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Sunil Girish Iyer, Michele Stanchina, Terrence J Bradley, Justin Watts Department of Medicine, Division of Hematology, University of Miami Miller School of Medicine, Miami, FL, USACorrespondence: Terrence J Bradley, Department of Medicine, Division of Hematology, University of Miami Miller School of Medicine, 90 SW 3rd Street #2210, Miami, FL, 33130, USA, Tel +1 3052439290, Fax +1 305-243-9161, Email TBradley@med.miami.eduAbstract: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy primarily affecting older adults. Historically, the highest rates of response have been achieved with intensive induction chemotherapy; however, a significant portion of older or unfit adults with AML are unable to tolerate intensive therapy or have chemotherapy-resistant disease, creating a large need for active and less intensive treatment strategies. Glasdegib, an oral inhibitor of the transmembrane protein Smoothened (SMO) involved in the Hedgehog (Hh) signaling pathway, was approved in 2018 for older or unfit adults with AML and attained a role in clinical practice after showing an overall survival (OS) advantage when combined with the established agent low-dose cytarabine (LDAC). Since that time, however, several other highly active lower intensity therapies such as venetoclax plus a hypomethylating agent (HMA) have garnered a dominant role in the treatment of this patient population. In this review, we summarize the role of glasdegib in the current treatment landscape of newly diagnosed AML and discuss ongoing investigations into its role in novel combination therapies.Keywords: acute myeloid leukemia, glasdegib, lower intensity induction, Hedgehog signaling pathway

Measurable residual disease (MRD) in adults with acute myeloid leukemia (AML) in complete remission is an important prognostic marker, but detection methodology requires optimization. Persistence of mutated NPM1 or FLT3-ITD in the blood of adult patients with AML in first complete remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT) associates with increased relapse and death after transplant. The prognostic implications of persistence of other common AML-associated mutations, such as IDH1, at this treatment landmark however remain incompletely defined. We performed testing for residual IDH1 variants (IDH1m) in pre-transplant CR1 blood of 148 adult patients undergoing alloHCT for IDH1-mutated AML at a CIBMTR reporting site between 2013 and 2019. No statistically significant post-transplant differences were observed between those testing IDH1m positive (n = 53, 36%) and negative pre-transplant (overall survival (OS): p = 0.4; relapse: p = 0.5). For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD for increased post-transplant relapse risk., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Abstract: Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multicenter analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later. In total, 202 patients were identified; median overall survival (OS) was 0.86 years. We also analyzed patients based on first-line treatment; the 3 most common approaches were intensive chemotherapy (n = 65), DNA methyltransferase inhibitor (DNMTi)-based regimens (n = 65), and DNMTi + venetoclax-based regimens (n = 54). Median OS was not significantly different by treatment type. In addition, we evaluated response by 2017 European LeukemiaNet AML criteria and 2012 MPN-BP criteria in an effort to understand the association of response with survival outcomes. We also analyzed outcomes in 65 patients that received allogeneic hematopoietic stem cell transplant (allo-HSCT); median OS was 2.30 years from time of allo-HSCT. Our study demonstrates that survival among patients with MPN-AP/BP is limited in the absence of allo-HSCT even in the current era of therapeutics and underscores the urgent need for new agents and approaches., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Use of tumor-suppressive microRNAs (miRNAs) as anti-cancer agents is hindered by the lack of effective delivery vehicles, entrapment of the miRNA within endocytic compartments, and rapid degradation of miRNA by nucleases. To address these issues, we developed a miRNA delivery strategy that includes (1) a targeting ligand, (2) an endosomal escape agent, nigericin and (3) a chemically modified miRNA. The delivery ligand, DUPA (2-[3-(1,3-dicarboxy propyl) ureido] pentanedioic acid), was selected based on its specificity for prostate-specific membrane antigen (PSMA), a receptor routinely upregulated in prostate cancer-one of the leading causes of cancer death among men. DUPA was conjugated to the tumor suppressive miRNA, miR-34a (DUPA-miR-34a) based on the ability of miR-34a to inhibit prostate cancer cell proliferation. To mediate endosomal escape, nigericin was incorporated into the complex, resulting in DUPA-nigericin-miR-34a. Both DUPA-miR-34a and DUPA-nigericin-miR-34a specifically bound to, and were taken up by, PSMA-expressing cells  in vitro and in vivo . And while both DUPA-miR-34a and DUPA-nigericin-miR-34a downregulated miR-34a target genes, only DUPA-nigericin-miR-34a decreased cell proliferation in vitro and delayed tumor growth in vivo. Tumor growth was further reduced using a fully modified version of miR-34a that has significantly increased stability., Competing Interests: A.L.K. and P.S.L. are inventors on U.S. patent US20190298843A1 submitted by Purdue University that covers methods and uses of ligand-targeted delivery of miRNAs. A.L.K., A.M.A., and I.S.S. are inventors on U.S. provisional patent 63/454,177 submitted by Purdue University that covers methods and uses of modified miR-34a. A.L.K. is a co-founder of LigamiR Therapeutics, Incorporated, which develops ligand-conjugated microRNAs for therapeutic purpose., (© 2024 The Author(s).)

The field of oligonucleotide therapeutics is rapidly advancing, particularly for combating orphan diseases and cancer. However, the intrinsic instability of oligonucleotides, especially RNA, poses a substantial challenge in the face of the harsh conditions encountered intracellularly and in circulation. Therefore, evaluating the stability of oligos in serum is of great significance when developing oligonucleotide therapeutics. This protocol outlines a dependable and reproducible method for preparing oligonucleotide duplexes, coupled with confirmation by gel electrophoresis. Subsequently, the protocol defines a mechanism to assess the stability of the oligo duplexes in serum. This protocol seeks to establish a standardized reference for researchers, enabling them to compare the impact of various modifications on oligo stability and assess the degradation kinetics effectively. Key features • Adaptable for use with small interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotides (ASOs), and other unmodified and modified oligonucleotides. • Does not necessitate any Biological Safety Level clearance and offers a rapid, cost-effective, and entirely in vitro procedure. • Allows researchers to evaluate multiple modification patterns that, when coupled with targeting activity, allow for selecting the best modification pattern prior to in vivo analysis., Competing Interests: Competing interestsA.L.K. is an inventor on U.S. patent PCT/US2017/061997 submitted by Purdue University that covers methods and uses of ligand-targeted delivery of miRNAs. A.L.K. is an inventor on U.S. provisional patent 63/454,177 submitted by Purdue University that covers methods and uses of modified miR-34a. S.G.I. has no competing interests. A.L.K. is a co-founder and CEO of LigamiR Therapeutics that works on ligand-mediated delivery systems for delivery of microRNAs., (©Copyright : © 2024 The Authors; This is an open access article under the CC BY-NC license.)

Background: Endoscopic retrograde cholangiopancreatography is a common procedure performed for choledocholithiasis and gallstone pancreatitis. Although a relatively low risk procedure, it is not without its complications. Cases of impacted Dormia baskets during stone retrieval have been reported, but these are usually retrieved surgically during the same setting., Case Summary: A 40-year-old man presented to our hospital with an episode of epigastric pain and discomfort. He has a prior background of recurrent episodes of pancreatitis of which he underwent prior endoscopic therapy in his home country. Initial investigations revealed a metallic object seen on abdominal x-ray, computer tomographic scan of the abdomen and pelvis, and magnetic resonance imaging of the pancreas. Further evaluation was done with endoscopy, which revealed a retained stone extraction basket from a previous endoscopic retrograde pancreatography, resulting in recurrent episodes of acute chronic pancreatitis. Although the retained foreign body was removed, he subsequently developed further complications of portal vein thrombosis as a result of recurrent acute chronic pancreatitis, which required anticoagulation., Conclusion: This case highlights the importance of retrieving any foreign body from the pancreas, especially on the head, to prevent the development of further complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Lee, Tan, Koh, Iyer and Gao.)

