Portal thrombosis and steatosis after preoperative chemotherapy with FOLFIRI-bevacizumab for colorectal liver metastases

INTRODUCTIONSurgical resection of colorectal liver metastases is nowadays a standard of care for resectable disease with5-year survival rate approaching60%[1-3].Because of several theoretical benefits,preoperative systemic chemotherapy has been frequently…     

Chemokine receptor CCR6 expression level and aggressiveness of prostate cancer

Purpose  CCR6 is expressed in various tumors and has been implicated in the process of tumor progression and metastasis. Its chemokine ligand, CCL20, is present in different tissues including lymph nodes, but also the normal prostate. This study was performed to investigate a potential relationship between CCR6 and CCL20 expression and features of human prostate cancer (PCA) at time of primary treatment. Methods  Immunohistochemistry was used to detect CCR6 and CCL20 expression in archival tissue blocks of 80 PCA cases of various tumor grades and stages. Evaluation was semiquantitatively by visual scoring and quantitatively by digital image analysis (DIA). CCR6 and CCL20 expression was compared with Gleason score, stage, perineural invasion, nodal metastasis, age, and preoperative serum prostate-specific antigen (PSA) level by univariate and multivariate analyses. Results  Staining intensity of CCR6 in tumor cells varied considerably, with it being: weak in 21 tumors (26.2%), intermediate in 44 (55.0%), and strong in 15 (18.8%), with 3.6-log differences in DIA measurements. CCL20 expression was absent in eight tumors (10.0%), weak in 41 (51.2%), intermediate in 23 (28.8%), and strong in eight (10.0%). CCR6 and CCL20 expression did not correlate. CCR6 expression was associated with T-category (P < 0.0005), Gleason score (P = 0.003), and lymph node metastasis (P = 0.002). Conclusions  Expression levels of CCR6 in PCA were associated with clinical and pathologic features of more advanced and aggressive prostate cancer. Thus, CCR6 may directly or indirectly be involved in tumor progression and should be evaluated as novel candidate target molecule for specific treatment interventions.     

Chemokine expression in hepatocellular carcinoma versus colorectal liver metastases

INTRODUCTION Chemokines represent a family of small chemotactic cytokines, initially identified as mediators of leucocyte trafficking and homing. In the last few years, chemokines have been shown to participate also in tumor growth and the lymphatic and e…     

CCR6-CCL20对食管鳞癌患者体内Th17细胞分布的影响

目的研究CCR6-CCL20对食管鳞癌患者体内Th17细胞分布的影响。方法采用流式细胞术检测食管鳞癌患者手术切除的癌组织、癌旁组织及外周血中Th17细胞的比例及CCR6+Th17细胞的比例。RT-PCR方法检测组织中CCL20 mRNA水平。结果与癌旁组织及外周血相比,癌组织中Th17细胞明显升高(P<0.01);癌组织中CCR6+Th17细胞的比例高于癌旁组织及外周血(P<0.01);癌组织中CCL20 mRNA水平高于癌旁组织(P<0.01),并与Th17呈正相关。结论 CCR6-CCL20趋化轴可能在食管鳞癌患者Th17细胞浸润到肿瘤组织中发挥重要作用。     

Evaluation of aggressively treated patients with unresectable multiple liver metastases from colorectal cancer

PURPOSE: The aim of this study was to assess the value of aggressively treating patients with unresectable liver metastases from colorectal cancer and a poor prognosis. METHODS: From 1988 to 1999, 64 patients with unresectable multiple liver metastases from colorectal cancer who had received hepatic arterial infusion chemotherapy were investigated. All patients did not have synchronous extrahepatic metastases at the time of initiating our treatment. When liver metastases were suitable for resection after hepatic arterial infusion chemotherapy, we excised them and repeated prophylactic hepatic arterial infusion chemotherapy as long as possible. We evaluated the efficacy of hepatic arterial infusion chemotherapy by computed tomography and divided these patients into responders and nonresponders. We performed univariate analysis using the log-rank test to calculate predictive factors. In addition, the Cox proportional hazards model was used to perform multivariate analysis of factors related to survival. RESULTS: The survival rate of all patients was 67.8 percent after 1 year and 10 percent after 5 years. However, the survival rate for 16 patients who received hepatectomy after hepatic arterial infusion chemotherapy was 35.1 percent after five years. Multivariate analysis demonstrated that the response after hepatic arterial infusion chemotherapy was the most indicative prognostic factor. CONCLUSIONS: The prognosis of selected patients who responded to hepatic arterial infusion chemotherapy and received hepatectomy was improved. Applying aggressive treatment as outlined in our strategy may improve the chances of long-term survival.     

