Mixed Neuroendocrine Non-Neuroendocrine Tumor (MINEN) of the Liver: Report of Two Cases and Review of the Literature.

OBJECTIVE: To highlight two cases mixed neuroendocrine non-neuroendocrine tumors (MINEN) of the liver and to review the literature till date. To present two cases of MINEN of the liver diagnosed in our centre with clinical & diagnostic workup, the treatment modalities, and follow up. Extensive review of the literature and compilation of the presentation and treatment modalities used in those cases. CASE REPORTS: Thirty-three cases of MINEN of the liver have been reported till date including ours. Our cases presented as incidental masses in liver during workup for other symptoms. AFP levels were normal in both cases but PIVKA (Protein induced by vitamin K absence) levels were increased. Resection was done in one of the cases while the other patient had to undergo transplantation. A diagnosis of MINEN was made on H&E, and confirmed on IHC. One patient was unfit for systemic chemotherapy whereas the other patient received cisplastin and etoposide based chemotherapy. Both patients developed metastasis on follow up but are still alive after 12-15 months. CONCLUSION: MINEN is an uncommon tumor of the liver with a poor prognosis as shown by the few studies available. Recurrence and distant metastases are often described even after complete resection and the course is fatal. The role of adjuvant chemotherapy following surgical resection is not fully elucidated. Mean survival in the cases reported ranged from 1 month to 33 months. However, no significant differences were seen in the clinicopathologic profile of the cases described so far. Further multiinstitutional studies and follow up will help to further characterize this subtype for appropriate treatment.

Colistin versus polymyxin B: A pragmatic assessment of renal and neurological adverse effects and effectiveness in multidrug-resistant Gram-negative bacterial infections.

OBJECTIVES: Our study aimed to evaluate the real-world data on renal and neurological adverse effects and effectiveness of colistimethate sodium (CMS) and polymyxin B (PMB). MATERIALS AND METHODS: An observational prospective study was performed on inpatients receiving CMS and PMB for multidrug-resistant Gram-negative bacterial infections. CMS dose was titrated to renal function, and serum creatinine was assessed daily. The incidence of nephrotoxicity, the primary outcome, was evaluated based on an increase in serum creatinine from baseline as well as by the Risk, Injury, Failure, Loss of kidney function, and End-stage renal disease criteria. Neurological adverse effects were assessed based on clinical signs and symptoms, and the causality and severity were assessed by the Naranjo scale and modified Hartwig-Siegel scale, respectively. The effectiveness of polymyxin therapy was ascertained by a composite of microbiological eradication of causative bacteria and achievement of clinical cure. Thirty-day all-cause mortality was also determined. RESULTS: Between CMS and PMB, the incidence of nephrotoxicity (59.3% vs. 55.6%, P = 0.653) or neurotoxicity (8.3% vs. 5.6%, P = 0.525) did not significantly differ. However, reversal of nephrotoxicity was significantly more with patients receiving CMS than PMB (48.4% vs. 23.3%, P = 0.021). Favorable clinical outcomes (67.6% vs. 37%, P < 0.001) and microbiological eradication of causative bacteria (73.1% vs. 46.3%, P = 0.001) were significantly more with CMS than PMB. Patients treated with CMS had lower all-cause mortality than those with PMB treatment (19.4% vs. 42.6%, P = 0.002). CONCLUSION: There is no significant difference in the incidence of renal and neurotoxic adverse effects between CMS and PMB when CMS is administered following renal dose modification. CMS shows better effectiveness and lower mortality compared to PMB.

NOTTO Guidelines for Vaccine Induced Thrombotic Thrombocytopenia in Organ Donation and Transplantation.

From the context of organ donation, COVID-19 vaccine-induced thrombotic thrombocytopenia (VITT) is important as there is an ethical dilemma in utilizing versus discarding organs from potential donors succumbing to VITT. This consensus statement is an attempt by the National Organ and Tissue Transplant Organization (NOTTO) apex technical committees India to formulate the guidelines for deceased organ donation and transplantation in relation to VITT to help in appropriate decision making. VITT is a rare entity, but a meticulous approach should be taken by the Organ Procurement Organization's (OPO) team in screening such cases. All such cases must be strictly notified to the national authorities like NOTTO, as a resource for data collection and ensuring compliance withprotocols in the management of adverse events following immunization. Organs from any patient who developed thrombotic events up to 4 weeks after adenoviral vector-based vaccination should be linked to VITT and investigated appropriately. The viability of the organs must be thoroughly checked by the OPO, and the final decision in relation to organ use should be decided by the expert committee of the OPO team consisting of a virologist, a hematologist, and atreating team. Considering the organ shortage, in case of suspected/confirmed VITT, both clinicians and patients should consider the risk-benefit equationbased on available experience, and an appropriate written informed consent of potential recipients and family members should be obtained before transplantation of organs from suspected or proven VITT donors.

