Early experience with robot-assisted laparoscopic hepatobiliary and pancreatic surgery in Singapore: single-institution experience with 20 consecutive patients.

INTRODUCTION: Experience with robot-assisted laparoscopic (RAL) hepatobiliary and pancreatic (HPB) surgery remains limited worldwide. In this study, we report our early experience with RAL HPB surgery in Singapore. METHODS: A retrospective review of the first 20 consecutive patients who underwent RAL HPB surgery at a single institution over a 34-month period from February 2013 to November 2015 was conducted. The 20 cases were performed by three principal surgeons, of which 17 (85.0%) were performed by a single surgeon. RESULTS: The median age of patients was 56 (range 22-75) years and median tumour size was 4.0 (range 1.2-7.5) cm. The surgeries performed included left-sided pancreatectomies (n = 10), hepatectomies (n = 7), triple bypass with bile duct exploration for obstructing pancreatic head cancer with choledocholithiasis (n = 1), cholecystectomy for Mirizzi's syndrome (n = 1) and gastric resection for gastrointestinal stromal tumour (n = 1). The median operation time was 445 (range 80-825) minutes and median blood loss was 350 (range 0-1,200) mL. There was only 1 (5%) open conversion. There were 2 (10.0%) major morbidities (> Grade II on the Clavien-Dindo classification) and no 30-day/in-hospital mortalities. There was no reoperation for postoperative complications. The median postoperative stay was 5.5 (range 3-22) days. CONCLUSION: Our initial experience confirms the feasibility and safety of RAL HPB surgery.

Single administration of Selective Internal Radiation Therapy versus continuous treatment with sorafeNIB in locally advanced hepatocellular carcinoma (SIRveNIB): study protocol for a phase iii randomized controlled trial.

BACKGROUND: Approximately 20 % of hepatocellular carcinoma (HCC) patients diagnosed in the early stages may benefit from potentially curative ablative therapies such as surgical resection, transplantation or radiofrequency ablation. For patients not eligible for such options, prognosis is poor. Sorafenib and Selective Internal Radiation Therapy (SIRT) are clinically proven treatment options in patients with unresectable HCC, and this study aims to assess overall survival following either SIRT or Sorafenib therapy for locally advanced HCC patients. METHODS: This investigator-initiated, multi-centre, open-label, randomized, controlled trial will enrol 360 patients with locally advanced HCC, as defined by Barcelona Clinic Liver Cancer stage B or stage C, without distant metastases, and which is not amenable to immediate curative treatment. Exclusion criteria include previous systemic therapy, metastatic disease, complete occlusion of the main portal vein, or a Child-Pugh score of >7. Eligible patients will be randomised 1:1 and stratified by centre and presence or absence of portal vein thrombosis to receive either a single administration of SIRT using yttrium-90 resin microspheres (SIR-Spheres®, Sirtex Medical Limited, Sydney, Australia) targeted at HCC in the liver by the trans-arterial route or continuous oral Sorafenib (Nexavar®, Bayer Pharma AG, Berlin, Germany) at a dose of 400 mg twice daily until disease progression, no further response, complete regression or unacceptable toxicity. Patients for both the Sorafenib and SIRT arms will be followed-up every 4 weeks for the first 3 months and 12 weekly thereafter. Overall survival is the primary endpoint, assessed for the intention-to-treat population. Secondary endpoints are tumour response rate, time-to-tumour progression, progression free survival, quality of life and down-staging to receive potentially curative therapy. DISCUSSION: Definitive data comparing these two therapies will help to determine clinical practice in the large group of patients with locally advanced HCC and improve outcomes for such patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01135056 , first received 24, May 2010.

National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world, but the second most common cause of cancer death. There is no universally accepted consensus practice guidelines for HCC owing to rapid developments in new treatment modalities, the heterogeneous epidemiology and clinical presentation of HCC worldwide. However, a number of regional and national guidelines currently exist which reflect practice relevant to the epidemiology and collective experience of the consensus group. In 2014, clinicians at the multidisciplinary Comprehensive Liver Cancer Clinic (CLCC) at the National Cancer Centre Singapore (NCCS) reviewed the latest published scientific data and existing international and regional practice guidelines, such as those of the National Comprehensive Cancer Network, American Association for the Study of Liver Diseases and the Asian Pacific Association for the Study of the Liver, and modified them to reflect local practice. These would serve as a template by which treatment outcomes can be collated and benchmarked against international data. The NCCS Consensus Guidelines for HCC have been successfully implemented in the CLCC since their publication online on 26(th) September 2014, and the guidelines allow outcomes of treatment to be compared to international data. These guidelines will be reviewed periodically to incorporate new data.

Robotic hepatectomy: initial experience of a single institution in Singapore.

