Trends of liver transplantation in Asia.

Liver transplantation (LT) in Asia started comparatively early in 1964, just 1 year after Starzl's trail-blazing first attempt. Despite the quick start, LT was slow to develop in this region. Limited access to universal healthcare, lack of public understanding and support as well as the absence of strong legislation, on a backdrop of a wide range of diverse social, religious, economic and cultural background are all contributory factors. Through strong administrative efforts, the number of DDLTs in selected Asian countries has been slowly rising in recent years. However, Asians are generally still less likely to donate organs than Caucasians after death. The strong demand for LT with limited access to deceased organs has, therefore, led to constant need for innovation in LT this region, with the pioneering of various LDLT techniques and safe expansion of donor pool being driven primarily by Asian centers. Familiarity and the development of technical expertise in donor surgery have also resulted in Asian centers repeatedly pushing the boundaries on minimally invasive donor and recipient surgery. In this article, we focus on the past and present states of LT in Asia and explore the future trends of LT in this region.

Global Prevalence, Clinical Characteristics, Surveillance, Treatment Allocation, and Outcomes of Alcohol-Associated Hepatocellular Carcinoma.

BACKGROUND: Although the burden of alcohol-associated hepatocellular carcinoma (HCC) is increasing with rising alcohol consumption, clinical presentation and outcomes of alcohol-associated HCC have not been systematically assessed. We aimed to determine the prevalence, clinical characteristics, surveillance rates, treatment allocation, and outcomes of alcohol-associated HCC. METHODS: Medline and Embase were searched from inception to January 2023. Proportional data were analyzed using a generalized linear mixed model. The odds ratio (OR) or mean difference comparing alcohol-associated HCC and other causes was obtained with pairwise meta-analysis. Survival outcomes were evaluated using a pooled analysis of hazard ratios. RESULTS: Of 4824 records identified, 55 articles (86,345 patients) were included. Overall, 30.4% (95% confidence interval [CI], 24.0%-37.7%) of HCC was alcohol associated, with the highest proportion in Europe and the lowest in the Americas. People with alcohol-associated HCC were more likely male but were similar in age and comorbidities compared with other causes. A total of 20.8% (95% CI, 11.4%-34.9%) of people with alcohol-associated HCC underwent surveillance compared with 35.0%, 31.6%, and 21.4% in hepatitis B virus, hepatitis C virus, and metabolic dysfunction-associated HCC, respectively (all P < .05). Alcohol-associated HCC had a lower likelihood of Barcelona Clínic Liver Cancer C stage (0/A) (OR, 0.7; 95% CI, 0.6-0.9; P = .018) and curative therapy (24.5% vs 33.9%; OR, 0.7; 95% CI, 0.5-0.9; P = .003), and higher mortality (HR, 1.3; 95% CI, 1.1-1.5; P = .012) when compared with other causes. CONCLUSIONS: Alcohol-associated HCC is associated with lower surveillance rates, more advanced BCLC stage, lower likelihood of receiving curative therapy, and poorer survival. These data call for measures to reduce heavy alcohol consumption and improve strategies for effective HCC surveillance in high-risk individuals.

Case report: From palliative to potentially curative - the advent of immunotherapy providing hope to advanced gallbladder adenocarcinoma.

