Serum levels of iCAF-derived osteoglycin predict favorable outcome in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma, the main cellular constituents of which are cancer-associated fibroblasts (CAFs). Stroma-targeting agents have been proposed to improve the poor outcome of current treatments. However, clinical trials using these agents showed disappointing results. Heterogeneity in the PDAC CAF population was recently delineated demonstrating that both tumor-promoting and tumor-suppressive activities co-exist in the stroma. Here, we aimed to identify biomarkers for the CAF population that contribute to a favorable outcome. RNA-sequencing reads from patient-derived xenografts (PDXs) were mapped to the human and mouse genome to allocate the expression of genes to the tumor or stroma. Survival meta-analysis for stromal genes was performed and applied to human protein atlas data to identify circulating biomarkers. The candidate protein was perturbed in co-cultures and assessed in existing and novel single-cell gene expression analysis from control, pancreatitis, pancreatitis-recovered and PDAC mouse models. Serum levels of the candidate biomarker were measured in two independent cohorts totaling 148 PDAC patients and related them to overall survival. Osteoglycin (OGN) was identified as a candidate serum prognostic marker. Single-cell analysis indicated that Ogn is derived from a subgroup of inflammatory CAFs. Ogn-expressing fibroblasts are distinct from resident healthy pancreatic stellate cells and arise during pancreatitis. Serum OGN levels were prognostic for favorable overall survival in two independent PDAC cohorts (HR = 0.47, P = .042 and HR = 0.53, P = .006). Altogether, we conclude that high circulating OGN levels inform on a previously unrecognized subgroup of CAFs and predict favorable outcomes in resectable PDAC.

Implementation and Outcome of Robotic Liver Surgery in the Netherlands: A Nationwide Analysis.

OBJECTIVE: To determine the nationwide implementation and surgical outcome of minor and major robotic liver surgery (RLS) and assess the first phase of implementation of RLS during the learning curve. BACKGROUND: RLS may be a valuable alternative to laparoscopic liver surgery. Nationwide population-based studies with data on implementation and outcome of RLS are lacking. METHODS: Multicenter retrospective cohort study including consecutive patients who underwent RLS for all indications in 9 Dutch centers (August 2014-March 2021). Data on all liver resections were obtained from the mandatory nationwide Dutch Hepato Biliary Audit (DHBA) including data from all 27 centers for liver surgery in the Netherlands. Outcomes were stratified for minor, technically major, and anatomically major RLS. Learning curve effect was assessed using cumulative sum analysis for blood loss. RESULTS: Of 9437 liver resections, 400 were RLS (4.2%) procedures including 207 minor (52.2%), 141 technically major (35.3%), and 52 anatomically major (13%). The nationwide use of RLS increased from 0.2% in 2014 to 11.9% in 2020. The proportion of RLS among all minimally invasive liver resections increased from 2% to 28%. Median blood loss was 150 mL (interquartile range 50-350 mL] and the conversion rate 6.3% (n=25). The rate of Clavien-Dindo grade ≥III complications was 7.0% (n=27), median length of hospital stay 4 days (interquartile range 2-5) and 30-day/in-hospital mortality 0.8% (n=3). The R0 resection rate was 83.2% (n=263). Cumulative sum analysis for blood loss found a learning curve of at least 33 major RLS procedures. CONCLUSIONS: The nationwide use of RLS in the Netherlands has increased rapidly with currently one-tenth of all liver resections and one-fourth of all minimally invasive liver resections being performed robotically. Although surgical outcomes of RLS in selected patient seem favorable, future prospective studies should determine its added value.

Survival Benefit Associated With Resection of Locally Advanced Pancreatic Cancer After Upfront FOLFIRINOX Versus FOLFIRINOX Only: Multicenter Propensity Score-matched Analysis.

