Pathophysiology of Ascites: The importance of the intestine. A surgical contribution to the understanding of a medical problem.

The understanding of the mechanisms for the development of ascites has evolved over the years, involving the liver, peritoneum, heart, and kidneys as key responsible for its formation. In this article, we review the pathophysiology of ascites formation, introducing the role of the intestine as a major responsible for ascites production through "a game changer" case.

History of clinical intestinal transplantation.

The intestines have been considered the "forbidden organ" for years, and intestinal failure became the last organ failure recognized as such in the medical field. The impossibility of providing adequate nutritional support, turned these patients into recipients of just palliative comfort. In the 1960's, parenteral nutrition appeared as the most reasonable replacement therapy, but the initial success obtained with clinical kidney, heart, liver, lung and pancreas transplantation served as background to explore intestinal transplantation. The first clinical report of an isolated intestinal transplant was done by Richard Lillihei in 1967; in 1983, Thomas Starzl, performed the first multi visceral transplant, and in 1990, David Grant performed the first combined liver-intestinal transplant in an adult recipient in Canada. Since then, advances in immunosuppressive therapies and surgical innovations have allowed not only a continuous increase in indications, but also a worldwide application of all procedures, bringing clinical intestinal transplantation to reality. In this historical account, the most important contributions have been summarized, thus describing the steady progress, expansion and novelties developed over the last 56 years, since the first attempt. Clinical intestinal transplantation remains a complex and evolving field; ongoing research and technological advancements will continue shaping its future.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

Endoscopic Surveillance of the Intestinal Allograft: Recommendations From the Intestinal Rehabilitation and Transplant Association Working Group.

Intestinal transplant (ITx) rejection lacks a reliable noninvasive biomarker and rejection surveillance relies on serial endoscopies and mucosal biopsies followed by histologic assessment. Endoscopic biopsies are also essential for identifying other ITx-related complications such as infectious, allergic, and inflammatory graft enteritis as well as post-transplant lymphoproliferative disease or graft versus host disease. In spite of its central role in ITx, published guidelines on endoscopy and biopsy are lacking and significant variability between centers in terms of timing and technical performance exists. Therefore, an international expert group convened and discussed several aspects related to the surveillance endoscopy after ITx with the aim to summarize and standardize its practice. This article summarizes these considerations on endoscopic ITx monitoring and highlights practices of surveillance and for-cause endoscopy, biopsy techniques, pathologic evaluation, potential risks and complications, outsourcing, and less-invasive monitoring techniques.

Resección hepática laparoscópica versus hepatectomía abierta para lesiones benignas: estudio comparativo con propensity score matching / Laparoscopic liver resection versus open liver resection for benign lesions: a comparative study with propensity score matching

RESUMEN Antecedentes : las ventajas de la hepatectomía videolaparoscópica (HVL) hicieron que gane cada vez más campo para el tratamiento de los tumores hepáticos benignos (THB). Objetivo : comparar los resultados perioperatorios de pacientes sometidos a HVL con los de los operados con hepatectomía abierta (HA) por THB, emparejados con propensity score matching (PSM). Material y métodos : estudio descriptivo, retrospectivo y comparativo de HA y HVL por THB entre agosto de 2010 y junio de 2021. Se analizaron variables demográficas, preoperatorias, intraoperatorias y posoperatorias. Para evitar sesgos de las distintas covariables entre los grupos se realizó un PSM 1:1. Resultados : de 403 hepatectomías, se analizaron 82 por THB. De ellas 36 (44%) fueron HA y 46 (56%) HVL. Edad media 45 ±14 años, 65% mujeres. Tras realizar el PSM, quedaron dos grupos de 28 pacientes cada uno. En HA, 5 (18%) pacientes requirieron transfusiones y ninguno en HVL (p = 0,01). Las complicaciones mayores se presentaron en 4 (14%) pacientes en HA, y ninguna en HVL (p = 0,03). Se reoperaron 4 (14%) pacientes con HA y ningún paciente con HVL (p = 0,03). La estadía hospitalaria total fue significativamente mayor en las HA (p = 0,04). No se registraron muertes a los 90 días en ninguno de los dos grupos. Conclusión : la HVL por THB es una técnica segura y eficaz, ya que los pacientes presentaron menor requerimiento transfusional, número de reoperaciones, de complicaciones mayores y de estadía hospitalaria que con HA. Por las ventajas encontradas, la HVL podría ser considerada la técnica de elección en cirugía por THB.

