A methylation-based prognostic model predicts survival in patients with colorectal cancer

BackgroundTo construct a model that could effectively predict the prognosis of colorectal cancer (CRC) by searching for methylated-differentially expressed genes (MDEGs).MethodsWe identified MDEGs through four databases from Gene Expression Omnibus (GEO) and annotated their functions via bioinformatics analysis. Subsequently, after adjusting for gender, age, and grading, multivariate Cox hazard analysis was utilized to select MDEGs interrelated with the prognosis of CRC, and LASSO analysis was utilized to fit the prediction model in the training set. Furthermore, another independent dataset was harnessed to verify the effectiveness of the model in predicting prognosis.ResultsIn total, 252 hypomethylated and up-regulated genes and 132 hypermethylated and down-regulated genes were identified, 27 of which were correlated with the prognosis of CRC, and a 10-gene prognostic model was established after LASSO analysis. The overall survival rate could be effectively grouped into different risks by the median score of this model in the training set [risk ratio (HR) =2.27, confidence interval (95% CI), 1.69–3.13, P=8.15×10⁻⁸], and the validity of its effect in predicting prognosis in CRC was verified in the validation dataset (HR =1.75, 95% CI, 1.15–2.70, P=9.32×10^-3).ConclusionsOur model could effectively predict the overall survival rate of patients with CRC and provides potential application guidelines for its clinically personalized treatment.     

Multicentre validation of a clinical prognostic score integrating the systemic inflammatory response to the host for patients treated with curative-intent for colorectal liver metastases: The Liverpool score

BackgroundThis study aimed to create a new prognostic score integrating the systemic inflammatory response to predict survival in patients treated with curative intent for colorectal liver metastases (CLM).MethodsWe identified independent prognostic factors in patients who underwent liver surgery for CLM in a tertiary centre in the United Kingdom (UK) between 2010 and 2015. A pre- and a postoperative score (Liverpool score) were created by combining these factors to stratify patients into different risk groups. These new scores were validated in an international cohort of 219 patients from China and France.ResultsMultivariate cox regression analysis of the 364 patients of the UK cohort identified 6 preoperative and 1 postoperative prognostic factors for overall survival (OS): American society of anaesthesiologists (ASA) score, location and node status of the primary tumour, number and size of CLM, neutrophil-to-lymphocyte ratio (NLR) and resection margin. Both pre- and postoperative scores can be calculated with an online calculator at https://jscalc.io/calc/PXatrmjfrEFpYy2t. Using the pre-operative model on the UK cohort, median OS was 61.22 (50.23, not reached) months in the low-risk group (n = 162) and 30.36 (23.68, 35.95) months in the high-risk group (n = 162, p < 0.0001). The same difference was observed in the validation cohort. The Liverpool score outperformed previously published scoring system with a c-index of 0.619 pre-operatively and of 0.637 post-operatively.ConclusionWe developed a new prognostic score based on clinicopathologic characteristics including the site of the primary tumour location and on measurement of the systemic inflammatory response which could help to tailor patients’ management.     

Nomogram predicted disease free survival for colorectal liver metastasis patients with preoperative chemotherapy followed by hepatic resection

BackgroundHepatic resection is regarded to as a potentially curative option for colorectal cancer liver metastases (CRLM), but it is associated with a high rate of recurrence. The present study intended to establish an effective nomogram to predict disease free survival (DFS) and select candidates of hepatic resection.MethodsThe nomogram was based on a retrospective study on 447 CRLM patients treated with preoperative chemotherapy followed by hepatic resection using a multicentric database between January 1st, 2010 and December 31st, 2017. Results were validated using bootstrap resampling on 117 patients. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. Overall survival, disease free survival, and local recurrence rate for patients with colorectal cancer were measured.ResultsBased on multivariate analysis of the primary cohort, independent factors for DFS included tumor size larger than 5 cm, multiple liver metastases(>1), RAS mutation, primary lymph node metastasis and tumor size increase after preoperative chemotherapy. These five factors were all considered in the nomogram. The C-index of the nomogram for predicting survival was 0.675. With external validation, the C-index of the nomogram for the prediction of the DFS was 0.77, which demonstrated that this model has a good level of discriminative ability. For the 382 patients (66.7%) who developed recurrence, the optimal cutoff point for early recurrence was determined to be 12 months after hepatic resection.ConclusionsThe proposed nomogram demonstrated accurate prognostic prediction of DFS for CRLM patients with preoperative chemotherapy followed by hepatic resection.     

