IMMUNOREACT 6: weak immune surveillance characterizes early-onset rectal cancer.

BACKGROUND: Colon cancer in young patients is often associated with hereditary syndromes; however, in early-onset rectal cancer, mutations of these genes are rarely observed. The aim of this study was to analyse the features of the local immune microenvironment and the mutational pattern in early-onset rectal cancer. METHODS: Commonly mutated genes were analysed within a rectal cancer series from the University Hospital of Padova. Mutation frequency and immune gene expression in a cohort from The Cancer Genome Atlas ('TCGA') were compared and immune-cell infiltration levels in the healthy rectal mucosa adjacent to rectal cancers were evaluated in the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 ('IMMUNOREACT') series. RESULTS: In the authors' series, the mutation frequency of BRAF, KRAS, and NRAS, as well as microsatellite instability frequency, were not different between early- and late-onset rectal cancer. In The Cancer Genome Atlas series, among the genes with the most considerable difference in mutation frequency between young and older patients, seven genes are involved in the immune response and CD69, CD3, and CD8ß expression was lower in early-onset rectal cancer. In the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 series, young patients had a lower rate of CD4+ T cells, but higher T regulator infiltration in the rectal mucosa. CONCLUSION: Early-onset rectal cancer is rarely associated with common hereditary syndromes. The tumour microenvironment is characterized by a high frequency of mutations impairing the local immune surveillance mechanisms and low expression of immune editing-related genes. A constitutively low number of CD4 T cells associated with a high number of T regulators indicates an imbalance in the immune surveillance mechanisms.

A Personalized and Adaptive Insulin Bolus Calculator Based on Double Deep Q- Learning to Improve Type 1 Diabetes Management.

Mealtime insulin dosing is a major challenge for people living with type 1 diabetes (T1D). This task is typically performed using a standard formula that, despite containing some patient-specific parameters, often leads to sub-optimal glucose control due to lack of personalization and adaptation. To overcome the previous limitations here we propose an individualized and adaptive mealtime insulin bolus calculator based on double deep Q-learning (DDQ), which is tailored to the patient thanks to a personalization procedure relying on a two-step learning framework. The DDQ-learning bolus calculator was developed and tested using the UVA/Padova T1D simulator modified to reliably mimic real-world scenarios by introducing multiple variability sources impacting glucose metabolism and technology. The learning phase included a long-term training of eight sub-population models, one for each representative subject, selected thanks to a clustering procedure applied to the training set. Then, for each subject of the testing set, a personalization procedure was performed, by initializing the models based on the cluster to which the patient belongs. We evaluated the effectiveness of the proposed bolus calculator on a 60-day simulation, using several metrics representing the goodness of glycemic control, and comparing the results with the standard guidelines for mealtime insulin dosing. The proposed method improved the time in target range from 68.35% to 70.08% and significantly reduced the time in hypoglycemia (from 8.78% to 4.17%). The overall glycemic risk index decreased from 8.2 to 7.3, indicating the benefit of our method when applied for insulin dosing compared to standard guidelines.

Methods for Insulin Bolus Adjustment Based on the Continuous Glucose Monitoring Trend Arrows in Type 1 Diabetes: Performance and Safety Assessment in an In Silico Clinical Trial.