Introduction: Biliary tract cancers (BTC) are often diagnosed at an advanced stage where prognosis is poor and curative-intent surgery is infeasible. First-line cisplatin-gemcitabine chemotherapy for advanced gallbladder cancer has remained unchanged over more than a decade, but recent developments in immunotherapy such as durvalumab have highlighted promise as a combination treatment regime with current standard chemotherapy. Methods: In this case description, we present a case of locally-advanced gallbladder adenocarcinoma involving the biliary confluence that was initially planned for an extended right hepatectomy after portal vein embolization. Interval imaging revealed peritoneal metastasis, which was confirmed on diagnostic laparoscopy and biopsy. The patient underwent 8 cycles of cisplatin 25 mg/m2 and gemcitabine 1,000 mg/m2 chemotherapy on days 1 and 8 of each 21-day cycle, with durvalumab (Imfinzi®) 1,500 mg immunotherapy on day 1 of every cycle, in accordance with the treatment protocol of the TOPAZ-1 trial. Repeat imaging demonstrated a stable primary lesion with no further evidence of peritoneal disease. The patient subsequently underwent curative-intent conversion surgery with an extended right hepatectomy and Roux-en-Y hepaticojejunostomy, which were completed through a fully minimally-invasive laparoscopic approach. Results: Final pathological TNM classification was ypT1aN0, with near-complete pathological response to pre-surgical therapy, uninvolved margins (R0 resection) and tumour shrinkage from 2.5 centimetres on pre-operative cross-sectional imaging to 0.5 centimetres on final histology. The patient had an uneventful post-operative course, and was fit for discharge by the fourth post-operative day. He remained well after three months of routine post-operative follow-up, with no significant post-operative complications and biochemical or radiological evidence of disease recurrence. Conclusion: Our case description highlights the immense potential of combination durvalumab immunotherapy with cisplatin-gemcitabine chemotherapy in the treatment of advanced gallbladder adenocarcinoma. The patient's locally advanced disease was initially planned for complex open surgery, prior to discovery of peritoneal metastasis rendering it inoperable. This was successfully down-staged with combination therapy to eventual R0 resection via minimally-invasive surgery. In addition, this case description demonstrates the feasibility of a fully laparoscopic approach with postulated benefits of diagnostic re-evaluation of peritoneal disease, reduced wound pain and shorter length of hospital stay.

A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids.

Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC.

Early vs late drain removal after pancreatic resection-a systematic review and meta-analysis.

BACKGROUND: Reducing clinically relevant post-operative pancreatic fistula (CR-POPF) incidence after pancreatic resections has been a topic of great academic interest. Optimizing post-operative drain management is a potential strategy in reducing this major complication. METHODS: Studies involving pancreatic resections, including both pancreaticoduodenectomy (PD) and distal pancreatic resections (DP), with intra-operative drain placement were screened. Early drain removal was defined as removal before or on the 3rd post-operative day (POD) while late drain removal was defined as after the 3rd POD. The primary outcome was CR-POPF, International Study Group of Pancreatic Surgery (ISGPS) Grade B and above. Secondary outcomes were all complications, severe complications, post-operative haemorrhage, intra-abdominal infections, delayed gastric emptying, reoperation, length of stay, readmission, and mortality. RESULTS: Nine studies met the inclusion criteria and were included for analysis. The studies had a total of 8574 patients, comprising 1946 in the early removal group and 6628 in the late removal group. Early drain removal was associated with a significantly lower risk of CR-POPF (OR: 0.24, p < 0.01). Significant reduction in risk of post-operative haemorrhage (OR: 0.55, p < 0.01), intra-abdominal infection (OR: 0.35, p < 0.01), re-admission (OR: 0.63, p < 0.01), re-operation (OR: 0.70, p = 0.03), presence of any complications (OR: 0.46, p < 0.01), and reduced length of stay (SMD: -0.75, p < 0.01) in the early removal group was also observed. CONCLUSION: Early drain removal is associated with significant reductions in incidence of CR-POPF and other post-operative complications. Further prospective randomised trials in this area are recommended to validate these findings.

Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer.

Hepatocellular carcinoma (HCC) is the third deadliest and sixth most common cancer in the world. Histone-lysine N-methyltransferase EHMT2 (also known as G9a) is a histone methyltransferase frequently overexpressed in many cancer types, including HCC. We showed that Myc-driven liver tumours have a unique H3K9 methylation pattern with corresponding G9a overexpression. This phenomenon of increased G9a was further observed in our c-Myc-positive HCC patient-derived xenografts. More importantly, we showed that HCC patients with higher c-Myc and G9a expression levels portend a poorer survival with lower median survival months. We demonstrated that c-Myc interacts with G9a in HCC and cooperates to regulate c-Myc-dependent gene repression. In addition, G9a stabilises c-Myc to promote cancer development, contributing to the growth and invasive capacity in HCC. Furthermore, combination therapy between G9a and synthetic-lethal target of c-Myc, CDK9, demonstrates strong efficacy in patient-derived avatars of Myc-driven HCC. Our work suggests that targeting G9a could prove to be a potential therapeutic avenue for Myc-driven liver cancer. This will increase our understanding of the underlying epigenetic mechanisms of aggressive tumour initiation and lead to improved therapeutic and diagnostic options for Myc-driven hepatic tumours.