Combined portal vein embolization and preoperative chemotherapy prior to liver resection for colorectal cancer metastases

Abstract

Objective. Compare perioperative course and long-term mortality after liver resection for colorectal cancer (CRC) metastases between patients who had preoperative treatment with portal vein embolization (PVE) and chemotherapy or chemotherapy alone. Methods. Among patients undergoing liver resection for CRC metastases following preoperative chemotherapy treatment, 17 patients who had received preoperative PVE (group A) were compared with 17 matched controls who had no PVE (group B). Perioperative course and long-term mortality were compared between groups A and B and between group A and the entire group of 75 cases with preoperative chemotherapy (group C). Results. Baseline characteristics for the matched groups A and B were similar. Group C included less major resections. Median intraoperative bleeding was 1600 ml in group A, 1200 ml in group B, and 1000 ml in group C (p < 0.05 vs. group A). Median postoperative stay was comparable in all groups (8–9 days). Operation time was 542 min in group A and 464 min in group B (p < 0.01). Mortality after 30 days and 1, 2, and 5 years was similar in all groups. Conclusion. Perioperative outcome and long-term survival did not differ when comparing liver resection for CRC liver metastases preceded by PVE and chemotherapy or chemotherapy alone, except for the operation time. The study supports the safety of this “aggressive” combination approach in patients in need of tumor “downstaging” by chemotherapy and PVE to increase the remnant liver volume.     

CCL20单克隆抗体对小鼠嗯唑酮结肠炎的治疗作用

背景：趋化因子是一类具有趋化作用的小分子细胞因子,与免疫和炎症反应密切相关。炎症性肠病（IBD）是一组肠道慢性炎症性疾病．免疫反应异常为其特征性表现之一。目的：研究趋化因子CCL20及其受体CCR6在小鼠实验性结肠炎中的表达以及抗CCL20治疗对实验性结肠炎的疗效。方法：30只昆明小鼠随机分为正常对照组、结肠炎模型组和CCL20单抗组．后两组以嗯唑酮溶液灌肠诱导结肠炎模型。造模后每天予单抗组小鼠CCL20单抗1mg／kg腹腔注射一次,连续4d。第5d行疾病活动指数（DAI）评估后处死小鼠,行结肠大体形态和组织学损伤评分,测定结肠组织髓过氧化物酶（MPO）活性;以荧光定量聚合酶链反应（PCR）和酶联免疫吸附测定（ELISA）检测结肠组织CCL20mRNA和蛋白表达：分离肠黏膜固有层单个核细胞（LPMC）,流式细胞仪分析CCR6阳性CD4^＋T细胞比例。结果：与正常对照组相比．结肠炎模型组的DAI、结肠大体形态和组织学损伤评分、MPO活性以及结肠组织CCL20mRNA和蛋白表达、LPMC中CCR6阳性CD4^＋T细胞比例均显著增高（P〈0．05）;而CCL20单抗组上述指标均较结肠炎模型组显著降低（P〈0．05）。结论：CCL20／CCR6在嗯唑酮诱导的小鼠实验性结肠炎中表达增高,以CCL20单抗阻断CCL20／CCR6可有效缓解结肠炎症。     

Evaluation of peri-operative chemotherapy using a prognostic nomogram for survival after resection of colorectal liver metastases

Introduction:

Nomograms are statistical tools designed to predict outcomes. This study evaluates the effects of peri-operative chemotherapy on the accuracy of a prognostic nomogram for disease-specific survival (DSS) after resection of colorectal liver metastases (CRLM) established at Memorial-Sloan Kettering Cancer Center (MSKCC).

Methods:

An external cohort of 203 patients who underwent resection of CRLM between 1996 and 2006 was used to assess the nomogram.

Results:

After median follow-up of 30.4 months (range 0.33–150), Kaplan–Meier (KM) estimates for 3-, 5- and 8-year post-resection DSS were 56%, 41%, and 32%, respectively; similar to nomogram-predicted probabilities for DSS. The concordance index for the nomogram was higher (0.602) than for the Fong colorectal risk score (CRS; 0.533). KM DSS was longer for patients (n= 50) treated with at least 6 months of peri-operative irinotecan or oxaliplatin compared with all other patients (median 66 vs. 40 months, P= 0.06). KM DSS was greater than nomogram predicted DSS for treated patients and less than nomogram predicted DSS for all other patients.

