Compilation of Evidence Supporting the Role of a T Helper 2 Reaction in the Pathogenesis of Acute Appendicitis.

Despite being the most common abdominal surgical emergency, the cause of acute appendicitis (AA) remains unclear, since in recent decades little progress has been made regarding its etiology. Obstruction of the appendicular lumen has been traditionally presented as the initial event of AA; however, this is often the exception rather than the rule, as experimental data suggest that obstruction is not an important causal factor in AA, despite possibly occurring as a consequence of the inflammatory process. Type I hypersensitivity reaction has been extensively studied, involving Th2 lymphocytes, and cytokines such as IL-4, IL-5, IL-9 and IL-13, which have well-defined functions, such as a positive-feedback effect on Th0 for differentiating into Th2 cells, recruitment of eosinophils and the release of eosinophilic proteins and the production of IgE with the activation of mast cells, with the release of proteins from their granules. Cytotoxic activity and tissue damage will be responsible for the clinical manifestation of the allergy. AA histological features are similar to those found in allergic reactions like asthma. The intestine has all the components for an allergic immune response. It has contact with hundreds of antigens daily, most of them harmless, but some can potentially induce an allergic response. In recent years, researchers have been trying to assess if allergy is a component of AA, with their latest advances in the understanding of AA as a Th2 reaction shown by the authors of this article.

Tryptase in Acute Appendicitis: Unveiling Allergic Connections through Compelling Evidence.

The aetiology of acute appendicitis (AA), the most frequent abdominal surgical emergency, is still unclarified. Recent epidemiologic, clinical and laboratorial data point to an allergic component in the pathophysiology of AA. Mastocytes participate in the Th2 immune response, releasing inflammatory mediators from their granules upon stimulation by IgE-specific antigens. Among the well-known mediators are histamine, serotonin and tryptase, which are responsible for the clinical manifestations of allergies. We conducted a prospective single-centre study to measure histamine and serotonin (commercial ELISA kit) and tryptase (ImmunoCAP System) concentrations in appendicular lavage fluid (ALF) and serum. Consecutive patients presenting to the emergency department with a clinical diagnosis of AA were enrolled: 22 patients with phlegmonous AA and 24 with gangrenous AA The control group was composed of 14 patients referred for colectomy for colon malignancy. Appendectomy was performed during colectomy. Tryptase levels were strikingly different between histological groups, both in ALF and serum (p < 0.001); ALF levels were higher than serum levels. Tryptase concentrations in ALF were 109 times higher in phlegmonous AA (APA) (796.8 (194.1-980.5) pg/mL) and 114 times higher in gangrenous AA (AGA) (837.4 (272.6-1075.1) pg/mL) than in the control group (7.3 (4.5-10.3) pg/mL. For the diagnosis of AA, the discriminative power of serum tryptase concentration was good (AUC = 0.825), but discriminative power was weak (AUC = 0.559) for the differential diagnosis between APA and AGA. Mastocytes are involved in AA during clinical presentations of both phlegmonous and gangrenous appendicitis, and no significant differences in concentration were found. No differences were found in serum and ALF concentrations of histamine and serotonin between histological groups. Due to their short half-lives, these might have elapsed by the time the samples were collected. In future research, these determinations should be made immediately after appendectomy. Our findings confirm the hypersensitivity type I reaction as an event occurring in the pathogenesis of AA: tryptase levels in ALF and serum were higher among patients with AA when compared to the control group, which is in line with a Th2 immune response and supports the concept of the presence of an allergic reaction in the pathogenesis of acute appendicitis. Our results, if confirmed, may have clinical implications for the treatment of AA.

Fellowship in surgical oncology: The results of an experience in Portuguese-speaking African countries.

Cancer incidence rates are increasing worldwide including in Portuguese speaking African countries. We present the results of the fellowship in surgical oncology promoted by the Portuguese Institute of Oncology in Porto (IPO), Fernando Pessoa University, Portugal, and the Calouste Gulbenkian Foundation, which involved the training of residents and surgeons from Portuguese-speaking African countries in Portugal. The program's structure and content was the same of UMES/ESSO. The hands-on activity took place at the IPO. After the fellowship, a theoretical and practical assessment was held, and all fellows scored above the threshold to pass. The surgical performance of the fellows was assessed in their workplaces in Africa. The impact of the training was evaluated by a questionnaire completed by all the fellows. It was reported an increase in knowledge, skills and organizational skills that fellows are committed to implement. As the fellowship is certified by a Portuguese University, it may be recognized by the Local Health and University Authorities, impacting on the professional progression of fellows.

