Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review.

BACKGROUND: Perihilar cholangiocarcinoma (phCCC) is a dismal malignancy. There is no consensus regarding the best treatment for patients with unresectable phCCC. The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice. DATA SOURCES: The search was conducted in PubMed, Embase, Cochrane, and LILACS. The related references were searched manually. Inclusion criteria were: reports in English or Portuguese literature that a) patients with confirmed diagnosis of phCCC; b) patients treated with a curative intent; c) patients with the outcomes of liver resection and liver transplantation. Case reports, reviews, letters, editorials, conference abstracts and papers with full-text unavailability were excluded from the analysis. RESULTS: Most of the current literature is based on observational retrospective studies with low grades of evidence. Liver resection has better long-term outcomes than systemic chemotherapy or palliation therapy and liver transplantation is a good alternative for selected patients with unresectable phCCC. All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahepatic diseases. As a general rule, patients presenting with a tumor having a longitudinal size > 3 cm or extending below the cystic duct, lymph node disease, confirmed extrahepatic dissemination; intraoperatively diagnosed metastatic disease; a history of other malignancies within the last five years, and did not complete chemoradiation regimen and were medically unfit should not be considered for transplantation. Some of these criteria should be individually assessed. Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers, and any decision-making must be based on a multidisciplinary evaluation. CONCLUSIONS: phCCC is a complex condition with high morbidity. Surgical therapies, including hepatectomy and liver transplantation, are the best option for better long-term disease-free survival.

Prevalence of chronic venous insufficiency and deep vein thrombosis in cirrhotic patients.

Summary: People with cirrhosis of the liver are at risk for complications that can worsen their quality of life and increase morbidity and mortality. Contrary to previous beliefs, cirrhosis does not protect against the development of thromboembolic events, and cirrhotic patients may have higher rates of deep vein thrombosis (DVT). Background and aims: The study of chronic venous disease and its impact on patients with cirrhosis is unknown in the literature and may be an important fact since this condition also had impact on quality of life and morbidity. The aim of this study is to evaluate the prevalence of DVT (Deep Venous thrombosis) in outpatients with cirrhosis and the degree of chronic venous insufficiency, evaluating possible correlations between clinical and laboratory aspects of cirrhotic patients with these pathologies. Methods: Patients with cirrhosis were evaluated in the outpatient clinic of the Liver Transplantation and Hepatology Service of HC-FMUSP from November 2018 to November 2022, with clinical evaluation, venous disease questionnaires, data collection of imaging and laboratory tests, and venous color Doppler ultrasound. The information was analyzed by the University of São Paulo (USP) Statistics Department. Results: There was a prevalence of 7.6% of DVT in studied patients, VCSS score 6.73 and severe CEAP classification (C4-6) 32.1%. There was no association of DVT with qualitative variables by the Fisher test such as Child Turcotte Pugh Scale (CTP) (p = 0.890), dichotomized INR values (p = 0.804), etiology of cirrhosis (p = 0.650) and chronic kidney disease (p > 0.999), nor with quantitative variables by t-student's such as age (p = 0.974), Body Mass Index (BMI) (p = 0.997), MELD score (p = 0.555), Albumin (p = 0.150) and Platelets (p = 0.403). We found that as the severity of ascites increases, there is an increase in the proportion of patients classified in the category indicating more severe clinical manifestations of chronic venous disease (C4 to C6). The mean age (54 years) was higher in patients with DVT than in those without. The mean BMI of patients without DVT (25.7 kg/m2) is lower than that of patients with DVT (27.0 kg/m2). The prevalence of DVT is higher in patients with thrombophilia (20.0%) than in those without (7.0%). This suggests an association between the two variables. The descriptive measures of the MELD score, the cirrhosis scale used for liver transplant waiting lists, did not indicate an association of this scale with the occurrence of DVT. Conclusion: The incidence of VTE (Venous Thromboembolic Events) and CVD (Chronic Venous Disease) within the sample surpassed that of the general population; nevertheless, more studies are required to validate these results. Concerning venous thromboembolism, no correlation was observed between the variables within the sample and the augmented risk of VTE. Regarding chronic venous disease, studies have shown that edema and orthostatism are correlated with increased severity of CVD on the VCSS scales. Statistical dispersion methods suggest that patients with higher BMI and more severe liver disease (according to the Child-Pugh score) are more likely to experience worsening of CVD. About chronic venous disease, studies have shown that edema and orthostatism are correlated with increased severity of CVD on the VCSS scales.

High versus low mean arterial pressure target in liver transplant patients. An open, controlled, single-center, randomized clinical trial - Protocol and methods (LIVER-PAM).

