Colorectal Liver Metastases Patients Research Articles

High-throughput and affordable genome-wide methylation profiling of circulating cell-free DNA by methylated DNA sequencing (MeD-seq) of LpnPI digested fragments

BackgroundDNA methylation detection in liquid biopsies provides a highly promising and much needed means for real-time monitoring of disease load in advanced cancer patient care. Compared to the often-used somatic mutations, tissue- and cancer-type specific epigenetic marks affect a larger part of the cancer genome and generally have a high penetrance throughout the tumour. Here, we describe the successful application of the recently described MeD-seq assay for genome-wide DNA methylation profiling on cell-free DNA (cfDNA). The compatibility of the MeD-seq assay with different types of blood collection tubes, cfDNA input amounts, cfDNA isolation methods, and vacuum concentration of samples was evaluated using plasma from both metastatic cancer patients and healthy blood donors (HBDs). To investigate the potential value of cfDNA methylation profiling for tumour load monitoring, we profiled paired samples from 8 patients with resectable colorectal liver metastases (CRLM) before and after surgery.ResultsThe MeD-seq assay worked on plasma-derived cfDNA from both EDTA and CellSave blood collection tubes when at least 10 ng of cfDNA was used. From the 3 evaluated cfDNA isolation methods, both the manual QIAamp Circulating Nucleic Acid Kit (Qiagen) and the semi-automated Maxwell® RSC ccfDNA Plasma Kit (Promega) were compatible with MeD-seq analysis, whereas the QiaSymphony DSP Circulating DNA Kit (Qiagen) yielded significantly fewer reads when compared to the QIAamp kit (p < 0.001). Vacuum concentration of samples before MeD-seq analysis was possible with samples in AVE buffer (QIAamp) or water, but yielded inconsistent results for samples in EDTA-containing Maxwell buffer. Principal component analysis showed that pre-surgical samples from CRLM patients were very distinct from HBDs, whereas post-surgical samples were more similar. Several described methylation markers for colorectal cancer monitoring in liquid biopsies showed differential methylation between pre-surgical CRLM samples and HBDs in our data, supporting the validity of our approach. Results for MSC, ITGA4, GRIA4, and EYA4 were validated by quantitative methylation specific PCR.ConclusionsThe MeD-seq assay provides a promising new method for cfDNA methylation profiling. Potential future applications of the assay include marker discovery specifically for liquid biopsy analysis as well as direct use as a disease load monitoring tool in advanced cancer patients.

Changes in serum lactate dehydrogenase levels as markers of pathological response and prognosis in colorectal liver metastases patients receiving neoadjuvant chemotherapy followed by resection.

This study sought to evaluate the effects of pre-neoadjuvant chemotherapy lactate dehydrogenase (pre-NAC LDH) levels, preoperative LDH levels, and changes in LDH levels on the pathological response and outcomes of colorectal liver metastases (CRLM) patients treated with liver resection after NAC. This study included 152 colorectal CRLM patients, who underwent NAC followed by liver resection. Patients were excluded if they were diagnosed with other malignancies or lacked follow-up and clinical data. Demographic and clinicopathological data were collected from hospital records. Pathological response and postoperative complications were measured according to the tumor regression grade (TRG) and Clavien-Dindo classification system, respectively. The optimal cutoff values were determined by the receiver operating characteristic curve and the X-tile analysis. Changes in LDH levels were graded as 0, 1, and 2. A logistic regression analysis was conducted to identify the independent predictors of pathological response and postoperative major complications. Univariate and multivariate Cox regression analyses were used to identify the independent risk factors of progression-free survival (PFS) and overall survival (OS). The multivariate analysis indicated that a grade 2 LDH level change was a risk factor of an unfavorable histological response [odds ratio (OR) 0.249, 95% confidence interval (CI): 0.066-0.942; P=0.041] and major postoperative complications (OR 2.523, 95% CI: 1.179-10.530; P=0.024), which were independent of other clinical covariates. A pre-NAC LDH level ≥145 IU/L [hazards ratio (HR) 0.584, 95% CI: 0.359-0.950; P=0.030], a grade 1 LDH level change (HR 0.584, 95% CI: 0.359-0.950; P=0.030) and a grade 2 LDH level change (HR 0.447, 95% CI: 0.231-0.864; P=0.017) were independent prognostic predictors of PFS. A preoperative a LDH level ≥231 IU/L (HR 0.405, 95% CI: 0.192-0.852; P=0.017) and a grade 2 LDH level change (HR 0.362, 95% CI: 0.157-0.834; P=0.017) were independent prognostic factors of OS, which were independent of other clinical covariates. LDH levels and changes in LDH levels are potentially useful biomarkers for predicting the pathological response and prognosis of CRLM patients receiving NAC followed by liver resection.