Textbook Oncological Outcome in European GASTRODATA.

OBJECTIVE: To assess the rate of textbook outcome (TO) and textbook oncological outcome (TOO) in the European population based on the GASTRODATA registry. BACKGROUND: TO is a composite parameter assessing surgical quality and strongly correlates with improved overall survival. Following the standard of treatment for locally advanced gastric cancer, TOO was proposed as a quality and optimal multimodal treatment parameter. METHODS: TO was achieved when all the following criteria were met: no intraoperative complications, radical resection according to the surgeon, pR0 resection, retrieval of at least 15 lymph nodes, no severe postoperative complications, no reintervention, no admission to the intensive care unit, no prolonged length of stay, no postoperative mortality and no hospital readmission. TOO was defined as TO with the addition of perioperative chemotherapy compliance. RESULTS: Of the 2558 patients, 1700 were included in the analysis. TO was achieved in 1164 (68.5%) patients. The use of neoadjuvant chemotherapy [odds ratio (OR) = 1.33, 95% CI: 1.04-1.70] and D2 or D2+ lymphadenectomy (OR = 1.55, 95% CI: 1.15-2.10) had a positive impact on TO achievement. Older age (OR = 0.73, 95% CI: 0.54-0.94), pT3/4 (OR = 0.79, 95% CI: 0.63-0.99), ASA 3/4 (OR = 0.68, 95% CI: 0.54-0.86) and total gastrectomy (OR = 0.56, 95% CI: 0.45-0.70), had a negative impact on TO achievement. TOO was achieved in 388 (22.8%) patients. Older age (OR = 0.37, 95% CI: 0.27-0.53), pT3 or pT4 (OR = 0.52, 95% CI: 0.39-0.69), and ASA 3 or 4 (OR = 0.58, 95% CI: 0.43-0.79) had a negative impact on TOO achievement. CONCLUSIONS: Despite successively improved surgical outcomes, stage-appropriate chemotherapy in adherence to the current guidelines for multimodal treatment of gastric cancer remains poor. Further implementation of oncologic quality metrics should include greater emphasis on perioperative chemotherapy and adequate lymphadenectomy.

Eosinophil Granule Proteins Involvement in Acute Appendicitis-An Allergic Disease?

Several pieces of evidence point to an allergic component as a trigger of acute appendicitis. As the Th2 immune response is characterized by eosinophil mobilization to the target organ and release of their cationic granule proteins, it is reasonable to investigate if the degranulation of eosinophils could be associated with the local injury. The primary aim of this study is to evaluate the participation of eosinophils granules proteins in acute appendicitis, both at local and systemic levels and the secondary aim is to evaluate the diagnostic accuracy of eosinophils granules proteins for the detection of acute appendicitis, as well as for distinguishing between complicated and uncomplicated acute appendicitis. Eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP) and eosinophil peroxidase (EP) are the most well-known eosinophil granule proteins. From August 2021 to April 2022, we present a prospective single-center study to evaluate the EDN, ECP, and EP concentrations simultaneously in appendicular lavage fluid (ALF) and the serum of 22 patients with acute phlegmonous appendicitis (APA), 24 with acute gangrenous appendicitis (AGA), and 14 normal controls. Concerning EDN, no differences were found between groups. ECP concentrations in ALF and serum were significantly higher in the histologically confirmed acute appendicitis compared to the control groups (p < 0.0001 and p < 0.0001, respectively). In ALF, no differences were found between ECP levels in APA: 38.85 ng/mL (IQR 26.50-51.77) and AGA 51.55 ng/mL (IQR 39.55-70.09) groups (p = 0.176). In the serum, no difference was found between ECP levels at APA: 39 ng/mL (IQR 21.30-56.90) and AGA: 51.30 ng/mL (IQR 20.25-62.59) (p = 0.100). For EP, the concentrations in ALF (p < 0.001) and serum (p < 0.001) were both higher in acute appendicitis compared to the control. In ALF, no difference was found between APA: 240.28 ng/mL (IQR 191.2-341.3) and AGA: 302.5 (IQR 227.7-535.85) (p = 0.236). In the serum, no differences were found between APA: 158.4 ng/mL (IQR 111.09-222.1) and AGA: 235.27 (IQR 192.33-262.51) (p = 0.179). Globally, the ALF concentrations were higher than serum concentrations, reflecting an intense inflammatory local reaction in AA. The optimal ECP cut-off for discriminating between acute appendicitis and the controls was >11.41 ng/mL, with a sensitivity of 93.5%, but with a specificity for identifying appendicitis of 21.4%, good discriminative power (AUC = 0.880). For EP, the optimal cut-off was >93.20 ng/mL, with a sensitivity of 87%, but with a specificity of 14.3% (AUC = 0.901), excellent discriminative power. For the diagnosis of perforated AA, the discriminative power of ECP and EP serum concentrations are weak (AUC = 0.562 and AUC = 0.664, respectively). Concerning the presence of peritonitis, the discriminative power of ECP and EP serum concentrations is acceptable, respectively: AUC = 0.724 and AUC = 0.735. Serum levels of EDN (p = 0.119), ECP (p = 0.586) and EP (p = 0.08) in complicated appendicitis were similar to uncomplicated appendicitis. Serum concentrations of ECP and EP can be added to decision-making AA diagnosis. A Th2-type immune response is present in AA. These data bring forward the role of an allergic reaction in the pathogenesis of acute appendicitis.