OBJECTIVE: To explain the rationale and protocol of the methods and analyses to be used in the LIVER-PAM randomized clinical trial, which seeks to understand whether a higher mean arterial pressure is capable of reducing the incidence of renal dysfunction postoperatively after liver transplantation. METHODS: LIVER-PAM is an open-label, randomized, controlled, singlecenter clinical trial. Patients randomized to the intervention group will have a mean arterial pressure of 85 - 90mmHg in the initial 24 hours of postoperative management, while patients in the control group will have a mean arterial pressure of 65 - 70mmHg in the same period. A sample of 174 patients will be required to demonstrate a 20% reduction in the absolute incidence of renal dysfunction, with a power of 80% and an alpha of 0.05. CONCLUSION: If a 20% reduction in the absolute incidence of renal dysfunction in the postoperative period of liver transplantation is achieved with higher target mean arterial pressure in the first 24 hours, this would represent an inexpensive and simple therapy for improving current outcomes in the management of liver transplant patients.ClinicalTrials.gov Registry: NCT05068713.

ACUTE CHOLECYSTITIS IN HIGH-RISK PATIENTS. SURGICAL, RADIOLOGICAL, OR ENDOSCOPIC TREATMENT? BRAZILIAN COLLEGE OF DIGESTIVE SURGERY POSITION PAPER.

Acute cholecystitis (AC) is an acute inflammatory process of the gallbladder that may be associated with potentially severe complications, such as empyema, gangrene, perforation of the gallbladder, and sepsis. The gold standard treatment for AC is laparoscopic cholecystectomy. However, for a small group of AC patients, the risk of laparoscopic cholecystectomy can be very high, mainly in the elderly with associated severe diseases. In these critically ill patients, percutaneous cholecystostomy or endoscopic ultrasound gallbladder drainage may be a temporary therapeutic option, a bridge to cholecystectomy. The objective of this Brazilian College of Digestive Surgery Position Paper is to present new advances in AC treatment in high-risk surgical patients to help surgeons, endoscopists, and physicians select the best treatment for their patients. The effectiveness, safety, advantages, disadvantages, and outcomes of each procedure are discussed. The main conclusions are: a) AC patients with elevated surgical risk must be preferably treated in tertiary hospitals where surgical, radiological, and endoscopic expertise and resources are available; b) The optimal treatment modality for high-surgical-risk patients should be individualized based on clinical conditions and available expertise; c) Laparoscopic cholecystectomy remains an excellent option of treatment, mainly in hospitals in which percutaneous or endoscopic gallbladder drainage is not available; d) Percutaneous cholecystostomy and endoscopic gallbladder drainage should be performed only in well-equipped hospitals with experienced interventional radiologist and/or endoscopist; e) Cholecystostomy catheter should be removed after resolution of AC. However, in patients who have no clinical condition to undergo cholecystectomy, the catheter may be maintained for a prolonged period or even definitively; f) If the cholecystostomy catheter is maintained for a long period of time several complications may occur, such as bleeding, bile leakage, obstruction, pain at the insertion site, accidental removal of the catheter, and recurrent AC; g) The ideal waiting time between cholecystostomy and cholecystectomy has not yet been established and ranges from immediately after clinical improvement to months. h) Long waiting periods between cholecystostomy and cholecystectomy may be associated with new episodes of acute cholecystitis, multiple hospital readmissions, and increased costs. Finally, when selecting the best treatment option other aspects should also be considered, such as costs, procedures available at the medical center, and the patient's desire. The patient and his family should be fully informed about all treatment options, so they can help making the final decision.

Immunomodulatory response in an experimental model of brain death.

Liver transplantation has come a long way and is now regarded as the gold standard treatment for end-stage liver failure. The great majority of livers utilized in transplantation come from brain-dead donors. A broad inflammatory response characterizes BD, resulting in multiorgan damage. This process is primarily mediated by cytokines, which increase the immunogenicity of the graft. In male Lewis rats, we evaluated the immune response in a BD liver donor and compared it to that of a control group. We studied two groups: Control and BD (rats subjected to BD by increasing intracranial pressure). After the induction of BD, there was an intense rise in blood pressure followed by a fall. There were no significant differences observed between the groups. Blood tissue and hepatic tissue analyzes showed an increase in plasma concentrations of liver enzymes (AST, ALT, LDH and ALP), in addition to pro-inflammatory cytokines and macrophages in liver tissue in animals submitted to BD. The current study found that BD is a multifaceted process that elicits both a systemic immune response and a local inflammatory response in liver tissue. Our findings strongly suggested that the immunogenicity of plasma and liver increased with time following BD.

Multivisceral transplantation of pelvic organs in rats.