T cells recognize tumor-derived mutated peptides presented on MHC by tumors. The recognition of these neo-epitopes leads to rejection of tumors, an event that is critical for successful cancer immunosurveillance. Determination of tumor-rejecting neo-epitopes in human tumors has proved difficult, though recently developed systems approaches are becoming increasingly useful at evaluating their immunogenicity. We have used the differential aggretope index to determine the neo-epitope burden of sarcomas and observed a conspicuously titrated antigenic landscape, ranging from the highly antigenic osteosarcomas to the low antigenic leiomyosarcomas and liposarcomas. We showed that the antigenic landscape of the tumors inversely reflected the historical T cell responses in the tumor-bearing patients. We predicted that highly antigenic tumors with poor antitumor T cell responses, such as osteosarcomas, would be responsive to T cell-based immunotherapy regimens and demonstrated this in a murine osteosarcoma model. Our study presents a potentially novel pipeline for determining antigenicity of human tumors, provides an accurate predictor of potential neo-epitopes, and will be an important indicator of which cancers to target with T cell-enhancing immunotherapy.

Background: Delayed subdural fluid collections can occur after Ommaya reservoir placement and can cause neurological symptoms and interfere with treatment. We performed a retrospective chart review to study risk factors for delayed subdural fluid collections and clinical outcomes., Methods: Retrospective chart review was performed for patients undergoing Ommaya reservoir placement between 2010-2019 at our institution., Results: Out of 53 patients who had Ommaya reservoir placement during the study period, 11 developed delayed subdural fluid collections (21%). HIV infection was the only statistically significant risk factor (P=0.001, Fisher's Exact Test). Thrombocytopenia, ventricle size, use of the reservoir, and suboptimal catheter placement were not associated with development of delayed subdural fluid collections. 2 patients, both HIV positive, required surgical evacuation., Conclusions: Delayed subdural fluid collections occur in a significant minority of patients after Ommaya reservoir placement, and some patients require surgical intervention. HIV infection is associated with a higher risk of development of delayed subdural fluid collections. This patient subpopulation may benefit from closer monitoring or adjustment of management protocols.

Laparoscopic donor right hepatectomy (LDRH) is a technically challenging procedure. There is increasing evidence demonstrating the safety of LDRH in high-volume expert centers. We report our center's experience in implementing an LDRH program in a small- to medium-sized transplantation program., Methods: Our center systematically introduced a laparoscopic hepatectomy program in 2006. We started with minor wedge resections followed by major hepatectomies with increasing complexities. In 2017, we performed our first laparoscopic living donor left lateral sectionectomy. Since 2018, we have performed 8 cases of right lobe living donor hepatectomy (laparoscopy-assisted: 4 and pure laparoscopic: 4)., Results: The median operative time was 418 (298-540) min, whereas the median blood loss was 300 (150-900) mL. Two patients (25%) had surgical drain placed intraoperatively. The median length of stay was 5 (3-8) d, and the median time to return to work was 55 (24-90) d. None of the donors sustained any long-term morbidity or mortality., Conclusions: Small- to medium-sized transplant programs face unique challenges in adopting LDRH. Progressive introduction of complex laparoscopic surgery, a mature living donor liver transplantation program, appropriate patient selection, and the invitation of an expert to proctor the LDRH are necessary to ensure success., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

The transformation of acute promyelocytic leukemia (APL) from an often fatal to highly curable cancer with long-term survival exceeding 90% is one of the greatest and most inspiring successes in oncology. A deeper understanding of the pathogenesis of APL heralded the introduction of highly effective therapies targeting the mutant protein that drives the disease, leading to the chemotherapy-free approach to cure almost all patients. In this review, we discuss the paradigm of treatment of APL in 2023, reinforce the high risk of early death without prompt initiation of treatment at first clinical suspicion, and dedicate a special focus to novel agents and future directions to improve cure rates and quality of life in patients affected by APL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Iyer, Elias, Stanchina and Watts.)

Comprehensive information on clinical features and long-term outcomes of primary conjunctival extranodal marginal zone lymphoma (PCEMZL) is scarce. We present a large single-institution retrospective study of 72 patients. The median age was 64 years, and 63.9% were female. Stage I was present in 87.5%. Radiation therapy (RT) alone was the most common treatment (70.8%). Complete response (CR) was 87.5%, and 100% in RT-treated patients. With a median follow-up of 6.7 years, relapse/progression and death occurred in 19.4% each, with one relapse within the RT field. The 10-year progression-free survival (PFS) and overall survival (OS) were 68.4% (95% CI 52.8%-79.8%) and 89.4% (95% CI 77.4%-95.2%), respectively. The 10-year rate for time to progression from diagnosis was 22.5% (95% CI 11.6%-35.7%). The 10-year PFS and OS of MALT-IPI 0 versus 1-2 were 83.3% versus 51.3%, (p = .022) and 97.6% versus 76.6%, (p = .0052), respectively. The following characteristics were associated with shorter survival: age > 60 years (PFS: HR = 2.93, 95% CI 1.08-7.95; p = .035, OS: HR = 9.07, 95% CI 1.17-70.26; p = .035) and MALT-IPI 1-2 (PFS: HR = 2.67, 95% CI 1.12-6.31; p = .027, OS: HR = 6.64, 95% CI 1.45-30.37; p = .015). CR following frontline therapy was associated with longer PFS (HR = 0.13, 95% CI 0.04-0.45; p = .001), but not OS. Using the Fine and Gray regression model with death without relapse/progression as a competing risk, RT and CR after frontline therapy were associated with lower risk of relapse (SHR = 0.34, 95% CI 0.12-0.96 p = .041 and SHR = 0.11, 95% CI 0.03-0.36; p < .001, respectively). Patients with PCEMZL treated with frontline RT exhibit excellent long-term survival, and the MALT-IPI score appropriately identifies patients at risk for treatment failure., (© 2022 Wiley Periodicals LLC.)

Pheochromocytomas (PCC) are rare and functional neuroendocrine tumors developing from adrenal chromaffin cells. Predicting malignant behavior especially in the absence of metastasis can be quite challenging even in the era of improved understanding of the molecular mechanisms involved in PCCs. Currently, two histopathological grading systems Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) score are used in clinical practice, but these are subject to significant interobserver variability. Some of the most useful clinical factors associated with malignancy are large size ([4-5 cm), and genetic features such as presence of SDHB germline mutations. Local invasion is uncommon in PCC and metastasis seen in 10 to 17% but higher in germline mutations and when this occurs management can be challenging. Here, we report on a case with challenges faced by the pathologist and clinicians alike in diagnosis and management of PCC recurrence., (© 2022. The Author(s).)

