Erin Maynard

Targeting the Wnt/β-Catenin Signaling Pathway in Liver Cancer Stem Cells and Hepatocellular Carcinoma Cell Lines with FH535

Activation of the Wnt/β-catenin pathway has been observed in at least 1/3 of hepatocellular carcinomas (HCC), and a significant number of these have mutations in the β-catenin gene. Therefore, effective inhibition of this pathway could provide a novel method to treat HCC. The purposed of this study was to determine whether FH535, which was previously shown to block the β-catenin pathway, could inhibit β-catenin activation of target genes and inhibit proliferation of Liver Cancer Stem Cells (LCSC) and HCC cell lines. Using β-catenin responsive reporter genes, our data indicates that FH535 can inhibit target gene activation by endogenous and exogenously expressed β-catenin, including the constitutively active form of β-catenin that contains a Serine37Alanine mutation. Our data also indicate that proliferation of LCSC and HCC lines is inhibited by FH535 in a dose-dependent manner, and that this correlates with a decrease in the percentage of cells in S phase. Finally, we also show that expression of two well-characterized targets of β-catenin, Cyclin D1 and Survivin, is reduced by FH535. Taken together, this data indicates that FH535 has potential therapeutic value in treatment of liver cancer. Importantly, these results suggest that this therapy may be effective at several levels by targeting both HCC and LCSC.

Long-term outcome of patients undergoing liver transplantation for mixed hepatocellular carcinoma and cholangiocarcinoma: an analysis of the UNOS database

BACKGROUND Mixed hepatocellular and cholangiocarcinoma (HCC-CC) have been associated with a poor prognosis after liver transplantation (LT). We aimed to evaluate long-term outcomes in patients undergoing LT for HCC-CC versus patients with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC). METHODS Retrospective analysis of the United Network for Organ Sharing (UNOS) database from 1994-2013. Overall survival (OS) in patients with HCC-CC, HCC, and CC, were compared. RESULTS We identified 4049 patients transplanted for primary malignancy (94 HCC-CC; 3515 HCC; 440 CC). Mean age of patients with HCC-CC was 57 ± 10 years, and 77% were male. MELD score did not differ among the groups (p = 0.637). Hepatitis C virus was the most common secondary diagnosis within the HCC-CC (44%) and HCC (36%) cohorts, with primary sclerosing cholangitis in the CC (16%) cohort. OS rates at 1, 3 and 5 years for HCC-CC (82%, 47%, 40%) were similar to CC (79%, 58%, 47%), but significantly worse than HCC (86%, 72%, and 62% p = 0.002). DISCUSSION Patients undergoing LT for HCC had significantly better survival compared to those transplanted for HCC-CC and CC. LT for mixed HCC-CC confers a survival rate similar to selected patients with CC. Efforts should be made to identify HCC-CC patients preoperatively.

Increased morbidity and mortality of a concomitant colectomy during a pancreaticoduodenectomy: an NSQIP propensity-score matched analysis

BACKGROUND Select patients with peri-ampullary cancers require concomitant colon resection (CR) during a pancreaticoduodenectomy (PD) for margin-negative resections. This study analysed the impact of concomitant CR on major morbidity (MM) and mortality. METHODS National Surgical Quality Improvement Program (NSQIP) patients undergoing PD for peri-ampullary cancers were identified from 2005 to 2012. A 4 : 1 propensity-score matched analysis isolated the impact of CR upon PD. Risk factors for 30-day MM and mortality were analysed to determine post-operative sequelae of PD+CR. RESULTS From 10 965 PD and 159 PD+CR patients, 624 and 156, respectively, were selected for 4 : 1 matched analysis. PD+CR resulted in a higher MM and mortality (50.0% and 9.0%) versus PD alone (28.8% and 2.9%, respectively, P < 0.001). Multivariate analysis identified risk factors for MM after PD: concomitant CR [odds ratio (OR)-3.19, P < 0.001], smoking (OR-1.92, P = 0.005), a lack of functional independence (OR-3.29, P = 0.018), cardiac disease (OR-2.39, P = 0.011), decreased albumin (per g/dl, OR-1.38, P = 0.033) and a longer operative time (versus median time, OR-1.56, P = 0.029). Independent predictors of mortality included concomitant CR (OR-3.16, P = 0.010), ventilator dependence (OR-13.87, P < 0.001) and septic shock (OR-6.02, P < 0.001). CONCLUSIONS CR was an independent predictor of MM and mortality after a PD. Patients requiring PD+CR should be identified pre-operatively, maximally optimized and referred to experienced surgeons at expert centres.