INTRODUCTION: In this study, we report our initial experience with robotic hepatectomy. METHODS: Consecutive patients who underwent robotic hepatectomy at Singapore General Hospital, Singapore, from February 2013 to February 2015 were enrolled in this study. The difficulty level of operations was graded using a novel scoring system for laparoscopic hepatectomies. RESULTS: During the two-year period, five consecutive robotic hepatectomies were performed (one left lateral sectionectomy, one non-anatomical segment II/III resection, one anatomical segment V resection with cholecystectomy, one extended right posterior sectionectomy and one non-anatomical segment V/VI resection). Two hepatectomies were performed for suspected hepatocellular carcinoma, two for solitary liver metastases and one for a large symptomatic haemangioma. The median age of the patients was 53 (range 38-66) years and the median tumour size was 2.5 (range 2.1-7.3) cm. The median total operation time was 340 (range 155-825) minutes and the median volume of blood loss was 300 (range 50-1,200) mL. There were no open conversions and no mortalities or major morbidities (> Clavien-Dindo Grade II). The difficulty level of the operations was graded as low in one case (Score 2), intermediate in three cases (Score 5, 6 and 6) and high in one case (Score 10). There was one minor morbidity, where the patient experienced Grade A bile leakage, which resolved spontaneously. The median length of postoperative hospital stay was 5 (range 4-7) days. CONCLUSION: Our initial experience confirmed the feasibility and safety of robotic hepatectomy.

First experience with robotic spleen-saving, vessel-preserving distal pancreatectomy in Singapore: a report of three consecutive cases.

INTRODUCTION: The use of laparoscopic distal pancreatectomy (LDP) has increased worldwide due to the reported advantages associated with this minimally invasive procedure. However, widespread adoption is hindered by its technical complexity. Robotic distal pancreatectomy (RDP) was introduced to overcome this limitation, but worldwide experience with RDP is still lacking. There is presently evidence that RDP is associated with decreased conversion rate and increased splenic preservation as compared to LDP. METHODS: We conducted a prospective study on our initial experience with robotic spleen-saving, vessel-preserving distal pancreatectomy (SSVP-DP) between July 2013 and April 2014. RESULTS: Three consecutive patients underwent attempted robotic SSVP-DP. The indications were a 2.1-cm indeterminate cystic neoplasm, 4.5-cm solid pseudopapillary neoplasm and 1.2-cm pancreatic neuroendocrine tumour. For all three patients, the procedure was completed without conversion, and the spleen, with its main vessels, was successfully conserved. The median total operation time, blood loss and postoperative stay were 350 (range 300-540) minutes, 200 (range 50-300) mL and 7 (range 6-14) days, respectively. Two patients had minor Clavien-Dindo Grade I complications (one Grade A pancreatic fistula and one postoperative ileus). One patient had a Clavien-Dindo Grade IIIa complication (Grade B pancreatic fistula requiring percutaneous drainage). All patients were well at the time of reporting after at least six months of follow-up. CONCLUSION: Our preliminary experience with robotic SSVP-DP confirmed the feasibility of the procedure.

Factors associated with and outcomes of open conversion after laparoscopic minor hepatectomy: initial experience at a single institution.

BACKGROUND: Laparoscopic liver resection has been increasingly adopted worldwide as a result of the rapid advancement in surgical techniques and equipment. This study aims to determine the factors associated with and outcomes of open conversion after laparoscopic minor hepatectomy (LMH) based on a single center multi-surgeon experience. METHODS: This is a retrospective review of the first 147 consecutive LMH performed between 2006 and April 2014 at a single institution. Data on patient demographics, pathology results, perioperative outcomes, and operative results were collected. Factors associated with open conversion were analyzed via univariate analysis and a P value <.05 was considered statistically significant. RESULTS: LMH was performed for malignancy in 114 (77.6%) patients of which hepatocellular carcinoma (n = 82) and colorectal metastases (n = 16) were the most common pathologies. Forty-one (27.9%) patients had cirrhotic livers and 18 (15.7%) had fibrotic livers. Fifty patients (44%) had concomitant surgery in addition to LMH. Twenty (13.6%) procedures required open conversion and the most common reason was for bleeding (n = 12). Twenty-five patients (17%) experienced postoperative complications. Univariate analyses demonstrated that only individual surgeon volume (n ≤ 10 cases) [15 (24.2%) vs 5 (5.9%), P = .001] and institution volume (n ≤ 25 cases) [8 (32%) vs 12 (9.8%), P = .003] were factors associated with open conversion. Open conversion was significantly associated with increased intra-operative blood loss, increased intra-operative blood transfusion, increased postoperative morbidity, and longer postoperative stay. CONCLUSIONS: Individual surgeon and institution volumes were important factors associated with open conversion after LMH. Open conversion after LMH resulted in poorer outcomes compared to procedures that were successfully completed laparoscopically.