Prognostic impact of inter-metastatic heterogeneity of viable tumour cells in colorectal liver metastases

BackgroundHeterogenous response to neoadjuvant chemotherapy in patients with multiple colorectal liver metastases (CRLM) has been associated with an acquired resistance to systemic therapy. This study evaluated the occurrence of a heterogenous inter-metastatic tumour response with regards to the proportion of viable tumour cells, and its prognostic impact.MethodsA retrospective cohort study was conducted, including all patients with CRLM surgically treated at Karolinska University Hospital, Stockholm, Sweden, from 2013 to 2018. Factors associated with the proportion of viable tumour cells and inter-metastatic heterogeneity were analysed with regression and survival analyses.ResultsOut of 640 surgically treated patients, 405 patients (1357 CRLM), received neoadjuvant chemotherapy. Multiple CRLM were present in 314 patients (78%), out of whom 72 patients (23%) presented with a heterogenous tumour response. The median overall survival (OS) for patients with a heterogenous inter-metastatic tumour response was 36 months, compared to 57 months for patients with a homogenous inter-metastatic tumour response (p < .001). Poor OS in patients receiving preoperative chemotherapy was significantly associated with a heterogenous inter-metastatic tumour response (hazard ratio (HR) 1.68 (1.02–2.78)), right-sided primary tumour (HR 2.01 (1.29–3.43)) and CRLM diameter >5 cm (HR 1.83 (1.06–3.17)).ConclusionOutcome in patients with a heterogenous inter-metastatic tumour response, illustrated by the proportion of viable tumour cells, is inferior to that of patients with a homogenous response. These results suggest that heterogeneity in treatment response is an important marker of aggressive disease and could be of clinical value for decisions on post-operative therapy.     

A prognostic nomogram for colorectal cancer liver metastases after percutaneous thermal ablation

Purpose: To assess the efficacy of percutaneous thermal ablation in treating colorectal cancer liver metastases (CRCLM), and to propose a prognostic nomogram for overall survival (OS).

Materials and methods: Seventy-one patients with CRCLM undergoing thermal ablation at our institute from 2009 to 2013 were identified and analysed to formulate a prognostic nomogram. The concordance index (C-index) and calibration curve were calculated to evaluate the predictive accuracy of the nomogram. The nomogram was compared with two current prognostic nomograms for patients with CRCLM who had undergone hepatectomy (Kattan) and selective internal radiation therapy (Fendler). Predictive validity was assessed in the validation cohort of 25 patients who had undergone thermal ablation from 2014 to 2016.

Results: The median OS in the primary cohort was 26.4?months, whereas the 1-, 3- and 5-year OS rates were 72.2%, 37.2% and 17%, respectively. The median progression-free survival was 4.2?months. After univariate and multivariate analysis, a prognostic nomogram was formulated based on four predictors, including the number of tumours, maximum diameter of the tumour, CA19–9 level and ablation margin. The C-index of the nomogram was 0.815. Based on the patients of this study, the C-index was significantly higher than that of the Fendler nomogram (C-index, 0.698) and Kattan nomogram (C-index, 0.514, p?Conclusions: Thermal ablation was an effective therapy for CRCLM. Moreover, the nomogram was effective and simple for CRCLM patients undergoing thermal ablation.     

300例结直肠癌肝转移患者的临床预后分析

目的 探讨结直肠癌肝转移患者的临床特征及预后因素.方法 对300例结直肠癌首发肝转移患者的临床特征及肝转移后的生存情况进行回顾性分析.结果 300例患者中,原发病灶位于结肠者152例,位于直肠者148例.原发肿瘤为管状腺癌272例,黏液腺癌18例,类癌5例,印戒细胞癌4例,鳞癌1例.原发肿瘤为高分化19例,中分化217例,低分化27例.无区域淋巴结转移104例,有区域淋巴结转移162例.原发肿瘤分期为Ⅰ、Ⅱ期62例,Ⅲ、Ⅳ期为237例.同时性肝转移206例,异时性肝转移94例.肝转移灶为单发48例,多发252例.肝转移灶最大直经≤5 cm249例,>5 cm 51例.300例患者转移后中位生存期为19.0个月,肝转移后1、2和5年生存率分别为79.0%、29.0%和3.0%.单因素分析结果显示,患者KPS评分、组织学分级、原发肿瘤T分期、有无区域淋巴结转移、原发肿瘤分期、有无脉管瘤栓、肝转移灶部位、肝转移灶最大直径、肝转移灶数目、同时合并其他转移均与预后有关.多因素分析结果显示,KPS评分、脉管瘤栓、肝转移灶数目、肝转移灶最大直径是结直肠癌肝转移患者预后的独立影响因素.结论 KPS评分、脉管瘤栓、肝转移灶数目和最大直径是结直肠癌肝转移患者预后的影响因素,KPS评分越高、无脉管瘤栓、肝转移灶数目越少、转移灶最大直径越小的患者预后越好.     