Defining the optimal timing of adjuvant therapy for resected pancreatic adenocarcinoma: A statewide cancer registry analysis

Long‐term results of the ESPAC‐3 trial suggest that while completing adjuvant therapy (AT) is necessary after resection of pancreatic ductal adenocarcinoma (PDAC), early initiation (within 8 weeks) may not be associated with improved overall survival (OS). The primary aim of this study was to evaluate the OS impact of early versus late AT in a statewide analysis.

Role of Transplantation in the Treatment of Benign Solid Tumors of the Liver: A Review of the United Network of Organ Sharing Data Set

IMPORTANCE The role of orthotopic liver transplantation for the treatment of benign solid liver tumors (BSLT) is not well defined. OBJECTIVE To analyze outcomes in the United Network of Organ Sharing data set of patients with a diagnosis of BSLT who underwent transplantation. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of the United Network of Organ Sharing data set was performed for all (N = 87,280) patients who underwent transplantation for BSLT in the United States from October 1, 1988, through January 31, 2013. MAIN OUTCOMES AND MEASURES Demographics, clinicopathological characteristics, distribution of the procedures by region and state, and overall survival rates. RESULTS During the study period, 147 liver transplants (0.17%) were to treat BSLT. Sixty-two patients (42.2%) had adenomas, 29 (19.7%) had focal nodular hyperplasia, 25 (17.0%) had hemangiomas, 11 (7.5%) had hepatic epithelioid hemangioendotheliomas, and 20 (13.6%) were classified as having unknown benign tumors. The overall 1-, 3-, and 5-year survival rates were 90.9%, 85.2%, and 81.8%, respectively. Using multivariable analysis, we found that age was the only independent factor associated with patient survival. The overall 5-year survival rate for patients older than 50 years was 88% compared with 91% in younger individuals (95% CI, 148-384; P = .005). Region 3 (Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, and Puerto Rico) contributed the maximum number (33 [22.4%]) of these transplants. CONCLUSIONS AND RELEVANCE Although liver transplantation cannot be considered a first-line treatment, it is a valid therapeutic option in selected patients who are not amenable to resection. Only 0.17% of the transplants in the United States are performed for this indication, with satisfying long-term results. Age was an independent predictor of patient survival. Further studies are needed to better understand the role of liver transplantation in the treatment of BSLT.

Tu1608 Risk Factors for 30-Day Readmissions After Hepatectomy: Analysis of 2,444 Patients From the ACS-NSQIP Database

Aims The aim of this study was to identify risk factors associated with unplanned readmissions after hepatectomies.

Impact of center volume and the adoption of laparoscopic donor nephrectomy on outcomes in pediatric kidney transplantation

Reports for pediatric kidney transplant recipients suggested better outcomes for ODN compared to LDN. Contemporary outcomes stratified by donor type and center volume have not been evaluated in a national dataset. UNOS data (2000‐2014) were analyzed for pediatric living donor kidney transplant recipients. The primary outcome was GF; secondary outcomes were DGF, rejection, and patient survival. Live donor nephrectomies for pediatric recipients decreased 30% and transitioned from ODN to LDN. GF rates did not differ for ODN vs LDN (P = .24). GF was lowest at high volume centers (P < .01). Donor operative approach did not contribute to GF. LDN was associated with less rejection than ODN (OR 0.66, CI 0.5‐0.87, P < .01). Analysis of the 0‐ to 5‐yr recipient group showed no effect of ODN vs LDN on GF or rejection. For the contemporary era, there was no association between DGF and LDN in the 0‐ to 5‐yr group (OR 1.12, CI 0.67‐1.89, P = .67). Outcomes of kidney transplants in pediatric recipients following LDN have improved since its introduction and LDN should be the approach for live donor nephrectomy regardless of recipient age. The association between case volume and improved outcomes highlights future challenges in organ transplantation.

Training Surgeons in the Current US Healthcare System: A Review of Recent Changes in Resident Education

Purpose of ReviewThis review highlights research focusing on the quality of surgical education within the current constraints of healthcare delivery in the United States.Recent FindingsThe Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) trial has provided the first evidence from a randomized controlled trial regarding duty hour regulations. Results of the FIRST trial were instrumental in the 2017 ACGME Common Core Requirement changes that allow for more flexibility in clinical hours to encourage professionalism and accommodate both patient care and educational opportunities. Research focusing on resident autonomy has highlighted multiple factors necessary to ensure appropriate graduated levels of responsibility during training. Lastly, competency-based education provides a structured format to ensure minimum standards of performance in all graduates.SummaryMore flexible hours, increasing autonomy, and competency-based evaluations may help improve confidence and competence of surgery residency graduates.

A prospective analysis of factors associated with decreased physical activity in patients with cirrhosis undergoing transplant evaluation

Physical activity (PA) has been associated with improved recovery time after transplantation. Handgrip strength has been related to post‐transplant outcomes.