Laparoscopic liver resection for posterosuperior and anterolateral lesions-a comparison experience in an Asian centre.

BACKGROUND: Minimally invasive surgery has been one of the recent developments in liver surgery, laparoscopic liver resection (LLR) was initially performed for benign lesions at easily accessible locations. As the surgical techniques, technology and experience improved over the past decades, LLR surgery had evolved to tackle malignant lesions, major resections and even in difficult locations without compromising safety and principles of oncology. It was also shown to be beneficial in cirrhotic patients. We describe our initial experience with LLR in a population with significant proportion having cirrhosis, emphasising our approach for lesions in the posterosuperior (PS) segments of the liver (segments 1, 4a, 7, and 8). METHODS: A review of patients undergoing LLR in single institution from 2006 to 2015 was performed from a prospective surgical database. Clinicopathological, operative and perioperative parameters were analyzed to compare outcomes in patients who underwent LLR for PS vs. anterolateral lesions (AL). RESULTS: LLR was performed in consecutive 197 patients, with a mean age of 60 years. The indications for resection were hepatocellular carcinoma (HCC) (n=105; 53%), colorectal cancer liver metastasis (n=31; 16%), other malignancies (n=19; 10%) and benign lesions (n=42; 21%). A significant proportion had liver cirrhosis (25.9%). More females underwent surgery in the AL group and indications for surgery were similar between both groups. Major liver resection was performed more frequently for the PS group than for the AL group (P<0.001) and significantly more PS resections was performed in our latter experience (P=0.02). The mean operative time and the conversion rate were significantly greater in the PS group than in the AL group (P≤0.001 and 0.03, respectively). However, the estimated blood loss (EBL), rate of blood transfusion and mean postoperative stay were similar in the two groups (P=0.04, 0.88 and 0.92, respectively). The overall 90-day morbidity and mortality rate was 21.3% and 0.5% respectively, with no differences between the two groups. Surrogates of difficulty such as operative time, blood loss, conversion and outcomes e.g., morbidity and mortality, were similar in patients who underwent PS resections with or without cirrhosis. CONCLUSIONS: LLR in selected patients is technically feasible and safe including cirrhotic patients with lesions in the PS segments.

Number of nodules, Child-Pugh status, margin positivity, and microvascular invasion, but not tumor size, are prognostic factors of survival after liver resection for multifocal hepatocellular carcinoma.

BACKGROUND: Presently, the role of liver resection (LR) for multifocal hepatocellular carcinoma (HCC) remains controversial. However, in many regions worldwide, LR remains the only treatment modality available to such patients which offers the possibility of long-term cure. The aim of this study is to determine the outcomes and prognostic factors of patients with multifocal HCC after LR. METHODS: This is a retrospective analysis of 110 patients who underwent potentially curative LR for pathologically proven multifocal HCC between 2000 and 2011. RESULTS: The median age was 64 (range, 18-84) years, and there were 88 males (80.0 %). Sixty-one patients underwent a major hepatectomy, and the overall postoperative mortality was 1.8 %. Sixty-eight patients had liver cirrhosis, of which, 58 were child's A and 10 were child's B. The 1- and 5-year overall survival (OS) was 82 and 44 %, respectively. The corresponding 1- and 5-year recurrence-free survival (RFS) was 57 and 19 %, respectively. Multivariate analysis demonstrated that the number of nodules (>3) and presence of microvascular invasion were associated with RFS. Number of nodules (>3), margin positivity, Child-Pugh status, and presence of microvascular invasion were independent prognostic factors of OS. CONCLUSIONS: LR followed by treatment of recurrences may result in reasonable long-term survival and should be considered in a selected group of patients with multifocal HCC. Number of nodules (>3), margin positivity, Child-Pugh status, and presence of microvascular invasion, but not tumor size, were independent negative predictors of OS. These findings have potential implications on the AJCC staging for multifocal HCC.

Are the Sendai and Fukuoka consensus guidelines for cystic mucinous neoplasms of the pancreas useful in the initial triage of all suspected pancreatic cystic neoplasms? A single-institution experience with 317 surgically-treated patients.