Differences of intraoperative outcomes and postoperative complications between intrahepatic cholangiocarcinoma and colorectal liver metastasis in different surgical methods.

BackgroundHepatectomy is the only potentially curable treatment for intrahepatic cholangiocarcinoma (IHCC) and colorectal liver metastasis (CRLM). This study aimed to explore the difference in intraoperative outcomes and postoperative complications between IHCC and CRLM in different surgical methods including major hepatectomy and minor hepatectomy.MethodsWe included 319 patients with IHCC or CRLM who underwent hepatectomy at our hospital. According to major hepatectomy and minor hepatectomy, eligible patients were divided into two groups. In each group, the clinicopathological characteristics of IHCC and CRLM patients were compared, then propensity score matching (PSM) was performed based on the results. Intraoperative outcomes and postoperative complications were compared between IHCC and CRLM before and after PSM. Intraoperative variables, including intraoperative blood transfusion, duration of operation, and intraoperative blood loss, were used to evaluate the intraoperative conditions of patients. The postoperative complications were measured according to the Clavien-Dindo classification. Grade III to V complications were defined as major complications.ResultsThe major hepatectomy group included 118 patients with IHCC and 93 patients with CRLM. IHCC patients presented a longer operation time and a higher postoperative complication rate than CRLM patients. The infection-related complication rate of the CRLM patients was significantly higher than the IHCC patients. In multivariate analysis, major hepatectomy for IHCC was independently associated with the presence of postoperative complications. The minor hepatectomy group included 146 IHCC patients and 62 CRLM patients. Compared with CRLM patients, IHCC patients presented a longer operation time. There was no significant difference in the intra-operative blood loss, postoperative complication rate, the major complications rate, and the minor complications rate between the IHCC patients and CRLM patients.ConclusionsThis study revealed major hepatectomy for IHCC led to significantly higher morbidity of postoperative complications than CRLM patients. For minor hepatectomy, there was no difference in postoperative complications between IHCC and CRLM. More attention should be paid to improving the preoperative planning and surgical management of hepatic malignancies especially in the setting of IHCC.

Predictive value of red blood cell distribution width level on histological response and prognosis in colorectal liver metastases.

The red blood cell distribution width (RDW) level is a potential prognostic factor for solid tumours. We aimed to investigate the predictive value of pre-neoadjuvant chemotherapy (pre-NAC) RDW, preoperative RDW and the change in RDW on the pathological response and prognosis of patients with colorectal liver metastasis (CRLM), which was helpful for treatment decision-making, surveillance and prognostication. This retrospective study analyzed clinicopathologic data, treatments and outcomes of 150 CRLM patients treated with NAC followed by liver resection at our hospital. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The secondary outcome was postoperative major complications. The RDW level was presented as the RDW-SD level and the RDW-CV level. The optimal cut-off of RDW level was determined by X-tile analysis. The change in RDW was scored as 0 (decreased pre-NAC RDW and decreased preoperative RDW), 2 (elevated pre-NAC RDW and elevated preoperative RDW), or 1 (all other combinations). Multivariable logistic regression analysis was performed to determine the relationships between the tumour characteristics and pathological response and the postoperative major complications. A multivariate Cox proportional hazards model was used to evaluate the prognostic factors associated with survival. The optimal cut-off values of the RDW-CV and RDW-SD levels for survival were 13.5% and 42.2 fl, respectively. The multivariate analysis showed that a preoperative RDW-CV ≥13.5% (OR =3.215, 95% CI: 1.299-7.958, P=0.012) significantly predicted a favorable pathological response. The multivariate analysis revealed that a pre-NAC RDW-CV ≥13.5% (OR =2.462, 95% CI: 1.080-5.615, P=0.032) significantly predicted postoperative major complications. In the multivariate analysis, an RDW-CV change =2 (HR =0.487, 95% CI: 0.309-0.768, P=0.002) was a significant predictor of better PFS. The multivariate analysis also revealed that an RDW-SD change =2 (HR =0.532, 95% CI: 0.332-0.854, P=0.009) were an independent predictor of better OS. This study revealed that pre-NAC RDW, preoperative RDW and RDW changes may be reliable markers that could predict a pathological response and prognosis in CRLM patients receiving NAC followed by liver resection.