OBJECTIVE: This study compared median OS after resection of LAPC after upfront FOLFIRINOX versus a propensity-score matched cohort of LAPC patients treated with FOLFIRINOX-only (ie, without resection). BACKGROUND: Because the introduction of FOLFIRINOX chemotherapy, increased resection rates in LAPC patients have been reported, with improved OS. Some studies have also reported promising OS with FOLFIRINOX-only treatment in LAPC. Multicenter studies assessing the survival benefit associated with resection of LAPC versus patients treated with FOLFIRINOX-only are lacking. METHODS: Patients with non-progressive LAPC after 4 cycles of FOLFIRINOX treatment, both with and without resection, were included from a prospective multicenter cohort in 16 centers (April 2015-December 2019). Cox regression analysis identified predictors for OS. One-to-one propensity score matching (PSM) was used to obtain a matched cohort of patients with and without resection. These patients were compared for OS. RESULTS: Overall, 293 patients with LAPC were included, of whom 89 underwent a resection. Resection was associated with improved OS (24 vs 15 months, P < 0.01), as compared to patients without resection. Before PSM, resection, Charlson Comorbidity Index, and Response Evaluation Criteria in Solid Tumors (RECIST) response were predictors for OS. After PSM, resection remained associated with improved OS [Hazard Ratio (HR) 0.344, 95% confidence interval (0.222-0.534), P < 0.01], with an OS of 24 versus 15 months, as compared to patients without resection. Resection of LAPC was associated with improved 3-year OS (31% vs 11%, P < 0.01). CONCLUSIONS: Resection of LAPC after FOLFIRINOX was associated with increased OS and 3-year survival, as compared to propensity-score matched patients treated with FOLFIRINOX-only.

Implementation and outcome of minor and major minimally invasive liver surgery in the Netherlands.

BACKGROUND: While most of the evidence on minimally invasive liver surgery (MILS) is derived from expert centers, nationwide outcomes remain underreported. This study aimed to evaluate the implementation and outcome of MILS on a nationwide scale. METHODS: Electronic patient files were reviewed in all Dutch liver surgery centers and all patients undergoing MILS between 2011 and 2016 were selected. Operative outcomes were stratified based on extent of the resection and annual MILS volume. RESULTS: Overall, 6951 liver resections were included, with a median annual volume of 50 resections per center. The overall use of MILS was 13% (n = 916), which varied from 3% to 36% (P < 0.001) between centers. The nationwide use of MILS increased from 6% in 2011 to 23% in 2016 (P < 0.001). Outcomes of minor MILS were comparable with international studies (conversion 0-13%, mortality <1%). In centers which performed ≥20 MILS annually, major MILS was associated with less conversions (14 (11%) versus 41 (30%), P < 0.001), shorter operating time (184 (117-239) versus 200 (139-308) minutes, P = 0.010), and less overall complications (37 (30%) versus 58 (42%), P = 0.040). CONCLUSION: The nationwide use of MILS is increasing, although large variation remains between centers. Outcomes of major MILS are better in centers with higher volumes.

Surgeons' assessment versus risk models for predicting complications of hepato-pancreato-biliary surgery (HPB-RISC): a multicenter prospective cohort study.

BACKGROUND: Several studies advise the use of risk models when counseling patients for hepato-pancreato-biliary (HPB) surgery, but studies comparing these models to the surgeons' assessment are lacking. The aim of this study was to assess whether risk prediction models outperform surgeons' assessment for the risk of complications in HPB surgery. METHODS: This prospective study included adult patients scheduled for HPB surgery in three centers in the UK and the Netherlands. Primary outcome was the rate of postoperative major complications. Surgeons assessed the risk prior to surgery while blinded for the formal risk scores. Risk prediction models were retrieved via a systematic review and risk scores were calculated. For each model, discrimination and calibration were evaluated. RESULTS: Overall, 349 patients were included. The rate of major complications was 27% and in-hospital mortality 3%. Surgeons' assessment resulted in an AUC of 0.64; 0.71 for liver and 0.56 for pancreas surgery (P = 0.020). The AUCs for nine existing risk prediction models ranged between 0.57 and 0.73 for liver surgery and between 0.51 and 0.57 for pancreas surgery. CONCLUSION: In HPB surgery, existing risk prediction models do not outperform surgeons' assessment. Surgeons' assessment outperforms most risk prediction models for liver surgery although both have a poor predictive performance for pancreas surgery. REGISTRATION INFORMATION: REC reference number (13/SC/0135); IRAS ID (119370). TRIALREGISTER.NL: NTR4649.