Improved outcomes of ABO incompatible living donor liver transplant with biologically related donors.

INTRODUCTION: Liver transplantation is considered to be the only curative treatment in decompensated liver disease. Shortage of liver allografts is a major impediment for widespread application of this procedure. ABO-incompatible grafts have been used successfully thereby increasing the LDLT donor pool. However, ABO-I liver transplantation is associated with complications like acute liver rejection, hepatic artery thrombosis and higher biliary stricture rates leading to transplant failure, re-transplantations or sepsis-related complications. Various desensitization strategies have been adopted which have improved outcomes. Biologically-related donor-recipient pairs have theoretical advantage of favourable HLA match. We have analysed the outcomes of ABO-incompatible LDLT and compared the results of HLA-matched (biologically-related) and HLA-unmatched (biologically-unrelated) donor-recipient pairs. Retrospective data of 90 cases of ABO-I liver transplant recipients: HLA matched (n=35) and HLA un-matched (n=55) for comparison of pre-operative and post-operative data. RESULTS: Peak bilirubin level in HLA-unmatched recipients were higher. Platelets count were lower than HLA-matched recipients (7.3 mg/dL vs 8.9 mg/dL). No significant difference in days-to-normal bilirubin, peak INR, hospital stay and discharge-day from transplant between both groups. Post-operatively, HLA-unmatched recipient required more pulse-steroids therapy than HLA-matched - 21/55 (38.2%) vs 11/35 (31.4%). Biliary complication and intervention were more in HLA-unmatched group (12/55, 21.8%) than HLA-matched (4/35, 11.4%). Renal complications requiring post-operative haemodialysis was more in HLA-unmatched group than HLA-matched group 9/55 (16.4%) vs 3/35 (8.6%). The incidence of vascular complications was similar. CONCLUSION: ABO-I LDLT is an effective and safe method for increasing the donor pool in absence of ABO-C liver donor. Long term outcomes of recipients with biologically-related donors are marginally better than biologically-unrelated ABO-I LDLT recipient. However, incidence of antibody-mediated graft rejection and biliary complications are more in biologically-unrelated ABO-I liver recipient.

Therapeutic and pharmacological efficacy of plant-derived bioactive compounds in targeting breast cancer.

Breast cancer (BC) ranks number one among cancers affecting women globally. Serious concerns include delayed diagnosis, poor prognosis, and adverse side effects of conventional treatment, leading to residual morbidity. Therefore, an alternative treatment approach that is safe and effective has become the need of the hour. In this regard, plant-based medicines via a combination of conventional drugs are gaining increasing acceptance worldwide, playing a pivotal role in cancer management as proven by their efficacy evaluation studies. This review aims to fill the knowledge gaps by providing the preclinical evidence of cellular and molecular mechanisms of Indian phytomedicines in targeting varied pathways of breast cancer progression. A comprehensive search was performed on different platforms, followed by screening of relevant studies for review. In this article, the in-depth of various botanical drugs covering their nomenclature, dosage, toxicity, and modus operandi in BC cells have been extensively discussed. Various signaling pathways like Notch signaling, MAPK signaling, apoptosis, Wnt signaling, etc. regulated by herbal medicine treatment in BC are also highlighted to understand the drug mechanism better. This will guide the researchers to plan future strategies and generate more robust integrated evidence of plant-based drugs or botanical formulations for their potential role in the management of BC.

Successful Surgical Management of Giant Mucinous Cystic Neoplasm of Liver (MCN-L) Presenting With Peritoneal Rupture and Biliary Prolapse: Case Report and Review of Literature.

Mucinous cystic neoplasms of liver (MCN-L) are generally considered benign indolent cystic liver lesions, not associated with significant clinical symptoms in majority of patients. However, rarely these benign-appearing lesions may have a complicated clinical course, presenting with jaundice, acute abdomen, or malignant transformation. We report one such rare clinical presentation of MCN-L presenting with obstructive jaundice and abdominal pain due to prolapse of cystic component in biliary system and peritoneal rupture occurring simultaneously. Despite the complex nature of presentation, it was successfully managed surgically with normal follow-up imaging.

Incidence, management and outcomes in hepatic artery complications after paediatric liver transplantation: protocol of the retrospective, international, multicentre HEPATIC Registry.