The prognostic significance of tumour FXYD-3 expression in patients with primary and secondary colorectal cancers

Purpose: The clinical significance of FXYD-3 expression in colorectal cancer (CRC) is uncertain. There are no studies examining FXYD-3 expression in colorectal liver metastases (CRLM). The aim was to examine the degree of FXYD-3 expression in CRC and CRLM and assess the relationship between expression and survival after resection of liver metastases. Methods: A matched case-control study, using conditional logistic regression, compared FXYD-3 expression in the primary tumours of patients without CRLM to those with CRLM. A retrospective cohort study on CRLM patients examined if FXYD-3 expression was associated with overall survival. Results: There were 220 patients; 110 CRLM patients and 110 CRC patients. There was no difference in FXYD-3 expression between primary tumours (p=0.62) and no difference in FXYD-3 expression between the primary tumour and liver metastases (p=0.55). Strong FXYD-3 expression in CRLM’s was associated with a reduced risk of mortality in comparison to weak FXYD-3 expression (HR: 0.51, 95% CI 0.28, 0.93). There was evidence of effect modification between FXYD-3 expression and chemotherapy (p&lt;0.001): patients with strong FXYD-3 expression in CRLM’s who received post-operative chemotherapy had longer survival compared to those who did not. Conclusion: There are no differences in FXYD-3 expression in primary tumours between patients who did or did not develop liver metastases. Similarly, no difference in FXYD-3 expression between the primary tumour and the corresponding liver metastases. However, strong FXYD-3 expression in CRLM proved to be a marker of long-term survival in patients who receive adjuvant chemotherapy post liver resection.

Liver transplantation versus liver resection for colorectal liver metastasis: a survival benefit analysis in patients stratified according to tumor burden score.

Liver transplantation (LT) for colorectal liver metastasis (CRLM) may provide excellent survival rates in patients with unresectable disease. High tumor load is a risk factor for recurrence and low overall survival (OS) after liver resection (LR). We tested the hypothesis that LT could offer better survival than LR in patients with high tumor load. LR performed at Padua University Hospital for CRLM was compared with LT for unresectable CRLM performed both at Oslo and Padua. High tumor load was defined as tumor burden score (TBS) ≥ 9, and inclusion criteria were as in the SECA-I transplant study. 184 patients were eligible: 128 LRs and 56 LTs. 5-year OS after LR and LT was 40.5% and 54.7% (P=0.102). In the high TBS cohort, 5-year OS after LR and LT was 22.7% and 52.2% (P=0.055). In patients with Oslo score ≤ 2 and TBS ≥ 9 (13 LR; 24 LT) the 5-year OS after LR and LT was 14.6% and 69.1% (P=0.002). The corresponding disease-free survival (DFS) was 0% and 22.9% (P=0.005). Selected CRLM patients with low Oslo score and high TBS could benefit from LT with survival outcomes that are far better than what is achieved by LR.

Recurrent colorectal liver metastasis patients could benefit from repeat hepatic resection

BackgroundLocal treatment remains the best option for recurrent colorectal liver metastasis (CRLM). The current study aimed to investigate predictive factors of survival outcomes and select candidates for local treatment for CRLM at first recurrence.MethodsData were collected retrospectively from CRLM patients who underwent hepatic resection and developed first recurrence between 2000 and 2019 at our institution. A nomogram predicting overall survival was established based on a multivariable Cox model of clinicopathologic factors. The predictive accuracy and discriminative ability of the nomogram were determined by the concordance index and calibration curve.ResultsAmong 867 patients who underwent curative hepatic resection, 549 patients developed recurrence. Three hundred patients were evaluated and had resectable and liver-limited disease. Among them, repeat liver resection and percutaneous radiofrequency ablation were performed in 88 and 85 patients, respectively. The other 127 patients received only systemic chemotherapy. Multivariable analysis identified primary lymph node positivity, tumor size > 3 cm, early recurrence, RAS gene mutation and no local treatment as independent risk factors for survival outcomes. Integrating these five variables, the nomogram presented a good concordance index of 0.707. Compared with patients who received only systemic chemotherapy, radical local treatment did not significantly improve survival outcomes (median OS: 21 vs. 15 months, p = 0.126) in the high-risk group (total score ≥ 13).ConclusionRadical local treatment improved the survival of recurrent CRLM patients. The proposed model facilitates personalized assessments of prognosis for patients who develop first recurrence in the liver.