ABSTRACT Background : The advantages of laparoscopic liver resection (LLR) have increased its use for the treatment of benign liver tumors (BLTs). Objective : The aim of this study was to compare the perioperative outcomes of patients undergoing LLR with those operated on with open liver resection (OLR) for BLTs using propensity score matching (PSM). Material and methods : We conducted a descriptive and retrospective study comparing OLRs with LLRs performed between August 2010 and June 2021. The demographic, perioperative, intraoperative and postoperative variables were analyzed. We used PSM with 1:1 matching to avoid biases of the different covariates between the groups. Results : Of 303 liver resections, 82 corresponded to BLTs and were included in the analysis; 36 (44%) were OLRs and 46 (56%) were LLRs. Mean age was 45 ±14 years and 65% were women. After PSM, two groups of 28 patients each were constituted. Five patients (18%) in the OLR group and none in the LLR required transfusions (p = 0.01). Major complications, occurred in 4 (14%) patients in the OLR group and in no cases in the LLR group (p = 0.03). Four (14%) undergoing OLR required reoperation versus no patients with LLR (p = 0.03). Total length of hospital stay was significantly longer in OLR (p = 0.04). There were no deaths in any of the groups within 90 days. Conclusion : LLR for BLTs is a safe and effective technique, with lower requirement for transfusions, fewer reoperations and major complications and shorter length of hospital stay than OLR, Therefore, LLR could be considered the surgical technique of choice for BLTs.

IL-22BP controls the progression of liver metastasis in colorectal cancer.

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC.

The Reality of Inadequate Patient Care and the Need for a Global Action Framework in Organ Donation and Transplantation.

BACKGROUND: Transplant therapy is considered the best and often the only available treatment for thousands of patients with organ failure that results from communicable and noncommunicable diseases. The number of annual organ transplants is insufficient for the worldwide need. METHODS: We elaborate the proceedings of the workshop entitled "The Role of Science in the Development of International Standards of Organ Donation and Transplantation," organized by the Pontifical Academy of Sciences and cosponsored by the World Health Organization in June 2021. RESULTS: We detail the urgency and importance of achieving national self-sufficiency in organ transplantation as a public health priority and an important contributor to reaching relevant targets of the United Nations Agenda for Sustainable Development. It details the elements of a global action framework intended for countries at every level of economic development to facilitate either the establishment or enhancement of transplant activity. It sets forth a proposed plan, by addressing the technical considerations for developing and optimizing organ transplantation from both deceased and living organ donors and the regulatory oversight of practices. CONCLUSIONS: This document can be used in governmental and policy circles as a call to action and as a checklist for actions needed to enable organ transplantation as treatment for organ failure.

First registry of adult patients with chronic intestinal failure due to short bowel syndrome in Argentina: The RESTORE project.

BACKGROUND: Short bowel syndrome (SBS) is considered a low prevalence disease. In Argentina, no registries are available on chronic intestinal failure (CIF) and SBS. This project was designed as the first national registry to report adult patients with this disease. METHODS: A prospective multicenter observational registry was created including adult patients with CIF/SBS from approved centers. Demographics, clinical characteristics, nutrition assessment, home parenteral nutrition (HPN) management, surgeries performed, medical treatment, overall survival, and freedom from HPN survival were analyzed. RESULTS: Of the 61 enrolled patients, 56 with available follow-up data were analyzed. At enrollment, the mean intestinal length was 59.5 ± 47.3 cm; the anatomy was type 1 (n = 41), type 2 (n = 10), and type 3 (n = 5). At the end of the interim analysis, anatomy changed to type 1 in 31, type 2 in 17, and type 3 in 8 patients. The overall mean time on HPN before enrollment was 33.5 ± 56.2 months. Autologous gastrointestinal reconstruction surgery was performed before enrollment on 21 patients, and afterward on 11. Nine patients (16.1%) were weaned off HPN with standard medical nutrition treatment; 12 patients received enterohormones, and 2 of them suspended HPN; one patient was considered a transplant candidate. In 23.7 ± 14.5 months, 11 of 56 patients discontinued HPN; Kaplan-Meier freedom from HPN survival was 28.9%. The number of cases collected represented 19.6 new adult CIF/SBS patients per year. CONCLUSION: The RESTORE project allowed us to know the incidence, the current medical and surgical approach for this pathology, as well as its outcome and complications at dedicated centers.