Uses of a dedicated 3D reconstruction software with augmented and mixed reality in planning and performing advanced liver surgery and living donor liver transplantation (with videos).

The development of digital intelligent diagnostic and treatment technology has opened countless new opportunities for liver surgery from the era of digital anatomy to a new era of digital diagnostics, virtual surgery simulation and using the created scenarios in real-time surgery using mixed reality. In this article, we described our experience on developing a dedicated 3 dimensional visualization and reconstruction software for surgeons to be used in advanced liver surgery and living donor liver transplantation. Furthermore, we shared the recent developments in the field by explaining the outreach of the software from virtual reality to augmented reality and mixed reality.

Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in hepatocellular carcinoma: the PLANET study.

Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% of patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.

Multimodal prehabilitation before major abdominal surgery: A retrospective study.

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.

Factors Attracting or Deterring Female Medical Students in Asia From Pursuing a Surgical Career, and the Impact of Surgical Clerkship, Mentorship, and Role Models: A Multicultural Asian Perspective From a National Prospective Cohort Study.

BACKGROUND: Female surgeons are highly underrepresented in Asian countries, where prescriptive gender norms are widespread and more deeply embedded in societies. MATERIALS AND METHODS: A nationwide structured questionnaire was completed by 1741 Singaporean third- and fifth-year medical students after the completion of an 8-week general surgery rotation, during 2015-2017. Results were analyzed using mixed-effects hierarchical models which took into account clustering of survey responses under the teaching hospitals which students were posted to and medical students' year of study. RESULTS: Female medical students had a poorer perception of general surgery than male students (3.22 ± 0.91 versus 3.41 ± 0.89; P < 0.0001) before the clerkship. However, the clerkship improved female students' opinion to a greater extent than male students (+0.84 ± 1.06 versus +0.59 ± 1.03; P < 0.0001), resulting in female and male students having comparable attitudes toward surgery after the clerkship (4.06 ± 0.79 versus 4.00 ± 0.87; P = 0.2435). A total of 40.4% of female students responded that they were inspired to pursue a surgical career after the clerkship, and we identified 13 pedagogical traits of faculty and resident mentors which were associated with female students' career aspirations. Female students were more likely to consider intellectual challenges arising from cases (ratio: 1.045 [95% confidence interval 1.004-1.088, P = 0.0292]) and the presence of role models (ratio: 1.068 [95% confidence interval: 1.020-1.118, P = 0.0048]) as "pull" factors compared with their male contemporaries, but were deterred from a surgical career to a greater extent by eight "push" factors. CONCLUSIONS: A surgical clerkship itself could be regarded as an effective intervention for improving female medical students' enthusiasm for surgery, which may help to address the "pipeline problem" of few female students applying for surgical training after medical school. A greater emphasis on "pull factors" and pedagogical qualities of mentors could be used to improve the clerkship experience, to attract more female students to surgery.

Push and pull factors, and the role of residents in nurturing medical students' interest in surgery as a career option in a multicultural Asian context: Results of a prospective national cohort study.

BACKGROUND: Studies in Caucasian populations suggest that interest among medical students in pursuing a surgical career is dwindling. We sought to investigate these trends and to evaluate the impact of resident teaching in a multiethnic Asian population. STUDY DESIGN: Between 2015 and 2017, 1780 Singaporean third- and fifth-year medical students completed a structured anonymized questionnaire following the completion of an 8-week general surgery rotation. Medical students' impressions of their faculty and resident mentors were analyzed using hierarchical multilevel mixed-effects models. RESULTS: Respondents' opinions of general surgery improved from 3.31 ± 0.91 points to 4.03 ± 0.83 points on a 5-point Likert scale (P < 0.0001). Medical students were more likely to regard their interaction with residents as a "pull" factor compared to their interaction with faculty members (74.7% vs 65.6%; P < 0.0001). Our analyses revealed 9 statistically-significant "pull" factors and 5 "push" factors which attract or deter Asian medical students from a career in surgery. Comparing the pedagogical qualities of resident and faculty mentors, we found that residents surpassed faculty mentors in 9 domains, had comparable appraisal scores on 3 domains, and fared worse than faculty on 8 domains. Importantly, residents fared better at promoting interest in a surgical career (P = 0.0006) and influencing the career aspirations of medical students (P < 0.0001) compared with faculty members. CONCLUSIONS: To our knowledge, this is the largest study from a Southeast Asian country providing representative sample numbers. With this knowledge of pull and push factors, the surgical clerkship can be improved by emphasizing pull factors and preparing students to cope with the push factors. Finally, our findings suggest that roping in residents as mentors to medical students may improve the pipeline of students interested in pursuing surgery after medical school.