From conventional two-stage hepatectomy to ALPPS: Fifteen years of experience in a hepatobiliary surgery unit

BackgroundHepatectomy in patients with large tumor load may result in postoperative liver failure and associated complications due to excessive liver parenchyma removal. Conventional two-stage hepatectomy (TSH) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) technique are possible solutions to this problem. Colorectal liver metastases (CRLM) is the most frequent indication, and there is a need to assess outcomes for both techniques to improve surgical and long-term oncological outcomes in these patients. MethodsA single-center retrospective study was designed to compare TSH with ALPPS in patients with initially unresectable bilateral liver tumors between January 2005 and January 2020. ALPPS was performed from January 2012 onwards as the technique of choice. Long-term overall survival (OS) and disease-free survival (DFS) were evaluated as primary outcome in CRLM patients. Postoperative morbidity, mortality and liver growth in all patients were also evaluated. ResultsA total of 38 staged hepatectomies were performed: 17 TSH and 21 ALPPS. Complete resection rate was 76.5% (n = 13) in the TSH group and 85.7% (n = 18) in the ALPPS group (P = 0.426). Overall major morbidity (Clavien-Dindo ≥ 3a) (stage 1 + stage 2) was 41.2% (n = 7) in TSH and 33.3% (n = 7) in ALPPS patients (P = 0.389), and perioperative 90-day mortalities were 11.8% (n = 2) vs. 19.0% (n = 4) in each group, respectively (P = 0.654). Intention-to-treat OS rates at 1 and 5 years in CRLM patients for TSH (n = 15) were 80% and 33%, and for ALPPS (n = 17) 76% and 35%, respectively. DFS rates at 1 and 5 years were 36% and 27% in the TSH group vs. 33% and 27% in the ALPPS group, respectively. ConclusionsALPPS is an effective alternative to TSH in bilateral affecting liver tumors, allowing higher resection rate, but patients must be carefully selected. In CRLM patients similar long-term OS and DFS can be achieved with both techniques.

Liver Venous Deprivation or Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy?: A Retrospective Multicentric Study.

To compare 2 techniques of remnant liver hypertrophy in candidates for extended hepatectomy: radiological simultaneous portal vein embolization and hepatic vein embolization (HVE); namely LVD, and ALPPS. Recent advances in chemotherapy and surgical techniques have widened indications for extended hepatectomy, before which remnant liver augmentation is mandatory. ALPPS and LVD typically show higher hypertrophy rates than portal vein embolization, but their respective places in patient management remain unclear. All consecutive ALPPS and LVD procedures performed in 8 French centers between 2011 and 2020 were included. The main endpoint was the successful resection rate (resection rate without 90-day mortality) analyzed according to an intention-to-treat principle. Secondary endpoints were hypertrophy rates, intra and postoperative outcomes. Among 209 patients, 124 had LVD 37 [13,1015] days before surgery, whereas 85 underwent ALPPS with an inter-stages period of 10 [6, 69] days. ALPPS was mostly-performed for colorectal liver metastases (CRLM), LVD for CRLM and perihilar cholangiocarcinoma. Hypertrophy was faster for ALPPS. Successful resection rates were 72.6% for LVD ± rescue ALPPS (n = 6) versus 90.6% for ALPPS (P < 0.001). Operative duration, blood losses and length-of-stay were lower for LVD, whereas 90-day major complications and mortality were comparable. Results were globally unchanged for CRLM patients, or after excluding the early 2 years of experience (learning-curve effect). This study is the first 1 comparing LVD versus ALPPS in the largest cohort so far. Despite its retrospective design, it yields original results that may serve as the basis for a prospective study.

Circulating PD-L1 is associated with T cell infiltration and predicts prognosis in patients with CRLM following hepatic resection.

