MRNA expression profiles of colorectal liver metastases as a novel biomarker for early recurrence after partial hepatectomy

Background: Identification of specific risk groups for recurrence after surgery for isolated colorectal liver metastases (CRLM) remains challenging due to the heterogeneity of the disease. Classical clinicopathologic parameters have limited prognostic value. The aim of this study was to identify a gene expression signature measured in CRLM discriminating early from late recurrence after partial hepatectomy. Methods: CRLM from two patient groups were collected: I) with recurrent disease ≤12 months after surgery (N = 33), and II) without recurrences and disease free for ≥36 months (N = 30). The patients were clinically homogeneous; all had a low clinical risk score (0-2) and did not receive (neo-) adjuvant chemotherapy. Total RNA was hybridised to Illumina arrays, and processed for analysis. A leave-one-out cross validation (LOOCV) analysis was performed to identify a prognostic gene expression signature. Results: LOOCV yielded an 11-gene profile with prognostic value in relation to recurrent disease ≤12 months after partial hepatectomy. This signature had a sensitivity of 81.8%, with a specificity of 66.7% for predicting recurrences (≤12 months) versus no recurrences for at least 36 months after surgery (X2 P < 0.0001). Conclusion: The current study yielded an 11-gene signature at mRNA level in CRLM discriminating early from late or no relapse after partial hepatectomy

Salvage treatment for recurrences after first resection of colorectal liver metastases: the impact of histopathological growth patterns

The majority of patients recur after resection of colorectal liver metastases (CRLM). Patients with CRLM displaying a desmoplastic histopathological growth pattern (dHGP) have a better prognosis and lower probability of recurrence than patients with non-dHGP CRLM. The current study evaluates the impact of HGP type on the pattern and treatment of recurrences after first resection of CRLM. A retrospective cohort study was performed, including patients with known HGP type after complete resection of CRLM. All patients were treated between 2000 and 2015. The HGP was determined on the CRLM resected at first partial hepatectomy. The prognostic value of HGPs, in terms of survival outcome, in the current patient cohort were previously published. In total 690 patients were included, of which 492 (71%) developed recurrent disease. CRLM displaying dHGP were observed in 103 patients (21%). Amongst patients with dHGP CRLM diagnosed with recurrent disease, more liver-limited recurrences were seen (43% vs. 31%, p=0.030), whereas patients with non-dHGP more often recurred at multiple locations (34% vs. 19%, p=0.005). Patients with dHGP CRLM were more likely to undergo curatively intended local treatment for recurrent disease (adjusted odds ratio: 2.37; 95% confidence interval (CI) [1.46–3.84]; p<0.001) compared to patients with non-dHGP. The present study demonstrates that liver-limited disease recurrence after complete resection o

Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases

Abstract Background In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the

Histopathological growth patterns as biomarker for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases

Adjuvant systemic chemotherapy (CTx) is widely administered in patients with colorectal liver metastases (CRLM). Histopathological growth patterns (HGPs) are an independent prognostic factor for survival after complete resection. This study evaluates whether HGPs can predict the efectiveness of adjuvant CTx in patients with resected CRLM. Two main types of HGPs can be distinguished; the desmoplastic type and the non-desmoplastic type. Uni- and multivariable analyses for overall survival (OS) and disease-free survival (DFS) were performed, in both patients treated with and without preoperative chemotherapy. A total of 1236 patients from two tertiary centers (Memorial Sloan Kettering Cancer Center, New York, USA; Erasmus MC Cancer Institute, Rotterdam, The Netherlands) were included (period 2000–2016). A total of 656 patients (53.1%) patients received preoperative chemotherapy. Adjuvant CTx was only associated with a superior OS in non-desmoplastic patients that had not been pretreated (adjusted hazard ratio (HR) 0.52, 95% confdence interval (CI) 0.37–0.73, p<0.001), and not in desmoplastic patients (adjusted HR 1.78, 95% CI 0.75–4.21, p=0.19). In pretreated patients no signifcant efect of adjuvant CTx was observed, neither in the desmoplastic group (adjusted HR 0.83, 95% CI 0.49–1.42, p=0.50) nor in the non-desmoplastic group (adjusted HR 0.96, 95% CI 0.71–1.29, p=0.79). Similar results were found for DFS, with a superior DFS in non-desmoplastic patients treated with adjuvant CTx (HR 0.71, 95% CI 0.55–0.93, p<0.001) that were not pretreated. Adjuvant CTx seems to improve OS and DFS after resection of non-desmoplastic CRLM. However, this efect was only observed in patients that were not treated with chemotherap

Neo-adjuvant chemotherapy followed by surgery versus surgery alone in high-risk patients with resectable colorectal liver metastases: The CHARISMA randomized multicenter clinical trial

Background: Efforts to improve the outcome of liver surgery by combining curative resection with chemotherapy have failed to demonstrate de

Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab’)2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients

Short term and long term results of patients with colorectal liver metastases undergoing surgery with or without radiofrequency ablation

PURPOSE: The combination of resection and radiofrequency ablation (RFA) may provide an alternative treatment for patients with unresectable colorectal liver metastases (CRLM). Although the results in literature look promising, uncertainty exists with regard to complication risks and survival for this therapy. METHODS: From January 2000 to May 2013, patients were included in a prospective multicenter database when treated for CRLM. Exclusion criteria were: two-staged treatment, synchronous resection of liver metastases and primary tumor, loss to follow-up or extrahepatic metastases. Patients were divided in a resection-only group (ROG) and combination group (CG). Outcome variables were retrospectively analyzed. RESULTS: In CG, 98 patients were included versus 534 patients in ROG. There were no differences in general patient characteristics. Patients in CG had a higher Fong clinical risk score (CRS; P = 0.001), better ASA classification (P = 0.04) and received more neoadjuvant chemotherapy (P = 0.001). There was no difference in postoperative morbidity or 90-day mortality. The 5-year disease-free survival (DFS) for CG and ROG was 25% and 36.1% (P = 0.03), respectively. For the 5-year overall survival (OS) this was respectively 42% and 62.2% (P = 0.001). On multivariate analysis, Fong CRS was a significant predictor for DFS. For OS, Fong CRS, ASA class IV and the combination therapy were significant predictors. CONCLUSION: The combination of hepatic resection and intraoperative RFA is a safe procedure, without increase in postoperative morbidity or mortality. Combining RFA and resection in one session is a valid treatment option for patients who would otherwise be inoperable

Results after simultaneous surgery and RFA liver ablation for patients with colorectal carcinoma and synchronous liver metastases

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