Background: Multivisceral transplantation of pelvic organs would be a potential treatment for severe pelvic floor dysfunction with fecal and urinary incontinence, extensive perineal trauma, or congenital disorders. Here, we describe the microsurgical technique of multivisceral transplantation of pelvic organs, including the pelvic floor, in rats. Donor operation: We performed a perineal (including the genitalia, anus, muscles, and ligaments) and abdominal incision. The dissection progressed near the pelvic ring, dividing ligaments, muscles, external iliac vessels, and pudendal nerves, allowing pelvic floor mobilization. The aorta and vena cava were isolated distally, preserving the internal iliac and gonadal vessels. The graft containing the skin, muscles, ligaments, bladder, ureter, rectum, anus and vagina, uterus and ovarian (female), or penile, testis and its ducts (male) was removed en bloc, flushed, and cold-stored. Recipient operation: The infrarenal aorta and vena cava were isolated and donor/recipient aorta-aorta and cava-cava end-to-side microanastomoses were performed. After pelvic floor and viscera removal, we performed microanastomoses between the donor and the recipient ureter, and the rectum and pudenda nerves. The pelvic floor was repositioned in its original position (orthotopic model) or the abdominal wall (heterotopic model). We sacrificed the animals 2 h after surgery. Results: We performed seven orthotopic and four heterotopic transplantations. One animal from the orthotopic model and one from the heterotopic model died because of technical failure. Six orthotopic and three heterotopic recipients survived up to 2 h after transplantation. Conclusion: The microsurgical technique for pelvic floor transplantation in rats is feasible, achieving an early survival rate of 81.82%.

High versus low mean arterial pressure target in liver transplant patients. An open, controlled, single-center, randomized clinical trial - Protocol and methods (LIVER-PAM) / Alto versus baixo alvo de pressão arterial média em pacientes submetidos a transplante hepático. Um estudo clínico aberto, controlado, unicêntrico e randomizado -Protocolo e métodos (LIVER-PAM)

ABSTRACT Objective: To explain the rationale and protocol of the methods and analyses to be used in the LIVER-PAM randomized clinical trial, which seeks to understand whether a higher mean arterial pressure is capable of reducing the incidence of renal dysfunction postoperatively after liver transplantation. Methods: LIVER-PAM is an open-label, randomized, controlled, singlecenter clinical trial. Patients randomized to the intervention group will have a mean arterial pressure of 85 - 90mmHg in the initial 24 hours of postoperative management, while patients in the control group will have a mean arterial pressure of 65 - 70mmHg in the same period. A sample of 174 patients will be required to demonstrate a 20% reduction in the absolute incidence of renal dysfunction, with a power of 80% and an alpha of 0.05. Conclusion: If a 20% reduction in the absolute incidence of renal dysfunction in the postoperative period of liver transplantation is achieved with higher target mean arterial pressure in the first 24 hours, this would represent an inexpensive and simple therapy for improving current outcomes in the management of liver transplant patients. ClinicalTrials.gov Registry:NCT05068713

RESUMO Objetivo: Explicitar o racional e o protocolo de métodos e análises a serem utilizadas no ensaio clínico randomizado LIVER-PAM, que busca entender se um nível mais alto de pressão arterial média é capaz de reduzir a incidência de disfunção renal no pós-operatório de transplante hepático. Métodos: O LIVER-PAM é um estudo clínico randomizado, controlado, unicêntrico e aberto. Pacientes randomizados para o grupo intervenção terão como alvo de pressão arterial média 85 - 90mmHg nas 24 horas iniciais do manejo pós-operatório, enquanto pacientes do grupo controle terão como alvo de pressão arterial média 65 - 70mmHg no mesmo período. Uma amostra de 174 pacientes será necessária para demonstrar redução de 20% na incidência absoluta de disfunção renal, com poder de 80% e alfa de 0,05. Conclusão: Se a redução de 20% da incidência absoluta de disfunção renal no pós-operatório de transplante hepático for obtida com alvos maiores de pressão arterial média nas primeiras 24 horas, o manejo do paciente nesse cenário encontraria uma terapia barata e simples para a melhoria dos desfechos atuais. Registro Cliniclatrials.gov:NCT05068713

Registry of the International Society of Uterus Transplantation: First Report.

BACKGROUND: Uterus transplantation (UTx) is a novel type of transplantation to treat infertility in women with an absent or nonfunctioning uterus. The International Society of Uterus Transplantation (ISUTx) has developed a registry to monitor worldwide UTx activities while serving as a repository for specific research questions. METHODS: The web-based registry has separate data fields for donor, recipient, surgeries, immunosuppression, rejections, pregnancies with live birth(s), and transplant hysterectomies. Data are prospectively registered. RESULTS: A total of 45 UTx procedures have been registered; the majority (78%) of those procedures were live donor (LD) transplants. Median age of the LDs, deceased donors, and recipients were 50 y (range 32-62), 38.5 y (19-57), and 29 y (22-38), respectively. The duration of LD surgery was approximately twice as long as the recipient surgery. Postoperative complications of any Clavien-Dindo grade were registered in 20% of LDs and 24% of recipients. Rejection episodes were more frequent (33%) early after transplantation (months 1-5) compared with later time points (months 6-10; 21%). Healthy neonates were delivered by 16 recipients, with 3 women giving birth twice. The total live birth rate per embryo transfer was 35.8%. Median length of pregnancy was 35 gestational weeks. Twelve uteri were removed without childbirth, with 9 transplant hysterectomies occurring during the initial 7 mo post-UTx. CONCLUSIONS: A mandatory registry is critical to determine quality and process improvement for any novel transplantation. This registry provides a detailed analysis of 45 UTx procedures performed worldwide with a thorough analysis of outcomes and complications.

