A multimodal atlas of hepatocellular carcinoma reveals convergent evolutionary paths and 'bad apple' effect on clinical trajectory.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies. METHODS: Through the Asia-Pacific Hepatocellular Carcinoma trials group (NCT03267641), we recruited one of the largest prospective cohorts of patients with HCC, with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients. RESULTS: Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival. CONCLUSIONS: Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provides a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories. IMPACT AND IMPLICATIONS: This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected hepatocellular carcinoma (HCC), reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of HCC. These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for personalized treatment strategies tailored to specific tumor evolutionary and transcriptomic profiles. The coexistence of multiple subtypes within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making. CLINICAL TRIAL NUMBER: NCT03267641 (Observational cohort).

The friendly incidental portal vein thrombus in liver transplantation.

Improved outcomes have been shown in liver transplantation (LT) with portal vein thrombosis (PVT). However, PVT is still discovered incidentally during surgery despite careful preoperative imaging. Data are limited comparing the outcomes of incidental PVT with PVT diagnosed via preoperative imaging before LT. This study aims to compare the overall outcomes of patients with PVT. From 2008 to 2012, 369 patients had LT, and 58 patients with PVT were identified. They were divided into those with non-PVT (group 0; n = 311), preoperatively identified PVT (group 1; n = 28), and incidental PVT (group 2; n = 30). The demographics, characteristics, preoperative assessment, and postoperative outcomes were compared. A survival analysis was also performed. Baseline characteristics and preoperative evaluations of all 3 groups were comparable (P > 0.05) except for Model for End-Stage Liver Disease score, tumor status, platelet levels, and serum bilirubin. A multivariate analysis only showed a high serum bilirubin level to be a predictor of PVT (P = 0.004; odds ratio, 3.395; 95% confidence interval, 1.467-7.861). Postoperative outcomes were also comparable (P > 0.05). Compared to group 2, group 1 had more patients with a Yerdel classification of 3 or 4 with more extensive surgical intervention required (P = 0.02). The survival analysis in all 3 groups was comparable with 5-year survival rate of 87.4%, 84.6%, and 91.8% in group 0, 1, and 2, respectively (P = 0.66). In conclusion, recipients with PVT undergoing LT can have similar outcomes as the non-PVT patients even if PVTs were discovered incidentally. Discovery of incidental PVT only requires thrombectomy with no substantial change of treatment strategy, and the outcome is not adversely affected because most incidental PVTs are of a lower Yerdel grade. Preoperative imaging is useful to identify those with a higher Yerdel grade to allow planning of surgical strategy during transplantation.

Efficacy of radiofrequency ablation compared with transarterial chemoembolization for the treatment of recurrent hepatocellular carcinoma: a comparative survival analysis.

BACKGROUND: This study aims to assess if radiofrequency ablation (RFA) has any oncological superiority over transarterial chemoembolization(TACE) on post-hepatectomy recurrence. METHODS: From 2002 to 2011, 60.15% of 823 patients developed recurrence after hepatectomy for HCC. One hundred and two patients with recurrence underwent RFA (n = 42) or TACE (n = 60) for tumour size ≤5 cm and number of lesions ≤ 3 when tumours were not resectable or transplantable. Those with renal impairment, portal vein thrombosis and poor liver reserve were excluded. The primary outcome was overall survival, which was determined using log-rank test and Kaplan-Meier plots performed. Categorical data were analysed using the chi-square test and continuous variable were analysed using the Mann-Whitney U-test. RESULTS: Demographics and primary tumour characteristics were similar in both groups (P > 0.05). Overall survival (OS) after an initial hepatectomy and salvage treatment for recurrence was similar (P > 0.05) in both groups with a 5-year OS after salvage treatment for RFA and TACE at 24.1% and 25.7%, respectively. For patients with the second recurrence after salvage treatment, an interchangeable treatment strategy of RFA and TACE conferred a better survival outcome than a stand-alone treatment with RFA or TACE (P < 0.05). CONCLUSIONS: RFA and TACE may be equally effective for intrahepatic recurrence after hepatectomy when the tumour size is ≤ 5 cm and ≤ 3 lesions when re-resection or salvage transplantation is not considered feasible.

Heterotopic pancreas - An expert in hide and seek.