BACKGROUND: Providing real-time magnitude and direction of glucose rate-of-change (ROC) via trend arrows represents one of the major strengths of continuous glucose monitoring (CGM) sensors in managing type 1 diabetes (T1D). Several literature methods were proposed to adjust the standard formula (SF) used for insulin bolus calculation by accounting for glucose ROC, but each of them provides different suggestions, making it difficult to understand which should be applied in practice. This work aims at performing an extensive in-silico assessment of their performance and safety. METHODS: The methods of Buckingham (BU), Scheiner (SC), Pettus/Edelman (PE), Klonoff/Kerr (KL), Aleppo/Laffel (AL), Ziegler (ZI), and Bruttomesso (BR) were evaluated using the UVa/Padova T1D simulator, in single-meal scenarios, where ROC and glucose at mealtime varied between [-2,+2] mg/dL/min and [80,200] mg/dL, respectively. Efficacy of postprandial glucose control was quantitatively assessed by time in, above and below range (TIR, TAR, and TBR, respectively). RESULTS: For negative ROCs, all methods proved to increase TIR and decrease TAR and TBR vs SF, with KL, PE, and BR being the most effective. For positive ROCs, a general worsening of the performances is present, only BR improved the glycemic control when mealtime glucose was close to hypoglycemia, while SC resulted the safest in the other conditions. CONCLUSIONS: Insulin bolus adjustment methods are effective for negative ROCs, but they generally appear to overdose for positive ROCs, calling for safer strategies in such a scenario. These results can be useful in outlining guidelines to identify which adjustment to apply based on the mealtime condition.

An Ensemble Learning Algorithm Based on Dynamic Voting for Targeting the Optimal Insulin Dosage in Type 1 Diabetes Management.

People with type 1 diabetes (T1D) need exogenous insulin administrations several times a day. The amount of injected insulin is key for maintaining the concentration of blood glucose (BG) within a physiological safe range. According to well-established clinical guidelines, insulin dosing at mealtime is calculated through an empirical formula which, however, does not take advantage of the knowledge of BG trend provided in real-time by continuous glucose monitoring (CGM) sensors. To overcome suboptimal insulin dosage, we recently used machine learning techniques to build two new models, one linear and one nonlinear, which incorporate BG trend information.In this work, we propose an ensemble learning method for mealtime insulin bolus estimation based on dynamic voting, which combines the two models by taking advantage of where each alternative performs better. Being the resulting model black-box, a tool that enables its interpretability was applied to evaluate the contribution of each feature. The proposed model was trained using a synthetic dataset having information on 100 virtual subjects with different mealtime conditions, and its performance was evaluated within a simulated environment.The benefit given by the ensemble method compared to the single models was confirmed by the high time within the target glycemic range, and the trade-off reached in terms of time spent below and above this range. Moreover, the model interpretation pointed out the key role played by the information on BG dynamics in the estimation of insulin dosage.

A New Decision Support System for Type 1 Diabetes Management.

Type 1 diabetes (T1D) is a chronic life-threatening metabolic condition which needs to be accurately and continuously managed with care by multiple daily exogenous insulin injections, frequent blood glucose concentration monitoring, ad-hoc diet, and physical activity. In the last decades, new technologies, such as continuous glucose monitoring sensors, eased the burden for T1D patients and opened new therapy perspectives by fostering the development of decision support systems (DSS). A DSS for T1D should be able to provide patients with advice aimed at improving metabolic control and reducing the number of actions related to therapy handling. Major challenges are the vast intra-/inter-subject physiological variability and the many factors that impact glucose metabolism. The present work illustrates a new DSS for T1D management. The algorithmic core includes a module for optimal, personalized, insulin dose calculation and a module that triggers the assumption of rescue carbohydrates to avoid/mitigate impending hypoglycemic events. The algorithms are integrated within a prototype communication platform that comprises a mobile app, a real-time telemonitoring interface, and a cloud server to safely store patients' data. Tests made in silico show that the use of the new algorithms lead to metabolic control indices significantly better than those obtained by the standard care for T1D. The preliminary test of the prototype platform suggests that it is robust, performant, and well-accepted by both patients and clinicians. Future work will focus on the refinement of the communication platform and the design of a clinical trial to assess the system effectiveness in real-life conditions.Clinical Relevance- The presented DSS is a promising tool to facilitate T1D daily management and improve therapy efficacy.

Case Report: Liver Cysts and SARS-CoV-2: No Evidence of Virus in Cystic Fluid.

