Impact of merging two university hospitals on surgical outcome after esophagogastric and hepato-pancreato-biliary surgery: Results from a retrospective study.

Background: Due to centralization and super-specialization in medicine, hospital mergers are increasingly common. Their effect on postoperative outcomes in highly specialized surgical departments is unclear. As quality metrics often worsen after major organizational changes, preservation of quality of care during an hospital merge is of the utmost importance. Objective: To evaluate the effect of a merger of two Dutch university hospitals on quality of surgical care, volume, and timeliness of care. Methods: The upper gastro-intestinal and hepato-biliary-pancreatic sections merged on the 27th of January 2020 and the 31th of May 2021 respectively. Outcomes of all adult surgical patients were compared six months before and six months after the merger. Short-term quality metrics, volume, and timeliness of care were assessed. Results: Overall, a cohort of 631 patients were included of whom 195 were upper gastro-intestinal (97 prior to the merger, 98 after the merger) and 436 (223 prior to the merger, 213 after) hepato-biliary-pancreatic patients. There were no differences in mortality, readmission, number and severity of complications, volume, and timeliness of care six months post-merger as compared to before merger. Conclusion: This study shows that a hospital merger of two university hospitals can be performed without jeopardizing patient safety and while benefitting from centralization of highly specialized care and enhancement of medical research. Key message: This study investigated the impact of a merger of two Dutch university hospitals on quality of care, timeliness of care, and volume. It showed no deterioration in the evaluated short-term quality metrics, volume or timeliness for upper GI and HPB surgery, suggesting that a hospital merger of two university hospitals can be performed safely, while benefitting from centralization of highly specialized care and enhancement of medical research.

Dragon 1 Protocol Manuscript: Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy.

STUDY PURPOSE: The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. METHODS: The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. RESULTS: Not applicable. CONCLUSION: DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04272931 (February 17, 2020). Toestingonline.nl: NL71535.068.19 (September 20, 2019).

Value of routine intraoperative frozen sections of proximal bile duct margins in perihilar cholangiocarcinoma, a retrospective multicenter and matched case-control study.

BACKGROUND: Currently, the potential benefits of additional resection after positive proximal intraoperative frozen sections (IFS) in perihilar cholangiocarcinoma (pCCA) on residual disease and oncological outcome remain uncertain. Therefore, the aim of this study is to investigate the number of R0 resections after additional resection of a positive proximal IFS and the influence of additional resections on overall survival (OS) in patients with pCCA. MATERIALS AND METHODS: A retrospective, multicenter, matched case-control study was performed, including patients undergoing resection for pCCA between 2000 and 2019 at three tertiary centers. Primary outcome was the number of achieved 'additional' R0 resections. Secondary outcomes were OS, recurrence, severe morbidity and mortality. RESULTS: Forty-four out of 328 patients undergoing resection for pCCA had a positive proximal IFS. An additional resection was performed in 35 out of 44 (79.5%) patients, which was negative in 24 (68.6%) patients. Nevertheless, seven out of these 24 patients were eventually classified as R1 resection due to other positive resection margins. Therefore, 17 (48.6%) patients could be classified as "true" R0 resection after additional resection. Ninety-day mortality after R1 resections was high (25%) and strongly influenced OS. After correction for 90-day mortality, median OS after negative additional resection was 33 months (95%CI:29.5-36.5) compared to 30 months (95%CI:24.4-35.6) after initial R1 (P = 0.875) and 46 months (95%CI:32.7-59.3) after initial R0 (P = 0.348). CONCLUSION: There were only 17 patients (out of a total of 328 patients) that potentially benefitted from routine IFS. Additional resection for a positive IFS leading to R0 resection was not associated with improved long-term survival.

Predictive Factors for Hypertrophy of the Future Liver Remnant After Portal Vein Embolization: A Systematic Review.

This systematic review was conducted to determine factors that are associated with the degree of hypertrophy of the future liver remnant following portal vein embolization. An extensive search on September 15, 2020, and subsequent literature screening resulted in the inclusion of forty-eight articles with 3368 patients in qualitative analysis, of which 18 studies were included in quantitative synthesis. Meta-analyses based on a limited number of studies showed an increase in hypertrophy response when additional embolization of segment 4 was performed (pooled difference of medians = - 3.47, 95% CI - 5.51 to - 1.43) and the use of N-butyl cyanoacrylate for portal vein embolization induced more hypertrophy than polyvinyl alcohol (pooled standardized mean difference (SMD) = 0.60, 95% CI 0.30 to 0.91). There was no indication of a difference in degree of hypertrophy between patients who received neo-adjuvant chemotherapy and those who did not receive pre-procedural systemic therapy(pooled SMD = - 0.37, 95% CI - 1.35 to 0.61), or between male and female patients (pooled SMD = 0.19, 95% CI - 0.12 to 0.50).The study was registered in the International Prospective Register of Systematic Reviews on April 28, 2020 (CRD42020175708).