INTRODUCTION: Hepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications. METHODS AND ANALYSIS: The HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age <18 years) after paediatric LT within a 20-year time period will be included. The primary outcomes are graft and patient survivals. The secondary outcomes are technical success of the intervention, primary and secondary patency after HAC intervention, intraprocedural and postprocedural complications, description of current management practices, and incidence of HAC. ETHICS AND DISSEMINATION: All participating sites will obtain local ethical approval and (waiver of) informed consent following the regulations on the conduct of observational clinical studies. The results will be disseminated through scientific presentations at conferences and through publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: The HEPATIC registry is registered at the ClinicalTrials.gov website; Registry Identifier: NCT05818644.

Youngest Living Donor Liver Transplant for End-Stage Liver Disease in a 6-Month-Old With a Novel Aggressive Mutation in KIF12 Gene.

BACKGROUND: Kinesin family member 12 (KIF12) mutation-related cholestatic disorder represents a rare subtype of progressive familial intrahepatic cholestasis (PFIC), referred to as PFIC Type 8, with only 21 reported cases globally to date. METHODS: Here, we present a unique case of a 6-month-old boy diagnosed with homozygous KIF12 gene mutation, who successfully underwent a living donor liver transplant at our center for end-stage liver disease. RESULTS: This case marks the youngest patient of KIF12-related cholestatic disorder necessitating a liver transplant to date. The child initially presented with neonatal cholestasis and then developed infantile hepatic decompensation. Our report discusses the diagnostic process and management strategies employed. It underscores the importance of prompt diagnosis through clinical suspicion, biochemical parameters, and genetic testing, as well as the adoption of suitable management strategies, including the early contemplation of liver transplant in such exceptional and rare cases of genetic intrahepatic cholestasis. CONCLUSION: KIF12-related genetic disease should be considered in neonatal cholestasis cases with high gamma glutamyl transpeptidase to differentiate from conditions like biliary atresia. Favorable outcomes post liver transplant stress the importance of early genetic testing and referral to liver transplant centers for unresponsive patients, potentially saving lives.

Hepatitis A Liver Failure in Children: Native Liver Survival Despite Poor Prognosis.

Background: Hepatitis A virus (HAV) infection is the commonest cause of pediatric acute liver failure (PALF) in developing countries. Literature has shown good outcomes of HAV-induced PALF as compared to other etiologies. The advanced critical care and use of extracorporeal liver assist devices (ELAD) have improved the survival with native liver in PALF and overall outcomes. Various liver transplant listing criteria have been proposed in PALF, however none of them is specific enough to predict the outcome. The timing of liver transplant in living donor setting has never been straightforward. Dynamic clinical and biochemical monitoring of the ALF child is the key to decide for LT. Cases: Here we report three children with HAV-induced PALF presented with advanced hepatic encephalopathy (HE) and high international normalized ratio (INR > 10). These children survived with native liver despite fulfilling the liver transplant criteria. The first child is a 14-year-old male who had peak INR of more than 10.2 and grade 3-4 HE with cerebral edema and acute kidney injury. He responded to medical management and CRRT as liver assist device. The second one is a 7-year-old male child who also recovered well with native liver despite advanced HE and INR of more than 10. Third child is a 16-year-old male who had peak INR of 12.6 and grade 2 HE. He received ELAD (Therapeutic plasma exchange and CRRT) and survived with native liver. Conclusion: Children with HAV-induced PALF can recover with their native liver despite extremely poor prognostic markers like very high INR, ammonia and advanced HE.

APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.

Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency-related cholestasis.

BACKGROUND AND AIMS: The study aimed to describe the clinical course and outcomes, and analyze the genotype-phenotype correlation in patients with tight junction protein 2 (TJP2) deficiency. APPROACH AND RESULTS: Data from all children with chronic cholestasis and either homozygous or compound heterozygous mutations in TJP2 were extracted and analyzed. The patients were categorized into 3 genotypes: TJP2-A (missense mutations on both alleles), TJP2-B (missense mutation on one allele and a predicted protein-truncating mutation [PPTM] on the other), and TJP2-C (PPTMs on both alleles). A total of 278 cases of genetic intrahepatic cholestasis were studied, with TJP2 deficiency accounting for 44 cases (15.8%). Of these, 29 were homozygous and 15 were compound heterozygous variants of TJP2 . TJP2-A genotype was identified in 21 (47.7%), TJP2-B in 7 cases (15.9%), and TJP2-C in 16 cases (36.4%), respectively. Patients with the TJP2-C genotype were more likely to experience early infantile cholestasis (87.5% vs. 53.5%, p =0.033), less likely to clear jaundice (12.5% vs. 52.2%, p =0.037), more likely to develop ascites, and had higher serum bile acids. Patients with the TJP2-C genotype were more likely to die or require liver transplantation (native liver survival: 12.5% vs. 78.6%, p <0.001), with a median age at death/liver transplantation of 2.5 years. Cox regression analysis revealed that TJP2-C mutations ( p =0.003) and failure to resolve jaundice ( p =0.049) were independent predictors of poor outcomes. CONCLUSIONS: Patients with the TJP2-C genotype carrying PPTMs in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.