Molecular Profile of Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study is to review the molecular profile of intrahepatic cholangiocarcinoma and its implications for prognostication and decision-making. This comprehensive characterization of ICC tumors sheds light on the disease's underlying biology and offers a foundation for more personalized treatment strategies. This is a narrative review of the prognostic and therapeutic role of the molecular profile of ICC. Knowing the molecular profile of tumors helps determine prognosis and support certain target therapies. The molecular panel in ICC helps to select patients for specific therapies, predict treatment responses, and monitor treatment responses. Precision medicine in ICC can promote improvement in prognosis and reduce unnecessary toxicity and might have a significant role in the management of ICC in the following years. The main mutations in ICC are in tumor protein p53 (TP53), Kirsten rat sarcoma virus (KRAS), isocitrate dehydrogenase 1 (IDH1), and AT-rich interactive domain-containing protein 1A (ARID1A). The rate of mutations varies significantly for each population. Targeting TP53 and KRAS is challenging due to the natural characteristics of these genes. Different stages of clinical studies have shown encouraging results with inhibitors of mutated IDH1 and target therapy for ARID1A downstream effectors. Fibroblast growth factor receptor 2 (FGFR2) fusions are an important target in patients with ICC. Immune checkpoint blockade can be applied to a small percentage of ICC patients. Molecular profiling in ICC represents a groundbreaking approach to understanding and managing this complex liver cancer. As our comprehension of ICC's molecular intricacies continues to expand, so does the potential for offering patients more precise and effective treatments. The integration of molecular profiling into clinical practice signifies the dawn of a new era in ICC care, emphasizing personalized medicine in the ongoing battle against this malignancy.

Acute cholecystitis in high-risk patients. surgical, radiological, or endoscopic treatment? brazilian college of digestive surgery position paper / Colecistite aguda em pacientes de alto risco. tratamento cirúrgico, radiológico ou endoscópico? posicionamento do colégio brasileiro de cirurgia digestiva

ABSTRACT Acute cholecystitis (AC) is an acute inflammatory process of the gallbladder that may be associated with potentially severe complications, such as empyema, gangrene, perforation of the gallbladder, and sepsis. The gold standard treatment for AC is laparoscopic cholecystectomy. However, for a small group of AC patients, the risk of laparoscopic cholecystectomy can be very high, mainly in the elderly with associated severe diseases. In these critically ill patients, percutaneous cholecystostomy or endoscopic ultrasound gallbladder drainage may be a temporary therapeutic option, a bridge to cholecystectomy. The objective of this Brazilian College of Digestive Surgery Position Paper is to present new advances in AC treatment in high-risk surgical patients to help surgeons, endoscopists, and physicians select the best treatment for their patients. The effectiveness, safety, advantages, disadvantages, and outcomes of each procedure are discussed. The main conclusions are: a) AC patients with elevated surgical risk must be preferably treated in tertiary hospitals where surgical, radiological, and endoscopic expertise and resources are available; b) The optimal treatment modality for high-surgical-risk patients should be individualized based on clinical conditions and available expertise; c) Laparoscopic cholecystectomy remains an excellent option of treatment, mainly in hospitals in which percutaneous or endoscopic gallbladder drainage is not available; d) Percutaneous cholecystostomy and endoscopic gallbladder drainage should be performed only in well-equipped hospitals with experienced interventional radiologist and/or endoscopist; e) Cholecystostomy catheter should be removed after resolution of AC. However, in patients who have no clinical condition to undergo cholecystectomy, the catheter may be maintained for a prolonged period or even definitively; f) If the cholecystostomy catheter is maintained for a long period of time several complications may occur, such as bleeding, bile leakage, obstruction, pain at the insertion site, accidental removal of the catheter, and recurrent AC; g) The ideal waiting time between cholecystostomy and cholecystectomy has not yet been established and ranges from immediately after clinical improvement to months. h) Long waiting periods between cholecystostomy and cholecystectomy may be associated with new episodes of acute cholecystitis, multiple hospital readmissions, and increased costs. Finally, when selecting the best treatment option other aspects should also be considered, such as costs, procedures available at the medical center, and the patient's desire. The patient and his family should be fully informed about all treatment options, so they can help making the final decision.

