Case-mix adjustment to compare nationwide hospital performances after resection of colorectal liver metastases

Background: Differences in patient demographics and disease burden can influence comparison of hospital performances. This study aimed to provide a case-mix model to compare short-term postoperative outcomes for patients undergoing liver resection for colorectal liver metastases (CRLM). Methods: This retrospective, population-based study included all patients who underwent liver resection for CRLM between 2014 and 2018 in the Netherlands. Variation in case-mix variables between hospitals and influence on postoperative outcomes was assessed using multivariable logistic regression. Primary outcomes were 30-day major morbidity and 30-day mortality. Validation of results was performed on the data from 2019. Results: In total, 4639 patients were included in 28 hospitals. Major morbidity was 6.2% and mortality was 1.4%. Uncorrected major morbidity ranged from 3.3% to 13.7% and mortality ranged from 0.0% to 5.0%. between hospitals. Significant differences between hospitals were observed for age higher than 80 (0.0%-17.1%, p <0.001), ASA 3 or higher (3.3%-36.3%, p <0.001), histopathological parenchymal liver disease (0.0%-47.1%, p <0.001), history of liver resection (8.1%-36.3%, p <0.001), major liver resection (6.7%-38.0%, p <0.001) and synchronous metastases (35.5%-62.1%, p <0.001). Expected 30-day major morbidity between hospitals ranged from 6.4% to 11.9% and expected 30-day mortality ranged from 0.6% to 2.9%. After case-mix correction no significant outliers concerning major morbidity and mortality remained. Validation on patients who underwent liver resection for CRLM in 2019 affirmed these outcomes. Conclusion: Case-mix adjustment is a prerequisite to allow for institutional comparison of short-term postoperative outcomes after liver resection for CRLM. (C) 2020 University Medical Center Groningen. Published by Elsevier Ltd

Nationwide oncological networks for resection of colorectal liver metastases in the Netherlands:Differences and postoperative outcomes

INTRODUCTION: Widespread differences in patient demographics and disease burden between hospitals for resection of colorectal liver metastases (CRLM) have been described. In the Netherlands, networks consisting of at least one tertiary referral centre and several regional hospitals have been established to optimize treatment and outcomes. The aim of this study was to assess variation in case-mix, and outcomes between these networks. METHODS: This was a population-based study including all patients who underwent CRLM resection in the Netherlands between 2014 and 2019. Variation in case-mix and outcomes between seven networks covering the whole country was evaluated. Differences in case-mix, expected 30-day major morbidity (Clavien-Dindo ≥3a) and 30-day mortality between networks were assessed. RESULTS: In total 5383 patients were included. Thirty-day major morbidity was 5.7% and 30-day mortality was 1.5%. Significant differences between networks were observed for Charlson Comorbidity Index, ASA 3+, previous liver resection, liver disease, preoperative MRI, preoperative chemotherapy, ≥3 CRLM, diameter of largest CRLM ≥55 mm, major resection, combined resection and ablation, rectal primary tumour, bilobar and extrahepatic disease. Uncorrected 30-day major morbidity ranged between 3.3% and 13.1% for hospitals, 30-day mortality ranged between 0.0% and 4.5%. Uncorrected 30-day major morbidity ranged between 4.4% and 6.0% for networks, 30-day mortality ranged between 0.0% and 2.5%. No negative outliers were observed after case-mix correction. CONCLUSION: Variation in case-mix and outcomes are considerably smaller on a network level as compared to a hospital level. Therefore, auditing is more meaningful at a network level and collaboration of hospitals within networks should be pursued

Trends and overall survival after combined liver resection and thermal ablation of colorectal liver metastases:a nationwide population-based propensity score-matched study