Conclusions:

The CRLM nomogram was validated by an external cohort and more accurately predicted post-resection survival than the commonly used CRS. Differences in observed and nomogram-predicted survival may reflect the effect of treatment factors, such as peri-operative chemotherapy.     

Feasibility and short-term outcome of adjuvant FOLFOX after resection of colorectal liver metastases

Background

The role of adjuvant chemotherapy for stage IV colorectal cancer has so far been under-investigated. The aim of this study was to assess the feasibility and short-term outcome of adjuvant chemotherapy with the FOLFOX regimen following liver resection for patients with colorectal liver metastasis (CRLM).

Methods

From May 2005 to September 2010, 86 patients with CRLM underwent hepatic resection in the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University. Of these patients, 24 received FOLFOX4 or modified FOLFOX6 as postoperative adjuvant chemotherapy.

Results

Nineteen male and 5 female patients received adjuvant chemotherapy following liver resection. Twenty-one (87.5 %) of these patients completed 6 cycles of adjuvant chemotherapy. Five patients required a dose reduction due to neutropenia, and the dose intensities of oxaliplatin and 5-FU were 93.6 and 94.1 %, respectively. There were no severe adverse events from the treatments. The median follow-up period was 48.4 months. Recurrences developed in 12 patients, and 3 patients died during the follow-up period. The 3- and 5-year disease-free survival and overall survival were 51.6 and 45.1 % and 95.5 and 76.0 %, respectively.

Conclusions

Adjuvant FOLFOX is feasible and might provide a good prognosis for CRLM patients who undergo liver resection.     

chemokine/chemokine receptor pair ccL20/ccR6 in human colorectal malignancy:An overview

Chemokines belong to a superfamily of small, cytokinelike proteins, which induce multiple physiological functions, particularly cytoskeletal rearrangement and compartment-specific migration through their interaction with G-protein-coupled receptors. Chemokines and their receptors have been widely acknowledged as essential and selective mediators in leukocyte migration in inflammatory response. It is now established that the chemokine/chemokine receptor system is also used by cancer cells to direct lymphatic and haematogenous spreading and additionally has an impact on the site of metastatic growth of different tumours. In recent years an increasing number of studies have drawn attention to CC-chemokine cysteine motif chemokine ligand 20(CCL20) and its physiological sole receptor CCR6 to play a role in the onset, development and metastatic spread of various gastrointestinal cancer entities. Among various cancer types CCR6 was also demonstrated to be significantly overexpressed in colorectal cancer(CRC) and stimulation by its physiological ligand CCL20 has been reported to promote CRC cell proliferation and migration in vitro. Further, the CCL20/CCR6 system apparently plays a role in the organ-selective liver metastasis of CRC. Here we review the literature on expression patterns of CCL20 and CCR6 and their physiological interactions as well as the currently presumed role of CCL20 and CCR6 in the formation of CRC and the development of liver metastasis, providing a potential basis for novel treatment strategies.     

An update on chemotherapy of colorectal liver metastases

Surgical resection of liver metastases of colorectal cancer greatly improves the clinical outcome of patients with advanced disease. Developments in chemotherapeutic agents and strategies bring hope of a cure to patients with initially unresectable colorectal liver metastases (CLM). Perioperative chemotherapy significantly improves the survival time of patients who receive curative-intent hepatectomy. Even for unresectable CLM, recent studies demonstrated that active preoperative chemotherapy could achieve shrinkage of liver metastasis and thus render some for resection. Furthermore, an increase in tumor resection rate and prolonged survival time among patients with CLM has been observed following the application of monoclonal antibodies in recent years. However, the value of chemotherapy via hepatic arterial infusion is still unclear. More trials should be conducted in patients with CLM in order to improve survival.     