Basics and Art of Immunosuppression in Liver Transplantation.

Liver transplantation is one of the most challenging areas in the medical field. Despite that, it has already been established as a standard treatment option, especially in decompensated cirrhosis and selected cases of hepatocellular carcinoma and acute liver failure. Complications due to graft rejection, including mortality and morbidity, have greatly improved over time due to better immunosuppressive agents and management protocols. Currently, immunosuppression in liver transplant patients makes use of the best possible combinations of effective agents to achieve optimal immunosuppression for long-term graft survival. Induction agents are no longer used routinely, and the aim is to provide minimal immunosuppression in the maintenance phase. Currently available immunosuppressive agents are mainly classified as biological and pharmacological agents. Though the protocols may vary among the centers and over time, the basics of effective use usually remain similar. Most protocols use the combination of multiple agents with different mechanisms of action to reduce the dose and minimize the side effects. Along with the improvement in operative and perioperative techniques, this art of immunosuppression has contributed to the recent progress made in the outcomes of liver transplants. In this review, we will discuss the various types of immunosuppressive agents currently in use, the different protocols of immunosuppression used, and the art of optimal use for achieving maximum immunosuppression without increasing toxicity. We will also discuss the practical aspects of various immunosuppression regimens, including drug monitoring, and briefly discuss the concepts of immunosuppression minimization and withdrawal.

MYCN immunohistochemistry as surrogate marker for MYCN-amplified spinal ependymomas.

MYCN (master regulator of cell cycle entry and proliferative metabolism) gene amplification defines a molecular subgroup of spinal cord ependymomas that show high-grade morphology and aggressive behavior. Demonstration of MYCN amplification by DNA methylation or fluorescence-in situ hybridization (FISH) is required for diagnosis. We aimed to (i) assess prevalence and clinicopathological features of MYCN-amplified spinal ependymomas and (ii) evaluate utility of immunohistochemistry (IHC) for MYCN protein as a surrogate for molecular testing. A combined retrospective-prospective study spanning 8 years was designed during which all spinal cord ependymomas with adequate tissue were subjected to MYCN FISH and MYCN IHC. Among 77 spinal cord ependymomas included, MYCN amplification was identified in 4 samples from 3 patients (3/74, 4%) including two (1st and 2nd recurrences) from the same patient. All patients were adults (median age at diagnosis of 32 years) including two females and one male. The index tumors were located in thoracic (n = 2) and lumbar (n = 1) spinal cord. One of the female patients had neurofibromatosis type 2 (NF2). All four tumors showed anaplastic histology. Diffuse expression of MYCN protein was seen in all four MYCN-amplified samples but in none of the non-amplified cases, thus showing 100% concordance with FISH results. On follow-up, the NF2 patient developed widespread spinal dissemination while another developed recurrence proximal to the site of previous excision. To conclude, MYCN-amplified spinal ependymomas are rare tumors, accounting for ~ 4% of spinal cord ependymomas. Within the limitation of small sample size, MYCN IHC showed excellent concordance with MYCN gene amplification.

ABO Incompatible Living Donor Liver Transplantation in Children: A Single Centre Experience from India.

Background: In recent years, paediatric ABO incompatible (ABOi) living donor liver transplant (LT) has shown promising outcomes and can potentially eliminate organ shortage. This study aims to report paediatric ABOi LT experience, including short- and long-term outcomes. Methods: It is a single-centre retrospective study. Out of 108 LTs, 20 were done in children. We compared the outcomes between ABOi (n = 20) and non-ABOi (n = 220) paediatric living donor liver transplantation (LDLT) performed during the study period. All the children received pre-LT desensitization therapy comprising rituximab and plasmapheresis targeting pre-LT isohemagglutinin (IHA) titres of ≤1:16. Results: Out of 239 paediatric LDLTs from 2017 to 2022, 19 children (11 females) underwent 20 ABOi LTs (including one retransplant with an ABOi domino allograft) at a median age of 12 (12, 51) months, with the majority being biliary atresia (60%). The median change in CD19 cell%, CD20 cell%, and IHA titres after rituximab from day -14 to day -1 (before LT) was satisfactory. In the first 3 months following LT, acute cellular rejection, culture-proven sepsis, and biliary and vascular complications were seen in 10%, 20%, 20%, and 15%, respectively. None of the ABOi LT recipients developed antibody-mediated rejection. ABOi LT recipients, as compared to non-ABOi LT recipients, had a higher incidence of bile leaks and prolonged hospital stay, with the rest of the complications, including biliary strictures and long-term outcomes, being comparable. At a median follow-up of 21 (14, 33) months, 4 children expired (21%). Conclusion: ABOi LT in children shows excellent outcomes and can be performed safely with prior desensitization when a compatible liver is unavailable.

