Conditional Genetic Elimination of Hepatocyte Growth Factor in Mice Compromises Liver Regeneration after Partial Hepatectomy

Hepatocyte growth factor (HGF) has been shown to be indispensable for liver regeneration because it serves as a main mitogenic stimulus driving hepatocytes toward proliferation. We hypothesized that ablating HGF in adult mice would have a negative effect on the ability of hepatocytes to regenerate. Deletion of the HGF gene was achieved by inducing systemic recombination in mice lacking exon 5 of HGF and carrying the Mx1-cre or Cre-ERT transgene. Analysis of liver genomic DNA from animals 10 days after treatment showed that a majority (70-80%) of alleles underwent cre-induced genetic recombination. Intriguingly, however, analysis by RT-PCR showed the continued presence of both unrecombined and recombined forms of HGF mRNA after treatment. Separation of liver cell populations into hepatocytes and non-parenchymal cells showed equal recombination of genomic HGF in both cell types. The presence of the unrecombined form of HGF mRNA persisted in the liver in significant amounts even after partial hepatectomy (PH), which correlated with insignificant changes in HGF protein and hepatocyte proliferation. The amount of HGF produced by stellate cells in culture was indirectly proportional to the concentration of HGF, suggesting that a decrease in HGF may induce de novo synthesis of HGF from cells with residual unrecombined alleles. Carbon tetrachloride (CCl4)-induced regeneration resulted in a substantial decrease in preexisting HGF mRNA and protein, and subsequent PH led to a delayed regenerative response. Thus, HGF mRNA persists in the liver even after genetic recombination affecting most cells; however, PH subsequent to CCl4 treatment is associated with a decrease in both HGF mRNA and protein and results in compromised liver regeneration, validating an important role of this mitogen in hepatic growth. © 2013 Nejak-Bowen et al

Neoadjuvant chemotherapy with FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy for borderline resectable and resectable pancreatic cancer (PREOPANC-2):A multicenter randomized controlled trial

BackgroundThe PREOPANC trial demonstrated an overall survival (OS) benefit of neoadjuvant gemcitabine-based chemoradiotherapy compared with upfront surgery in patients with borderline resectable and resectable pancreatic cancer (PDAC). FOLFIRINOX may further improve OS in the neoadjuvant setting.MethodsThis multicenter, phase 3, randomized trial included patients with borderline resectable and resectable PDAC from 19 Dutch centers. Patients received FOLFIRINOX every 14 days for 8 cycles followed by surgery without adjuvant treatment (FFX arm) versus 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions during the second cycle), followed by surgery and 4 cycles of adjuvant gemcitabine (CRT arm). Randomization was stratified by center and resectability status. Primary endpoint was OS. Secondary endpoints included resection rate and serious adverse event (SAE) rate. To demonstrate a hazard ratio (HR) of 0.70 with two-sided α = 0.05 and 80% power, 368 patients (252 events) were needed. HR and 95% CI were estimated using a stratified Cox model.ResultsBetween June 2018 and January 2021, 375 patients were randomized to the FFX arm (n=188) or the CRT arm (n=187). Six patients (3 per arm) were excluded because of ineligibility (n=4) or withdrawal of informed consent immediately after randomization (n=2). After a median follow-up of 41.7 months with 254 events, median OS was 21.9 months in the FFX arm and 21.3 months in the CRT arm (HR 0.87; 95% CI 0.68-1.12, p=0.28). Resection rates were 77% in the FFX arm and 75% in the CRT arm (p=0.69). SAE rates were 49% in the FFX arm and 43% in the CRT arm (p=0.26).ConclusionsNeoadjuvant chemotherapy with FOLFIRINOX did not improve OS compared with neoadjuvant gemcitabine-based chemoradiotherapy in patients with borderline resectable and resectable PDAC

Neoadjuvant chemotherapy with FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy for borderline resectable and resectable pancreatic cancer (PREOPANC-2):A multicenter randomized controlled trial