IL-5 Serum and Appendicular Lavage Fluid Concentrations Correlate with Eosinophilic Infiltration in the Appendicular Wall Supporting a Role for a Hypersensitivity Type I Reaction in Acute Appendicitis.

Appendicitis is the most common abdominal surgical emergency, but its aetiology is not fully understood. We and others have proposed that allergic responses play significant roles in its pathophysiology. Eosinophils and Interleukin (IL)-5 are involved in a hypersensitivity type I reaction. Eosinophil infiltration is common in the allergic target organ and is dependent on IL-5. In the presence of an allergic component, it is expected that the eosinophil count and IL-5 local and systemic concentrations become elevated. To address this hypothesis, we designed a prospective study that included 65 patients with acute appendicitis (grouped as acute phlegmonous or gangrenous according to the histological definition) and 18 patients with the clinical diagnosis of acute appendicitis, but with normal histological findings (control group) were enrolled. Eosinophil blood counts and appendicular wall eosinophil infiltration were determined. IL-5 levels in blood and appendicular lavage fluid were evaluated. Appendicular lavage fluid was collected by a new methodology developed and standardized by our group. Appendicular wall eosinophil infiltration was higher in acute phlegmonous appendicitis than in gangrenous appendicitis (p = 0.000). IL-5 blood levels were similar in both pathologic and control groups (p > 0.05). In the appendicular lavage fluid, the higher levels of IL-5 were observed in the phlegmonous appendicitis group (p = 0.056). We found a positive correlation between the appendicular wall eosinophilic infiltration and the IL-5 concentrations, in both the blood and the appendicular lavage fluid, supporting the IL-5 reliance in eosinophil local infiltration. We observed the highest presence of eosinophils at phlegmonous appendicitis walls. In conclusion, the present data are compatible with a hypersensitivity type I allergic reaction in the target organ, the appendix, during the phlegmonous phase of appendicitis.

Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic development.

Colorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin and consequences in CRC outcome is not fully understood. Therefore, we assessed intra- and inter-tumor heterogeneity of a prospective cohort of 136 CRC samples. We demonstrate that CRC diversity is forged by asynchronous forms of molecular alterations, where mutational and chromosomal instability collectively boost CRC genetic and microenvironment intra-tumor heterogeneity. We were able to depict predictor signatures of cancer-related genes that can foresee heterogeneity levels across the different tumor consensus molecular subtypes (CMS) and primary tumor location. Finally, we show that high genetic and microenvironment heterogeneity are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development and polyclonal seeding. This study provides an exhaustive portrait of the interplay between genetic and microenvironment intra-tumor heterogeneity across CMS subtypes, depicting molecular events with predictive value of CRC progression and metastasis development.

IPOscore: An interactive web-based platform for postoperative surgical complications analysis and prediction in the oncology domain.

BACKGROUND: The performance of traditional risk score systems to predict (post)-operative outcomes is limited. This weakness reduces confidence in its use to support clinical risk mitigation decisions. However, the rapid growth of health data in the last years offers principles to deal with some of these limitations. In this regard, the data allows the extraction of relevant information for both patients stratification and the rigorous identification of associated risk factors. The patients can then be targeted to specific preoperative optimization programs, thus contributing to the reduction of associated morbidity and mortality. OBJECTIVES: The main goal of this work is, therefore, to provide a clinical decision support system (CDSS) based on data-driven modeling methods for surgical risk prediction specific for cancer patients in Portugal. RESULTS: The result is IPOscore, a single web-based platform aimed at being an innovative approach to assist clinical decision-making in the surgical oncology domain. This system includes a database to store/manage the clinical data collected in a structured format, data visualization and analysis tools, and predictive machine learning models to predict postoperative outcomes in cancer patients. IPOscore also includes a pattern mining module based on biclustering to assess the discriminative power of a pattern towards postsurgical outcomes. Additionally, a mobile application is provided to this end. CONCLUSIONS: The IPOscore platform is a valuable tool for surgical oncologists not only for clinical data management but also as a preventative and predictive healthcare system. Currently, this clinical support tool is being tested at the Portuguese Institute of Oncology (IPO-Porto), and can be accessed online at https://iposcore.org.