(1) Background: the SARS-CoV-2 (COVID-19) pandemic continues, and patients actively receiving chemotherapy are known to be at enhanced risk for developing symptomatic disease with poorer outcomes. Our study evaluated the prevalence of COVID-19 among patients and providers of our community-facing county health system during the B1.1.529 ("Omicron") COVID-19 variant wave. (2) Methods: We retrospectively analyzed patients that received care and clinical providers whom worked at the Jackson Memorial Hospital Hematology/Oncology clinic in Miami, Florida, USA, from 1 December 2021 through 30 April 2022. We assessed demographic variables and quality outcomes among patients. (3) Results: 1031 patients and 18 providers were retrospectively analyzed. 90 patients tested positive for COVID-19 (8.73%), while 6 providers tested positive (33.3%) ( p = 0.038). There were 4 (10.3%) COVID-19-related deaths (and another outside our study timeframe) and 39 non-COVID-19-related deaths (89.7%) in the patient population ( p = 0.77). COVID-19 accounted for 4.44% of our clinic's total mortality, and delayed care in 64.4% of patients. (4) Conclusions: The prevalence of COVID-19 positivity in our patient cohort mirrored local, state, and national trends, however a statistically significant greater proportion of our providers tested positive. Almost two-thirds of patients experienced a cancer treatment delay, significantly impacting oncologic care.

Background: Evidence for use of graft from older donors in living donor liver transplantation (LDLT) has been conflicting. This study aims to clarify the impact of donor age on recipient morbidity and mortality after adult LDLT., Methods: A total of 90 live liver donors and recipients who underwent primary adult-to-adult LDLT were divided into three groups according to donor age: donors in 20s (D-20s) group, donors in 30s and 40s (D-30s and 40s) group and donors in 50s & 60s (D-50s and 60s) group. Multivariate analyses were conducted to look for independent risk/prognostic factors. Donor age was analysed as a continuous variable to determine an optimal cut off., Results: Overall donor morbidity was 4/90 (4.44%), major donor morbidity was 1/90 (1.11%) and there was no donor mortality. Recipients in the D-20s group had better 1-, 3- and 5-year recipient survival than recipients in the D-50s and 60s group (96%, 91%, 91% versus 73%, 58%, 58%, respectively) (P = 0.020). Donor age was identified to be an independently significant risk factor for increased major complications (P = 0.007) and prognostic factor for reduced overall survival (P = 0.014). The optimal donor age cut off was determined to be 46.5 years old., Conclusion: Older donors are associated with poorer recipient outcomes after adult-to-adult LDLT. Usage of liver grafts from older donors should be carefully considered when choosing liver grafts for patients undergoing LDLT., (© 2022 Royal Australasian College of Surgeons.)

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3' UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3' UTR splicing and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). 3' UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3' UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3' UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3' UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3' UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics., (© 2022. The Author(s).)

Colon extranodal marginal zone lymphoma (EMZL) is poorly characterized in the literature. We performed a retrospective review of patients with colon EMZL at our institution and from the Surveillance Epidemiology and End Results (SEER) database. Eight patients were identified in our institution with majority (88%) presenting with stage-I disease. Initial management included active surveillance, polypectomy followed by surveillance, and surgical resection followed by chemotherapy. One patient with concurrent prostate carcinoma received radiation to the rectum. Initial therapy led to complete remission in five out of six treated patients with four of them maintaining remission at 88 months. SEER database identified 361 patients with stage-I colon EMZL. Overall survival for this cohort was 73.9% at 10 years with no significant difference in outcomes between treatment groups. Our single institution experience and the SEER data analysis emphasize indolent nature of colon EMZL and need for non-aggressive therapeutic approaches.

Background: Given the complexity of living donor hepatectomy, it is expected that high hospital volume will better outcomes. This study aims to evaluate post-operative outcomes for living donor hepatectomy in a medium volume liver transplant centre and compare to outcomes in high volume centres. Also, it serves as a validation tool for framework of structure-process-outcome model for safe living donor hepatectomy program., Methods: 204 donors who underwent donor hepatectomy between June 1996 to September 2019 were reviewed retrospectively and compared to outcomes in high volume centres., Results: At 6 months, overall donor morbidity rate was 20/204 (9.8%). Wound complications were most common at 5/204 (2.5%). Majority of complications were either Clavien grade 1 or 2 and only 3 donors had Clavien grade 3 complications. There was zero donor mortality., Discussion: Our centre's donor morbidity rate of 9.8% is the one of the lowest reported in the published literature. With increased experience, stringent donor selection and enhanced perioperative care by a multi-disciplinary team, outcomes in a medium volume centre can match the outcomes reported in high volume centres. The framework for quality in terms of structure, process and outcomes is presented which can be adopted for developing programs., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Breast extranodal marginal zone lymphoma (EMZL) is a rare malignancy. We performed the largest published to date single-center retrospective analysis of 13 patients with breast EMZL focusing on clinical characteristics and treatment-related outcomes. The rarity of this disease at our center was concordant with the prevalence reported in the literature, with breast EMZL comprising 2% of 654 MZL cases. Most patients presented with stage I-II disease however four (30.8%) patients had stage IV disease mostly due to occult bone marrow (BM) involvement. Interestingly, EMZL was frequently non-FDG avid (66.7%) on staging PET/CT. With a median follow-up of 3.1 years (range 5 months to 10.2 years), the 3-year progression free survival was 68.7% (95%CI 30.2%-88.9%) and overall survival 80.2% (95%CI 40.3%-94.8%). No patient experienced higher-grade transformation. Herein we show that localized breast EMZL can be effectively treated with radiation therapy providing long term disease control.

Purpose of the Systematic Review: To determine the efficacy and safety of percutaneous trans-hepatic balloon and/or stent angioplasty (PTA) in the management of portal vein (PV) stenosis following paediatric liver transplantation., Methods: Articles were included from a systematic search of Medline, Embase, Cochrane CENTRAL, ClinicalTrials.gov and International Clinical Trials Registry from inception to the 29th of August 2020., Results: There were 213 paediatric liver recipients who underwent PTA for PV stenosis in 19 included studies published between 1991 and 2019. Balloon angioplasty was the initial treatment in the majority (n = 153). Primary stent placement (n = 34) was performed for elastic recoil, intimal tears and PV kinks and rescue stent placement (n = 14) for recurrent PV stenosis following primary balloon angioplasty. The technical success was 97.6%-100% overall, 97.6%-100% for balloon-angioplasty-only and 100% for primary stenting. The clinical success was 50%-100% overall, 50%-100% for balloon-angioplasty-only and 100% for primary stenting. Long-term PV patency was 50%-100% overall, 37.5%-100% for balloon-angioplasty-only and 100% for primary stenting. Primary balloon angioplasty was successful in 78% of the cases. Of the recurrent PV stenoses, 9% resolved with stent placement and one required a meso-Rex shunt. There was one re-transplantation without stenting. The complication rate was 2.6% for balloon-angioplasty-only (bleeding, liver abscess, 2 PV thromboses) and 5.9% for primary stenting (bleeding, stent-fracture). There was no procedure-related mortality., Conclusion: Percutaneous transhepatic balloon angioplasty may be the initial management of portal vein stenosis in paediatric liver recipients. Stent placement may be a primary option in selected cases and a reliable rescue option for recurrent portal vein stenosis following balloon-angioplasty-only., (© 2021 Wiley Periodicals LLC.)