Exosomal PD-L1 (exoPD-L1) could induce immunosuppression functionally, thus impairing patients' survival in melanoma, NSCLC, and gastric cancer. However, no evidence demonstrates the feasibility of circulating exoPD-L1 and soluble PD-L1 (sPD-L1) as biomarkers for prognosis and early recurrence in colorectal liver metastasis (CRLM) patients following hepatectomy or their association with T cell infiltration at liver metastases. In cohort 1, exoPD-L1 and sPD-L1 were preoperatively tested using ELISA. CD3, CD8, granzyme B (GB) and PD1 expressed at liver metastases were evaluated using immunohistochemistry. In cohort 2, exoPD-L1 and sPD-L1 were detected at baseline, before hepatectomy, after hepatectomy, and after disease progression. In cohort 1, higher preoperative exoPD-L1 or sPD-L1 significantly impaired RFS (exoPD-L1, P=0.0043; sPD-L1, P=0.0041) and OS (exoPD-L1, P=0.0034; sPD-L1, P=0.0061). Furthermore, preoperative exoPD-L1 was negatively correlated with CD3+T-lymphocytes infiltrated at tumor center (CT), and GB and PD1 were expressed at tumor invasive margin (IM). Preoperative sPD-L1 was negatively correlated with CD3+and CD8+T-lymphocytes' infiltration at IM and CT, GB and PD1 expression at IM. In cohort 2, exoPD-L1 and sPD-L1 levels decreased following hepatectomy but increased when tumor progressed. Moreover, higher postoperative exoPD-L1 and sPD-L1 or a small reduction in exoPD-L1 and sPD-L1 levels after hepatectomy suggested higher early recurrence rate. Both preoperative exoPD-L1 and sPD-L1 had promising prognostic values and were associated with T cell infiltration at liver metastases in CRLM patients following hepatectomy. Dynamically tracking exoPD-L1 and sPD-L1 levels could monitor disease status and detect early recurrence.

Treatment efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization versus regorafenib monotherapy in colorectal cancer liver metastasis patients who fail standard treatment regimens

ObjectiveThis study aimed to evaluate the efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization (DEB-TACE) versus regorafenib monotherapy in colorectal cancer liver metastases (CRLM) patients who failed standard treatment regimens.MethodsTotally, 76 eligible CRLM patients were analyzed, among which 42 patients received regorafenib monotherapy (as regorafenib group) and 34 patients received regorafenib plus DEB-TACE (as regorafenib plus DEB-TACE group).ResultsObjective response rate (35.3% versus 7.1%, P = 0.002) and disease control rate (76.5% versus 47.6%, P = 0.011) were both increased in regorafenib plus DEB-TACE group compared with regorafenib group; meanwhile, negative conversion rate of carcinoembryonic antigen (66.7% versus 28.6%, P = 0.008) after treatment was elevated in regorafenib plus DEB-TACE group compared with regorafenib group. Notably, progression-free survival (PFS) (median value: 7.6 versus 4.1 months, P < 0.001) and overall survival (OS) (median value: 15.7 versus 9.2 months, P < 0.001) were both higher in regorafenib plus DEB-TACE group compared with regorafenib group. Furthermore, liver function indexes (alanine transaminase, aspartate aminotransferase, and cholinesterase levels) after treatment were all similar between the two groups (all P > 0.05). In addition, the occurrences of upper abdominal distending pain (P < 0.001), nausea and vomiting (P = 0.002) and fever (P = 0.002) were higher in regorafenib plus DEB-TACE group compared with regorafenib group, while the majority of these adverse events were mild and tolerable.ConclusionsRegorafenib plus DEB-TACE is superior to regorafenib monotherapy regarding treatment response, PFS and OS, while induces tolerable post-embolization syndrome in CRLM patients who fail standard treatment regimens.

Abstract 651: A novel gene signature that predicts recurrence following hepatectomy in patients with colorectal liver metastasis