Background: In December 2019, an outbreak of pneumonia, caused by a new type of coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It quickly spread worldwide, resulting in a pandemic. The clinical manifestations of SARS-CoV-2 range from mild non-specific symptoms to severe pneumonia with organ function damage. In addition, up to 60% of patients have liver impairment or dysfunction, confirmed by several studies by the presence of SARS-CoV-2 in the liver tissue. Methods: We report two cases of symptomatic liver cyst requiring fenestration after recent SARS-CoV-2 infection. Both patients had hospital admission due to documented SARS-CoV-2 infection. Recently, after the infection, they developed symptoms caused by an enlarged hepatic cyst: one had abdominal pain, and the other had jaundice. They underwent surgery after two negative swab tests for SARS-CoV-2. Results: Cystic fluid was sent for microbiological test, and real-time fluorescence polymerase chain reaction COVID-19 nucleic-acid assay of the cyst fluid was found to be negative in both cases. Discussion: Although there are no current data that can document a viral contamination of cystic fluid, there are data that document a hepatotropism of COVID-19 virus. Herein we report that after viral clearance at pharyngeal and nasal swab, there is no evidence of viral load in such potential viral reservoir.

A "Slide Rule" to Adjust Insulin Dose Using Trend Arrows in Adults with Type 1 Diabetes: Test in Silico and in Real Life.

INTRODUCTION: In persons with type 1 diabetes (T1D) insulin dosing can be adjusted based on trend arrows derived from continuous glucose monitoring (CGM). We propose a slide rule with narrower blood glucose intervals and more classes of insulin sensitivity than are available in current models. METHODS: The slide rule was tested in silico, in which a meal was simulated in 100 virtual subjects and the insulin bolus was calculated either in the standard way based on the insulin-to-carbohydrate ratio and the correction factor or according to the slide rule, following which the percentage time spent in range (70-180 mg/dl; %TIR), hypoglycemia (< 70 mg/dl; %THYPO), and hyperglycemia (> 180 mg/dl; %THYPER) was compared between the methods during the 4 h after the meal. Slide rule performance was also tested in real life by analyzing the same variables at during the 4 h postprandial period in 27 individuals with T1D. Only meals starting while the rate of change was at least 1 mg/dl per minute (increasing or decreasing) were considered for analysis. RESULTS: In silico, when the preprandial trend arrow was increasing, our slide rule reduced %THYPER and increased %TIR (p < 0.05), whereas when the preprandial trend arrow was decreasing, it reduced %THYPO and slightly increased %THYPER (p < 0.05). In real life, our slide rule kept subjects on target for 70.8 and 91.6% of postprandial time when preprandial trend arrows were increasing or decreasing, respectively. CONCLUSION: The proposed slide rule performed well both in silico and in real life, suggesting that it could be safely adopted by individuals with T1D to improve glucose control.

Complications and mortality in a cohort of patients undergoing emergency and elective surgery with perioperative SARS-CoV-2 infection: an Italian multicenter study. Teachings of Phase 1 to be brought in Phase 2 pandemic.

Since the beginning of the pandemic due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its related disease, coronavirus disease 2019 (COVID-19), several articles reported negative outcomes in surgery of infected patients. Aim of this study is to report results of patients with COVID-19-positive swab, in the perioperative period after surgery. Data of COVID-19-positive patients undergoing emergent or oncological surgery, were collected in a retrospective, multicenter study, which involved 20 Italian institutions. Collected parameters were age, sex, body mass index, COVID-19-related symptoms, patients' comorbidities, surgical procedure, personal protection equipment (PPE) used in operating rooms, rate of postoperative infection among healthcare staff and complications, within 30-postoperative days. 68 patients, who underwent surgery, resulted COVID-19-positive in the perioperative period. Symptomatic patients were 63 (92.5%). Fever was the main symptom in 36 (52.9%) patients, followed by dyspnoea (26.5%) and cough (13.2%). We recorded 22 (32%) intensive care unit admissions, 23 (33.8%) postoperative pulmonary complications and 15 (22%) acute respiratory distress syndromes. As regards the ten postoperative deaths (14.7%), 6 cases were related to surgical complications. One surgeon, one scrub nurse and two circulating nurses were infected after surgery due to the lack of specific PPE. We reported less surgery-related pulmonary complications and mortality in Sars-CoV-2-infected patients, than in literature. Emergent and oncological surgery should not be postponed, but it is mandatory to use full PPE, and to adopt preoperative screenings and strategies that mitigate the detrimental effect of pulmonary complications, mostly responsible for mortality.