Background: The volume-outcome relation for complex surgical procedures such as living donor liver transplantation (LDLT) generally favors high volume (HV) centers. It is important for low to medium volume (MV) centers to evaluate their centers' performance against HV centers to allow early detection and correction of potential systemic issues. There is a dearth of national and international comprehensive registries for LDLT that may allow reasonable risk-adjusted comparisons for benchmarking. This study aims to evaluate the LDLT program by comparing our center's performance against HV centers of the Adult-to-Adult Living Donor Liver Transplantation cohort., Study Design: Patient outcomes from a MV transplant center were compared with 11 HV transplant centers from the Adult-to-Adult Living Donor Liver Transplantation cohort. Outcomes evaluated included length of hospital stay, same admission mortality, 90-day mortality, and overall survival., Results: A total of 1381 patients were analzyed. HV 1 to 4, 6, 8, 9, and 11 centers had a shorter median length of hospital stay compared with the MV center (All Dunnett corrected P values all less than .05). HV 9 and 11 centers had lower same admission mortality compared with the MV center (Dunnett corrected P = .023 and .015). After adjusting for other significant predictors, the MV center had comparable 90-day mortality rates and overall survival rates to all HV centers., Conclusion: This benchmarking exercise has demonstrated that the limitation of low institutional case volume can be overcome with a protocol-based framework to implement a safe LDLT program. This framework presented can be adopted for developing programs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Prehabilitation may benefit older patients undergoing major surgeries. Currently, its efficacy has not been conclusively proven. This is a retrospective review of a multimodal prehabilitation programme., Methods: Patients aged 65 years and above undergoing major abdominal surgery between May 2015 and December 2019 in the National University Hospital were included in our institutional programme that incorporated aspects of multimodal prehabilitation and Enhanced Recovery After Surgery concepts as 1 holistic perioperative pathway to deal with issues specific to older patients. Physical therapy, nutritional advice and psychosocial support were provided as part of prehabilitation., Results: There were 335 patients in the prehabilitation cohort and 256 patients whose records were reviewed as control. No difference in postoperative length of stay ( P =0.150) or major complications ( P =0.690) were noted. Patients in the prehabilitation group were observed to ambulate a longer distance and participate more actively with their physiotherapists from postoperative day 1 until 4. In the subgroup of patients with cancer, more patients had undergone neoadjuvant therapy in the prehabilitation group compared to the control group (21.7% versus 12.6%, P =0.009). Prehabilitation patients were more likely to proceed to adjuvant chemotherapy (prehabilitation 87.2% vs control 65.6%, P <0.001) if it had been recommended., Conclusion: The current study found no differences in traditional surgical outcome measures with and without prehabilitation. An increase in patient mobility in the immediate postoperative period was noted with prehabilitation, as well as an association between prehabilitation and increased adherence to postoperative adjuvant therapy. Larger prospective studies will be needed to validate the findings of this retrospective review.

Background: Liver transplantation (LT) activities during the COVID-19 pandemic have been curtailed in many countries. The impact of various policies restricting LT on outcomes of potential LT candidates is unclear., Methods: We studied all patients on the nationwide LT waitlists in Hong Kong and Singapore between January 2016 and May 2020. We used continuous time Markov chains to model the effects of different scenarios and varying durations of disruption on LT candidates., Findings: With complete cessation of LT, the projected 1-year overall survival (OS) decreased by 3•6%, 10•51% and 19•21% for a 1-, 3- and 6-month disruption respectively versus no limitation to LT, while 2-year OS decreased by 4•1%, 12•55%, and 23•43% respectively. When only urgent (acute-on-chronic liver failure [ACLF] or acute liver failure) LT was allowed, the projected 1-year OS decreased by a similar proportion: 3•1%, 8•41% and 15•20% respectively. When deceased donor LT (DDLT) and urgent living donor LT (LDLT) were allowed, 1-year projected OS decreased by 1•2%, 5•1% and 8•85% for a 1-, 3- and 6-month disruption respectively. OS was similar when only DDLT was allowed. Complete cessation of LT activities for 3-months resulted in an increased projected incidence of ACLF and hepatocellular carcinoma (HCC) dropout at 1-year by 49•1% and 107•96% respectively. When only urgent LT was allowed, HCC dropout and ACLF incidence were comparable to the rates seen in the scenario of complete LT cessation., Interpretation: A short and wide-ranging disruption to LT results in better outcomes compared with a longer duration of partial restrictions., Funding: None to disclose., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by Elsevier Ltd.)

Colorectal cancer is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Despite advances in improving resectability, most patients present with non-resectable colorectal liver metastases requiring palliative systemic therapy and locoregional disease control strategies. There is a growing interest in the use of liver transplantation to treat non-resectable colorectal liver metastases in well selected patients, leading to a surge in the number of studies and prospective trials worldwide, thereby fuelling the emerging field of transplant oncology. The interdisciplinary nature of this field requires domain-specific evidence and expertise to be drawn from multiple clinical specialities and the basic sciences. Importantly, the wider societal implication of liver transplantation for non-resectable colorectal liver metastases, such as the effect on the allocation of resources and national transplant waitlists, should be considered. To address the urgent need for a consensus approach, the International Hepato-Pancreato-Biliary Association commissioned the Liver Transplantation for Colorectal liver Metastases 2021 working group, consisting of international leaders in the areas of hepatobiliary surgery, colorectal oncology, liver transplantation, hepatology, and bioethics. The aim of this study was to standardise nomenclature and define management principles in five key domains: patient selection, evaluation of biological behaviour, graft selection, recipient considerations, and outcomes. An extensive literature review was done within the five domains identified. Between November, 2020, and January, 2021, a three-step modified Delphi consensus process was undertaken by the workgroup, who were further subgrouped into the Scientific Committee, Expert Panel, and Transplant Centre Representatives. A final consensus of 44 statements, standardised nomenclature, and a practical management algorithm is presented. Specific criteria for clinico-patho-radiological assessments with molecular profiling is crucial in this setting. After this, the careful evaluation of biological behaviour with bridging therapy to transplantation with an appropriate assessment of the response is required. The sequencing of treatment in synchronous metastatic disease requires special consideration and is highlighted here. Some ethical dilemmas within organ allocation for malignant indications are discussed and the role for extended criteria grafts, living donor transplantation, and machine perfusion technologies for non-resectable colorectal liver metastases are reviewed. Appropriate immunosuppressive regimens and strategies for the follow-up and treatment of recurrent disease are proposed. This consensus guideline provides a framework by which liver transplantation for non-resectable colorectal liver metastases might be safely instituted and is a meaningful step towards future evidenced-based practice for better patient selection and organ allocation to improve the survival for patients with this disease., Competing Interests: Declaration of interests PT receives honoraria from Astellas Pharma Europe, outside the current study. GS receives research grants from Bayer and Roche, and consulting fees from Astrazeneca, Novartis, and Roche, outside the current study. RA receives honoraria for symposia from Merck Serono and Sanofi, outside the current study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Organ shortage is still a world-wide problem, resulting in long waiting lists for kidney, liver, and heart transplant candidates across many transplant centers globally. This has resulted in the move toward presumed consent to increase deceased organ donation rates. However, there remains a paucity of literature on public attitude and barriers regarding the opt-out system, with existing studies limited to Western nations. Therefore, this study aimed to understand public sentiment and different barriers toward organ donation from the perspective of Singapore, a highly diverse and multiethnic Asian society. Methods: A cross-sectional community semi-structured interview was conducted in a public housing estate in Singapore. Pilot test was undertaken before participants were interviewed face-to-face by trained personnel. All statistical evaluations were conducted using Stata. The χ 2 -test compared subgroups based on patient characteristics while multivariable logistic regression identified predictors of willingness to donate/ assent. Effect estimates were quantified using odds ratio (OR). Findings: Out of 799 individuals, 85% were agreeable to organ donation after death and 81% were willing to assent to donations of family members' organs, which declined by 16% ( p < 0.001) after a clinical scenario was presented. Demographic factors including ethnicity, education, marital, and employment status affected willingness to donate and assent. Knowledge correlated significantly with willingness to donate and assent. In particular, knowledge regarding brain death irreversibility had the strongest correlation (AOR 2.15; 95% CI 1.60-2.89). Conclusions: Organ donation rates remain low albeit presumed consent legislation, due to patient-level barriers, including but not limited to knowledge gaps, cultural values, religious backgrounds, and emotional impact at relatives' death. To effectively boost donor rates, it is crucial for policy makers to invest in public education and improve transplant provisions and family protocols., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Muthiah, Chua, Griva, Low, Lim, Ng, Hwang, Yap, Iyer, Bonney, Anantharaman, Huang, Tan, Lee, Kow and Tai.)