Abstract Background: Cancer recurrence is an important predictor of survival outcomes in patients with colorectal liver metastasis (CRLM), undergoing curative resection. While cancer recurrence occurs frequently in patients with CRLM, perioperative treatment remains arbitrary and the NCCN guidelines recommended several treatment options, including colectomy, hepatectomy, or systemic chemotherapy. Therefore, identification of patients who are at highest risk of recurrence is critical for developing a precision oncology strategy which might include just frequent surveillance (in low-risk patients) or a more aggressive treatment approach with chemotherapy or other treatments (in high-risk patients). Herein, we performed a genomewide expression profiling analysis to identify and develop a gene signature for predicting recurrence in patients with CRLM. Methods: We analyzed a total of 383 CRLM patients, which included a genomewide expression dataset of 63 patients (GSE81423) and 320 patients from independent clinical cohorts. During the biomarker discovery phase, we utilized rigorous bioinformatic approaches to analyze transcriptomic profiling data in CRLM patients with and without recurrence. The robustness and performance of this gene signature was subsequently interrogated in independent clinical cohorts (training cohort, n=169; validation cohort, n=151) using qRT-PCR assays. Finally, using Cox regression analysis, we evaluated the clinical significance of the gene signature by comparing its performance with several key clinicopathological factors. Results: We identified a 6-gene panel, which robustly categorized patients with recurrence in the discovery cohort (AUC = 0.90, 95% CI = 0.79-0.96). The validation efforts in the clinical cohorts revealed that the panel was a significant predictor of recurrence in the training (AUC = 0.83, 95% CI = 0.76-0.88) and validation cohorts (AUC = 0.81, 95% CI = 0.74-0.87). In univariate and multivariate analysis using the Cox's proportional hazard regression model along with other clinicopathological factors, high-risk patients defined by the transcriptomic panel associated with a significantly higher risk of recurrence in both cohorts [training cohort: Hazard ratio (HR) = 3.18; 95% CI = 2.03-4.98; P &amp;lt; 0.01, validation cohort: HR = 2.60; 95% CI = 1.73-3.92; P &amp;lt; 0.01]. By combining our transcriptomic panel with key clinical features, we established a risk-stratification model which was even superior than the gene panel, and emerged as an independent predictor for recurrence (AUC = 0.85, 95% CI = 0.78-0.90). Conclusions: We identified and developed a novel gene signature that robustly predicts recurrence in CRLM patients; highlighting its clinical impact in the a more appropriate patient selection and development of improved precision treatment strategies in patients with advanced metastatic colorectal cancer. Citation Format: Yuma Wada, Mitsuo Shimada, Ajay Goel. A novel gene signature that predicts recurrence following hepatectomy in patients with colorectal liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 651.

Therapeutic Strategy of Colorectal Liver Metastasis Using Modified-JHBPS Nomogram.

We attempted to stratify prognosis using the modified Journal of Hepato-Biliary-Pancreatic Sciences (mJHBPS) nomogram upon identification of colorectal liver metastasis (CRLM) and to investigate which strategy is better, surgery first (SF) or chemotherapy first (CF), in each risk group. A total of 137 patients with CRLM who underwent resection of the primary tumor were included. Patients with brain, bone, or perihilar lymph node metastases were excluded. Patients were scored using the mJHBPS nomogram upon identification of CRLM. Prognosis was investigated using event-free survival (EFS) and overall survival (OS). The nomogram allowed stratification of patients using EFS and OS: low-risk (0-6 score, n=38), medium-risk (7-11 score, n=42), and high-risk (12≥ score, n=57). In the low-risk group, the EFS and OS of the CF group were significantly poorer than those of the SF group (p=0.019 and p=0.014, respectively). CF was an independent prognostic factor for both EFS and OS. The mJHBPS nomogram can stratify CRLM patients with sufficient differences in EFS and OS. SF was recommended for patients in the low-risk group.

Contemporary outcome of liver transplantation for bilobar multiple colorectal liver metastasis

During the last decade, increasing evidence suggest that highly selected patients with colorectal liver metastases (CRLM) can obtains superior survival by liver transplantation. Three scoring systems may be utilized to predict post-transplant survival in CRLM. Pre transplant factors associated with unfavorable outcome are maximal tumor diameter > 55 mm, CEA > 80 micrograms/mL, unresponsiveness to chemotherapy and a time interval from diagnosis to transplant less than 24 months. These 4 factors are assessed in the Oslo Score, and scores from 0-2 yield a 5-year overall survival of about 67%-70%. Further refined selection include the metabolic tumor volume (MTV) at PET CT. This is defined as an uptake of 40% of standardized maximal uptake (SUVmax). Calculated per patient as the sum of MTV in all lesions, a MTV value < 70 cc is associated with post-transplant survival of 78%. The Fong Clinical Risk Score (FCRS) offers an even more stringent selection of candidates and scores of 0-2 have in the published literature demonstrated 100% 5-year overall survival. Caution against transplantation is advised in patients with right sided primary tumors, undifferentiated og signet ring cell differentiation, N" status of the primary og BRAF mutation. The outcomes referenced are probably not limited only to non-resectable CRLM. It is therefore possible that some few patients currently offered liver resection could have a clinically significant treatment benefit by liver transplantation, but future studies are needed to clarify this question. Since CRLM patients, by definition have metastatic disease, recurrence remains a problem. Thus, assessing the balance between survival and recurrence after transplantation remains a difficult dilemma. About two thirds of the recurrences are slow growing lung metastases. The experience to date indicates that pulmonary recurrence alone has a modest impact on survival outcomes, since many of them can be resected with curative intent. Further studies focusing on this group of patients will be important for the development of this field of transplant oncology. Liver transplantation for secondary liver tumors should be implemented in accordance with stringent transplant criteria and preferably in the context of prospective trials. Expansion of the donor pool by utilizing extended criteria donors, partial liver transplantation and possibly living donor liver transplantation could be considered for this indication.