RESUMO A colecistite aguda (CA) é um processo inflamatório agudo da vesícula biliar que pode estar associado a complicações potencialmente graves, como empiema, gangrena, perfuração da vesícula biliar e sepse. O tratamento padrão para a CA é a colecistectomia laparoscópica. No entanto, para um pequeno grupo de pacientes com CA, o risco de colecistectomia laparoscópica pode ser muito alto, principalmente em idosos com doenças graves associadas. Nestes pacientes críticos, a colecistectomia percutânea ou a drenagem endoscópica da vesícula biliar guiada por ultrassom podem ser uma opção terapêutica temporária, como ponte para a colecistectomia. O objetivo deste artigo de posicionamento do Colégio Brasileiro de Cirurgia Digestiva é apresentar novos avanços no tratamento da CA em pacientes cirúrgicos de alto risco, para auxiliar cirurgiões, endoscopistas e clínicos a selecionar o melhor tratamento para os seus pacientes. A eficácia, segurança, vantagens, desvantagens e resultados de cada procedimento são discutidos. As principais conclusões são: a) Pacientes com CA e risco cirúrgico elevado devem ser tratados preferencialmente em hospitais terciários onde a experiência e os recursos cirúrgicos, radiológicos e endoscópicos estão disponíveis. b) A modalidade de tratamento ideal para pacientes com elevado risco cirúrgico, deve ser individualizada, com base nas condições clínicas e na experiência disponível. c) A colecistectomia laparoscópica continua sendo uma excelente opção de tratamento, principalmente em hospitais em que a drenagem da vesícula biliar percutânea ou endoscópica não está disponível. d) A colecistostomia percutânea e a drenagem endoscópica da vesícula biliar devem ser realizadas apenas em hospitais bem equipados e com radiologista intervencionista e/ou endoscopista experientes. e) O cateter de colecistostomia deve ser removido após a resolução da CA. No entanto, em pacientes que não têm condição clínica para realizar colecistectomia, o cateter pode ser mantido por um período prolongado ou mesmo definitivamente. f) Se o cateter de colecistostomia for mantido por longo período de tempo podem ocorrer várias complicações, como sangramento, fístula biliar, obstrução, dor no local de inserção, remoção acidental do cateter e CA recorrente. g) O tempo de espera ideal entre a colecistostomia e a colecistectomia ainda não foi estabelecido, e vai desde imediatamente após a melhoria clínica, até meses após. h) Longos períodos de espera entre colecistostomia e colecistectomia podem estar associados a novos episódios de CA, múltiplas readmissões hospitalares e aumento dos custos. Finalmente, ao selecionar a melhor opção de tratamento, outros aspectos também devem ser considerados, como custos, disponibilidade dos procedimentos no centro médico e o desejo do paciente. O paciente e sua família devem ser completamente informados sobre todas as opções de tratamento, para que possam ajudar a tomar a decisão final.

Venous thromboembolism in in-hospital cirrhotic patients: A systematic review.

Introduction: Patients with liver cirrhosis are at a higher risk of hospitalization. The present review aimed to assess the risk of thromboembolism and its burden on hospitalized cirrhotic patients. Materials and methods: A systematic review (PROSPERO: CRD42021256869) was conducted in PubMed, Embase, Cochrane, Lilacs, and a manual search of references. It evaluated studies that compare cirrhotic patients with venous thromboembolism (VTE) with cirrhotic patients without VTE or studies that compare cirrhotic patients with non-cirrhotic patients. No restrictions were set for the date of publication or language. The last search was conducted in June 2021. Results: After selection, 17 studies were included from an initial search of 5,323 articles. The chronic liver disease etiologies comprise viral, alcohol, autoimmune, NASH (non-alcoholic steatohepatitis), cryptogenic, hemochromatosis, cholestasis, and drug-related. The included studies were conflicted regarding the outcomes of VTE, pulmonary embolism, or bleeding. Patients with cirrhosis associated with VTE had prolonged length of hospital stay, and patients with cirrhosis were at higher risk of portal thrombosis. Conclusion: In-hospital cirrhotic patients are a heterogeneous group of patients that may present both thrombosis and bleeding risk. Clinicians should take extra caution to apply both prophylactic and therapeutic anticoagulation strategies. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021256869].

Cirrhosis and hernia repair in a cohort of 6352 patients in a tertiary hospital: Risk assessment and survival analysis.

The prevalence of hernias in patient with cirrhosis can reach up to 40%. The pathophysiology of cirrhosis is closely linked to that of the umbilical hernia, but other types are also common in this population. The aim of this study is to evaluate factors that influence in the prognosis after hernia repair in patients with cirrhosis. A historical cohort of 6419 patients submitted to hernia repair was gathered. Clinical, epidemiological data and hernia characteristics were obtained. For patient with cirrhosis, data from exams, surgery and follow-up outcomes were also analyzed. Survival curves were constructed to assess the impact of clinical and surgical variables on survival. 342 of the 6352 herniated patients were cirrhotic. Patient with cirrhosis had a higher prevalence of umbilical hernia (67.5% × 24.2%, P < .001) and a lower prevalence of epigastric (1.8% × 9.0%, P < .001) and lumbar (0% × 0.18%, P = .022). There were no significant differences in relation to inguinal hernia (P = .609). Ascites was present in 70.1% of patient with cirrhosis and its prevalence was different in relation to the type of hernia (P < .001). The survival curve showed higher mortality for emergency surgery, MELD > 14 and ascites (HR 12.6 [3.79-41.65], 4.5 [2.00-10.34], and 6.1 [1.15-20.70], respectively, P < .05). Hernia correction surgery in patient with cirrhosis has a high mortality, especially when performed under urgent conditions associated with more severe clinical conditions of patients, such as the presence of ascites and elevated MELD.

MICRObiota on BILIOpancreatic malignant diseases [MICROBILIO]: A systematic review.