Hepatic vascular inflow occlusion is associated with reduced disease free survival following resection of colorectal liver metastases

Background

Hepatic vascular inflow occlusion (VIO) can be applied during resection of colorectal liver metastases (CRLM) to control intra-operative blood loss, but has been linked to accelerated growth of micrometastases in experimental models. This study aimed to investigate the effects of hepatic VIO on disease-free and overall survival (DFS and OS) in patients following resection for CRLM.

围手术期预后营养指数对结直肠癌患者预后评估的价值

目的 探讨围手术期预后营养指数(PNI)对结直肠癌患者3年无进展生存(PFS)期和总生存(OS)期评估的价值。方法 选取2012年12月至2020年1月中国人民解放军总医院海南医院经术后病理确诊的结直肠癌患者153例,根据围手术期PNI并将患者分为不同亚组,通过Kaplan-Meier分析不同亚组患者预后差异,通过多因素Cox回归分析评估患者预后的影响因子。结果 根据约登指数,术前、术后PNI分别以48.73、45.40为界将患者分为低组和高组,两者对患者生存预测敏感度分别为71.40%、83.70%,特异度分别为59.60%、46.20%;术前PNI低组多见于T₃+T₄(P=0.02)、M₁期患者(P=0.02),而术后PNI低组则多见于年龄较大患者(P=0.03),两者低组均多见于肿瘤较大患者(均P=0.04);术前、术后PNI低组患者PFS、OS均劣于高组(均P<0.01);围手术期PNI是患者PFS、OS的预测因子,但相比术前PNI,术后PNI预测较为可靠(PFS:HR=0.31,95%CI=0.14～0....     

Management of patients with colorectal liver metastasis in eleven questions and answers

Introduction: Colorectal liver metastasis (CRLM) is the most frequent indication for liver resection in many centers. Recent improvements in oncology, surgery, interventional radiology, pathology and anesthesiology allow curative treatment in a larger proportion of patients with CRLM.

Areas covered: We illustrate the various aspects of the management of CRLM through 11 questions that summarize the topic, from the current obtained survival to future perspectives such as transplantation. The limits of a curative treatment are also presented from different angles, such as the benefits of pathology, the surgical options for extreme resections, the available chemotherapies and their efficacy, or the non-surgical ablative treatments.

Expert commentary: Given the increasing therapeutic possibilities, we strengthen the importance to analyze the situation of each patient with CRLM in a dedicated multidisciplinary team, in order to offer the best individualized treatment combination.     

Impact of treatment modality and number of lesions on recurrence and survival outcomes after treatment of colorectal cancer liver metastases

Background

Ablative strategies have been used to treat and facilitate hepatic resection (HR) in patients with otherwise unresectable colorectal liver metastases (CLM). We evaluated the efficacy of HR, concomitant HR and ablation and isolated ablation on recurrence and survival outcomes after treatment of CLM in patients with 1-4 and ≥5 lesions, respectively.

Methods

A retrospective review of a prospectively collected hepatobiliary surgery database was performed on patients who underwent treatment for isolated CLM between 1990 and 2010. Pre-operative and treatment characteristics were compared between patients who underwent HR, concomitant HR and ablation and ablation alone. The impact of treatment modality on survival and recurrence outcomes was determined.

Results

A total of 701 patients met inclusion criteria; 550 patients (78%) had 1-4 lesions and 151 patients (22%) had ≥5 lesions. Overall median survival for the entire cohort was 35 months with 5- and 10-year survival of 33% and 20%, respectively. Overall median and 5-year recurrence-free survival (RFS) was 13 months and 21%, respectively. For patients with 1-4 lesions, median survival was 37 months with 5-year survival of 36%. Stratified by procedure type, 5-year survival was 41% in patients who underwent HR, 35% in patients who underwent concomitant HR and ablation and 13% in patients who underwent ablation alone (P<0.001). For patients with ≥5 lesions, median survival was 28 months with 5-year survival of 23% without difference between treatment groups (P=0.078).