Oligometastasis scoring system for predicting survival of patients with colorectal liver metastasis after hepatectomy.

Oligometastasis, the presence of a small number of resectable metastatic tumors, usually has favorable outcomes. Here we examined whether the novel oligometastatic score (OLGS), which divides the number of colorectal liver metastases (CRLMs) by the time from colorectal resection to liver recurrence, better predicts CRLM patient survival than the commonly used clinical risk score. A total of 143 patients who underwent curative hepatectomy for CRLMs between 2007 and 2018 were analyzed. We investigated their clinical characteristics and outcomes using OLGS. Of the 143 CRLM patients, 70 had synchronous CRLMs and 73 had metachronous CRLMs. Patients with metachronous CRLMs were divided into OLGS-low (n = 59) and OLGS-high (n = 14) subgroups. The 5-year overall survival (OS) rates after hepatectomy differed significantly between the subgroups (p < .001). In the multivariate Cox model, a high OLGS was an independent predictor of 5-year OS (p < .001), and the hazard ratio (HR) of the OLGS-high group (HR = 7.171) was higher than that of the high clinical risk score group (HR = 4.337). The OLGS, a simple and handy scoring system, better predicts the 5-year OS of patients with CRLMs after hepatectomy and warrants prospective validation.

Long-Term Effects of Pedicle Clamping during Major Hepatectomy for Colorectal Liver Metastases.

The use of the Pringle maneuver (PM) varies widely among surgical departments. Its use depends on the operator and type of liver resection. The aim of this study was to determine the impact of the PM on patient outcomes when undergoing major liver resections. This retrospective study comprised 179 colorectal liver metastasis patients from two liver centers from Leeds and Warsaw. Only right or right extended hepatectomies with negative oncological margins were included. The primary outcome measure was the 5-year overall survival (OS). The PM was applied during 60 (33.5%) major hepatectomies included in the study and was associated with a higher peak 3-day postoperative bilirubin concentration (p = 0.002), yet not with the peak 3-day alanine aminotransferase activity (p = 0.415). The 5-year OS after liver resections with the PM and without the PM were 55.0% and 33.4%, respectively (p = 0.019). Following stratification by the Tumor Burden Score, after resections with the use of the PM, superior survival was particularly found in the subgroup of patients at intermediate risk of recurrence (p = 0.004). However, the use of the PM had no significant effect on the 5-year overall survival following adjustment for the confounding effect of the carcinoembryonic antigen concentration (p = 0.265). The use of the PM had no negative effects on the long-term outcomes in patients undergoing major, oncologically radical liver resections for colorectal metastases.

Effect of Adding Bevacizumab to Chemotherapy on Pathologic Response to Preoperative Systemic Therapy for Resectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis

BackgroundLiver-limited metastatic colorectal cancer is a potentially curable disease. Pathologic response (pR) to preoperative chemotherapy (CT) for colorectal liver metastases (CLM) is a surrogate endpoint for overall survival (OS). We conducted the first meta-analysis of observational studies to estimate the overall effect of bevacizumab on pR in preoperative systemic therapy for CLM. MethodsWe systematically searched PubMed, Cochrane Library, CINAHL, Web of Science, Embase, and LILACS for studies published between January 2004 and August 2019 that compared the pR of CT plus bevacizumab to CT alone as preoperative therapy for CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were pathologic major (pMaR) and minor (pMiR) response. Overall effects were expressed by odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. ResultsOf the 1,452 studies yielded by the search, 9 were eligible, totaling 1,202 patients (516 CT plus bevacizumab and 686 CT alone). The addition of bevacizumab to CT increased the pCR rate without reaching statistical significance (OR: 1.24, 95% CI 0.81 to 1.92, P = .32). However, pMaR was significantly higher (OR: 2.45, 95% CI 1.85 to 3.25, P < .001), and pMiR was significantly lower (OR: 0.41, 95% CI 0.31 to 0.54, P < .001), in the bevacizumab group. The analyses showed a low level of heterogeneity (I2 = 0% to 6%). Publication bias was not found. ConclusionsThis meta-analysis demonstrates that bevacizumab plus preoperative CT is associated with higher rates of pR in CLM. Antiangiogenics might improve the OS of CLM patients and should be evaluated in randomized clinical trials. MicroAbstractThe benefit of perioperative chemotherapy for colorectal liver metastases (CLM) is uncertain, but pathologic response (pR) to preoperative chemotherapy is a strong prognostic factor. Our meta-analysis of observational studies compared the pR of bevacizumab plus chemotherapy to chemotherapy alone as preoperative systemic therapy in the management of CLM. The addition of bevacizumab was associated with significantly higher rates of pR.