Impact of Covid-19 on gastrointestinal cancer surgery: A National Survey.

PURPOSE: To understand the actual impact of the Covid-19 pandemic and frame the future strategies, we conducted a pan India survey to study the impact on the surgical management of gastrointestinal cancers. METHODS: A national multicentre survey in the form of a questionnaire from 16 tertiary care gastrointestinal oncology centres across India was conducted from January 2019 to June 2021 that was divided into a 15-month pre-Covid era and a similar period of active Covid pandemic era. RESULTS: There was significant disruption of services; 13 (81%) centres worked as dedicated Covid care centres and 43% reported suspension of essential care for more than 6 months. In active Covid phase, there was a 14.5% decrease in registrations and proportion of decrease was highest in the centres from South zone (22%). There was decrease in resections across all organ systems; maximum reduction was noted in hepatic resections (33%) followed by oesophageal and gastric resections (31 and 25% respectively). There was minimal decrease in colorectal resections (5%). A total of 584 (7.1%) patients had either active Covid-19 infection or developed infection in the post-operative period or had recovered from Covid-19 infection. Only 3 (18%) centres reported higher morbidity, while the rest of the centres reported similar or lower morbidity rates when compared to pre-Covid phase; however, 6 (37%) centres reported slightly higher mortality in the active Covid phase. CONCLUSION: Covid-19 pandemic resulted in significant reduction in new cancer registrations and elective gastrointestinal cancer surgeries. Perioperative morbidity remained similar despite 7.1% perioperative Covid 19 exposure.

Technique of robotic right donor hepatectomy.

BACKGROUND: Although minimally invasive right donor hepatectomy (RDH) has been reported, this innovation is yet to be widely accepted by transplant community. Bleeding during transection, division of right hepatic duct (RHD), suturing of donor duct as well as retrieval with minimal warm ischemia are the primary concerns of most donor surgeons. We describe our simplified technique of robotic RDH evolved over 144 cases. PATIENTS AND METHODS: Right lobe mobilization is performed in a clockwise manner from right triangular ligament over inferior vena cavae up to hepatocaval ligament. Transection is initiated using a combination of bipolar diathermy and monopolar shears controlled by console surgeon working in tandem with lap CUSA operated by assistant surgeon. With the guidance of indocyanine green cholangiography, RHD is divided with robotic endowrist scissors (Potts), and remnant duct is sutured with 6-0 PDS. Final posterior liver transection is completed caudocranial without hanging manoeuvre. Right lobe with intact vascular pedicle is placed in a bag, vascular structures then divided, and retrieved through Pfannenstiel incision. CONCLUSION: Our technique may be easy to adapt with the available robotic instruments. Further innovation of robotic platform with liver friendly devices could make robotic RDH the standard of care in future.

Update on Coronavirus 2019 Vaccine Guidelines for Transplant Recipients.

The coronavirus disease 2019 (COVID-19) vaccine and its utility in solid organ transplantation need to be timely revised and updated. These guidelines have been formalized by the experts-the apex technical committee members of the National Organ and Tissue Transplant Organization and the heads of transplant societies-for the guidance of transplant communities. We recommend that all personnel involved in organ transplantation should be vaccinated as early as possible and continue COVID-19-appropriate behavior despite a full course of vaccination. For specific guidelines of recipients, we suggest completing the full schedule before transplantation whenever the clinical condition permits. We also suggest a single dose, rather than proceeding unvaccinated for transplant, in case a complete course is not feasible. If vaccination is planned before surgery, we recommend a gap of at least 2 weeks between the last dose of vaccine and surgery. For those not vaccinated before transplant, we suggest waiting 4 to 12 weeks after transplant. For the potential living donors, we recommend the complete vaccination schedule before transplant. However, if this is not feasible, we suggest receiving at least a single dose of the vaccine 2 weeks before donation. We suggest that suitable transplant patients and those on the waiting list should accept a third dose of the vaccine when one is offered to them. We recommend that organs from a deceased donor with suspected/proven vaccine-induced thrombotic thrombocytopenia should be avoided and are justified only in cases of emergency situations with informed consent and counseling.

Liver Transplantation Society of India Guidelines for the Management of Acute Liver Injury Secondary to Yellow Phosphorus-Containing Rodenticide Poisoning Using the Modified Delphi Technique of Consensus Development.