BackgroundThe PREOPANC trial demonstrated an overall survival (OS) benefit of neoadjuvant gemcitabine-based chemoradiotherapy compared with upfront surgery in patients with borderline resectable and resectable pancreatic cancer (PDAC). FOLFIRINOX may further improve OS in the neoadjuvant setting.MethodsThis multicenter, phase 3, randomized trial included patients with borderline resectable and resectable PDAC from 19 Dutch centers. Patients received FOLFIRINOX every 14 days for 8 cycles followed by surgery without adjuvant treatment (FFX arm) versus 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions during the second cycle), followed by surgery and 4 cycles of adjuvant gemcitabine (CRT arm). Randomization was stratified by center and resectability status. Primary endpoint was OS. Secondary endpoints included resection rate and serious adverse event (SAE) rate. To demonstrate a hazard ratio (HR) of 0.70 with two-sided α = 0.05 and 80% power, 368 patients (252 events) were needed. HR and 95% CI were estimated using a stratified Cox model.ResultsBetween June 2018 and January 2021, 375 patients were randomized to the FFX arm (n=188) or the CRT arm (n=187). Six patients (3 per arm) were excluded because of ineligibility (n=4) or withdrawal of informed consent immediately after randomization (n=2). After a median follow-up of 41.7 months with 254 events, median OS was 21.9 months in the FFX arm and 21.3 months in the CRT arm (HR 0.87; 95% CI 0.68-1.12, p=0.28). Resection rates were 77% in the FFX arm and 75% in the CRT arm (p=0.69). SAE rates were 49% in the FFX arm and 43% in the CRT arm (p=0.26).ConclusionsNeoadjuvant chemotherapy with FOLFIRINOX did not improve OS compared with neoadjuvant gemcitabine-based chemoradiotherapy in patients with borderline resectable and resectable PDAC

Outcomes of Resectability Assessment of the Dutch Colorectal Cancer Group Liver Metastases Expert Panel

BACKGROUND: Decision making on optimal treatment strategy in patients with initially unresectable colorectal cancer liver metastases (CRLM) remains complex because uniform criteria for (un) resectability are lacking. This study reports on the feasibility and short-term outcomes of The Dutch Colorectal Cancer Group Liver Expert Panel. STUDY DESIGN: The Expert Panel consists of 13 hepatobiliary surgeons and 4 radiologists. Resectability assessment is performed independently by 3 randomly assigned surgeons, and CRLM are scored as resectable, potentially resectable, or permanently unresectable. In absence of consensus, 2 additional surgeons are invited for a majority consensus. Patients with potentially resectable or unresectable CRLM at baseline are evaluated every 2 months of systemic therapy. Once CRLM are considered resectable, a treatment strategy is proposed. RESULTS: Overall, 398 panel evaluations in 183 patients were analyzed. The median time to panel conclusion was 7 days (interquartile range [IQR] 5-11 days). Intersurgeon disagreement was observed in 205 (52%) evaluations, with major disagreement (resectable vs permanently unresectable) in 42 (11%) evaluations. After systemic treatment, 106 patients were considered to have resectable CRLM, 84 of whom (79%) underwent a curative procedure. R0 resection (n = 41), R0 resection in combination with ablative treatment (n = 26), or ablative treatment only (n = 4) was achieved in 67 of 84 (80%) patients. CONCLUSIONS: This study analyzed prospective resectability evaluation of patients with CRLM by a panel of radiologists and liver surgeons. The high rate of disagreement among experienced liver surgeons reflects the complexity in defining treatment strategies for CRLM and supports the use of a panel rather than a single-surgeon decision. (C) 2019 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved

A Nationwide Comparison of Laparoscopic and Open Distal Pancreatectomy for Benign and Malignant Disease

BACKGROUND: Cohort studies from expert centers suggest that laparoscopic distal pancreatectomy (LDP) is superior to open distal pancreatectomy (ODP) regarding postoperative morbidity and length of hospital stay. But the generalizability of these findings is unknown because nationwide data on LDP are lacking. STUDY DESIGN: Adults who had undergone distal pancreatectomy in 17 centers between 2005 and 2013 were analyzed retrospectively. First, all LDPs were compared with all ODPs. Second, groups were matched using a propensity score. Third, the attitudes of pancreatic surgeons toward LDP were surveyed. The primary outcome was major complications (Clavien-Dindo grade >= III). RESULTS: Among 633 included patients, 64 patients (10%) had undergone LDP and 569 patients (90%) had undergone ODP. Baseline characteristics were comparable, except for previous abdominal surgery and mean tumor size. In the full cohort, LDP was associated with fewer major complications (16% vs 29%; p = 0.02) and a shorter median [interquartile range, IQR] hospital stay (8 days [7-12 days] vs 10 days [8-14 days]; p = 0.03). Of all LDPs, 33% were converted to ODP. Matching succeeded for 63 LDP patients. After matching, the differences in major complications (9 patients [14%] vs 19 patients [30%]; p = 0.06) and median [IQR] length of hospital stay (8 days [7-12 days] vs 10 days [8-14 days]; p = 0.48) were not statistically significant. The survey demonstrated that 85% of surgeons welcomed LDP training. CONCLUSIONS: Despite nationwide underuse and an impact of selection bias, outcomes of LDP seemed to be at least noninferior to ODP. Specific training is welcomed and could improve both the use and outcomes of LDP. (C) 2015 by the American College of Surgeon