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.

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.

Incidence and Grading of Complications After Gastrectomy for Cancer Using the GASTRODATA Registry: A European Retrospective Observational Study.

OBJECTIVE: Utilizing a standardized dataset based on a newly developed list of 27 univocally defined complications, this study analyzed data to assess the incidence and grading of complications and evaluate outcomes associated with gastrectomy for cancer in Europe. SUMMARY BACKGROUND DATA: The absence of a standardized system for recording gastrectomy-associated complications makes it difficult to compare results from different hospitals and countries. METHODS: Using a secure online platform (www.gastrodata.org), referral centers for gastric cancer in 11 European countries belonging to the Gastrectomy Complications Consensus Group recorded clinical, oncological, and surgical data, and outcome measures at hospital discharge and at 30 and 90 days postoperatively. This retrospective observational study included all consecutive resections over a 2-year period. RESULTS: A total of 1349 gastrectomies performed between January 2017 and December 2018 were entered into the database. Neoadjuvant chemotherapy was administered to 577 patients (42.8%). Total (46.1%) and subtotal (46.4%) gastrectomy were the predominant resections. D2 or D2+ lymphadenectomy was performed in almost 80% of operations. The overall complications' incidence was 29.8%; 402 patients developed 625 complications, with the most frequent being nonsurgical infections (23%), anastomotic leak (9.8%), other postoperative abnormal fluid from drainage and/or abdominal collections (9.3%), pleural effusion (8.3%), postoperative bleeding (5.6%), and other major complications requiring invasive treatment (5.6%). The median Clavien-Dindo score and Comprehensive Complications Index were IIIa and 26.2, respectively. In-hospital, 30-day, and 90-day mortality were 3.2%, 3.6%, and 4.5%, respectively. CONCLUSIONS: The use of a standardized platform to collect European data on perioperative complications revealed that gastrectomy for gastric cancer is still associated with heavy morbidity and mortality. Actions are needed to limit the incidence of, and to effectively treat, the most frequent and most lethal complications.

Prehabilitation program for African sub-Saharan surgical patients is an unmet need.

Approximately 4.2 million people worldwide die within 30 days of surgery each year. Half of these deaths occur in low- and middle-income countries. Postoperative deaths account for 7.7% of all deaths globally, making it the third-highest contributor to deaths, after heart disease and stroke. In sub-Saharan Africa, there is a higher rate of mortality following postoperative complications compared to high-income countries. The WHO has tools to help countries provide safer surgery. However, implementation remains poor in most African countries. Interventions focused on intraoperative or postoperative measures to improve perioperative prognosis may be too late for high-risk patients. Poor preoperative cardiorespiratory functional capacity, poor management of pre-existing comorbidities and risk factors and no assessment of the patient´s surgical risk is associated with adverse postoperative outcomes, including mortality, complications, slower recovery, longer intensive care stay, extended hospital length of stay and reduced postoperative quality of life. To significantly decrease morbidity and mortality following surgery in Africa, we propose the implementation of a comprehensive preoperative intervention, that must include: i) risk assessment of surgical patients to identify those at greater risk of postoperative complications for elective surgery; ii) increase the preoperative functional reserve of these high-risk patients, to enhance their tolerance to surgical stress and improve postoperative recovery; iii) anticipate postoperative care needs and organize tools, resources and establish simple workflows to manage postoperative complications. We believe this approach is simple, feasible and will significantly reduce postoperative burden for both patients, hospitals and society.

The impact of negative lymph nodes in the survival outcomes of pN+ patients following radical gastrectomy: the inverse lymph node ratio as a better score to study negative lymph nodes.