Expression of integrin ανß6 differentiates perihilar cholangiocarcinoma (PHC) from benign disease mimicking PHC.

BACKGROUND: Approximately 15% of patients undergoing resection for presumed perihilar cholangiocarcinoma (PHC) have benign disease at final pathological assessment. Molecular imaging targeting tumor-specific biomarkers could serve as a novel diagnostic tool to reduce these futile surgeries. Imaging agents have been developed, selectively binding integrin ανß6, a cell receptor upregulated in pancreatobiliary malignancies, for both (preoperative) PET and (intraoperative) fluorescent imaging. Here, expression of integrin ανß6 is evaluated in PHC, intrahepatic cholangiocarcinoma (ICC), hepatocellular carcinoma (HCC) and benign disease mimicking PHC using immunohistochemistry. MATERIALS & METHODS: Three tissue microarrays (TMA) including 103 PHC tumor cores and sixty tissue samples were selected from resection specimens of pathologically proven PHC (n = 20), ICC (n = 10), HCC (n = 10), metastatic PHC lymph nodes (n = 10) and benign disease (presumed PHC with benign disease at pathological assessment, n = 10). These samples were stained for integrin ανß6 and quantified using the H-score. RESULTS: Immunohistochemical staining for integrin ανß6 showed membranous expression in all twenty PHC whole mount slides (100%) and 93 out of 103 (92%) PHC tumor cores. Mean H-score of PHC samples was 195 ± 71, compared to a mean H-score of 126 ± 57 in benign samples (p = 0.013). In both benign and PHC samples, inflammatory infiltrates and pre-existent peribiliary glands showed integrin ανß6 expression. The mean H-score across ten ICC was 33 ± 53, which was significantly lower compared to PHC (p < 0.001) but too weak to consistently discriminate ICC from HCC (H-score 0)(p = 0.062). CONCLUSION: Integrin ανß6 is abundantly expressed in PHC and associated metastatic lymph nodes. Expression is significantly higher in PHC as compared to benign disease mimicking PHC, ICC and HCC, emphasizing its potential as a target for tumor-specific molecular imaging.

Extended Resections for Advanced Gallbladder Cancer: Results from a Nationwide Cohort Study.

BACKGROUND: Extended resections (i.e., major hepatectomy and/or pancreatoduodenectomy) are rarely performed for gallbladder cancer (GBC) because outcomes remain inconclusive. Data regarding extended resections from Western centers are sparse. This Dutch, multicenter cohort study analyzed the outcomes of patients who underwent extended resections for locally advanced GBC. METHODS: Patients with GBC who underwent extended resection with curative intent between January 2000 and September 2018 were identified from the Netherlands Cancer Registry. Extended resection was defined as a major hepatectomy (resection of ≥ 3 liver segments), a pancreatoduodenectomy, or both. Treatment and survival data were obtained. Postoperative morbidity, mortality, survival, and characteristics of short- and long-term survivors were assessed. RESULTS: The study included 33 patients. For 16 of the patients, R0 resection margins were achieved. Major postoperative complications (Clavien Dindo ≥ 3A) occurred for 19 patients, and 4 patients experienced postoperative mortality within 90 days. Recurrence occurred for 24 patients. The median overall survival (OS) was 12.8 months (95% confidence interval, 6.5-19.0 months). A 2-year survival period was achieved for 10 patients (30%) and a 5-year survival period for 5 patients (15%). Common bile duct, liver, perineural and perivascular invasion and jaundice were associated with reduced survival. All three recurrence-free patients had R0 resection margins and no liver invasion. CONCLUSION: The median OS after extended resections for advanced GBC was 12.8 months in this cohort. Although postoperative morbidity and mortality were significant, long-term survival (≥ 2 years) was achieved in a subset of patients. Therefore, GBC requiring major surgery does not preclude long-term survival, and a subgroup of patients benefit from surgery.

Effect of structured use of preoperative portal vein embolization on outcomes after liver resection of perihilar cholangiocarcinoma.