The gut microbiome is a complex microbial community, recognized for its potential role in physiology, health, and disease. The available evidence supports the role of gut dysbiosis in pancreatic disorders, including acute pancreatitis (AP). In AP, the presence of gut barrier damage resulting in increased mucosal permeability may lead to translocation of intestinal bacteria, necrosis of pancreatic and peripancreatic tissue, and infection, often accompanied by multiple organ dysfunction syndrome. Preserving gut microbial homeostasis may reduce the systemic effects of AP. A growing body of evidence suggests the possible involvement of the gut microbiome in various pancreatic diseases, including AP. This review discusses the possible role of the gut microbiome in AP. It highlights AP treatment and supplementation with prebiotics, synbiotics, and probiotics to maintain gastrointestinal microbial balance and effectively reduce hospitalization, morbidity and mortality in an early phase. It also addresses novel therapeutic areas in the gut microbiome, personalized treatment, and provides a roadmap of human microbial contributions to AP that have potential clinical benefit., Competing Interests: Conflict-of-interest statement: The authors declare having no conflicts of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

We present long-term combined results of two clinical trials implementing R-MACLO-IVAM induction followed by thalidomide or rituximab maintenance in 44 patients with untreated mantle cell lymphoma (MCL). The first 22 patients (UM-MCL1 ClinicalTrials.gov identifier NCT00450801) received maintenance with thalidomide (200 mg daily until relapse/intolerable toxicity) and a subsequent cohort of 22 patients (UM-MCL2 ClinicalTrials.gov identifier NCT00878254) received rituximab (375 mg/m 2 IV weekly × 4, repeated every 6 months for 3 years). Considering all 44 patients, 41 (93.2%) achieved complete response (CR), two (4.5%) partial response (PR), and one (2.3%) was not evaluated for response. With a median follow up of 7.2 years (range < 1 month to 16 years), the 5-year progression-free survival (PFS) was 55.6% (95% CI: 38.9%-69.4%) and median PFS 7.9 years (95% CI: 3.7-11 years). The 5-year OS was 83.3% (95% CI: 68.1%-91.7%) and median OS was not reached. Patients with blastic variant (n = 6) had a 5-year PFS and OS of 20.8% and 60%, respectively. Myelosuppression was the most common adverse event during immunochemotherapy. Long-term treatment-related mortality was 6.8%. Note, R-MACLO-IVAM followed by maintenance therapy is an effective regimen to induce long-term remission in MCL without need for consolidation with ASCT., (© 2021 Wiley Periodicals LLC.)

Objective: This study was conducted to better understand the pervasive gender barriers obstructing the progression of women in surgery by synthesising the perspectives of both female surgical trainees and surgeons., Methods: Five electronic databases, including Medline, Embase, PsycINFO, CINAHL and Web of Science Core Collection, were searched for relevant articles. Following a full-text review by three authors, qualitative data was synthesized thematically according to the Thomas and Harden methodology and quality assessment was conducted by two authors reaching a consensus., Results: Fourteen articles were included, with unfavorable work environments, male-dominated culture and societal pressures being major themes. Females in surgery lacked support, faced harassment, and had unequal opportunities, which were often exacerbated by sex-blindness by their male counterparts. Mothers were especially affected, struggling to achieve a work-life balance while facing strong criticism. However, with increasing recognition of the unique professional traits of female surgeons, there is progress towards gender quality which requires continued and sustained efforts., Conclusion: This systematic review sheds light on the numerous gender barriers that continue to stand in the way of female surgeons despite progress towards gender equality over the years. As the global agenda towards equality progresses, this review serves as a call-to-action to increase collective effort towards gender inclusivity which will significantly improve future health outcomes., Competing Interests: The authors have declared that no competing interests exist.

Aims: To assess the efficacy and safety of autologous mid-urethral sling (MUS) in women with predominant stress urinary incontinence (SUI)., Materials and Methods: This prospective cohort study included adult women with predominant SUI seen in our urology clinic between January 2018 and March 2019. Patients with: negative cough stress test, history of prior incontinence surgery, urogenital malignancy, pelvic radiation, neurological disease, body mass index more than 40 kg/m 2 , the presence of more than Stage I pelvic organ prolapse, active urinary tract infection, maximum flow rate less than 15 ml/sec, postvoid residual urine more than 100 ml, abdominal leak point pressure less than 60 cm of H 2 O, and pregnant women were excluded. Eligible patients underwent a transobturator MUS procedure using rectus fascia as a sling. Before the procedure, patients filled the International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract Symptom (ICIQ-FLUTS) and the Female Sexual Function Index (FSFI) questionnaire. Urinary outcomes were assessed at 3- and 12-months while sexual outcomes were assessed at 12-months., Results: Thirty patients with median age of 44.5 years were included. All patients had a negative cough stress test during follow up. A significant improvement was noted in the ICIQ-FLUTS scale, bother scale, filling and incontinence subscales at 3 and 12 month follow-up. A significant improvement was also noted in the FSFI full scale score and FSFI domains of mean sexual desire, arousal and lubrication at 12 months follow-up. Two patients developed voiding dysfunction requiring urethral dilatation., Conclusion: Autologous transobturator MUS surgery appears to be safe and efficacious in the short term. More research is needed to clarify its role in the surgical management of SUI in women., (© 2020 Wiley Periodicals LLC.)

Phenomenon: Research literacy remains important for equipping clinicians with the analytical skills to tackle an ever-evolving medical landscape and maintain an evidence-based approach when treating patients. While the role of research in medical education has been justified and established, the nuances involving modes of instruction and relevant outcomes for students have yet to be analyzed. Institutions acknowledge an increasing need to dedicate time and resources towards educating medical undergraduates on research but have individually implemented different pedagogies over differing lengths of time., Approach: While individual studies have evaluated the efficacy of these curricula, the evaluations of educational methods and curriculum design have not been reviewed systematically. This study thereby aims to perform a systematic review of studies incorporating research into the undergraduate medical curriculum, to provide insights on various pedagogies utilized to educate medical students on research., Findings: Studies predominantly described two major components of research curricula-(1) imparting basic research skills and the (2) longitudinal application of research skills. Studies were assessed according to the 4-level Kirkpatrick model for evaluation. Programs that spanned minimally an academic year had the greatest proportion of level 3 outcomes (50%). One study observed a level 4 outcome by assessing the post-intervention effects on participants. Studies primarily highlighted a shortage of time (53%), resulting in inadequate coverage of content., Insights: This study highlighted the value in long-term programs that support students in acquiring research skills, by providing appropriate mentors, resources, and guidance to facilitate their learning. The Dreyfus model of skill acquisition underscored the importance of tailoring educational interventions to allow students with varying experience to develop their skills. There is still room for further investigation of multiple factors such as duration of intervention, student voluntariness, and participants' prior research experience. Nevertheless, it stands that mentoring is a crucial aspect of curricula that has allowed studies to achieve level 3 Kirkpatrick outcomes and engender enduring changes in students., Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-020-01183-w., Competing Interests: Conflict of InterestThe authors declare that they have no competing interests., (© International Association of Medical Science Educators 2021.)

