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The PNPLA3 rs738409 single-nucleotide polymorphism is known to promote nonalcoholic steatohepatitis (NASH), but its association with fibrosis severity and hepatocellular carcinoma (HCC) risk is less well-defined. The objectives of this study were to determine the association between PNPLA3 and liver fibrosis severity, HCC risk, and HCC prognosis among patients with liver disease. We performed a systematic literature review using the Medline, PubMed, Scopus, and Embase databases through May 2013 and a manual search of national meeting abstracts from 2010 to 2012. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios (ORs), according to PNPLA3 genotype, were calculated using the DerSimonian and Laird method for a random effects model. Among 24 studies, with 9,915 patients, PNPLA3 was associated with fibrosis severity (OR 1.32, 95% confidence interval (CI) 1.20-1.45), with a consistent increased risk across liver disease etiologies. Among nine studies, with 2,937 patients, PNPLA3 was associated with increased risk of HCC in patients with cirrhosis (OR 1.40, 95% CI 1.12-1.75). On subgroup analysis, increased risk of HCC was demonstrated in patients with NASH or alcohol-related cirrhosis (OR 1.67, 95% CI 1.27-2.21) but not in those with other etiologies of cirrhosis (OR 1.33, 95% CI 0.96-1.82). Three studies, with 463 patients, do not support an association between PNPLA3 and HCC prognosis but are limited by heterogeneous outcome measures. For all outcomes, most studies were conducted in homogenous Caucasian populations, and studies among racially diverse cohorts are needed. PNPLA3 is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with nonalcoholic steatohepatitis or alcohol-related cirrhosis.

Only 40% of patients with hepatocellular carcinoma (HCC) are diagnosed at an early stage, suggesting breakdowns in the surveillance process. The aim of our study was to assess the reasons behind surveillance process failures among patients in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial (HALT-C), which prospectively collected HCC surveillance data on a large cohort of patients. Binary regression analysis was used to identify predictors of consistent surveillance, which was defined as having an ultrasound and alpha-fetoprotein every 12 months. Surveillance failures among patients who developed HCC were classified into one of three categories: absence of screening, absence of follow-up, or absence of detection. Over a mean follow-up of 6.1 years, 692 (68.9%) of 1,005 patients had consistent surveillance. Study site was the strongest predictor of consistent surveillance (P<0.001). After adjusting for study site, patient-level predictors of consistent surveillance included platelet count >150,000/mm(3) (hazard ratio (HR) 1.28; 95% confidence interval (CI): 1.05-1.56) and complete clinic visit adherence (HR 1.72, 95% CI: 1.11-2.63). Of 83 patients with HCC, 23 (27.7%) were detected beyond Milan criteria. Three (13%) had late-stage HCC due to the absence of screening, 4 (17%) due to the absence of follow-up, and 16 (70%) due to the absence of detection. Surveillance process failures, including absence of screening or follow-up, are common and potentially contribute to late-stage tumors in one-third of cases. However, the most common reason for finding HCC at a late stage was an absence of detection, suggesting better surveillance strategies are needed.

BackgroundMinimally invasive pancreaticoduodenectomy (MIPD) is being performed with increasing frequency for pancreatic cancer, but the most oncologically efficacious surgical platform, whether robotic or laparoscopic, is yet to be determined. Currently, there are no national studies comparing the oncological outcomes between robotic (RPD) and laparoscopic (LPD) pancreaticoduodenectomy.MethodsThis was a retrospective study using the National Cancer Database between 2010 and 2013. We compared the perioperative, pathological, and mid-term oncological outcomes between RPD and LPD.ResultsThere were 1623 MIPD cases, of which 90% were LPD and 10% were RPD. Most LPD (63%) and RPD (51%) cases were performed at institutions with a volume of ≤ 5 MIPDs per year. There were no differences in patient- and tumor-related factors between the groups. The majority of treated tumors were adenocarcinoma (90.1% for RPD and 89.1% for LPD). RPDs were more likely to be performed at academic centers (89.1%) compared to LPDs (68.1%, P < 0.001) and at higher-volume centers (median MIPD/year of 4.7 for RPD vs 3.6 for LPD, P < 0.001). There was no difference in the median number of examined lymph nodes, margin status, median length of stay, 90-day mortality, or 30-day readmission between groups. There was no difference in median overall survival for pancreatic adenocarcinoma between LPD (20.7 months) and RPD (22.7 months; log-rank P = 0.445). The 1- and 3-year overall survival rates were 74 and 31% for LPD and 71 and 33% for RPD.ConclusionIn this national cohort of patients, LPD and RPD were associated with equivalent perioperative, pathological, and mid-term oncological outcomes.

Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3–11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment. Bavituximab is a genetically engineered IgG1 chimeric antibody that targets phosphatidylserine. Here the authors report the results of a single-arm phase 2 trial of bavituximab in combination with pembrolizumab (anti-PD1) for patients with unresectable hepatocellular carcinoma.

BackgroundPerformance of technically complex surgery at high-volume (HV) centers is associated with improved outcomes.ObjectiveThe aim of this study was to assess whether hospital gastrectomy volume is associated with surgical outcomes, and what threshold of case volume meaningfully impacts surgical outcomes.MethodsWe conducted a retrospective review of adult NCDB patients with gastric adenocarcinoma undergoing gastrectomy between 2004 and 2015. A multivariable Cox proportional hazards model with restricted cubic splines was used to examine the association of annual hospital gastrectomy volume and overall survival. Bootstrap simulation was used to estimate the cut-point corresponding to maximum change in log hazard ratio. Hospitals were divided into HV (≥ 17 cases/year) and low-volume (LV; < 17 cases/year) groups. We examined the relationship between volume groups and adequate nodal examination, R0 resection, unplanned readmission, and 30- and 90-day mortality.ResultsOur cohort consisted of 29,559 patients (7.8% treated at an HV center). Treatment at an HV center was associated with an increased likelihood of adequate nodal examination [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.94–2.32] and R0 resection among patients with cardia tumors (OR 1.42, 95% CI 1.07–1.88). Patients treated at HV centers had decreased 30- and 90-day postoperative mortality, which was more pronounced in those undergoing total gastrectomy.ConclusionsTreatment at an HV gastrectomy center is associated with improved surgical outcomes. Our study identified 17 cases/year as a clinically meaningful distinction between HV and LV centers. This definition of an HV center should be considered when evaluating regionalization of gastric cancer care to improve patient outcomes.

Background An increasing body of literature is supporting the safety of minimally invasive pancreaticoduodenectomy compared to open pancreaticoduodenectomy, but there are limited comparative studies between laparoscopic and robotic pancreaticoduodenectomy. The aim of this study was to compare the rate of postoperative 30-day overall complications between laparoscopic and robotic pancreaticoduodenectomy. Methods Patients who underwent laparoscopic and robotic pancreaticoduodenectomy were abstracted from the 2014–2015 pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program. A multivariable logistic regression model was developed to determine if the type of minimally invasive approach was associated with 30-day overall complications. Results We identified 428 minimally invasive pancreaticoduodenectomy cases, of which 235 (55%) were performed laparoscopically and 193 (45%) robotically. Patients who underwent the robotic approach were more likely to be white compared to those who underwent the laparoscopic approach and were less likely to have pulmonary disease, undergo preoperative radiotherapy, and have vascular and multivisceral resection. On multivariable analysis, we found that the type of minimally invasive approach, whether laparoscopic or robotic, was not associated with overall complications. The predictors of 30-day overall complications were higher body mass index (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02–1.09), vascular resection (OR, 2.10; 95% CI, 1.23–3.58), and longer operative time (OR, 1.002; 95% CI, 1.001–1.004). Conclusions Robotic pancreaticoduodenectomy was associated with a similar 30-day overall complication rate to laparoscopic pancreaticoduodenectomy. Further studies are needed to corroborate these findings and to establish the best approach to perform this complex operation.