BACKGROUND: Portal vein embolization (PVE) is performed to reduce the risk of liver failure and subsequent mortality after major liver resection. Although a cut-off value of 2·7 per cent per min per m2 has been used with hepatobiliary scintigraphy (HBS) for future remnant liver function (FRLF), patients with perihilar cholangiocarcinoma (PHC) potentially benefit from an additional cut-off of 8·5 per cent/min (not corrected for body surface area). Since January 2016 a more liberal approach to PVE has been adopted, including this additional cut-off for HBS of 8·5 per cent/min. The aim of this study was to assess the effect of this approach on liver failure and mortality. METHODS: This was a single-centre retrospective study in which consecutive patients undergoing liver resection under suspicion of PHC in 2000-2015 were compared with patients treated in 2016-2019, after implementation of the more liberal approach. Primary outcomes were postoperative liver failure (International Study Group of Liver Surgery grade B/C) and 90-day mortality. RESULTS: Some 191 patients with PHC underwent liver resection. PVE was performed in 6·4 per cent (9 of 141) of the patients treated in 2000-2015 and in 32 per cent (16 of 50) of those treated in 2016-2019. The 90-day mortality rate decreased from 16·3 per cent (23 of 141) to 2 per cent (1 of 50) (P = 0·009), together with a decrease in the rate of liver failure from 19·9 per cent (28 of 141) to 4 per cent (2 of 50) (P = 0·008). In 2016-2019, 24 patients had a FRLF greater than 8·5 per cent/min and no liver failure or death occurred, suggesting that 8·5 per cent/min is a reliable cut-off for patients with suspected PHC. CONCLUSION: The major decrease in liver failure and mortality rates in recent years and the simultaneous increased use of PVE suggests an important role for PVE in reducing adverse outcomes after surgery for PHC.

ANTECEDENTES: La embolización de la vena porta (portal vein embolization, PVE) se realiza para reducir el riesgo de insuficiencia hepática y de mortalidad asociada después de una resección hepática mayor. Aunque con la gammagrafía hepato-biliar (hepato-biliary scintigraphy, HBS) se ha utilizado un punto de corte de 2,7%/min/m2 para la función hepática remanente futura (future remnant liver function, FRLF), los pacientes con colangiocarcinoma perihilar (perihilar cholangiocarcinoma, PHC) se beneficiarían potencialmente de un punto de corte adicional de 8,5%/min (no corregido para el área de superficie corporal). Desde enero de 2016, se adoptó un enfoque más liberal para la PVE, incluyendo este punto de corte adicional para la HBS de 8,5%/min. El objetivo de este estudio fue evaluar el efecto de este enfoque sobre la insuficiencia hepática y la mortalidad. MÉTODOS: Se trata de un estudio retrospectivo de un solo centro, en el que los pacientes consecutivos sometidos a resección hepática por sospecha de PHC entre 2000-2016 se compararon con los pacientes tratados entre 2016-2019, después de la implementación de un enfoque más liberal. Los objetivos primarios fueron la insuficiencia hepática postoperatoria (ISGLS grado B/C) y la mortalidad a los 90 días. RESULTADOS: Un total de 191 pacientes con PHC se sometieron a resección hepática. Se realizó PVE en el 6% (9/141) de los pacientes antes de 2016 y en el 32% (16/50) de los pacientes después de 2016. La mortalidad disminuyó del 16% (23/141) al 2% (1/50) (P = 0,009), junto con una disminución de la insuficiencia hepática del 20% (28/141) al 4% (2/50) (P = 0,008). Después de 2016, 20 pacientes tuvieron un FRLF > 8,5%/min y no se produjo insuficiencia hepática o mortalidad, lo que sugiere que el 8,5%/min es un punto de corte fiable para los pacientes con sospecha de PHC. CONCLUSIÓN: La disminución marcada de la insuficiencia hepática y de la mortalidad en los últimos años y el aumento simultáneo del uso de la PVE, sugiere que la PVE ha jugado un importante papel en el descenso de los resultados adversos después de la cirugía para el PHC.

Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

Histological and Molecular Subclassification of Pancreatic and Nonpancreatic Periampullary Cancers: Implications for (Neo) Adjuvant Systemic Treatment.

The benefit of adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC) has been confirmed in randomized controlled trials. For nonpancreatic periampullary cancers (NPPC) originating from the distal bile duct, duodenum, ampulla, or papilla of Vater, the role of adjuvant therapy remains largely unclear. This review describes methods for distinguishing PDAC from NPPC by means of readily available and recently developed molecular diagnostic methods. The difficulties of reliably determining the exact origin of these cancers pathologically also is discussed. The review also considers the possibility of unintentional inclusion of NPPC in the most important adjuvant trials on PDAC and the subsequent implications for interpretation of the results. The authors conclude that correct determination of the origin of periampullary cancers is essential for clinical management and should therefore be systematically incorporated into clinical practice and future studies.