Background & Aims: The outbreak of COVID-19 has vastly increased the operational burden on healthcare systems worldwide. For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources., Methods: We performed an international multicenter study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the quadripartite equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources., Results: Seventeen large- and medium-sized liver transplant centers from 12 countries across 4 continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a "sickest-first" approach. Conversely, some larger centers opted to continue routine transplant activity in order to balance waiting list mortality. To model these and other ethical tensions, we computed a QE score using 4 factors - recipient outcome, donor/graft safety, waiting list mortality and healthcare resources - for 7 countries. The fluctuation of the QE score over time accurately reflects the dynamic changes in the ethical tensions surrounding transplant activity in a pandemic., Conclusions: This four-dimensional model of quadripartite equipoise addresses the ethical tensions in the current pandemic. It serves as a universally applicable framework to guide regulation of transplant activity in response to the increasing burden on healthcare systems., Lay Summary: There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources during the COVID-19 pandemic. We describe a four-dimensional model of quadripartite equipoise that models these ethical tensions and can guide the regulation of transplant activity in response to the increasing burden on healthcare systems., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Combined checkpoint inhibition therapy targeting the programmed cell death 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 pathways has been a successful approach in the treatment of metastatic melanoma, leading to its investigation in the treatment of head and neck squamous cell carcinoma (HNSCC) with PD-L1 expression. Despite the potential for excellent responses, an increased rate of autoimmune neurological toxicity and paraneoplastic conditions has been observed when using these treatment modalities. We present the case of a patient with metastatic HNSCC treated with combination ipilimumab/nivolumab who experienced severe cerebellar ataxia with a positive screen for the anti-Zic4 antibody. This is the first case, to our knowledge, of anti-Zic4 antibody-mediated cerebellar toxicity reported in association with HNSCC. Although the patient experienced an impressive partial response with dual checkpoint inhibition, he suffered grade 4 neurotoxicity. Despite exciting advances in cancer immunotherapy, clinicians must be aware of the rare, debilitating and possibly previously undescribed paraneoplastic and autoimmune toxicities that may occur., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pulmonary marginal zone lymphoma (PMZL) is the most common non-Hodgkin lymphoma affecting the lung. PMZL is usually an indolent disease. Clinical and radiological variables associated with shorter survival are largely unknown and no consensus exists on preferred treatment strategy in PMZL. Herein we aimed to identify clinical and radiological features associated with shorter survival and inferior treatment outcomes. Forty patients with PMZL were analyzed. FDG-avid disease was evident in most patients (93%) with staging PET/CT (n = 15). With a median follow-up in treated patients (n = 38) of 8.4 years (range 0.07-18.44), the median progression-free survival (PFS) and overall survival (OS) were 7.5 years (95% CI 1.8-9.5) and 15.7 years (95% CI 9.3-NE) respectively. Shorter PFS was observed in patients who presented at diagnosis with elevated LDH, B symptoms, advanced stage and failed to achieve complete response (CR) after initial treatment. Patients with multifocal lung disease, extrapulmonary MZL and cavitary lesions on CT scans exhibited shorter PFS. Nevertheless, no clinical or radiologic findings were associated with shorter OS. All patients treated with surgery (n = 4) and radiation therapy (n = 3) achieved and remained in CR. No higher grade transformations occurred during the follow-up period. PMZL exhibited excellent outcomes with a 15-year PMZL-related OS of 94.9% (95% CI: 81.25%-98.7%). Radiation therapy and surgery are potentially curative strategies in localized PMZL., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Intravenous maintenance fluid (IMF) tonicity and composition influence plasma electrolyte balance., Objective: To determine if hypotonic IMF therapy contributes to post-surgical hyponatremia., Setting: Single-center tertiary institution., Participants: Adults who underwent major surgery and received peri-surgical IMF, with exclusive administration of hypotonic pre-mixed 0.33% saline, 5% dextrose and potassium chloride (DK0.33%S), or isotonic 0.9% saline with or without 5% dextrose (NS/DNS)., Outcomes and Measures: We examined post-surgical hyponatremia, hypokalemia and acute kidney injury (AKI), associated with use of either IMF., Results: We studied 659 patients, of whom 161 patients (24%) developed post-surgical hyponatremia. DK0.33%S (versus NS/DNS) IMF was administered in 52% of patients who developed hyponatremia, compared to 38% of patients with stable natremia (p = 0.001). More patients with hyponatremia underwent gastrointestinal-hepatobiliary or abdominal (GI/HBS/Abd) surgery versus other surgical-sites (p = 0.001). Hypokalemia developed in 1% versus 10% of patients who received DK0.33%S and NS/DNS IMF respectively (p< 0.001), with corresponding AKI rates of 3% versus 7% (p = 0.02). On multivariate analysis, adjusted for timing of biochemistry post-surgery, IMF infusion rate and volume; independent factors associated with post-surgical hyponatremia included DK0.33%S administration, GI/HBS/Abd surgery (versus other sites), and post-surgical AKI (p < 0.05). Subgroup analysis by surgical sites showed that association of DK0.33%S administration with hyponatremia was most evident in GI/HBS/Abd surgery., Conclusions: Administration of DK0.33%S IMF, compared with NS/DNS, is associated with post-surgical hyponatremia in adults after major surgery, but with less hypokalemia. The higher rate of AKI observed with NS/DNS IMF requires further evaluation., (Copyright © 2019 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: This study aims to review the clinical management of patients with acute pancreatitis in a tertiary institute in Singapore, and to identify areas qualiy improvement based on validation against the recommendations in the IAP/APA and the Japanese guidelines., Methods: 391 patients from a prospective electronic database were included and reviewed for compliance to the International Association of Pancreatology (IAP)/American Pancreatic Association (APA) guidelines (2013) and the Japanase Guidelines (2015)., Results: The 90 day mortality was 8.4% for moderately severe and 11.9% for severe pancreatitis. The accuracy of SIRS in predicting severe acute pancreatitis on admission was 72.1% and at 48 h 80.8%. Only 61.1% patients had ultrasound scan during their admission of whom 32.9% had it within 24 h of admission. 18.3% patients with initial diagnosis of idiopathic pancreatitis had EUS. 50% received Ringer lactate for initial fluid resuscitation. 38.7% received antibiotics as prophylaxis. 21.4% with severe acute pancreatitis had early enteral nutrition. Only 21.4% patients with biliary pancreatitis had index admission cholecystectomy., Conclusion: The compliance to existing guidelines for management of acute pancreatitis is variable. Identifying gaps and implementing measures to address them allows for continued improvement in the management of patients with acute pancreatitis., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: To compare the presentations and outcomes of anti-HBc seropositive Hepatocellular Carcinoma (HBc-HCC) with anti-HBc seronegative (NHBc-HCC) patients in HBsAg negative Non-HBV Non-HCV (NBNC-HCC) HCC population., Methods: 515 newly diagnosed HCC patients from January 2011 to September 2016 were retrospectively reviewed. 145 (66.5%) NHBc-HCC and 73 (33.5%) HBc-HCC patients were identified. Patient demographics, disease characteristics, details of treatments, recurrence and survival outcomes were analysed., Results: A significantly lower proportion of HBc-HCC patients were diagnosed through surveillence (6.8% vs 26.2%, p = 0.001). HBc-HCC patients were less likely cirrhotic (p < 0.001), portal hypertensive (p < 0.001), ascitic (p = 0.008) and thrombocytopenic (p = 0.003). A higher proportion of HBc-HCC patients had treatment with curative intent (46.6% vs 30.3%, p = 0.018) and surgery (39.7% vs 16.6%, p < 0.001). Although HBc-HCC patients had larger median tumor size (74.0 mm vs 55.0 mm, p = 0.016) with a greater proportion of patients having tumors ≥5 cm, there was no difference in the overall median survival (19.0 months vs 22.0 months, p = 0.919) and recurrence rates (38.2% vs 40.9%)., Conclusion: Isolated anti-HBc seropositivity in HbsAg negative patients tend to present incidentally with delayed diagnoses resulting in larger tumors, but their long-term survival remain comparable., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been widely described for colorectal liver metastases with insufficient future liver remnant (FLR). However, its role in hepatocellular carcinoma (HCC) remains poorly defined and not widely accepted., Methods: A retrospective comparison of clinical data, liver volumetry, histological characteristics, and surgical outcomes between nine HCC and four non-HCC patients who underwent ALPPS was performed., Results: Patients with HCC were more likely to have histological evidence of hepatic fibrosis (HCC vs. non-HCC, 66.7 vs. 0%, p = 0.049). Baseline demographic and disease characteristics were otherwise comparable between both groups. FLR growth after ALPPS-Stage 1 was significantly less in HCC patients (HCC vs. non-HCC, 154.5 vs. 251.0 ml, p = 0.012). FLR growth was also significantly decreased in patients with hepatic fibrosis (fibrosis vs. non-fibrosis, 157.5 vs. 247.5 ml, p = 0.033). There was no difference in post-hepatectomy liver failure (HCC vs. non-HCC, 28.6 vs. 25%, p = 0.721) or 90-day mortality (HCC vs. non-HCC, 11.1 vs. 0%, p = NS)., Discussion: In our study, HCC patients demonstrated significantly less FLR growth after ALPPS-Stage 1 compared to non-HCC patients. Hepatic fibrosis was also found to negatively impact FLR growth. When considering suitability for ALPPS, patients with HCC may benefit from additional pre-operative assessment of fibrosis.