INTRODUCTION: The increase in the incidence of pancreatic and biliary cancers has attracted the search for methods of early detection of diseases and biomarkers. The authors propose to analyze new findings on the association between microbiota and Pancreatic Ductal Adenocarcinoma (PDAC) or Cholangiocarcinoma (CCA). METHODS: This systematic review was carried out according to the items of Preferred Reports for Systematic Reviews and Protocol Meta-Analysis (PRISMA-P). This study was registered by the Prospective Register of Systematic Reviews (PROSPERO), identification code CRD42020192748 before the review was carried out. Articles were selected from the PUBMED, EMBASE, and Cochrane databases. RESULTS: Most studies (86.67%) used 16s rRNA as a sequencing method. The main comorbidities found were diabetes mellitus, systemic arterial hypertension, and dyslipidemia. Many studies were limited by the small number of participants, but the biases were mostly low. There was very little concordance about the composition of the microbiome of different sites, for both case and control groups when compared to other studies' results. Bile sample analysis was the one with a greater agreement between studies, as three out of four studies found Escherichia in cases of CCA. CONCLUSION: There was great disagreement in the characterization of both the microbiota of cases and control groups. Studies are still scarce, making it difficult to adequately assess the data in this regard. It was not possible to specify any marker or to associate any genus of microbiota bacteria with PDAC or CCA.

Thalidomide modulates renal inflammation induced by brain death experimental model.

BACKGROUND: Brain death (BD) is characterized by a complex inflammatory response, resulting in dysfunction of potentially transplantable organs. This process is modulated by cytokines, which amplify graft immunogenicity. We have investigated the inflammatory response in an animal model of BD and analyzed the effects of thalidomide, a drug with powerful immunomodulatory properties. METHODS: BD was induced in male Lewis rats. We studied three groups: Control (sham-operated rats) (n = 6), BD (rats subjected to brain death) (n = 6) and BD + Thalid (BD rats treated with one dose of thalidomide (200 mg/Kg), administered by gavage) (n = 6). Six hours after BD, serum levels of urea and creatinine, as well as systemic and renal tissue protein levels of TNF-α and IL-6, were analyzed. We also determined the mRNA expression of ET-1, and macrophage infiltration by immunohistochemistry. RESULTS: BD induced a striking inflammatory status, demonstrated by a significant increase of plasma cytokines: TNF-α (2.8 ± 4.3 pg/mL [BD] vs. 9.4 ± 2.8 pg/mL [Control]), and IL-6 (6219.5 ± 1380.6 pg/mL [BD] vs. 1854.7 ± 822.6 pg/mL [Control]), and in the renal tissue: TNF-α (2.5 ± 0.3 relative expression [BD] vs. 1.0 ± 0.4 relative expression [Control]; p < 0.05), and IL-6 (4.0 ± 0.4 relative expression [BD] vs. 1.0 ± 0.3 relative expression [Control]; p < 0.05). Moreover, BD increased macrophages infiltration (2.47 ± 0.07 cells/field [BD] vs. 1.20 ± 0.05 cells/field [Control]; p < 0.05), and ET-1 gene expression (2.5 ± 0.3 relative expression [BD] vs. 1.0 ± 0.2 relative expression [Control]; p < 0.05). In addition, we have observed deterioration in renal function, characterized by an increase of urea (194.7 ± 25.0 mg/dL [BD] vs. 108.0 ± 14.2 mg/dL [Control]; p < 0.05) and creatinine (1.4 ± 0.04 mg/dL [BD] vs. 1.0 ± 0.07 mg/dL [Control]; p < 0.05) levels. Thalidomide administration significantly reduced plasma cytokines: TNF-α (5.1 ± 1.4 pg/mL [BD + Thalid] vs. BD; p < 0.05), and IL-6 (1056.5 ± 488.3 pg/mL [BD + Thalid] vs. BD; p < 0.05), as well as in the renal tissue: TNF-α (1.5 ± 0.2 relative expression [BD + Thalid] vs. BD; p < 0.05), and IL-6 (2.1 ± 0.3 relative expression [BD + Thalid] vs. BD; p < 0.05). Thalidomide treatment also induced a significant decrease in the expression of ET-1 (1.4 ± 0.3 relative expression [BD + Thalid] vs. BD; p < 0.05), and macrophages infiltration (1.17 ± 0.06 cells/field [BD + Thalid] vs. BD; p < 0.05). Also thalidomide prevented kidney function failure by reduced urea (148.3 ± 4.4 mg/dL [BD + Thalid] vs. BD; p < 0.05), and creatinine (1.1 ± 0.14 mg/dL [BD + Thalid] vs. BD; p < 0.05). CONCLUSIONS: The immunomodulatory properties of thalidomide were effective in decreasing systemic and local immunologic response, leading to diminished renal damage, as reflected in the decrease of urea and creatinine levels. These results suggest that use of thalidomide may represent a potential strategy for treating in BD kidney organ donors.

