscopy training in Canada is currently inadequate to produce competent endoscopists. The main qualitative themes emerging from the survey were the inadequacy of current postgraduate endoscopy training (37.5%) and the absence of standardization in training (25.0%). CONCLUSION: Endoscopy is considered integral to academic and community general surgeons' practices; however, the adequacy of training seems to be questioned. Postgraduate training in endoscopy needs to be formalized and standardized, with a greater emphasis placed on teaching endoscopy.

CONTEXTE: La qualité des services d'endoscopie est largement tributaire de la compétence des endoscopistes. La formation en endoscopie pendant la résidence en chirurgie générale et la qualité connexe des services d'endoscopie fournis par les chirurgiens généraux font l'objet d'une importante controverse. En collaboration avec le conseil de direction de l'Association canadienne des chirurgiens généraux (ACCG), nous avons produit un sondage pour évaluer l'état global, chez les chirurgiens généraux au Canada, de la pratique et de la formation en matière d'endoscopie. MÉTHODES: L'étude s'est effectuée sous forme de sondage transversal. Des chirurgiens généraux membres de l'ACCG ont été choisis pour participer à l'étude et ont reçu par courriel un lien vers le questionnaire en ligne sur l'importance de l'endoscopie. On leur a demandé de comparer leur formation à celle que reçoivent maintenant les médecins résidents. RÉSULTATS: En tout, 69 questionnaires ont été remplis. Les chirurgiens généraux ont indiqué en majorité (95,7 %) que l'endoscopie constituait une importante technique à maîtriser, et plus de 85,5 % l'utilisent dans leur pratique. Presque la moitié (46,4 %) étaient toutefois d'avis que la formation actuelle en endoscopie en chirurgie générale au Canada ne peut produire des endoscopistes compétents. Les principaux thèmes qualitatifs que dégage le sondage portent sur la déficience de la formation en endoscopie que reçoivent actuellement les résidents (37,5 %) et sur le manque de normalisation de la formation (25,0 %). CONCLUSION: On considère que l'endoscopie fait partie intégrante des pratiques universitaires et communautaires des chirurgiens généraux, mais on semble douter que la formation soit adéquate. Il faut structurer et normaliser la formation en endoscopie que reçoivent les résidents et insister davantage sur son enseignement.