Conclusions

HR appears to be the most effective strategy for patients with 1-4 lesions. When ≥5 lesions are present, ablative strategies are useful in facilitating HR in otherwise unresectable patients.     

Neutrophil-to-lymphocyte ratio as a prognostic factor for survival in patients with colorectal liver metastases: A systematic review

BACKGROUNDThe inflammatory response to tumor has been proven to be closely related to the prognosis of colorectal cancer. Neutrophil to lymphocyte ratio (NLR) is a widely available inflammatory biomarker that may have prognostic value for patients with colorectal liver metastasis (CRLM).AIMTo assess the role of NLR as a prognostic factor of survival and tumor recurrence in patients with CRLM.METHODSA systematic literature search of PubMed, Cochrane Library and clinicaltrials.gov was conducted by two independent researchers in order to minimize potential errors and bias. Conflicts were discussed and settled between three researchers. Studies including patients undergoing different types of medical interventions for the treatment of CRLM and evaluating the correlation between pretreatment NLR and disease-free survival (DFS) and overall survival (OS) were included in the review. Nineteen studies, involving 3283 patients matched our inclusion criteria.RESULTSIn the studies included, NLR was measured before the intervention and the NLR thresholds ranged between 1.9 and 7.26. Most studies used 5 as the cut-off value. Liver metastases were treated with hepatectomy with or without chemotherapy regimens in 13 studies and with radiofrequency ablation, radioembolization, chemoembolization or solely with chemotherapy in 6 studies. High NLR was associated with decreased OS and DFS after liver resection or other medical intervention. Moreover, high NLR was associated with poor chemosensitivity. On the contrary, CRLM patients with low pretreatment NLR demonstrated improved OS and DFS. NLR could potentially be used as a predictive factor of survival and tumor recurrence in patients with CRLM treated with interventions of any modality, including surgery, chemotherapy and ablative techniques.CONCLUSIONNLR is an inflammatory biomarker that demonstrates considerable prognostic value. Elevated pretreatment NLR is associated with poor OS and DFS in patients with CRLM who are submitted to different treatments.     

Radiological heterogeneity in response to chemotherapy is associated with poor survival in patients with colorectal liver metastases

BackgroundIn patients with colorectal liver metastases (CLM) there is limited knowledge about the occurrence of radiological heterogeneity in response to chemotherapy.MethodsA retrospective analysis was performed in the CAIRO and CAIRO II studies on the incidence of intermetastatic heterogeneity in patients with CLM and its association with survival. Mixed response (MR) was defined as >30% difference in individual lesion response, with all lesions showing a similar behaviour; true mixed response (TMR) as two lesions showing progression versus response; homogeneous response (HR) as similar behaviour of all lesions. Patients were classified according to the Response Evaluation Criteria in Solid Tumours (RECIST) categories (partial response (PR), stable disease (SD), progressive disease (PD), complete response (CR)) and then subdivided into MR and TMR in order to compare survival.ResultsIn the CAIRO and CAIRO II studies, 140 and 150 patients with liver-only disease were identified. 73/290 (25.2%) patients showed MR, and 25/290 (8.6%) patients TMR, and 192/290 (66.2%) patients HR. Overall survival (OS) at 1–4 years was significantly higher for the homogeneous partial responders category compared to other response categories. Median OS was 22.0 months for the entire population. In the partial response category, patients with MR showed significant poorer survival compared to patients with HR (median OS 23.7 versus 36.0 months, respectively, p = 0.019). Multivariate analysis identified four independent predictors for OS: serum lactate dehydrogenase (LDH) level (p = 0.002), number of first-line chemotherapy cycles (p = 0.001), resection of primary tumour (p = 0.001) and response category (p = 0.012).ConclusionRadiological heterogeneity is present in approximately 35% of patients with CLM. Partial responders according to the RECIST criteria, show a significant poorer survival if classified as heterogeneous partial responder compared to homogeneous partial responders.     