Background Data on the risk factors for conversion during minimally invasive distal pancreatectomy (MIDP) and its effect on postoperative outcomes are limited. Methods This retrospective study used the pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program database to compare MIDP requiring unplanned conversion with completed MIDP and open distal pancreatectomy (ODP). Results Of the 2926 cases identified in this study, 48.8% had ODP, 42.8% had MIDP, and 7.9% had conversion to MIDP. The conversion rate was 15.3% overall, 17.3% for laparoscopic surgery, and 8.5% for robotic surgery ( p  < 0.001). The risk factors associated with conversion were higher body mass index (BMI), low preoperative albumin level, a current smoking habit, and malignant T3/T4 disease or chronic pancreatitis compared with benign tumor smaller than 5 cm. A robotic approach was associated with a lower adjusted conversion rate than laparoscopy (odds ratio [OR] 0.32; 95% confidence interval [CI] 0.19–0.52). After adjustment, conversion was associated with a higher overall complication rate than MIDP (OR 1.89; 95% CI 1.35–2.66) or ODP (OR 1.41; 95% CI 1.00–1.98). Conclusions Chronic pancreatitis, large malignant tumors, higher BMI, lower serum albumin, and a current smoking habit were shown to be independent risk factors for conversion during MIDP. A robotic approach was associated with a lower conversion rate than laparoscopic MIDP. Conversion of MIDP was associated with a higher overall complication rate than completed MIDP or ODP. Adequate patient selection for MIDP may prevent conversion and associated increased morbidity.

Professional society guidelines recommend semiannual screening for hepatocellular carcinoma (HCC) in patients with cirrhosis; however, studies suggest underuse of screening in clinical practice. Our study’s aim was to characterize reasons for HCC screening underuse among patients with cirrhosis. We conducted a retrospective cohort study of patients with cirrhosis diagnosed with HCC in two large health systems from 2011 to 2019. We classified screening receipt as consistent, inconsistent, or no screening in the year before HCC diagnosis. We categorized reasons for screening underuse as a potential failure at each of the following steps required for HCC screening: receipt of regular outpatient care, recognition of liver disease, recognition of cirrhosis, screening orders in patients with cirrhosis, and adherence to screening ultrasound appointments. Among 1,014 patients with cirrhosis with HCC, only 377 (37.2%) had regular outpatient care in the year before HCC presentation. Consistent screening was observed in 93 (24.7%) patients under regular outpatient care, whereas 161 (42.7%) had inconsistent screening and 123 (32.6%) no screening. We found screening underuse related to failures at each step in the screening process, although nearly half (49.6%) were due to lack of screening orders in patients with known cirrhosis. Conclusion: The most common reasons for HCC screening underuse in patients with cirrhosis are lack of regular outpatient care and lack of screening orders in those with known cirrhosis, highlighting the need for interventions targeted at these steps to increase HCC screening use. In a retrospective cohort study of 1014 cirrhosis patients diagnosed with HCC in two large health systems, we categorized reasons for screening underuse: receipt of regular outpatient care, recognition of liver disease, recognition of cirrhosis, screening orders in patients with cirrhosis, and adherence to screening ultrasound appointments. Only 377 (37.2%) patients had regular outpatient care in the year prior to HCC presentation, of whom 93 (24.7%) had consistent screening, 161 (42.7%) had inconsistent screening, and 123 (32.6%) no screening. We found screening underuse related to failures at each step in the screening process, although nearly half (49.6%) were due to lack of screening orders in patients with known cirrhosis.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related deaths worldwide. Once considered an experimental treatment with dismal survival rates, liver transplantation for HCC entered a new era with the establishment of the Milan criteria over 20 years ago. In the modern post‐Milan‐criteria era, 5‐year survival outcomes are now upwards of 70% in select patients. Liver transplantation (LT) is now considered the optimal treatment for patients with moderate to severe cirrhosis and HCC, and the rates of transplantation in the United States are continuing to rise. Several expanded selection criteria have been proposed for determining which patients with HCC should be candidates for undergoing LT with similar overall and recurrence‐free survival rates to patients within the Milan criteria. There is also a growing experience with downstaging of patients who fall outside conventional LT criteria at the time of HCC diagnosis with the goal of tumor shrinkage via locoregional therapies to become a candidate for transplantation. The aim of this review article is to characterize the various patient selection criteria for LT, discuss balancing organ stewardship with outcome measures in HCC patients, present evidence on the role of downstaging for large tumors, and explore future directions of LT for HCC. Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related deaths worldwide. Once considered experimental treatment with dismal survival rates, liver transplantation for HCC entered a new era with the establishment of the Milan criteria over 20 years ago. The aim of this review article is to characterize the various patient selection criteria for liver transplantation, discuss balancing organ stewardship with outcome measures in HCC patients, present evidence on the role of downstaging for large tumors, and explore future directions of liver transplantation for HCC.