Transplantation versus liver resection in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common solid cancers in the world. Its treatment strategies have evolved significantly over the past few decades but the best treatment outcomes remain in the surgical arena. Especially for early HCCs, the options are abundant. However, surgical resection and liver transplantation provide the best long-term survival. In addition, there are evidence the ablative therapy such as radiofrequency ablation, could provide equivalent outcome as compared to resection. However, HCC is a unique malignancy as the majority of patients develop this cancer in the background of cirrhotic livers. As such, the treatment consideration should not only look at the oncological perspective but also the functional status of the liver parenchyma, i.e., the state of cirrhosis and presence of portal hypertension. Even with the most widely adopted staging systems for HCC such as the Barcelona Clinic Liver Cancer (BCLC) staging system and many other staging systems, none of them are ideal in including the various considerations for patients with HCCs. In this article, the key issues between choosing surgical resection and liver transplantation are discussed. A comprehensive review of the current surgical options are outlined in order to explore the pros and cons of each option.

Hepatic metastasis from colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers in the world. About two third of patients with CRC will develop distant recurrence at some point in time. Liver is the most common site where distant metastasis takes place. While the overall survival (OS) of patients with metastatic CRC was poor about 3 decades ago, there has been tremendous improvement in this area in the recent years. With the advent of effective systemic chemotherapy and biologic agents and better understanding of the biological behaviour of the tumour, aggressive treatment strategies such as metastatectomy of the liver metastases (or lung metastases) are now acceptable. More importantly, it has transformed the way how stage IV CRCs are being managed. From predominantly palliative as the primary aim, a comprehensive multidisciplinary approach is now the mainstay of treatment with very successful outcomes. Combination of systemic therapies with liver resection has been shown to be effective in providing promising survival benefits. In addition, other adjunctive modalities in targeting the liver metastases such as ablation, combining resection and ablation, transarterial chemoembolization, stereotactic body radiotherapy (SBRT), hepatic artery perfusion, etc. have also been demonstrated variable outcome in treating colorectal liver metastasis (CRLM). Very recently, transplant oncologists have also explored using liver transplantation as a treatment modality for unresectable CRLM, which has demonstrated very good long-term survival in well selected cases. The new paradigm in the treatment of metastatic CRC has dawned.

Health-related quality of life, clinical outcomes, and subjective experiences of parent donors of pediatric liver transplant recipients.

PURPOSE: The understanding of the HRQOL issues for parent donors of children who underwent LDLT is lacking. We evaluated the HRQOL of donor and non-donor parents, described their subjective experiences and identified factors associated with lower HRQOL post-donation. METHODS: This is a cross-sectional study of parent donors whose children underwent LDLT, using SF-36v2 Health Survey to measure HRQOL, and a self-developed questionnaire to evaluate their subjective experiences. RESULTS: Of 32 pairs of donor and non-donor parents, 27 donor and 19 non-donor parents responded. The data of respondents were analyzed. Both donor and non-donor parents' SF-36v2 norm-based scores were average or above average as compared to the Singapore population. Donors who made lifestyle changes post-donation (adopting a healthy balanced diet, regular physical activity, quitting smoking, and moderate alcohol intake) were associated with lower GH (P = 0.009) and PF (P = 0.002) scores. Donors who took more than 3 months for full recovery had lower RP (P = 0.022) and BP scores (P = 0.038). On multivariate analysis, recipient complication of Clavien grade 3 or 4 was associated with increased RP score by 8.71 points (95% CI: 1.74-15.68), after adjusting for time taken for full recovery. Majority (88.8%) had self-reported recovery time under 6 months and returned to work within 3 months (74.0%). CONCLUSIONS: Donors with factors potentially associated with lower HRQOL may need more support to ensure better HRQOL outcomes post-donation.

Bridging therapies to liver transplantation for hepatocellular carcinoma: A bridge to nowhere?

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.