INTRODUCTION AND IMPORTANCE: Heterotopic pancreas is rare and difficult to diagnose pre-operatively. Common sites for heterotopic pancreas such as the upper gastrointestinal tract, rarely involve the thorax, spleen, and kidney. Endoscopy imaging and CT imaging have been advocated to aid in diagnosis; however, they still present challenges. The majority of heterotopic pancreas patients are asymptomatic. CASE PRESENTATION: Our patient presented left-sided abdominal pain intermittently, each time after meals, with weight loss over the past three months. Imaging showed a small intraluminal growth at the posterior wall of the duodenum, with no metabolic activity detected from the PET scan. Given the symptomatic presentation, we proceeded with laparotomy and small bowel resection with primary anastomosis. HPE confirmed the presence of a heterotopic pancreas. Here, we discuss the management of the heterotopic pancreas and provide a literature review. CLINICAL DISCUSSION: The heterotopic pancreas shares a similar genetic makeup, physiological function, and local environment exposure as the pancreas. Similar complications, such as acute or chronic pancreatitis, abscesses, pseudocyst formation, and, rarely malignancy can also occur in the heterotopic pancreas. It is often difficult to detect a heterotopic pancreas. Factors such as the site, size, and characteristics of the lesion usually aid in diagnosis, whether through endoscopy or imaging. Biopsies can be taken via endoscopy if the lesion is accessible, but most biopsies are non-diagnostic. CONCLUSION: Heterotopic pancreas is rare and challenging to diagnose. Knowledge of common locations and characteristic imaging appearances of heterotopic pancreatic tissue aids in diagnosing. The definitive treatment is surgical resection.

Endoscopic Ultrasound-Guided Biliary Drainage: Endoscopic Ultrasound-Guided Hepaticogastrostomy in Malignant Biliary Obstruction.

Patients with unresectable malignant biliary obstruction often require biliary drainage to decompress the biliary system. Endoscopic Retrograde Cholangiopancreatography (ERCP) is the primary biliary drainage method whenever possible. Percutaneous Transhepatic Biliary Drainage (PTBD) is used as a salvage method if ERCP fails. Endoscopic Ultrasound-Guided Biliary Drainage (EUS-BD) provides a feasible alternative biliary drainage method where one of the methods is EUS guided Hepaticogastrostomy (EUS-HGS). Here we describe the EUS-HGS technique in a case of unresectable malignant hilar biliary obstruction to achieve biliary drainage. Presented here is the case of a 71-year-old female with painless jaundice and weight loss for 2 weeks. Computed Tomography (CT) imaging showed a 4 x 5 cm hilar tumor with lymphadenopathy and liver metastasis. EUS fine needle biopsy (FNB) of the lesion was consistent with cholangiocarcinoma. Her bilirubin levels were 212 µmol/L (<15) during presentation. A linear echoendoscope was used to locate the left dilated intrahepatic ducts (IHD) of the liver. The segment 3 dilated IHD was identified and punctured using a 19 G needle. Contrast was used to opacify the IHDs under fluoroscopic guidance. The IHD was cannulated using a 0.025-inch guidewire. This was followed by the dilation of the fistula tract using a 6 Fr electrocautery dilator along with a 4 mm biliary balloon dilator. A partially covered metallic stent of 10 cm in length was deployed under fluoroscopic guidance. The distal part opens in the IHD and the proximal part was deployed within the working channel of the echoendoscope that subsequently released into the stomach. The patient was discharged three days after the procedure. Follow up performed in the second and fourth weeks showed that the bilirubin levels were 30 µmol/L and 14 µmol/L, respectively. This indicates that EUS-HGS is a safe method for biliary drainage in unresectable malignant biliary obstruction.

Non-alcoholic fatty liver disease and obesity among adult donors are major challenges to living-donor liver transplantation: A single-center experience.