The impact of negative lymph nodes (LNs) on survival of pN+ patients has been recognized. The weight of negative LNs in an inverse lymph node ratio (nR) should be related to its prognostic impact. Five hundred and two consecutive gastric cancer patients, who underwent radical gastrectomy, were included. Patients were split into groups according to the number of harvested nodes and a cross-tabulation with pTNM stages was performed to test differences in the tumor burden. pN+ patients (n = 296) were split into groups of negative LNs harvested. We tested an alternative formula for computing a lymph node ratio: nR = total number of harvested nodes/total number of positive nodes. The median number of negative LNs was significantly different (p < 0.01) between dissection groups, but not the median of positive nodes (p > 0.05). No difference in pTNM percentage distribution was found between these groups (p > 0.05). When tested, the overall survival improved significantly for groups with larger numbers of negative LNs (p < 0.001). A cutoff of nR ≥ 6 was an independent prognostic factor for survival (p = 0.001), and the survival of pN+ patients with nR ≥ 6 was not different from pN0 patients. The impact of the number of negative LNs on the survival of the pN+ patients was demonstrated. The higher numbers in the numerator of the nR was due to the disproportion between harvested negative LNs and metastatic LNs. Larger ratios imply more negative lymph nodes in relation to positive lymph nodes, which was significantly associated with survival. We believe that the proposed nR is a friendlier to use format because of its intuitive interpretation.

Recurrent midgut volvulus in an adult patient - The case for pexy? A case report and review of the literature.

INTRODUCTION: Intestinal malrotation is a rare condition, with an incidence estimated between 0,2 to 1%. Most cases are diagnosed and treated during childhood. Adult presentations are rare and most adults present with chronic nonspecific complaints. Midgut volvulus is the most feared complication of intestinal malrotation, far more common among the pediatric than the adult population. Presentation in adulthood with a midgut volvulus accounts for a minority of these patients (15%). The Ladd procedure is the standard surgical management of midgut volvulus and intestinal malrotation. Most evidence on the outcomes of the Ladd procedure originates from studies on pediatric population and the recurrence among children who have had a Ladd procedure is low (2-7%). PRESENTATION OF CASE: We report an exceedingly rare case of a patient who presented in adulthood with a midgut volvulus and less than two years after undergoing Ladd procedure presented with a recurrence of the midgut volvulus. The recurrent midgut volvulus was successfully treated by a fixation procedure (cecopexy and duodenopexy). CONCLUSION: Reports of midgut volvulus in adult patients are scarce and reports of recurrence even scarcer hence the rate of recurrence among adult patients has yet to be determined. The recurrence rate in some of the available adult series is much higher than the rate reported among children. Should the rate of recurrence among adult patients prove higher, it poses the question of whether the Ladd procedure should be modified to include bowel fixation when performed in adults.

Root causes and outcomes of postoperative pulmonary complications after abdominal surgery: a retrospective observational cohort study.

BACKGROUND: Postoperative pulmonary complications (PPCs) contribute significantly to overall postoperative morbidity and mortality. In abdominal surgery, PPCs remain frequent. The study aimed to analyze the profile and outcomes of PPCs in patients submitted to abdominal surgery and admitted in a Portuguese polyvalent intensive care unit. METHODS: From January to December 2017 in the polyvalent intensive care unit of Hospital Garcia de Orta, Almada, Portugal, we conducted a retrospective, observational study of inpatients submitted to urgent or elective abdominal surgery who had severe PPCs. We evaluated the perioperative risk factors and associated mortality. Logistic regression was performed to find which perioperative risk factors were most important in the occurrence of PPCs. RESULTS: Sixty patients (75% male) with a median age of 64.5 [47-81] years who were submitted to urgent or elective abdominal surgery were included in the analysis. Thirty-six patients (60%) developed PPCs within 48 h and twenty-four developed PPCs after 48 h. Pneumonia was the most frequent PPC in this sample. In this cohort, 48 patients developed acute respiratory failure and needed mechanical ventilation. In the emergency setting, peritonitis had the highest rate of PPCs. Electively operated patients who developed PPCs were mostly carriers of digestive malignancies. Thirty-day mortality was 21.7%. The risk of PPCs development in the first 48 h was related to the need for neuromuscular blocking drugs several times during surgery and preoperative abnormal arterial blood gases. Median abdominal surgical incision, long surgery duration, and high body mass index were associated with PPCs that occurred more than 48 h after surgery. The American Society of Anesthesiologists physical status score 4 and COPD/Asthma determined less mechanical ventilation needs since they were preoperatively optimized. Malnutrition (low albumin) before surgery was associated with 30-day mortality. CONCLUSION: PPCs after abdominal surgery are still a major problem since they have profound effects on outcomes. Our results suggest that programs before surgery, involve preoperative lifestyle changes, such as nutritional supplementation, exercise, stress reduction, and smoking cessation, were an effective strategy in mitigating postoperative complications by decreasing mortality.