Living donor liver transplant in acute on chronic liver failure grade 3: Who not to transplant.

BACKGROUND AND AIM: Liver transplantation(LT)offers definitive treatment for acute on chronic liver failure(ACLF) patients. This study was done to analyze and compare the outcomes of living donor LT(LDLT) in patients with ACLF versus Chronic liver disease(CLD) and within the grades of ACLF. Factors affecting mortality in patients with ACLF and ACLF grade3 (ACLF3) following LDLT were also derived. METHODS: Records of adult LDLT between 1/2/2017 and 30/9/2021 were analyzed. ACLF was classified based on EASL-CLIF definition. Post-transplant outcomes of ACLF were compared with CLD and within ACLF grades. Post LDLT mortality predictors were identified in ACLF and ACLF3 patients. RESULTS: Out of 853 patients who had LT in that period; 704 patients with CLD and 103 with ACLF [of which 54 (52.42%) had ACLF3] underwent LDLT. The one month and one-year post LDLT mortality was 8.81% and 9.80% in CLD; 19.42% and 31.06% in ACLF; and 25.92% and 38.89% in ACLF3 respectively. On log regression analysis, use of grafts from older donors and pre-operative respiratory failure in recipients was associated with poor survival in ACLF, while respiratory failure was a predictor of poor survival in ACLF3 following LDLT. CONCLUSION: Outcomes following LDLT are poorer in ACLF as compared to after CLD. Higher donor age and preoperative respiratory failure with PF Ratio<200 were associated with poor survival post LDLT in ACLF and ACLF3.

Metabolic imaging in recurrent gliomas: comparative performance of 18F-FDOPA, 18F-fluorocholine and 18F-FDG PET/CT.

PURPOSE: The aim of this study was to directly evaluate glucose, amino-acid and membrane metabolism in tumor cells for diagnosis and prognostication of recurrent gliomas. METHODS: Fifty-five patients (median age = 36 years; 33 men) with histologically proven gliomas and suspected recurrence were prospectively recruited and underwent 18F-FDG (Fluorodeoxyglucose), 18F-FDOPA (fluorodopa) and 18F-Fluorocholine-PET/CT. Images were evaluated by two physicians visually and quantitatively [lesion-SUVmax, tumor (T) to gray-matter (G) and metabolically-active tumor volumes (MTV)]. After median follow-up of 51.5 months, recurrence was diagnosed in 49 patients. Thirty-one patients died with a median survival of 14 months. RESULTS: Diagnostic-accuracies for 18F-FDOPA, 18F-Fluorocholine,18F-FDG and contrast-enhanced-MRI were 92.7% (95% CI 82.7-97.1), 81.8% (69.7-89.8), 45.5% (33.0-58.5) and 44.7% (30.2-60.3), respectively. Among the 20 lesions, missed by MRI; 18F-FDOPA, 18F-Fluorocholine and 18F-FDG were able to detect 19, 14 and 4 lesions. Corresponding area-under-the-curves (T/G ratios) were 0.817 (0.615-1.000), 0.850 (0.736-0.963) and 0.814 (0.658-0.969), when differentiating recurrence from treatment-induced changes. In univariate-survival-analysis, 18F-FDOPA-T/G, visually detectable recurrence in 18F-FDG, 18F-FDOPA-MTV, cell-lineage and treatment-type were significant parameters. In Multivariate-Cox-regression analysis, 18F-FDOPA-MTV [HR = 1.009 (1.001-1.017); P  = 0.024 (~0.9% increase in hazard for every mL increase of MTV)] and cell-lineage [3.578 (1.447-8.846); P  = 0.006] remained significant. 18F-FDOPA-MTV cutoff <29.59 mL predicted survival higher than 2 years. At cutoff ≥29.59 mL, HR at 2 years was 2.759 (1.310-5.810). CONCLUSION: 18F-FDOPA-PET/CT can diagnose recurrence with high accuracy and MTV predicts survival. 18F-Fluorocholine is a good alternative. Higher 18F-FDG uptake is an adverse prognostic indicator.