A Prognostic Scoring System to Predict Survival Outcome of Resectable Colorectal Liver Metastases in this Modern Era.

An individualized treatment decision is based on theaccurate evaluation of clinical risk factors and prognosis for resectable colorectal liver metastases. The current study aimed to develop an effective nomogram to predict progression-free survival (PFS) and to design a treatment schedule preoperatively. The study enrolled a primary cohort of 532 patients with resectable colorectal liver metastases (CRLM) who underwent hepatic resection at two institutions and a validation cohort of 237 patients at two additional institutions with resectable CRLM between 1 January 2008 and 31 December 2018. A nomogram was created based on the independent predictors in the multivariable analysis of progression-free survival in the primary cohort. The predictive accuracy and discriminative ability of the nomogram were determined by the concordance index (C-index) and the calibration curve. The score was compared with the current standard Fong score and validated with an external cohort. The independent risk factors for CRLM patients identified in the multivariable analysis were tumor larger than 5 cm, more than one tumor, RAS mutation, primary lymph node metastasis, and primary tumor located on the right side. All five factors were considered in the nomogram. The C-index of the nomogram for predicting survival was 0.696. With external validation, the C-index of the nomogram for the prediction of the PFS was 0.682, which demonstrated that this model has a good level of discriminative ability. For high-risk patients (score > 16), neoadjuvant chemotherapy improved PFS and overall survival (OS) after hepatic resection. The current nomogram demonstrated an accurate performance in predicting PFS for resectable CRLM patients with liver-limited disease. Based on the current nomogram, high-risk patients (nomogram score > 16) might benefit from neoadjuvant chemotherapy.

Failure to Cure Patients with Colorectal Liver Metastases: The Impact of the Liver Surgeon.

Lack of a liver surgeon (LS) may lead to failure to cure in patients with possibly resectable colorectal liver metastases (CRLM). This study aims to quantify the failure-to-cure rate due to noninclusion of an LS. All patients who underwent chemotherapy with palliative intent for CRLM at a community oncology network between 2010 and 2018 were identified from a prospectively maintained cancer registry. Two LS blinded to patient management and outcome reviewed pretreatment imaging and assigned each scan a newly developed resectability score. Nominal group technique and independent scores were combined to determine probability of curative-intent resection. Interobserver agreement was calculated using κ testing. This study included 72 palliative CRLM patients. Demographic factors were: 44 (59%) male, median age 68 years (range 36-94 years), 23 (32%) rectal primary, 24 (33%) receiving oxaliplatin-based chemotherapy. Of the 72 patients with CRLM, 6 had left-sided metastases only. The median number of CRLM was 6 (1-8). Agreement on resectability was achieved in 32 (44%) patients for the entire cohort and 17 (54%) in patients without extrahepatic disease. A lower median number of CRLM was found in the group considered to be resectable by the two LS (2 versus 8; p = 0.001). Substantial agreement was found between liver surgeons in the group of patients without extrahepatic disease (κ = 0.9043). Over44% of patients who were assigned palliative chemotherapy at tumor boards without an LS were considered potentially resectable upon independent LS review.

Abstract No. 109 Primary tumor location and genomic expression as predictive factors of survival outcomes in colorectal liver metastasis patients undergoing Y90: single-institution retrospective analysis of 45 patients

Abstract No. 109 Primary tumor location and genomic expression as predictive factors of survival outcomes in colorectal liver metastasis patients undergoing Y90: single-institution retrospective analysis of 45 patients