Autologous gastrointestinal reconstruction surgery for short bowel syndrome: the cornerstone for intestinal rehabilitation.

PURPOSE OF REVIEW: Intestinal failure (IF) evolved from being the last recognized organ failure, to become one of the most progressive fields in terms of therapeutic alternatives and results. Short bowel syndrome (SBS) is the main cause of IF in adults and children. The use of surgery allowed patients with unfavorable anatomy type and length to be wean off parenteral nutrition. We aim to evaluate its current impact on intestinal rehabilitation. RECENT FINDINGS: Autologous gastro-intestinal reconstructive surgery (AGIRS), including bowel lengthening contributes by converting patient's anatomy to a more favorable one, improving quality of life, and modifying the natural history of the disease, allowing to recover intestinal autonomy in approximately 70% of the adults and 50% of the children's with SBS-IF. The current use of postsurgical medical rehabilitation strategies including the use of enterohormones complement the path to sufficiency, increasing the chances of success in both age group of patients. SUMMARY: The development of AGIRS has changed the outcome of SBS-IF patients, becoming the main surgical procedure prescribed in multidisciplinary units, allowing to enhance the number of patients achieving intestinal autonomy throughout rehabilitation, leaving transplantation as the last surgical alternative.

Induction Versus Maintenance Immunosuppression After Intestinal Transplant: Determining Which Treatment Most Impacts Long-Term Patient And Graft Survival.

OBJECTIVES: Immunosuppressive strategies for intestinal transplant have changed over time. However, specific intestinal transplant-oriented protocols and reports on long-term maintenance regimens are scarce. Our objective was to evaluate the impact of 2 different initial immunosuppressive protocols based on thymoglobulin (group A) and basiliximab (anti-interleukin 2 antibody) (group B) and of changes to maintenance immunosuppression over long-term follow-up in intestinal transplant recipients. MATERIALS AND METHODS: We performed a retrospective analysis of a prospectively established protocol for intestinal transplant immunosuppression, conducted between May 2006 and December 2020. We analyzed 51 intestinal transplant recipients, with 6 patients excluded because of early death or graft loss. Acute cellular rejection frequency and grade, number of acute cellular rejection episodes, time to the first acute cellular rejection episode, response to treatment, number of patients who progressed to chronic allograft rejection, kidney function, infections, incidence of posttransplant lymphoproliferative disorder and graft-versus-host disease, and patient and graft survival were analyzed. RESULTS: In the study groups, there were 87 acute cellular rejection episodes in 45 patients (33 in group A and 54 in group B). We found degree of acute cellular rejection to be mild in 45 patients, moderate in 18, and severe in 24 (not significant between groups). Our comparison of induction therapy (thymoglobulin [group A] vs interleukin 2 antibody [group B]) did not show any statistical difference during clinical followup. Long-term review showed that all patients were on tacrolimus. Five-year patient and graft survival rates were 62% and 45% for group A and 54% and 46% for group B, respectively (not significant). CONCLUSIONS: Long-term patient and graft outcomes reflected the use of an individualized follow-up with adjustments and changes in immunosuppressive medications according to the patient's clinical course and complications rather than based on the induction immunosuppressive protocol used.