BACKGROUND: Acute liver failure caused by the ingestion of yellow phosphorus-containing rodenticide has been increasing in incidence over the last decade and is a common indication for emergency liver transplantation in Southern and Western India and other countries. Clear guidelines for its management are necessary, given its unpredictable course, potential for rapid deterioration and variation in clinical practice. METHODS: A modified Delphi approach was used for developing consensus guidelines under the aegis of the Liver Transplantation Society of India. A detailed review of the published literature was performed. Recommendations for three areas of clinical practice, assessment and initial management, intensive care unit (ICU) management and liver transplantation, were developed. RESULTS: The expert panel consisted of 16 clinicians, 3 nonclinical specialists and 5 senior advisory members from 11 centres. Thirty-one recommendations with regard to criteria for hospital admission and discharge, role of medical therapies, ICU management, evidence for extracorporeal therapies such as renal replacement therapy and therapeutic plasma exchange, early predictors of need for liver transplantation and perioperative care were developed based on published evidence and combined clinical experience. CONCLUSION: Development of these guidelines should help standardise care for patients with yellow phosphorus poisoning and identify areas for collaborative research.

NOTTO COVID-19 Vaccine Guidelines for Transplant Recipients.

In December 2019, novel coronavirus (SARS-CoV-2) infection started in Wuhan and resulted in a pandemic within a few weeks' time. Organ transplant recipients being at a risk for more severe COVID-19 if they get SARS CoV-2 viral infection, COVID-19 vaccine has a significant role in these patients. The vaccine is a safer way to help build protection and would either prevent COVID-19 infection or at least diminish the severity of the disease. It would also reduce the risk of the continuing transmission and enhance herd immunity. Immuno-compromised patients should not receive live vaccines as they can cause vaccine-related disease and hence the guidelines suggest that all transplant recipients should receive age-appropriate 'inactivated vaccine' as recommended for general population. Though trials have not been undertaken on transplant recipients, efficacy and safety of COVID-19 vaccine have been scientifically documented for few vaccines among the general population.

Endoscopic management of high-grade biliary strictures complicating living donor liver transplantation using soehendra stent retrievers.

BACKGROUND: Biliary strictures following living donor liver transplantation (LDLT) are usually managed by endoscopic retrograde cholangiography (ERC) with stricture dilation and stent placement. While current endoscopic techniques are successful in most cases, high-grade biliary strictures (HGBS) pose a challenge using currently employed techniques which have a low rate of technical success. AIMS: In this study, we have explored the safety and efficacy of Soehendra stent retrievers (SSR) for the dilation of HGBS complicating LDLT. METHODS: This was a prospective cohort study where all patients with anastomotic biliary strictures following LDLT from January 2016 till February 2018 were included. Patients with HGBS defined as the exclusive passage of 0.018-inch guidewire, were included in Group 1. In these patients, 5 Fr Soehendra stent retrievers were used to dilate HGBS over guidewire, using torsional movements. Technical success, safety and clinical response was compared with patients who required Per-cutaneous transhepatic cholangiography (PTC) with rendezvous procedure due to a failed ERC, before the commencement of the study (Group 2). RESULTS: Ten patients with HGBS were included into Group 1. Technical success defined as successful placement of a biliary stent across the stricture was achieved in all the patients in group 1. Favorable response to endotherapy was higher in group 1(8/10 patients (80%)) as compared to group 2(6/14 patients (42.8%)). There were no post procedure complications in patients of group 1, while 3 patients developed cholangitis in group 2. CONCLUSIONS: HGBS can be successfully treated with SSR for stricture dilation. It is safe with no significant complications and requires fewer procedures.

Differentiation of induced pluripotent stem cells to hepatocyte-like cells on cellulose nanofibril substrate.

Differentiation of hepatocyte-like cells (HLCs) from human induced pluripotent stem cells (iPSCs) in vitro has great potential in regenerative medicine. Current protocol uses matrigel of animal origin as a substrate for the differentiation of iPSCs to HLCs. Use of an appropriate non-xenogenic substrate is very important for potential future clinical applications. Towards this goal, we used Cellulose Nanofibril (CNF) gel, a natural, non-toxic, biocompatible and biodegradable polymer in humans as a thin film substrate for the differentiation of iPSCs to HLCs. Here we demonstrated that CNF as a substrate film can efficiently differentiate human iPSCs to HLCs. We investigated the expression profile of the endoderm markers (SOX17 and CXCR4), hepatoblast markers (EpCAM and AFP) and mature hepatocyte marker (ASGPR1) by flow cytometry during the differentiation of iPSCs to HLCs on both CNF and matrigel substrates. We also tested the HLCs generated from both the substrates for the expression of hepatic markers such as A1AT, HNF4A, CYP450 isotypes by Real Time-PCR and its mature hepatocyte functions (lipid accumulation and albumin expression). Our results showed that the differentiated HLCs from both the substrates are comparable and expressed stage specific hepatocyte markers as well as functional maturity. We have demonstrated that CNF, a natural biomaterial, may be used in tissue engineering applications as a potential substrate for the differentiation of iPSCs to HLCs.