Clinical Validation of a Novel Scoring System Based on Donor and Recipient Risk Factors for Predicting Outcomes in Liver Transplantation.

BACKGROUND Adequate donor and recipient matching in liver transplantation is crucial to improve patient survival. Our objective was to propose and validate a new model for predicting outcomes using donor and recipient scoring criteria. MATERIAL AND METHODS We retrospectively analyzed data of all patients (n=932) who underwent liver transplantation (n=1106) from January 2006 to December 2018. For score standardization, 30% (n=280) of patients were randomly selected for analysis and divided into 3 categories: ≤4 points, 5 to 8 points, and >8 points. Scoring system validation was performed on a dataset with 70% (n=652) of the patients. RESULTS Survival of the stratified group (30%) was significant (P<0.001). Scores of 4 to 8 points presented lower risk of death (1.74 [CI 0.97-3.13; P=0.062]), while >8 points presented higher risk (2.74 [CI 1.36-5.57; P=0.005]). In the validation score (70%), global survival was significant (P<0.0016); patients with scores of 4 to 8 points had lower risk of death (1.16 [CI 1.16-2.38; P=0.005]); and scores >8 points (2.22 [CI 1.40-3.50; P<0.001]), retransplant, fulminant hepatitis, previous large abdominal/biliary tree surgery, MELD score, and serum creatinine before liver transplantation >1.5 mg/dL (P<0.05) presented higher risk. Individual recipient factors with 4 to 8 points had a lower risk of death (2.29 [CI 1.82-2.87; P<0.0001]) than those with scores >8 points (4.02 [CI 2.22-7.26; P<0.0001]). CONCLUSIONS A novel prognostic-based scoring system using donor and recipient characteristics was proposed and clinically validated. Two-factor scoring indicated the superiority of the predictability outcome and improved prediction of higher mortality.

Liver transplant after SARS-CoV-2 infection: A systematic review.

BACKGROUND: The Coronavirus 19 (COVID-19) pandemic has dramatically impacted liver organ transplantation. The American Society of Transplantation recommends a minimum of 28 days after symptom resolution for organ donation. However, the exact time for transplantation for recipients is unknown. Considering that mortality on the waiting list for patients with MELD >25 or fulminant hepatitis is higher than that of COVID-19, the best time for surgery after SARS-CoV-2 infection remains undetermined. This study aims to expand the current knowledge regarding the Liver Transplantation (LT) time for patients after COVID-19 and to provide transplant physicians with essential decision-making tools to manage these critically ill patients during the pandemic. METHODS: Systematic review of patients who underwent liver transplantation after diagnosis of COVID-19. The MEDLINE, PubMed, Cochrane, Lilacs, Embase, and Scielo databases were searched until June 20, 2021. The MESH terms used were "COVID-19" and "Liver transplantation". RESULTS: 558 articles were found; of these 13 articles and a total of 18 cases of COVID-19 prior to liver transplantation were reported. The mean age was 38.7±14.6, with male prevalence. Most had mild symptoms of COVID. Five patients have specific treatment for COVID-19 with convalescent plasm or remdesivir/oseltamivir, just one patient received hydroxychloroquine, and 12 patients received only symptomatic treatment. The median time between COVID-19 to LT was 19 days (13.5‒44.5). Deceased donor liver transplantation accounted for 61% of cases, while living donor transplantation was 39%. CONCLUSION: Despite the concerns regarding the postoperative evolution, the mortality of patients with high MELD or fulminant hepatitis transplanted shortly after COVID-19 diagnosis does not seem to be higher. (PROSPERO, registration number = CRD42021261790).

COVID-19 Pandemic Impact on Liver Donation in the Largest Brazilian Transplantation Center.

BACKGROUND: COVID-19 has spread worldwide and has become a public health emergency and a pandemic of international concern. The solid organ donation system was no different. This study aimed to investigate the effect of COVID-19 on the liver transplant (LT) system in Brazilian territory. METHODS: We retrospectively reviewed all liver donor records allocated in São Paulo State, Brazil, 1 year before and 1 year during the COVID-19 pandemic. We defined the pre-COVID-19 (PRE) period as between April 2019 and April 2020 and the post-COVID-19 (POST) period as between April 2020 and April 2021. Moreover, we compared LT performed in our institution during these periods. To evaluate outcomes, we compared 30-day survival after LT. RESULTS: In the PRE period, 1452 livers were offered for donation in São Paulo State and other Brazilian territories. Of these, 592 were used in LT. In the POST period, 1314 livers were offered for donation, but only 477 were used in LT. Organ refusal was higher in the POST period (P < .05). Our center performed 127 and 156 LTs in these periods, respectively, and an increase above 20% was significant (P = .039). There was no difference in 30-day survival between the periods (87.2% vs 87.9%, P > .5, respectively). CONCLUSIONS: The COVID-19 pandemic harmed potential and allocated donors and LTs performed. However, it is possible to maintain the LT volume of a transplant center without compromising survival outcomes through preventive strategies against COVID-19 propagation.

