Impact of Preoperative Chemotherapy Features on Patient Outcomes after Hepatectomy for Initially Unresectable Colorectal Cancer Liver Metastases: A LiverMetSurvey Analysis

Liver metastases; Liver resection; Preoperative chemotherapyMetástasis hepáticas; Resección hepática; Quimioterapia preoperatoriaMetàstasis hepàtiques; Resecció hepàtica; Quimioteràpia preoperatòriaBackground: Prognostic factors have been extensively reported after resection of colorectal liver metastases (CLM); however, specific analyses of the impact of preoperative systemic anticancer therapy (PO-SACT) features on outcomes is lacking. Methods: For this real-world evidence study, we used prospectively collected data within the international surgical LiverMetSurvey database from all patients with initially-irresectable CLM. The main outcome was Overall Survival (OS) after surgery. Disease-free (DFS) and hepatic-specific relapse-free survival (HS-RFS) were secondary outcomes. PO-SACT features included duration (cumulative number of cycles), choice of the cytotoxic backbone (oxaliplatin- or irinotecan-based), fluoropyrimidine (infusional or oral) and addition or not of targeted monoclonal antibodies (anti-EGFR or anti-VEGF). Results: A total of 2793 patients in the database had received PO-SACT for initially irresectable diseases. Short (<7 or <13 cycles in 1st or 2nd line) PO-SACT duration was independently associated with longer OS (HR: 0.85 p = 0.046), DFS (HR: 0.81; p = 0.016) and HS-RFS (HR: 0.80; p = 0.05). All other PO-SACT features yielded basically comparable results. Conclusions: In this international cohort, provided that PO-SACT allowed conversion to resectability in initially irresectable CLM, surgery performed as soon as technically feasible resulted in the best outcomes. When resection was achieved, our findings indicate that the choice of PO-SACT regimen had a marginal if any, impact on outcomes

Impact of Preoperative Bevacizumab on Complications After Resection of Colorectal Liver Metastases: Case-Matched Control Study

Background: Chemotherapy may increase postoperative morbidity and mortality after liver surgery. Especially bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), could have a detrimental effect. To assess the impact of neoadjuvant bevacizumab on clinical outcome after hepatectomy for colorectal liver metastases (CRLMs) this case-matched control study was initiated. Methods: The multicentric data collection was performed in the Swiss HPB Center of the University Hospital Zurich (CH), the Department of Digestive Surgery and Transplantation Strasbourg (F), and the Division of Hepato-biliary-pancreatic surgery of "Josep Tureta” Hospital Girona (E). Consecutive patients operated onbetween July 2005 and December 2007 due to CRLMs who received neoadjuvant chemotherapy were assessed. Patients were divided in two groups: group A had neoadjuvant chemotherapy with bevacicumab, and group B had it without bevacizumab. Results: No differences in overall morbidity (56 vs. 40% in the bevacizumab and control groups, respectively, p=0.23) or mortality could be documented. Similarly, the incidence of severe postoperative complications was not statistically different between the bevacizumab and control groups (31 and 18%, respectively, p=0.31). Wound complications were comparable (11% in the bevacizumab group compared and 9% in the control group, p=1.00). However, bevacizumab was associated with a significantly decreased incidence of postoperative hepatic insufficiency (7 vs. 20%, p=0.03). Conclusions: No impact on the incidence or severity of complications by bevacizumab could be shown. Bevacizumab may even reduce the incidence of liver failure after liver surger

Liver resection for hepatocellular carcinoma in patients with clinically significant portal hypertension

Background & Aims: Liver resection (LR) in patients with hepatocellular carcinoma (HCC) and clinically significant portal hypertension (CSPH) defined as a hepatic venous pressure gradient (HVPG) >−10 mmHg is not encouraged. Here, we reap praised the outcomes of patients with cirrhosis and CSPH who underwent LR for HCC in highly specialised liver centres. Methods: This was a retrospective multicentre study from 1999 to 2019. Predictors for postoperative liver decompensation and textbook outcomes were identified. Results: In total, 79 patients with a median age of 65 years were included. The Child-Pugh grade was A in 99% of patients, and the median model for end-stage liver disease (MELD) score was 8. The median HVPG was 12 mmHg. Major hepatectomies and laparoscopies were performed in 28% and 34% of patients, respectively. Ninety-day mortality and severe morbidity rates were 6% and 27%, respectively. Postoperative and persistent liver decompensation occurred in 35% and 10% of patients at 3 months. Predictors of liver decompensation included increased preoperative HVPG (p = 0.004), increased serum total bilirubin (p = 0.02), and open approach (p = 0.03). Of the patients, 34% achieved a textbook outcome, of which the laparoscopic approach was the sole predictor (p = 0.004). The 5-year overall survival and recurrence-free survival rates were 55% and 43%, respectively. Conclusions: Patients with cirrhosis, HCC and HVPG >−10 mmHg can undergo LR with acceptable mortality, morbidity, and liver decompensation rates. The laparoscopic approach was the sole predictor of a textbook outcome

Liver-First Approach for Synchronous Colorectal Metastases : Analysis of 7360 Patients from the LiverMetSurvey Registry