BACKGROUND: The Sendai Consensus Guidelines (SCG) were formulated in 2006 and updated in Fukuoka in 2012 (FCG) to guide management of cystic mucinous neoplasms of the pancreas. This study aims to evaluate the clinical utility of the SCG and FCG in the initial triage of all suspected pancreatic cystic neoplasms. STUDY DESIGN: Overall, 317 surgically-treated patients with a suspected pancreatic cystic neoplasm were classified according to the SCG as high risk (HR(SCG)) and low risk (LR(SCG)), and according to the FCG as high risk (HR(FCG)), worrisome (W(FCG)), and low risk (LR(FCG)). Cystic lesions of the pancreas (CLP) were classified as potentially malignant/malignant or benign according to the final pathology. RESULTS: The presence of symptoms, proximal lesions with obstructive jaundice, elevated serum carcinoembryonic antigen/carbohydrate antigen 19-9 (CEA/CA 19-9), size ≥3 cm, presence of solid component, main pancreatic duct dilatation, thickened enhancing walls, and change in ductal caliber with distal atrophy were predictive of a potentially malignant/malignant CLP on univariate analyses. The positive predictive value (PPV) and negative predictive value (NPV) of HR(SCG) and HR(ICG2012) for a potentially malignant/malignant lesion was 67 and 88 %, and 88 and 92.5 %, respectively. There were no malignant lesions in both LR groups but some potentially malignant lesions such as cystic pancreatic neuroendocrine neoplasms with uncertain behavior were classified as LR. CONCLUSION: The updated FCG was superior to the SCG for the initial triage of all suspected pancreatic cystic neoplasms. CLP in the LR(FCG) group can be safely managed conservatively, and those in the HR(FCG) group should undergo resection.

Evaluation of the Sendai and 2012 International Consensus Guidelines based on cross-sectional imaging findings performed for the initial triage of mucinous cystic lesions of the pancreas: a single institution experience with 114 surgically treated patients.

BACKGROUND: The Sendai Consensus Guidelines (SCG) were formulated in 2006 to guide the management of mucinous cystic lesions of the pancreas (CLPs) and were updated in 2012 (International Consensus Guidelines, ICG 2012). This study aims to evaluate the clinical utility of the ICG 2012 with the SCG based on initial cross-sectional imaging findings. METHODS: One hundred fourteen patients with mucinous CLPs were reviewed and classified according to the ICG 2012 as high risk (HR(ICG2012)), worrisome (W(ICG2012)), and low risk (LR(ICG2012)), and according to the SCG as high risk (HR(SCG)) and low risk (LR(SCG)). RESULTS: On univariate analysis, the presence of symptoms, obstructive jaundice, elevated serum carcinoembryonic antigen (CEA)/carbohydrate antigen (CA)19-9, solid component, main pancreatic duct ≥ 10 mm, and main pancreatic duct ≥ 5 mm was associated with high grade dysplasia/invasive carcinoma in all mucinous CLPs. Increasing number of HR(SCG) or HR(ICG2012) features was associated with a significantly increased likelihood of malignancy. The positive predictive value of HR(SCG) and HR(ICG2012) for high grade dysplasia/invasive carcinoma was 46% and 62.5% respectively. The negative predictive value of both LR(SCG) and LR(ICG2012) was 100%. CONCLUSION: Both the guidelines were useful in the initial cross-sectional imaging evaluation of mucinous CLPs. The ICG 2012 guidelines were superior to the SCG guidelines.

Nonvirally modified autologous primary hepatocytes correct diabetes and prevent target organ injury in a large preclinical model.

BACKGROUND: Current gene- and cell-based therapies have significant limitations which impede widespread clinical application. Taking diabetes mellitus as a paradigm, we have sought to overcome these limitations by ex vivo electrotransfer of a nonviral insulin expression vector into primary hepatocytes followed by immediate autologous reimplantation in a preclinical model of diabetes. METHODS AND RESULTS: In a single 3-hour procedure, hepatocytes were isolated from a surgically resected liver wedge, electroporated with an insulin expression plasmid ex vivo and reimplanted intraparenchymally under ultrasonic guidance into the liver in each of 10 streptozotocin-induced diabetic Yorkshire pigs. The vector was comprised of a bifunctional, glucose-responsive promoter linked to human insulin cDNA. Ambient glucose concentrations appropriately altered human insulin mRNA expression and C-peptide secretion within minutes in vitro and in vivo. Treated swine showed correction of hyperglycemia, glucose intolerance, dyslipidemia and other metabolic abnormalities for > or = 47 weeks. Metabolic correction correlated significantly with the number of hepatocytes implanted. Importantly, we observed no hypoglycemia even under fasting conditions. Direct intrahepatic implantation of hepatocytes did not alter biochemical indices of liver function or induce abnormal hepatic lobular architecture. About 70% of implanted hepatocytes functionally engrafted, appeared histologically normal, retained vector DNA and expressed human insulin for > or = 47 weeks. Based on structural tissue analyses and transcriptome data, we showed that early correction of diabetes attenuated and even prevented pathological changes in the eye, kidney, liver and aorta. CONCLUSIONS: We demonstrate that autologous hepatocytes can be efficiently, simply and safely modified by electroporation of a nonviral vector to express, process and secrete insulin durably. This strategy, which achieved significant and sustained therapeutic efficacy in a large preclinical model without adverse effects, warrants consideration for clinical development especially as it could have broader future applications for the treatment of other acquired and inherited diseases for which systemic reconstitution of a specific protein deficiency is critical.