Background: Single-staged laparoscopic common bile duct exploration (LCBDE) offers clear benefits in terms of cost and shorter hospitalization stays. However, a failed LCBDE requiring conversion to open surgery is associated with increased morbidity. This study reviewed the factors determining success of LCBDE, and created a predictive nomogram to stratify patients for the procedure., Methods: A retrospective analysis of 109 patients who underwent LCBDE was performed. A nomogram was developed from factors significantly associated with conversion to open surgery and validated., Results: Sixty-two patients underwent a successful LCBDE, while 47 patients required a conversion to open CBDE. The presence of underlying cholangitis (crude OR 2.70, 95% CI: 1.12-6.56, p = 0.017), together with its subsequent interventions, seemed to adversely increase the rate of conversion to open surgery. The predictive factors included in the nomogram for a failed laparoscopic CBDE included prior antibiotic use (adjusted OR (AOR) 2.98, 95% CI: 1.17-7.57, p = 0.022), previous ERCP (AOR 4.99, 95% CI: 2.02-12.36, p = 0.001) and abnormal biliary anatomy (AOR 9.37, 95% CI: 2.18-40.20, p = 0.003)., Conclusion: LCBDE is useful for the treatment of choledocholithiasis. However, patients who were predicted to have an elevated risk for open conversion might not be ideal candidates for the procedure., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Backgrounds/aims: Liver Transplantation (LT) is a recognized treatment for Hepatocellular Carcinoma (HCC). The role of Bridging Therapies (BT) remains controversial., Methods: From January 2001 to October 2012, 192 patients were referred to the National University Hospital, Singapore for consideration of LT for HCC. Sixty-five patients (33.8%) were found suitable for transplant and were placed on the waitlist. Analysis was performed in these patients., Results: The most common etiology of HCC was Hepatitis B (n=28, 43.1%). Thirty-six patients (55.4%) received BT. Seventeen patients (47.2%) received TACE only, while 10 patients (27.8%) received radiofrequency ablation (RFA) only. The remaining patients received a combination of transarterial chemoembolization (TACE) and RFA. Baseline tumor and patient characteristics were comparable between the two groups. The overall dropout rate was 44.4% and 31.0% in the BT and non-BT groups, respectively ( p =0.269). The dropout rate due to disease progression beyond criteria was 6.9% (n=2) in the non-bridged group and 22.2% (n=8) in the bridged group ( p =0.089). Thirty-nine patients (60%) underwent LT, of which all patients who underwent Living Donor LT did not receive BT (n=4, 21.1%, p =0.030). The median time to LT was 180 days (range, 20-558 days) in the non-BT group and 291 days (range, 17-844 days) in the BT group ( p =0.214). There was no difference in survival or recurrence between the BT and non-BT groups ( p =0.862)., Conclusions: BT does not influence the dropout rate or survival after LT but it should be considered in patients who are on the waitlist for more than 6 months.

Background: Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) and conventional staged hepatectomy (CSH) are options for patients with unresectable liver tumors due to insufficient future liver remnant (FLR)., Methods: A retrospective comparison of clinical data, liver volumetry and surgical outcomes between 10 ALPPS and 29 CSH patients was performed., Results: Patient demographics and disease characteristics were similar between both groups. ALPPS induced superior FLR growth (ALPPS vs. CSH, 48.1% (IQR 39.4-96.9%) vs. 11.8% (IQR 4.3-41.9%), p = 0.013). However, post-operative day 5 international normalized ratio (INR) (ALPPS vs. CSH, 1.6 (IQR 1.5-1.8) vs. 1.4 (IQR 1.3-1.6), p = 0.015) and rate of post-hepatectomy liver failure (ALPPS vs. CSH, 25 vs. 0%, p = 0.032) was higher in the ALPPS group. 90-day mortality (ALPPS vs. CSH, 12.5% vs. 0%, p = 0.320) was similar in both groups., Conclusion: ALPPS was superior in inducing FLR growth but associated with increased post-hepatectomy liver failure compared to CSH., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sprouts of cereal grains, such as barley ( Hordeum vulgare L.), are a good source of beneficial phenolic bioactives. Such health relevant phenolic bioactives of cereal sprouts can be targeted to manage chronic hyperglycemia and oxidative stress commonly associated with type 2 diabetes (T2D). Therefore improving phenolic bioactives by stimulating plant endogenous defense responses such as protective pentose phosphate pathway (PPP) during sprouting has significant merit. Based on this metabolic rationale, this study aimed to enhance phenolic bioactives and associated antioxidant and anti-hyperglycemic functions in dark germinated barley sprouts using exogenous elicitor treatments. Dark-germinated sprouts of two malting barley cultivars (Pinnacle and Celebration), treated with chitosan oligosaccharide (COS) and marine protein hydrolysate (GP), were evaluated. Total soluble phenolic content (TSP), phenolic acid profiles, total antioxidant activity (TA) and in vitro inhibitory activities of hyperglycemia relevant α-amylase and α-glucosidase enzymes of the dark germinated barley sprouts were evaluated at day 2, 4, and 6 post elicitor treatments. Overall, TSP content, TA, and α-amylase inhibitory activity of dark germinated barley sprouts decreased, while α-glucosidase inhibitory activity and gallic acid content increased from day 2 to day 6. Among barley cultivars, high phenolic antioxidant-linked anti-hyperglycemic bioactives were observed in Celebration. Furthermore, GP and COS seed elicitor treatments in selective doses improved T2D relevant phenolic-linked anti-hyperglycemic bioactives of barley spouts at day 6. Therefore, such seed elicitation approach can be strategically used to develop bioactive enriched functional food ingredients from cereal sprouts targeting chronic hyperglycemia and oxidative stress linked to T2D.