Duodenal Necrosis and Nonvariceal Digestive Bleeding After Terlipressin Administration for Treatment of Hepatorenal Syndrome: a Case Report of a Novel Side Effect of a Commonly Used Drug.

BACKGROUND: Terlipressin is widely used for treatment of hepatorenal syndrome and variceal bleeding in cirrhotic patients. However, it may be associated with side effects, especially those related to vasoconstriction, such as myocardial infarction or intestinal ischemia. This is a case report of a cirrhotic patient with nonvariceal upper gastrointestinal bleeding after duodenal necrosis due to the use of terlipressin, a novel side effect not yet described in literature to the best of our knowledge. CASE REPORT: A 51-year-old male patient, with alcoholic liver cirrhosis and hepatitis C virus infection, was admitted presenting oliguria associated with severe ascites and lower limb edema. His Model for End Stage Liver Disease-Sodium score was 19 and his serum creatine level was 2.12 mg/dL. Albumin infusion was performed for 48 hours, but his serum creatinine level reached 3.46 mg/dL. Terlipressin infusion was started in continuous infusion and serum creatinine levels progressively decreased. However, the patient presented hemorrhagic shock secondary to hematemesis after 7 days. Upper digestive endoscopy showed an extensive ulcerated lesion in the duodenal bulb, reaching 70% of its lumen, with hematic residues and necrotic foci. Terlipressin was suspended and proton pump inhibitors were started. Despite intensive care, the patient developed severe encephalopathy and reentrant seizures. He eventually died 10 days after the bleeding event. CONCLUSIONS: We described a case of nonvariceal upper gastrointestinal bleeding secondary to duodenal necrosis, which was caused by visceral ischemia induced by terlipressin. Given its fatality potential, this novel side effect should be remembered when using this medication in cirrhotic patients.

Hepatic Venous Outflow Obstruction in Adult Deceased Donor Liver Transplantation: Classic Piggyback Implantation Versus a Modified Technique that Widens the Ostium of the Recipient's Left and Middle Hepatic Veins.

BACKGROUND: The classic piggyback technique uses the union of the 3 hepatic veins to perform the cavo-caval anastomosis. However, due to the lateral localization of the right hepatic vein, the partial clamping of the vena cava in this technique significantly reduces the venous return to the right atrium. To avoid this, we adopted in 2015 a modified piggyback technique, in which we use the common trunk of the middle and left hepatic veins and also perform a lateral incision toward the right in the anterior wall of the vena cava in order to widen the final ostium of the cavo-caval anastomosis. The aim of the study was to analyze the incidence of hepatic venous outflow obstruction between those 2 techniques. METHODS: Retrospective study of liver transplant recipients undergoing venography for suspected hepatic venous outflow obstruction from January 2009 to June 2021. Patients undergoing transplantation with living donors or split grafts and pediatric cases were excluded from the study. RESULTS: From January 2009 to December 2014 and from January 2015 to June 2021, 587 (group 1) and 730 (group 2) deceased-donor liver transplants were performed with the classic and the modified piggyback techniques, respectively. The incidence of cases with suspected hepatic venous outflow obstruction in groups 1 and 2 were 1.87% (n = 11) and 0.95% (n = 7), respectively (P = 0,15). The number of confirmed patients with outflow blockage that required endovascular treatment during venography in groups 1 and 2 were 4 (0.68%) and 5 (0.68%), respectively (P = 0,31). CONCLUSIONS: This modified piggyback technique did not increase the incidence of hepatic venous outflow obstruction at our service.

Septuagenarian Donors and Recipients in Deceased Donor Liver Transplantation: A Brazilian Single Center Experience and Literature Review.

BACKGROUND: The number of elderly patients who have end-stage liver disease and require liver transplantation has dramatically increased. On the other hand, liver grafts from elderly donors have been offered more frequently for transplantation. The present study aims to analyze the results of liver transplants performed with donors and recipients aged ≥70 years. METHODS: We performed a single-center retrospective study of deceased donors liver transplants that involved recipients aged ≥7070 years or recipients who received grafts from donors aged ≥70 years from 2011 to 2021. A literature review on the results of liver transplantation in elderly recipients was also performed. RESULTS: Thirty septuagenarian recipients were included; their overall 1- and 5-years survival was 80% and 76.6%, respectively. The prevalence of recipients aged ≥70 years in our department was 2.65%. Twenty recipients received grafts form septuagenarian donors; their overall 1- and 5-years survival was 75%. The prevalence of donors aged ≥70 years in our department was 1%. In the literature review, 17 articles were analyzed. The 5-years survival of recipients aged ≥70 years ranged from 47.1% to 78.5%. CONCLUSIONS: Septuagenarian recipients and patients who received grafts from elderly brain-dead donors present adequate overall survival after liver transplantation. Optimized donor-recipient matching is paramount for achieving good outcomes. The combination of high-risk donors with septuagenarian recipients should be avoided as well as using grafts of elderly donors that present others risk factors. Thus, the age of the donor or recipient alone cannot be considered an absolute contraindication for liver transplantation.