Machine-Learning Based Model to Improve Insulin Bolus Calculation in Type 1 Diabetes Therapy.

OBJECTIVE: This paper aims at proposing a new machine-learning based model to improve the calculation of mealtime insulin boluses (MIB) in type 1 diabetes (T1D) therapy using continuous glucose monitoring (CGM) data. Indeed, MIB is still often computed through the standard formula (SF), which does not account for glucose rate-of-change ( ∆G), causing critical hypo/hyperglycemic episodes. METHODS: Four candidate models for MIB calculation, based on multiple linear regression (MLR) and least absolute shrinkage and selection operator (LASSO) are developed. The proposed models are assessed in silico, using the UVa/Padova T1D simulator, in different mealtime scenarios and compared to the SF and three ∆G-accounting variants proposed in the literature. An assessment on real data, by retrospectively analyzing 218 glycemic traces, is also performed. RESULTS: All four tested models performed better than the existing techniques. LASSO regression with extended feature-set including quadratic terms (LASSO Q) produced the best results. In silico, LASSO Q reduced the error in estimating the optimal bolus to only 0.86 U (1.45 U of SF and 1.36-1.44 U of literature methods), as well as hypoglycemia incidence (from 44.41% of SF and 44.60-45.01% of literature methods, to 35.93%). Results are confirmed by the retrospective application to real data. CONCLUSION: New models to improve MIB calculation accounting for CGM- ∆G and easy-to-measure features can be developed within a machine learning framework. Particularly, in this paper, a new LASSO Q model was developed, which ensures better glycemic control than SF and other literature methods. SIGNIFICANCE: MIB dosage with the proposed LASSO Q model can potentially reduce the risk of adverse events in T1D therapy.

Rare Intraoperative and Postoperative Complications After Transabdominal Laparoscopic Hernia Repair: Results from the Multicenter Wall Hernia Group Registry.

Background: Inguinal hernioplasty is the most frequently performed operation in the Western world today. Although the laparoscopic approach for inguinal hernia repair has shown excellent results in terms of complications and recurrences, the anterior approach is still the most used. Postoperative pain and recurrences are the most widely studied complications in both approaches, but there is little information about the often more troublesome rare complications of laparoscopic surgery and their treatment. Methods: In the period from January 1, 2014 to December 31, 2019, 1874 hernioplasty operations were performed with the transabdominal approach and recorded prospectively in the Wall Hernia Group database. The mean follow-up was 47 months (range 3-64 months). All less frequent complications were analyzed and a literature review was carried out to assess the presence of similar cases and their treatment in other series. Results: Eight cases of rare complications were identified and subdivided according to the Clavien-Dindo classification. They included a bowel perforation, 4 cases of bleeding, 2 bowel obstructions, and an injury to the motor branch of the obturator nerve. The postoperative course in these patients was significantly longer than in patients with a regular postoperative course. In 2 cases the complication occurred during the first admission, while the remaining 6 patients had to be readmitted within 30 days after discharge. Conclusions: Although serious postoperative complications in laparoscopic inguinal hernioplasty are rare, all surgeons, also those who have completed the learning curve, should be aware of their possible occurrence.

Laparoscopic treatment of De Garengeot hernia with Progrip.