Laparoscopic liver resection compared to open approach in patients with colorectal liver metastases improves further resectability: Oncological outcomes of a case-control matched-pairs analysis

Aims

Liver resection is considered the standard treatment of colorectal metastases (CRLM). However, to date, no long term oncological results and data regarding repeat hepatectomy after laparoscopic approach are known. The aim of this study is to analyze single center long-term surgical and oncological outcomes after liver resection for CRLM.

Methods

A total of 57 open resections (OR) were matched with 57 laparoscopic resections (LR) for CRLM. Matching was based mainly on number of metastases, tumor size, segmental position of lesions, type of hepatectomy and type of resection.

Results

Morbidity rate was significantly less in the LR group (p = 0.002); the length of hospital stay was 6.5 ± 5 days for the LR group and 9.2 ± 4 days for the OR group (p = 0.005). After a median follow up of 53.7 months for the OR group and 40.9 months for the LR group, the 5-y overall survival rate was 65% and 60% respectively (p = 0.36) and the 5-y disease free survival rate was 38% and 29% respectively (p = 0.24). More patients in the LR group received a third hepatectomy for CRLM relapse than in the OR group (80% vs. 14.3% respectively; p = 0.015).

Conclusions

Laparoscopic resection for CRLM offers advantages in terms of reduced blood loss, morbidity rate and hospital stay. It provides comparable long-term oncological outcomes but can improve further resectability in patients with recurrent disease.     

Liver resection is justified for patients with bilateral multiple colorectal liver metastases: A propensity-score-matched analysis

Background

Increasingly, patients with multiple colorectal liver metastases (CLM) are surgically treated. Some studies have shown that patients with bilobar and unilobar multiple CLM have similar outcomes, but other have shown that patients with bilobar CLM have worse outcomes after resection. We aimed to compare clinical outcomes of surgical treatment of bilobar and unilobar CLM using propensity score matching.

Propensity score matching demonstrates similar results for radiofrequency ablation compared to surgical resection in colorectal liver metastases

PurposeMinimally invasive ablative treatments, such as radiofrequency ablation (RFA), are increasingly used in the curative treatment of patients with colorectal liver metastases (CRLM). Selection bias plays an important role in the evaluation of early and late results between RFA and surgery. The purpose of this study was to evaluate recurrences and oncological survival following these two treatment modalities using single pair propensity score matching.MethodsBetween 2000 and 2018, patients curatively treated for CRLM were included in a multicentre database. Patients were excluded when receiving two-staged treatment, synchronous treatment with primary tumor or combination of modalities. Propensity score matching was used to minimize influence of known covariates, i.e., age, ASA, FONG CRS, location and T-stage of the primary tumor.ResultsBefore matching, the RFA group contained 39 patients and the surgery group 982 patients, after matching both groups contained 36 patients. After matching, mean age was 69 years (53–86) for RFA and 68 (50–86) for surgery, with a mean tumor size of respectively 2.5 cm (0.8–6.5) and 3.4 cm (1–7.5). Both groups showed similar complication rate according to Clavien-Dindo (17vs.33%; p = 0.18), recurrence rate (58vs.64%; p = 0.09) without significant differences in 5-year DFS and OS (RFA compared to surgery respectively 25vs.37%; p = 0.09 and 42vs.53%; p = 0.09).ConclusionAfter propensity score matching, RFA showed lower complications and similar oncological survival compared to surgical resection. In patients who are suboptimal candidates for surgery, RFA seems to be a good and safe alternative.     

结直肠癌根治性手术后复发时间与生存时间的相关性分析

背景与目的：结直肠癌根治性手术后复发率达30%~40%,肿瘤复发影响患者生存时间。本研究旨在探讨结直肠癌复发时间(time to relapse,TTR)与肿瘤临床病理参数的关系,并进一步分析TTR对复发后生存时间的影响。方法：分析辽宁省肿瘤医院收治的375例结直肠癌患者的临床资料、病理结果及随访数据,比较结直肠癌复发与临床资料和病理类型的相关性,并研究TTR与复发后总体生存时间的关系。结果：TTR与确诊时肿瘤分期以及有无肺、肝脏转移密切相关。短期复发(<2年)与生存时间密切相关,2~5年内复发与5年以上复发的患者,其生存时间差异无统计学意义(P>0.05)。结论：结直肠癌患者术后复发时间与肿瘤分期及有无肺、肝脏转移密切相关,短期复发是预测复发后生存时间的重要指标。