A Decreased Response to Resistin in Mononuclear Leukocytes Contributes to Oxidative Stress in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Deregulation of immune response and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Resistin is a physiological modulator of inflammation and redox homeostasis of different cell types. Increased resistin serum concentration and the direct association between resistin hepatic expression and NAFLD severity suggest that resistin participates in NAFLD pathogenesis. AIMS: To evaluate resistin-induced regulation of redox homeostasis in mononuclear leukocytes from NAFLD patients and controls. METHODS: We evaluated basal and resistin-mediated modulation of reactive oxygen species (ROS) and glutathione content by flow cytometry, and antioxidant enzyme activities by spectrophotometry. RESULTS: Peripheral blood mononuclear cells (PBMC) from NAFLD patients showed higher ROS content and glutathione peroxidase activity and lower glutathione content, superoxide dismutase and glutathione reductase activities than control PBMC. Resistin decreased ROS levels and superoxide dismutase activity and increased glutathione reductase and catalase activities in PBMC from controls but not from patients. Resistin decreased glutathione content in PBMC from control and NAFLD patients, with greater effect on patient cells. Basal and resistin-modulated ROS levels were directly associated with obesity-related risk factors for NAFLD. Hepatic myeloid cells and T-lymphocytes from NAFLD patients showed higher basal ROS content than cells from controls. Resistin decreased ROS levels in hepatic T-lymphocytes from controls but not from patients. CONCLUSIONS: Resistin regulates redox homeostasis in mononuclear leukocytes. A decreased response to resistin in leukocytes from NAFLD patients is associated with an impaired redox homeostasis.

Immunosuppression in liver and intestinal transplantation.

Immunosuppression handling plays a key role in the early and long-term results of transplantation. The development of multiple immunosuppressive drugs led to numerous clincial trials searching to reach the ideal regimen. Due to heterogeneity of the studied patient cohorts and flaws in many, even randomized controlled, study designs, the answer still stands out. Nowadays triple-drug immunosuppression containing a calcineurin inhibitor (preferentially tacrolimus), an antimetabolite (using mycophenolate moffettil or Azathioprine) and short-term steroids with or without induction therapy (using anti-IL2 receptor blocker or anti-lymphocytic serum) is the preferred option in both liver and intestinal transplantation. This chapter aims, based on a critical review of the definitions of rejection, corticoresistant rejection and standard immunosuppression to give some reflections on how to reach an optimal immunosuppressive status and to conduct trials allowing to draw solid conclusions. Endpoints of future trials should not anymore focus on biopsy proven, acute and chronic, rejection but also on graft and patient survival. Correlation between early- and long-term biologic, immunologic and histopathologic findings will be fundamental to reach in much more patients the status of operational tolerance.

Surgical Management of Intestinal Failure; Initial Experiences from an Intestinal Failure, Rehabilitation and Transplant Unit in Iran.

BACKGROUND: Intestinal failure (IF) is a life-threatening medical condition. The management of IF in low- and middle-income countries without home parenteral nutrition (HPN) remains unclear. We recently established an intestinal rehabilitation unit (IRU) and aimed to provide our experience on the current management and outcomes of IF in Iran. METHODS: In this cross-sectional case series, data were collected from an established database on IF in the Shiraz Transplant Center in Abu Ali Sina hospital, affiliated to Shiraz University of Medical Sciences, Iran from January 2018 to October 2018. RESULTS: Overall, 30 patients with a mean age of 44.13 ± 10.32 years, which included 25 males, were recruited. Short bowel syndrome (SBS) (60%) and enterocutaneous fistulae (27%), as complication of previous surgeries, were the main causes of IF. The most common type of IF was type 3 (67 %). Mesenteric ischemia was the leading mechanism of IF (47%). Fifteen patients (50%) received autologous gastrointestinal reconstruction surgery (AGIRS), and two (7%) patients had serial transverse enteroplasty (STEP). At the end of follow-up, 15 patients recovered from IF (50%). The overall survival rate was 83.3%. CONCLUSION: This series introduced the results of a multidisciplinary program for the treatment of IF in a middle-income country that lacks facilities for HPN. Our protocol of care, understanding the need for development of HPN, showed promising clinical outcomes.

Bile Microbiota in Liver Transplantation: Proof of Concept Using Gene Amplification in a Heterogeneous Clinical Scenario.

Objective: Historically, bile in the biliary tract has been considered sterile. Most of the series are based on patients with biliary tract diseases or the bile has been obtained with procedures susceptible to contamination. Methods: We evaluated the bile in a heterogeneous cohort of liver donors and recipient patients, with samples obtained in a sterile way, directly from the gallbladder and the common bile duct. Results: We assessed the bile microbiota in six liver donors and in six liver recipients after whole or split liver procedures in adult or pediatric recipients. Bile samples were studied using PCR sequencing of the 16S ribosomal RNA gene amplification (rDNA). Conclusions: We demonstrated that the bile is sterile, thereby ruling this out as a source of contamination following transplant.