BACKGROUND: Many eponyms have been used to classify some rare conditions of incarceration of a hernia at the level of the groin and femoral canal. The incarceration of the appendix at the level of the groin canal was first described by Claudius Amyand, while the incarceration of the appendix inside the femoral canal is a condition known as De Garengeot hernia. The incidence of such an event is very low and surgical treatment is usually performed via inguinal approach. CASE PRESENTATION: We describe the case of a 63-year-old woman who presented upon arrival at the Emergency Room a sore tumefaction in the femoral region with skin erythema. The patient had never undergone surgery for groin or femoral hernias. After performing ultrasound reporting the presence of an incarcerated intestinal loop, the patient underwent surgery. Laparoscopic exploration highlighted the presence of a De Garengeot hernia. After exploration, it was decided to continue the laparoscopic operation: at first, the hernia sac was reduced, then a self-gripping mesh was put in place. Finally, after the closure of the peritoneum, the operation was completed by performing a laparoscopic appendectomy. The patient was discharged from hospital three days from surgery with an antibiotic therapy for further two days after discharge. After three months, upon clinical examination, no recurrences of hernia were evident. CONCLUSIONS: We describe a rare case of De Garengeot hernia treated laparoscopically. The treatment of such a condition is not standardized because of the few cases described. The laparoscopic approach should always be considered to perform at least an exploration of the abdominal cavity and evaluate the contents of the hernia sac. Laparoscopic hernia treatment should be carried out by experienced surgeons who are familiar with the technique and apply it routinely. KEY WORDS: Appendicitis, De Garengeot, Hernia, Laparoscopy.

Restaging Patients With Hepatocellular Carcinoma Before Additional Treatment Decisions: A Multicenter Cohort Study.

Prognostic assessment of patients with hepatocellular carcinoma (HCC) at the time of diagnosis remains controversial and becomes even more complex at the time of restaging when new variables need to be considered. The aim of the current study was to evaluate the prognostic utility of restaging patients before proceeding with additional therapies for HCC. Two independent Italian prospective databases were used to identify 1,196 (training cohort) and 648 (validation cohort) consecutive patients with HCC treated over the same study period (2008-2015) who had complete restaging before decisions about additional therapies. The performance of the Italian Liver Cancer (ITA.LI.CA) prognostic score at restaging was compared with that of the Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer, and Cancer of the Liver Italian Program systems. A multivariable Cox survival analysis was performed to identify baseline, restaging, or dynamic variables that were able to improve the predictive performance of the prognostic systems. At restaging, 35.3% of patients maintained stable disease; most patients were either down-staged by treatment (27.2%) or had disease progression (37.5%). The ITA.LI.CA scoring system at restaging demonstrated the best prognostic performance in both the training and validation cohorts (c-index 0.707 and 0.722, respectively) among all systems examined. On multivariable analysis, several variables improved the prognostic ability of the ITA.LI.CA score at restaging, including progressive disease after the first treatment, Model for End-Stage Liver Disease at restaging, and choice of nonsurgical treatment as additional therapy. A new ITA.LI.CA restaging model was created that demonstrated high discriminative power in both the training and validation cohorts (c-index 0.753 and 0.745, respectively). CONCLUSION: Although the ITA.LI.CA score demonstrated the best prognostic performance at restaging, other variables should be considered to improve the prognostic assessment of patients at the time of deciding additional therapies for HCC.

Esophageal cancer management: preoperative CA19.9 and CEA serum levels may identify occult advanced adenocarcinoma.

BACKGROUND: Esophagectomy is contraindicated in case of advanced cancer (i.e., carcinomatosis, distant metastasis, and invasion of other organs). In some cases, preoperative imaging may fail to identify advanced neoplasm and esophagectomy is inappropriately planned. The aim of the study was to identify preoperative biomarkers of occult advanced disease that force surgeons to abort the planned esophagectomy. METHODS: From 2008 to 2014, 244 consecutive patients were taken to the operative room to have esophagectomy for cancer in our department. All of them had blood test at admission and their preoperative biomarker data were retrieved. Their medical history was collected and the intraoperative findings and outcome were recorded. Non parametric tests, multiple regression analysis, and ROC curves analysis were performed. RESULTS: In our study group, 14 (5.7 %) patients, scheduled for esophagectomy, were discovered to have occult advanced disease at laparotomy/laparoscopy or at thoracotomy. Six of them had peritoneal carcinomatosis, three had advanced tumor invading other organs, three had small liver metastasis, and two pleural carcinomatosis. In all these cases, esophagectomy was aborted and a feeding jejunostomy was placed. In patients with unresectable esophageal cancer, CA19.9 and CEA serum levels were significantly higher than patients who could have esophagectomy (p < 0.001 and p = 0.003, respectively). CA19.9 and CEA resulted to be accurate biomarkers of occult advanced disease (AUC = 85 %, p < 0.001 and AUC = 73 %, p = 0.002, respectively). CONCLUSIONS: Preoperative CEA and CA19.9 serum levels should be taken in consideration when evaluating patients candidate to esophagectomy for esophageal cancer to prevent inappropriate laparotomy or thoracotomy. If any doubt arises minimally invasive exploration is warranted.