Background The liver-first approach in patients with synchronous colorectal liver metastases (CRLM) has gained wide consensus but its role is still to be clarified. We aimed to elucidate the outcome of the liver-first approach and to identify patients who benefit at most from this approach. Methods Patients with synchronous CRLM included in the LiverMetSurvey registry between 2000 and 2017 were considered. Three strategies were analyzed, i.e. liver-first approach, colorectal resection followed by liver resection (primary-first), and simultaneous resection, and three groups of patients were analyzed, i.e. solitary metastasis, multiple unilobar CRLM, and multiple bilobar CRLM. In each group, patients from the three strategy groups were matched by propensity score analysis. Results Overall, 7360 patients were analyzed: 4415 primary-first, 552 liver-first, and 2393 simultaneous resections. Compared with the other groups, the liver-first group had more rectal tumors (58.0% vs. 31.2%) and higher hepatic tumor burden (more than three CRLMs: 34.8% vs. 24.0%; size > 50 mm: 35.6% vs. 22.8%; p < 0.001). In patients with solitary and multiple unilobar CRLM, survival was similar regardless of treatment strategy, whereas in patients with multiple bilobar metastases, the liver-first approach was an independent positive prognostic factor, both in unmatched patients (3-year survival 65.9% vs. primary-first 60.4%: hazard ratio [HR] 1.321, p = 0.031; vs. simultaneous resections 54.4%: HR 1.624, p < 0.001) and after propensity score matching (vs. primary-first: HR 1.667, p = 0.017; vs. simultaneous resections: HR 2.278, p = 0.003). Conclusion In patients with synchronous CRLM, the surgical strategy should be decided according to the hepatic tumor burden. In the presence of multiple bilobar CRLM, the liver-first approach is associated with longer survival than the alternative approaches and should be evaluated as standard.Peer reviewe

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma

The invasive tumor front (the tumor-host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors

Outcomes and risk score for distal pancreatectomy with celiac axis resection (DP-CAR) : an international multicenter analysis

Background: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes. Methods: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival. Results: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P=0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P=0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19months (95 CI, 15-25months). Conclusions: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor

Resection of colorectal liver metastases after second-line chemotherapy : is it worthwhile? A LiverMetSurvey analysis of 6415 patients

Purpose: Patient outcome after resection of colorectal liver metastases (CLM) following second-line preoperative chemotherapy (PCT) performed for insufficient response or toxicity of the first-line, is little known and has here been compared to the outcome following first-line. Patients and methods: From January 2005 to June 2013, 5624 and 791 consecutive patients of a prospective international cohort received 1 and 2 PCT lines before CLM resection (group 1 and 2, respectively). Survival and prognostic factors were analysed. Results: After a mean follow-up of 30.1 months, there was no difference in survival from CLM diagnosis (median, 3-, and 5-year overall survival [OS]: 58.6 months, 76% and 49% in group 2 versus 58.9 months, 71% and 49% in group 1, respectively, P = 0.32). After hepatectomy, disease-free survival (DFS) was however shorter in group 2: 17.2 months, 27% and 15% versus 19.4 months, 32% and 23%, respectively (P = 0.001). Among the initially unresectable patients of group 1 and 2, no statistical difference in OS or DFS was observed. Independent predictors of worse OS in group 2 were positive primary lymph nodes, extrahepatic disease, tumour progression on second line, R2 resection and number of hepatectomies/year Conclusion: CLM resection following second-line PCT, after oncosurgically favourable selection, could bring similar OS compared to what observed after first-line. For initially unresectable patients, OS or DFS is comparable between first-and second-line PCT. Surgery should not be denied after the failure of first-line chemotherapy. (C) 2017 Elsevier Ltd. All rights reserved.Peer reviewe

One Is Enough: In Vivo Effective Population Size Is Dose-Dependent for a Plant RNA Virus

Effective population size (Ne) determines the strength of genetic drift and the frequency of co-infection by multiple genotypes, making it a key factor in viral evolution. Experimental estimates of Ne for different plant viruses have, however, rendered diverging results. The independent action hypothesis (IAH) states that each virion has a probability of infection, and that virions act independent of one another during the infection process. A corollary of IAH is that Ne must be dose dependent. A test of IAH for a plant virus has not been reported yet. Here we perform a test of an IAH infection model using a plant RNA virus, Tobacco etch virus (TEV) variants carrying GFP or mCherry fluorescent markers, in Nicotiana tabacum and Capsicum annuum plants. The number of primary infection foci increased linearly with dose, and was similar to a Poisson distribution. At high doses, primary infection foci containing both genotypes were found at a low frequency (<2%). The probability that a genotype that infected the inoculated leaf would systemically infect that plant was near 1, although in a few rare cases genotypes could be trapped in the inoculated leaf by being physically surrounded by the other genotype. The frequency of mixed-genotype infection could be predicted from the mean number of primary infection foci using the independent-action model. Independent action appears to hold for TEV, and Ne is therefore dose-dependent for this plant RNA virus. The mean number of virions causing systemic infection can be very small, and approaches 1 at low doses. Dose-dependency in TEV suggests that comparison of Ne estimates for different viruses are not very meaningful unless dose effects are taken into consideration