OBJECTIVES: Obesity and non-alcoholic fatty liver disease (NAFLD) are rampant in South East Asia. There is paucity of data exploring its' impact on donor suitability for living donor liver transplantation (LDLT). We aimed to describe and examine the factors related to non-utilization of potential donors in our LDLT programme. METHODS: This is an analysis of prospectively collected data on potential donors for an adult LDLT programme, between January 2017 and December 2019. RESULTS: Fifty-five donors for 33 potential recipients were evaluated. The mean age was 31.6 ± 8.5 years, 52.7% were female and the ethnic divisions were: Chinese (50.9%), Indian (25.5%) and Malay (23.6%). The mean body mass index (BMI) among potential donors was 25.1 ± 4.0 kg/m2; 25.5% of donors had normal BMI, 23.6% were overweight and 50.9% were obese. Using the CAP modality of Fibroscan®, we identified the following grades of hepatic steatosis: 36.6% S0, 19.5% S1, 2.4% S2 and 41.5% S3. The non-utilization rate of our donors was 74.5% (41/55) and the main reasons were significant hepatic steatosis and/or obesity. Compared to suitable donors, unsuitable donors had significantly greater mean BMI, mean CAP scores, higher rates of dyslipidaemia and NAFLD. CONCLUSION: NAFLD and obesity represent major challenges to an emerging LDLT programme in Malaysia.

Early identification of the critical view of safety in laparoscopic cholecystectomy using indocyanine green fluorescence cholangiography: A randomised controlled study.

BACKGROUND: Achieving critical view of safety (CVS) is vital during laparoscopic cholecystectomy (LC). There is no known study determining use of indocyanine green fluorescence cholangiography (ICGFC) in early identification of CVS during LC. This study aims to compare use of ICGFC in LC against conventional LC in early identification of CVS. METHODOLOGY: Patients undergoing LC in a single centre were randomized into ICGFC-LC and conventional LC. Surgery was performed by a single surgeon and the time taken to achieve CVS from the time of gallbladder fundus retraction was measured. Difficulty level for each surgery was rated and analysed using a modified scoring system (Level 1- Easy to Level 4-Very difficult). RESULTS: 63 patients were recruited where mean time (min) to achieve CVS was 22.3 ± 12.9 in ICGFC-LC (n = 30) and 22.8 ± 14.3 in conventional LC (p = 0.867). The time taken to achieve CVS was shorter in ICGFC-LC group across all difficulty levels, although not significant (p > 0.05). No major complication was observed in the study. CONCLUSIONS: This study had shown ICGFC-LC reduces time to CVS across all difficulty levels but not statistically significant. ICGFC-LC maybe useful in difficult LC and in surgical training. TRIAL REGISTRATION: Clinical Trials NCT04228835. STUDY GRANT: UMMI Surgical - Karl Storz Distributor (Malaysia).

Salmonella thyroid abscess-two case reports.

Acute suppurative thyroiditis account for <1% of thyroid diseases and is uncommon because of the gland's encapsulation, iodine-rich environment, good vascular supply and extensive lymphatic drainage. It has been reported in patients with underlying goiters, thyroid cancers and in immuno-compromised patients. The usual causative organisms are Staphylococci spp. and Streptococci spp. Rarer organisms include Klebsiella spp. and Salmonella spp. Due to its rarity (as there have been only 28 cases of Salmonella thyroid abscess being reported in the literature till 2020), only case reports are available to guide management. We report two cases of thyroid abscess due to Salmonella enteritidis in our institution that may herald the re-emergence of this uncommon infection of the thyroid gland and to raise awareness for all clinicians. Both patients presented with neck swelling, dysphagia and sepsis. Surgical intervention was warranted in both patients due to the severity of the disease and failed medical therapy. Recovery was uneventful following adequate surgical intervention and antibiotic therapy according to the culture and sensitivity report of the pathogen. This case report highlights that both patients were immunocompromised, and they contracted Salmonella thyroid abscess without any gastrointestinal involvement. Thus, a high index of suspicion for Salmonella thyroid abscess in immunocompromised patients can expedite the diagnosis and appropriate management can be commenced such as antibiotic therapy, percutaneous aspiration and surgical drainage in the event of failed medical therapy.

Adult-to-adult living donor liver transplantation: Operative techniques to optimize the recipient's outcome.