Incidence of New-Onset Diabetes and PostTransplant Metabolic Syndrome after Liver Transplantation - A Prospective Study from South India.

BACKGROUND AND AIMS: Liver transplantation has become an effective therapy for patients with end-stage liver disease. The risk of new-onset diabetes after transplantation (NODAT) and posttransplant metabolic syndrome (PTMS) is high among patients after liver transplantation. These are thought to be associated with increased risks of graft rejection, infection, cardiovascular disease, and death. Our study aimed to document the incidence of NODAT and PTMS and analyze pre and posttransplant predictive factors for their development in patients undergoing a liver transplant. METHODS: This was a prospective comparative study on 51 patients who underwent live donor liver transplantation. They were evaluated at baseline, 3 and 6 months after transplantation with fasting glucose, lipids, serum insulin levels, C-peptide, and HbA1C. They were followed up at 5 years to document any cardiovascular events or rejection. RESULTS: The incidence of preoperative diabetes mellitus (DM) in the study group was 25/51 (49%). The incidence of NODAT was 38.5% (10/26 patients) and PTMS 29% (10/35), respectively. Age (47.7 ± 5.4 vs 41.5 ± 12.7 years), HOMA2 - IR (2.3 ± 1.8 vs 2.1 ± 1.6), serum insulin (16.1 ± 12.0 vs 17.9 ± 14.5), and C-peptide (4.6 ± 0.5 vs 4.8 ± 0.7) were similar at baseline in the NODAT group compared to those who did not develop it. Mean tacrolimus levels were higher in PTMS group (6.8 ± 2.9 vs 5.0. ± 2.0 P value = 0.042). By the end of 5 years, 7 patients expired; 6 due to rejection and one due to cardiovascular disease. Moreover, 2 of these patients had preexisting DM and 2 had NODAT. CONCLUSIONS: None of the baseline metabolic factors in patients undergoing liver transplant were predictive of the development of NODAT or PTMS. Mean tacrolimus levels were significantly higher in the PTMS group. A 5-year follow-up showed no excess risk of cardiovascular events or rejection in those with preexisting DM or in those who developed NODAT.

Liver transplantation and COVID-19 (Coronavirus) infection: guidelines of the liver transplant Society of India (LTSI).

The Liver Transplant Society of India (LTSI) has come up with guidelines for transplant centres across the country to deal with liver transplantation during this evolving pandemic of COVID-19 infection. The guidelines are applicable to both deceased donor as well as living donor liver transplants. In view of the rapidly changing situation of COVID-19 infection in India and worldwide, these guidelines will need to be updated according to the emerging data.

Paradigm shift in the management of bile duct strictures complicating living donor liver transplantation.

AIM: Validation of new metrics to identify functionally significant obstruction (FSO), to better define biliary strictures complicating living donor liver transplantation (LDLT). METHODS: All LDLT recipients who presented with cholestasis were studied. Novel metrics for FSO are as follows: (1) magnetic resonance cholangiopancreatography (MRCP) ductal ratio (MDR): The ratio between hepatic duct and recipient duct diameter on the MRCP taken at presentation; (2) endoscopic retrograde cholangiography (ERC) ductal ratio (EDR): The ratio between hepatic duct and recipient duct diameter on the first ERC done for suspected biliary strictures; (3) delayed contrast drainage (DCD): > 50% contrast retained above the anastomotic site, in more than three consecutive fluoroscopic images taken at least 15 min after contrast instillation. Association between these metrics and endotherapy response was analyzed along with patient demographics, intraoperative variables (cold ischemia time, blood transfusions, biliary anastomosis) and perioperative complications (hepatic artery thrombosis [HAT], bile leak). Favorable response to endotherapy was defined as symptomatic relief with ≥ 80% reduction in total bilirubin/alkaline phosphatase. RESULTS: A total of 83 LDLT recipients presented with altered liver function tests. Favorable response was seen in 18/39 patients (46.2%). On univariate analysis, HAT, multiple biliary anastomoses, graft-to-recipient weight ratio (GRWR), MDR, EDR and DCD were significant (p value ≤ 0.05). On multivariate analysis, only MDR ≥ 1.15 was an independent predictor of favorable response to endotherapy (OR 48 [95% CI 7.096-324.71]). CONCLUSION: A paradigm shift in the approach to management of biliary strictures complicating LDLT is proposed whereby a multidimensional definition of FSO can help in reliable patient selection for endotherapy and improve patient outcome as a whole.