Laparoscopic microwave ablation in patients with hepatocellular carcinoma: a prospective cohort study.

OBJECTIVES: There are no prospective studies of laparoscopic microwave (MW) ablation in patients with hepatocellular carcinoma (HCC). The aim of this study was to demonstrate the safety and efficacy of laparoscopic MW ablation. METHODS: A prospective study group of consecutive HCC patients considered ineligible for liver resection and/or percutaneous ablation was conducted from December 2009 to December 2010. Short-term (3-month) outcomes included a centralized revision of radiological response, mortality and morbidity. Mid-term (24-month) outcomes included time to recurrence in the study group compared with that in a cohort of consecutive patients treated with laparoscopic radiofrequency (RF) ablation using propensity score analysis. RESULTS: A total of 42 patients were enrolled. Their median age was 64 years; 67% were positive for hepatitis C virus; 33% were of Child-Pugh class B status; the median tumour diameter was 2.5 cm, and 48% of patients had multinodular HCC. In 47 of 50 (94%) nodules treated with MW ablation, a complete radiological response was observed at 3 months. There was no perioperative mortality. The overall morbidity rate was 24%. The 2-year survival rate was 79% and the 2-year recurrence rate was 55%. Using propensity score analysis (in 28 MW ablation patients and 28 RF ablation controls), 2-year recurrence rates were 55% in the MW ablation group and 77% in the control group (P = 0.03). CONCLUSIONS: Laparoscopic MW ablation is a safe and effective therapeutic option for selected HCC patients who are ineligible for liver resection and/or percutaneous ablation.

Impact of jejunostomy during esophagectomy for cancer on health related quality of life.

BACKGROUND: The aim of this study was to evaluate the impact of jejunostomy during esophagectomy for cancer on postoperative health-related quality of life (HRQL). METHODS: We evaluate all consecutive patients who underwent esophagectomy for cancer at the surgical oncology unit of the Veneto Institute of Oncology (IOV-IRCCS) between January 2008 and March 2014. The primary outcome was HRQL, which was assessed using nine scales of EORTC C30 and OES18 questionnaires. General linear models were estimated to evaluate mean score difference (MD) of each selected scale in patients with and without jejunostomy, adjusting for clinically relevant confounders. The secondary outcomes were morbidity, hospital stay, postoperative weight loss and postoperative albumin impairment. RESULTS: Jejunostomy was performed in 40 on 109 patients (41.3%) who participated in quality of life investigation. A clinically and statistically significantly worse eating at admission (P=0.009) became not clinically significant at 3 months after surgery (MD =9.1). Jejunostomy was associated to clinically and statistically significantly poorer emotional function (EF) at 3 months after surgery (MD =-15.6; P=0.04). Hospital stay was longer in jejunostomy group (median, 20 vs. 17 days, P=0.02). CONCLUSIONS: In our series patients who had a jejunostomy during esophagectomy had been selected for their risk for postoperative complication. However, their postoperative outcome was actually similar compared to those without jejunostomy. Nevertheless, jejunostomy was associated to clinically and statistically significantly poorer EF at 3 months after surgery. Therefore, patient candidate to esophagectomy and feeding jejunostomy should receive additional psychological support.