Adult-to-adult living donor liver transplantation (LDLT) is widely accepted today with good outcomes and safety reported worldwide for both donor and recipient. Nonetheless, it remained a highly demanding technical and complex surgery if undertaken. The last two decades have seen an increased in adult-to-adult LDLT following our first report of right lobe LDLT in overcoming graft size limitation in adults. In this article, we discussed the operative techniques and challenges of adult right lobe LDLT incorporating the middle hepatic vein, which is practiced in our center for the recipient operation. The various issues and challenges faced by the transplant surgeon in ensuring good recipient outcome are explored and discussed here as well. Hence, it is important to understand that a successful recipient operation is dependent of multifactorial events starting at the preoperative stage of planning, understanding the intraoperative technical challenges and the physiology of flow modulation that goes hand-in-hand with the operation. Therefore, one needs to arm oneself with all the possible knowledge in overcoming these technical challenges and the ability to be flexible and adaptable during LDLT by tailoring the needs of each patient individually.

Liver cancer in Malaysia: epidemiology and clinical presentation in a multiracial Asian population.

OBJECTIVE: Hepatocellular carcinoma (HCC) is an important cancer in Malaysia. This study aimed to determine the epidemiological characteristics and clinical presentations of patients in a multiracial population consisting of three major Asian races: Malays, Chinese and Indians. METHODS: Consecutive patients with HCC were prospectively studied from 2006 to 2009. HCC was diagnosed principally on multiphasic computed tomography and magnetic resonance imaging scans of the liver. The tumor was staged according to the Barcelona Clinic Liver Cancer (BCLC) classification. RESULTS: Altogether, 348 patients were diagnosed with HCC. There were 239 (68.7%) Chinese patients, 71 (20.4%) Malays and 38 (10.9%) Indians, with the median age of 62.5 years and the male to female ratio of 3.4:1. The predominant etiology in Malay and Chinese patients was hepatitis B virus infection (>60%) and in Indian patients was alcohol intake (26.3%) and cryptogenic cause (29.0%). Hepatitis C was seen in 18.3% of Malays, but less than 10% in Chinese and Indians. BCLC staging was: Stage A, 120 (34.5%); Stage B, 75 (21.6%); Stage C, 84 (24.1%); and Stage D, 69 (19.8%). A larger proportion of Indian than Chinese and Malays patients (44.7%) presented with stage D disease. Portal vein invasion was noted in 124 patients (35.6%) and extrahepatic metastases in 68 (19.5%). Surgical resection and radiofrequency ablation with curative intent was carried out in >90% of stage A patients and transarterial chemoembolization in 49.3% and 21.4% of stages B and C patients, respectively. CONCLUSIONS: HCC is most common among Chinese, followed by Malays and Indians in Malaysia. The etiology of HCC shows a peculiar racial pattern.

Jaundice and life-threatening hemobilia: an uncommon presentation of choledochal cyst.

Hemobilia with jaundice as a result of cholestasis and bleeding from choledochal cyst is uncommon. Ascertaining the diagnosis is often challenging and delayed diagnosis can lead to significant consequences due to hemodynamic instability, particularly in elderly patients. Although surgery remains the definitive treatment modality, interventional radiology for hemostasis has been increasingly recognized as an option. In this manuscript, we described two Malaysian cases of jaundice and hemobilia associated with choledochal cysts and the challenges related with clinical diagnosis and management.

Concurrent amoebic and histoplasma colitis: a rare cause of massive lower gastrointestinal bleeding.

Infective colitis can be a cause of massive lower gastrointestinal bleeding requiring acute surgical intervention. Causative organisms include entamoeba and histoplasma species. However, concurrent colonic infection with both these organisms is very rare, and the in vivo consequences are not known. A 58-year-old male presented initially to the physicians with pyrexia of unknown origin and bloody diarrhea. Amoebic colitis was diagnosed based on biopsies, and he was treated with metronidazole. Five days later, the patient developed massive lower gastrointestinal bleeding with hemorrhagic shock. Emergency total colectomy with end-ileostomy was performed. However, he deteriorated and died on the second postoperative day. Histopathological examination revealed multiple deep ulcers at the hepatic flexure where fungal bodies of mycelial and yeast forms were noted. Isolated lymph nodes showed abscess formation with fungal bodies. Infective fungal colitis with Histoplasma capsilatum was diagnosed. In vitro, amoebic parasites can increase virulence and pathogenicity of histoplasma which may account for the fulminant presentation in this patient. Although rare, this unusual dual infection should be considered in the differential diagnosis of infective colitis, as appropriate antimicrobial treatment may prevent progression to massive lower gastrointestinal bleeding, obviating the need for urgent surgical intervention.