Live donor liver transplantation for antitubercular drug-induced acute liver failure.

Antitubercular therapy (ATT)-induced hepatotoxicity is often over looked and active tuberculosis is considered a contraindication for liver transplantation, however it might be the only lifesaving option to certain patients of acute liver failure (ALF) due to ATT. We have assessed the outcome of live donor liver transplantation in ATT-induced ALF. A retrospective analysis of all the cases of ALF that underwent liver transplantation from 2006 to 2014 at the Amrita Institute of Medical Sciences was done. A total of seven (7.7%) patients with ATT-induced ALF who had underwent live donor liver transplantation were included in the study. Out of seven patients, three (42.8%) had established diagnosis of tuberculosis and the remaining (58.2%) patients were started on ATT empirically. The median duration of ATT intake was 2 months. All the patients underwent live donor liver transplant as they met King's College criteria, and their model for end-stage liver disease score was above 35 on admission, receiving graft from first degree relatives. Histopathology of explant liver showed pan acinar necrosis. Restarting of ATT after transplant was individualized. It was restarted only in two (28%) patients with prior sputum-positive pulmonary tuberculosis after a median time of 27 days after transplant. ATT was not restarted in rest of the (72%) patients. Postoperative mortality was seen in two (28%) patients due to conditions that masquerade the ATT-induced acute liver failure. The overall survival rate was 71.4% with a median follow up of 22 months. Live donor-related transplantation is feasible option in ATT-induced acute liver failure. Restarting of ATT post liver transplant is feasible and should be individualized along with frequent monitoring of immunosuppressant levels; however, if the primary diagnosis of tuberculosis was empirical, reintroduction of ATT can be omitted.

Acute liver failure due to zinc phosphide containing rodenticide poisoning: Clinical features and prognostic indicators of need for liver transplantation.

Zinc phosphide (ZnP) containing rodenticide poisoning is a recognized cause of acute liver failure (ALF) in India. When standard conservative measures fail, the sole option is liver transplantation. Records of 41 patients admitted to a single centre with ZnP-induced ALF were reviewed to identify prognostic indicators for requirement of liver transplantation. Patients were analyzed in two groups: group I (n = 22) consisted of patients who either underwent a liver transplant (n = 14) or died without a transplant (n = 8); group II (n = 19) comprised those who survived without liver transplantation. International normalized ratio (INR) in group I was 9 compared to 3 in group II (p < 0.001). Encephalopathy occurred only in group I. Model for End-Stage Liver Disease (MELD) score in group I was 41 compared to 24 in group II (p < 0.001). MELD score of 36 (sensitivity of 86.7 %, specificity of 90 %) or a combination of INR of 6 and encephalopathy (sensitivity of 100 %, specificity of 83 %) were the best indicators of mortality. Such patients should undergo urgent liver transplantation.

Gastrointestinal intramural hematoma--analysis of clinical and radiological features for early differentiation from mesenteric ischemia.

INTRODUCTION: Long-term anticoagulation is associated with hemorrhage at various sites. Gastrointestinal intramural bleeds and hematomas (IMH) often mimic mesenteric ischemia (MI) due to similar clinical settings and imaging features, making early differentiation difficult. AIM: To compare the demography, clinical features and imaging characteristics of patients presenting with IMH with those of MI, so as to help in evolving clinical and imaging guidelines to differentiate both early in the course of the disease. METHODS: All radiologically (contrast-enhanced computed tomogram [CT]) diagnosed cases of gastrointestinal IMH from the hospital database during the period between 2006 and 2012 were retrospectively analyzed. This data was compared with the clinical and imaging features of a group of surgically confirmed MI during the same period. Patients not on anticoagulation therapy at the time of presentation and those with incomplete clinical or radiological data were excluded from the study. RESULTS: There were 16 patients in IMH group and 54 patients in MI group. Clinical features like overt rectal bleeding or melena, and prolonged prothrombin time-international normalized ratio (PT-INR) more than three, and CT features like proximal location in the bowel, increased bowel wall thickness, hyperdensity on plain scan (>40 Hounsfield units (HU)), and short segment bowel involvement were significantly associated with IMH. Visualization of embolus and absent mesenteric vasculature to a segment of intestine in CT was significantly associated with MI. CONCLUSION: Attention to clinical features and early CT scan can aid in early differentiation of IMH from MI, facilitating appropriate intervention early in the course of disease.