Background: In colorectal liver metastases (CRLM) patients, combination of liver resection and ablation permit a more parenchymal-sparing approach. This study assessed trends in use of combined resection and ablation, outcomes, and overall survival (OS). Methods: This population-based study included all CRLM patients who underwent liver resection between 2014 and 2022. To assess OS, data was linked to two databases containing date of death for patients treated between 2014 and 2018. Hospital variation in the use of combined minor liver resection and ablation versus major liver resection alone in patients with 2–3 CRLM and ≤3 cm was assessed. Propensity score matching (PSM) was applied to evaluate outcomes. Results: This study included 3593 patients, of whom 1336 (37.2%) underwent combined resection and ablation. Combined resection increased from 31.7% in 2014 to 47.9% in 2022. Significant hospital variation (range 5.9–53.8%) was observed in the use of combined minor liver resection and ablation. PSM resulted in 1005 patients in each group. Major morbidity was not different (11.6% vs. 5%, P = 1.00). Liver failure occurred less often after combined resection and ablation (1.9% vs. 0.6%, P = 0.017). Five-year OS rates were not different (39.3% vs. 33.9%, P = 0.145). Conclusion: Combined resection and ablation should be available and considered as an alternative to resection alone in any patient with multiple metastases.</p

Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017

Long-term follow-up of patients with a clinically benign extrahepatic biliary stenosis and K-ras mutation in endobiliary brush cytology

Background. K-ras mutations in endobiliary brush cytology are an early event in carcinogenesis and justify a suspicion of malignancy in patients with extrahepatic biliary stenosis. However, K-ras mutations have been detected in specimens obtained by brushing of clinically benign extrahepatic biliary stenosis. The aim of this study was to determine whether these findings represent an early or false-positive diagnosis of cancer. Methods: Cytologic specimens were obtained by brushing in 312 consecutive patients with extrahepatic biliary stenosis. Mutations in the K-ras oncogene were detected by an enriched polymerase chain reaction and allele-specific oligonucleotide hybridization assay. Eight patients with a K-ras mutation and a clinically benign extrahepatic biliary stenosis were followed. Results: After a median follow-up of 65 months, 6 of the 8 patients were alive without evidence of malignancy. One patient died of congestive heart failure. The other patient died 60 months after the specimen was obtained, possibly because of chronic pancreatitis, although previously there had been suspicion of malignancy. Biopsy specimens from the papilla were negative for neoplasia and the K-ras analysis harbored the same mutation as previously found in the brush specimen. Conclusion: Based on long-term follow-up, the K-ras mutations in all 8 patients with a clinically benign extrahepatic biliary stenosis must be considered as confirmed false-positives. Nevertheless, a false-positive result is infrequent. Therefore, patients with a positive K-ras mutation in biliary cytologic specimens obtained by brushing still require careful, continuing follow-u

Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma

To investigate the relationship between DNA hypomethylation and gene overexpression in pancreatic cancer, we analyzed the methylation status of a subset of 18 genes previously identified by global gene expression studies as overexpressed in pancreatic cancer tissues compared with normal pancreas. For comparison, we determined the methylation status of 14 genes not known to be overexpressed in pancreatic cancer. Methylation-specific PCR analysis revealed that 19 of these 32 genes were methylated at their 5' CpGs in normal pancreas. We then analyzed these 19 genes for their methylation pattern in pancreatic cancers and found that all 7 of the genes (claudin4, lipocalin2, 14-3-3sigma,, trefoil factor2, S100A4, mesothelin, and prostate stem cell antigen) that were overexpressed in the neoplastic cells of pancreatic cancers and not expressed in normal pancreatic duct displayed a high prevalence of hypomethylation in pancreatic cancer cell lines and primary pancreatic carcinomas. By contrast, only 1 of 12 genes not overexpressed in pancreatic cancer demonstrated hypomethylation (P = 0.0002). In pancreatic cancer cell lines that retained methylation of 1 or more of the 7 aforementioned overexpressed and hypomethylated genes, treatment with 5-aza-2'-deoxycytidine or with trichostatin A, either alone or in combination, almost invariably reactivated the transcription of each of these 7 genes. These results indicate that gene hypomethylation is a frequent epigenetic event in pancreatic cancer and is commonly associated with the overexpression of affected genes