Delayed diagnosis of bronchobiliary fistula complicating a pediatric living donor liver transplantation: a case report.

Bronchobiliary fistula (BBF) is a very rare condition in children. Only a few pediatric BBF cases have been reported, in the context of a ruptured hydatid cyst or liver abscess. BBF after living donor liver transplantation (LDLT) has not been reported in the pediatric literature. We report a 7-year-old female child with Wilson disease, who developed BBF post-LDLT. She had a clinically uneventful course in the immediate post-transplant period. She was readmitted on postoperative day (POD) 75 with a productive cough and respiratory difficulty, which was diagnosed as bilioptysis secondary to BBF. Endoscopic retrograde cholangiopancreaticography was attempted but failed. Exploratory laparotomy showed a fistula from the strictured biliary anastomotic site to the right thoracic cavity; it was excised, and a Roux-en-Y hepaticojejunostomy was performed. She tolerated the procedure well and remained clinically well on follow-up through POD 185. BBF is extremely rare in children. This is the first case report of BBF in a child following LDLT. BBF requires a high index of suspicion for a timely intervention to prevent subsequent complications.

Domino liver transplantation for maple syrup urine disease in children: A single-center case series.

BACKGROUND: Domino liver transplant (DLT) represents another type of liver donor to expand the donor pool. Recent reports of successful DLT in children with maple syrup urine disease (MSUD) show promising long-term outcomes. METHODS: It was a retrospective study. All children with MSUD were paired with either recipients with end-stage liver disease (ESLD) or non-MSUD metabolic disease. Each pair underwent simultaneous liver transplant (LT), where the MSUD recipient received the graft from a living-related donor and the liver explanted from the MSUD donor was transplanted to the respective paired domino recipient. We report our experience regarding the techniques and outcomes of DLT at our center. RESULTS: Eleven children with MSUD and 12 respective DLT recipients were enrolled, one of which was domino split-liver transplantation. DLT recipients included seven ESLD, two propionic acidemia (PA), one glycogen storage disease(GSD) type-1, one GSD type-3, and one Citrullinemia. Post-LT ICU and hospital stays were comparable (p > .05). Patient and graft survival was 100% and 66.6% in the MSUD group and DLT recipients at a mean follow-up of 13.5 and 15 months. There was no death in the MSUD group as compared to four in the DLT group. The amino acid levels rapidly normalized after the LT in the children with MSUD and they tolerated the normal unrestricted diet. No vascular, biliary, or graft-related complications were seen in the post-transplant period. No occurrence of MSUD was noted in DLT recipients. CONCLUSION: DLTs have excellent post-surgical outcomes. DLT should be strongly considered and adopted by transplant programs worldwide to circumvent organ shortage.

Breast cancer: miRNAs monitoring chemoresistance and systemic therapy.

With a high mortality rate that accounts for millions of cancer-related deaths each year, breast cancer is the second most common malignancy in women. Chemotherapy has significant potential in the prevention and spreading of breast cancer; however, drug resistance often hinders therapy in breast cancer patients. The identification and the use of novel molecular biomarkers, which can predict response to chemotherapy, might lead to tailoring breast cancer treatment. In this context, accumulating research has reported microRNAs (miRNAs) as potential biomarkers for early cancer detection, and are conducive to designing a more specific treatment plan by helping analyze drug resistance and sensitivity in breast cancer treatment. In this review, miRNAs are discussed in two alternative ways-as tumor suppressors to be used in miRNA replacement therapy to reduce oncogenesis and as oncomirs to lessen the translation of the target miRNA. Different miRNAs like miR-638, miR-17, miR-20b, miR-342, miR-484, miR-21, miR-24, miR-27, miR-23 and miR-200 are involved in the regulation of chemoresistance through diverse genetic targets. For instance, tumor-suppressing miRNAs like miR-342, miR-16, miR-214, and miR-128 and tumor-promoting miRNAs like miR101 and miR-106-25 cluster regulate the cell cycle, apoptosis, epithelial to mesenchymal transition and other pathways to impart breast cancer drug resistance. Hence, in this review, we have discussed the significance of miRNA biomarkers that could assist in providing novel therapeutic targets to overcome potential chemotherapy resistance to systemic therapy and further facilitate the design of tailored therapy for enhanced efficacy against breast cancer.