Background: Acute cholecystitis (AC) is an important cause of emergency admissions among the elderly. The use of percutaneous cholecystostomy (PC) as bridging therapy among high-risk patients is widely accepted. However, the use of PC as definitive treatment is controversial., Aim: To determine the characteristics, clinical outcomes and predictors of recurrence of AC among patients who underwent PC., Methods: A retrospective case series of 71 consecutive patients [73 (38-96) years, 43/71 males] treated with PC for AC at a tertiary hospital from 2007 to 2013, with data collected from case records., Results: Patients were followed up for 37.0 (0.1-110.8) months after PC. Mortality rate was 8.5 % (6/71) during the index admission and 32.4 % (23/71) at the end of follow-up. Recurrence rate for AC was 11.9 % (7/59). Median time to recurrence was 62 (13-464) days. PC was definitive treatment in 33/59. Predictors of recurrence were higher serum alkaline phosphatase (ALP) at diagnosis (OR = 1.01, 95 % CI 1.00-1.02, p = 0.021) and acute myocardial infarction (AMI) during index admission (OR = 8.00, 95 % CI 1.19-54.0, p = 0.033). Fifteen patients (26.3 %, 15/71) had post-procedural complications including dislodgement (14 %, 10/71), tube obstruction (7.0 %, 5/71), bile leaks (2.8 %, 2/71), gallbladder perforation (1.4 %, 1/71), bowels perforation (1.4 %, 1/71) and severe post-procedural haemorrhage (1.4 %, 1/71)., Conclusion: PC is effective and relatively safe in high-risk patients with AC. However, patients with higher ALP or AMI during index admission have higher risk of recurrence and might benefit from definitive cholecystectomy.

Introduction: Minimally invasive hepatectomy (MIH) for patients with hepatocellular carcinoma (HCC) is technically challenging, especially with large posteriorly located tumours or background of liver cirrhosis. This is a case-control study comparing the long-term oncological safety of HCC patients who underwent MIH and open hepatectomy (OH). Most of these patients have liver cirrhosis compared to other studies., Materials and Methods: Sixty patients were divided into 2 groups, 30 underwent MIH and 30 underwent OH for HCC resection. The patients in both groups were matched for extent of tumour resection, age and cirrhosis status. Patient characteristics, risk factors of HCC and all oncological data were studied., Results: Negative resection margins were achieved in 97% of patients in both groups. The mean blood loss during surgery was significantly lower in the MIH group compared to the OH group (361 mL vs 740 mL; 95% CI, 222.2, 734.9; P = 0.04). Hospitalisation is significantly shorter in MIH group (7 days vs 11 days; 95% CI, 6.9, 12.2,; P = 0.04). Eight patients (27%) in the MIH group and 13 patients (43%) in the OH group developed HCC recurrence (P = 0.17). One, 3 and 5 years disease-free survival between MIH and OH groups are 76% vs 55%, 58% vs 47%, and 58% vs 39% respectively (P = 0.18). One, 3 and 5 years overall survival between MIH and OH groups are 93% vs 78%, 89% vs 70%, and 59% vs 65% respectively (P = 0.41)., Conclusion: MIH is a safe and feasible curative treatment option for HCC with similar oncological outcomes compared to OH. MIH can be safely performed to remove tumours larger than 5 cm, in cirrhotic liver, as well as centrally and posterior located tumours. In addition, MIH patients have significant shorter hospitalisation and intraoperative blood loss.

Background: With improvements in patient survival after a liver transplantation (LT), long-term sequelae such as metabolic syndrome (MS) have become increasingly common. This study aims to characterize the prevalence, associations and long-term outcomes of post-LTMS and its components in an Asian population., Methods: A retrospective review of all adult patients who underwent LT at the National University Health System Singapore between December 1996 and May 2012 was performed. MS was defined using the Adult Treatment Panel (ATP) III criteria modified for an Asian population., Results: The median age of this cohort of 90 patients was 50.0 (16.0-67.0) years, with a median follow-up duration of 60.0 (7.0-192.0) months. The prevalence of post-LTMS was 35.6%, diabetes mellitus (DM) 51.1%, hypertension 60.0%, obesity 26.7% and dyslipidaemia 46.7%. On univariate analysis, factors significantly associated with post-LT MS include female gender (P = 0.066), pre-LT respiratory comorbidities (P = 0.038), pre-LT obesity (P = 0.014), pre-LTDM (P < 0.001), pre-LT hypertension (P = 0.039), pre-LTMS (P < 0.001), prednisolone use ≥24 months (P = 0.005) and mycophenolate mofetil use ≥24 months (P = 0.035). On multivariate analysis, independent associations of post-LT MS were pre-LTDM (P = 0.011) and pre-LTMS (P = 0.024). There was no difference in long-term survival of patients with and without post-LTMS (P = 0.425)., Conclusion: In conclusion, pre-LT components of the MS and the use of certain immunosuppressants are related to developing post-LTMS., (© 2015 International Hepato-Pancreato-Biliary Association.)

Introduction: An increasing body of evidence is being published about single-incision laparoscopic cholecystectomy (SILC), but there are no well-powered trials with an adequate evaluation of post-operative pain. This randomized trial compares SILC against four-port laparoscopic cholecystectomy (LC) with post-operative pain as the primary endpoint., Methods: Hundred patients were randomized to either SILC (n = 50) or LC (n = 50). Exclusion criteria were (1) Acute cholecystitis; (2) ASA 3 or above; (3) Bleeding disorders; and (4) Previous open upper abdominal surgery. Patients and post-operative assessors were blinded to the procedure performed. The site and severity of pain were compared at 4 h, 24 h, 14 days and 6 months post-procedure using the visual analog scale; non-inferiority was assumed when the lower boundary of the 95% confidence interval of the difference was above -1 and superiority when p ≤ 0.05., Results: The study arms were demographically similar. At 24 h post-procedure, SILC was associated with less pain at extra-umbilical sites (rest: p = 0.004; movement: p = 0.008). Pain data were inconclusive at 24 h at the umbilical site on movement; SILC was otherwise non-inferior for pain at all other points. Operating duration was longer in SILC (79.46 vs 58.88 min, p = 0.003). 8% of patients in each arm suffered complications (p = 1.000). Re-intervention rates, analgesic use, return to function, and patient satisfaction did not differ significantly., Conclusions: SILC has improved short-term pain outcomes compared to LC and is not inferior in both short-term and long-term pain outcomes. The operating time is longer, but remains feasible in routine surgical practice.