Recurrent disease after microscopically radical (R0) resection of periampullary adenocarcinoma in patients without adjuvant therapy

The survival rate after microscopically radical resection of pancreatic duct adenocarcinoma is still poor. Patients with ampulla of Vater and distal common bile duct adenocarcinoma indicate a much more favorable prognosis. Controversy exists as to whether adjuvant therapy could improve the outcome in these patients after resection. The aim of the present study was to analyze the pattern of recurrence in patients with periampullary adenocarcinoma after pancreatoduodenectomy. Between January 1992 and December 2002, all patients with an R0 resection were identified and used for this analysis. A total of 190 patients underwent a microscopically radical resection and received no adjuvant therapy. Of those, 72 patients were diagnosed with pancreatic duct adenocarcinoma, 86 patients were diagnosed with ampulla of Vater adenocarcinoma, and 31 patients were diagnosed with distal common bile duct adenocarcinoma. Recurrent disease was indicated in 81% of the patients with pancreatic duct adenocarcinoma, 50% of the patients with ampulla of Vater adenocarcinoma, and in 74% of the patients with bile duct adenocarcinoma. Multivariate analysis revealed that lymph node metastases were prognostic for recurrent disease in patients with pancreatic duct adenocarcinoma (P = 0.038). The depth of invasion (T4, P < 0.032) and lymph node metastases (P < 0.001) were prognostic in patients with ampulla of Vater adenocarcinoma. Poor tumor differentiation (P < 0.001) was prognostic in patients with distal bile duct adenocarcinoma. Selected patients with periampullary malignancies exhibited a high recurrence rate and should be encouraged to enroll in clinical trials for adjuvant treatment including local therapy (radiotherapy) according to the identified prognostic factor

Hospital volume and mortality after pancreatic resection - A systematic review and an evaluation of intervention in The Netherlands

Objectives: To evaluate the best available evidence on volume-outcome effect of pancreatic surgery by a systematic review of the existing data and to determine the impact of the ongoing plea for centralization in The Netherlands. Summary Background Data: Centralization of pancreatic resection (PR) is still under debate. The reported impact of hospital volume on the mortality rate after PR varies. Since 1994, there has been a continuous plea for centralization of PR in The Netherlands, based on repetitive analysis of the volume-outcome effect. Methods: A systematic search for studies comparing hospital mortality rates after PR between high- and low-volume hospitals was used. Studies were reviewed independently for design features, inclusion and exclusion criteria, cutoff values for high and low volume. and outcome. Primary outcome measure was hospital or 30-day mortality. Data were obtained from the Dutch nationwide registry on the outcome of PR from 1994 to 2004. Hospitals were divided into 4 volume categories based on the number of PRs performed per year. Interventions and their effect on mortality rates and centralization were analyzed. Results: Twelve observational studies with a total of 19,688 patients were included. The studies were too heterogeneous to allow a meta-analysis; therefore, a qualitative analysis was performed. The relative risk of dying in a high-volume hospital compared with a low-volume hospital was between 0.07 and 0.76, and was inversely proportional to the volume cutoff values arbitrarily defined. In 5 evaluations within a decade, hospital mortality rates were between 13.8% and 16.5% in hospitals with less than 5 PRs per year, whereas hospital mortality rates were between 0% and 3.5% in hospitals with more than 24 PRs per year. Despite the repetitive plea for centralization. no effect was seen. During 2001, 2002, and 2003, 454 of 792 (57.3%) patients underwent surgery in hospitals with a volume of less than 10 PRs per year, compared with 280 of 428 (65.4%) patients between 1994 and 1996. Conclusions: The data on hospital volume and mortality after PR are too heterogeneous to perform a meta-analysis, but a systematic review shows convincing evidence of an inverse relation between hospital volume and mortality and enforces the plea for centralization. The 10-year lasting plea for centralization among the surgical community did not result in a reduction of the mortality rate after PR or change in the referral pattern in The Netherland