结直肠癌肝转移综合治疗进展

虽然手术仍是目前唯一有可能治愈结直肠癌肝转移的手段,但是在结直肠癌肝转移的诊疗方面发展迅速。多学科团队综合治疗和分组治疗逐渐成为诊疗规范。对可切除的结直肠癌肝转移患者,在围手术期也应实施标准化疗,是否加用靶向药物尚无定论。实施转化性化疗时应选择高效化疗方案,并尽量缩短疗程,且一旦转移灶转化为可切除,就应积极安排手术。肝转移灶不可切除的患者,是否切除原发灶也存在争议。在肝转移灶局部治疗方面的新技术发展迅速,可改善患者生存。     

大肠癌肝转移介入治疗与静脉化疗的对比研究

目的　探讨结直肠癌肝转移的有效治疗方法。方法　肝动脉化疗灌注及栓塞治疗（ ＨＡＩＣＥ）２５ 例,第一次ＨＡＩＣＥ 后４ 周重复一次,以后每间隔３ － ６ 月行一次ＨＡＩＣＥ。静脉化疗（ＶＣ） 采用静脉给药,４ 周为１ 周期,２ 周期后间隔３－ ６ 月化疗一次。结果　ＨＡＩＣＥ 一疗程后上腹疼痛减轻或消失者占８８ ％ ,肝内肿块缩小占６８ ％ ,ＣＥＡ 降低病例占９２ ％ ;ＶＣ 一疗程后肝区疼痛减轻或消失者占１８ ％ ,肝内肿块缩小占８－３ ％ ;两组病例１ 、２ 、３ 年生存率分别为７２ ％ 、５２ ％ 、２４ ％ 和４１－７ ％ 、１６－７ ％ 、０ ％ （ Ｐ＜ ０－０１） 。结论　对于不能手术的结直肠癌肝转移,ＨＡＩＣＥ 在改善临床症状及延长生存期上较ＶＣ更有效,是一个较好的姑息性治疗方法     

Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases?

AIMS: This report describes three patients suffering from nodular regenerative hyperplasia (NRH). METHODS: These patients have received six, 16 and 20 cycles of neoadjuvant 5-fluorouracil and oxaliplatin-based chemotherapy before planned extended hepatectomy. Two patients underwent uneventful portal vein embolization to hypertrophy the future remnant liver. RESULTS: At the end of chemotherapy, liver function tests deteriorated and portal hypertension appeared in two patients, including ascites, splenomegaly and oesophageal varices. Liver biopsy was performed through a percutaneous (two patients) or a transjugular approach (one patient) and allowed the diagnosis of NRH, which was considered to be a contraindication for major liver resection in all three patients, associated with extrahepatic disease progression in one patient. All patients died from neoplastic disease progression despite further chemotherapy at 6, 17 and 31 months following the diagnosis of NRH. One patient developed liver failure and ascites at the time of death. CONCLUSIONS: Physicians should be aware of the potential occurrence and therapeutic impact of NRH in patients suffering from CRLM and treated by neoadjuvant 5FU-oxaliplatin-based chemotherapy before major liver surgery.     

Utility of preoperative imaging in evaluating colorectal liver metastases declines over time

Objectives

Reports on the sensitivity and accuracy of contrast-enhanced helical computed tomography (HCT) in the preoperative evaluation of colorectal liver metastases (CLM) have been conflicting. Few studies have controlled for and reported on the time interval between HCT and eventual surgery.

Methods

A multi-institution, retrospective review of consecutive patients who underwent hepatic resection for CLM from January 1999 to September 2004 was conducted. Data regarding lesion characteristics and resectability were extracted from radiology reports, operative findings and histopathological records. Findings in HCT were evaluated according to their sensitivity for detecting CLM and ability to predict resectability.

Results

A total of 217 consecutive patients who underwent hepatic resection for CLM were identified. The overall sensitivity of HCT for detection of CLM was 83.2%. Prolonged time between imaging and surgery was a negative predictor for HCT sensitivity in univariate and multivariate analysis (P < 0.001). In predicting resectability, preoperative HCT was accurate 77.0% of the time. The time interval to surgery was negatively correlated with HCT prediction accuracy in univariate and multivariate analyses (P < 0.001).

Conclusions

The utility of HCT as a preoperative tool to evaluate CLM is inversely proportional to the time interval between imaging and surgery. This may explain conflicting reports of the accuracy of HCT in the current literature.     

Location of liver metastases reflects the site of the primary colorectal carcinoma

Objective. The present study was designed to investigate whether the different venous return of different locations of colorectal carcinomas affects the lobar distribution of metastases to the liver, due to the “streaming” within the portal vein. Material and methods. The site of the primary colorectal carcinoma was divided into the right- and left hemicolon according to the different venous drainage via the superior and the inferior mesenteric/splenic vein. Both groups were analyzed for the distribution of the metastases in the liver. The anatomic site of the liver metastases was detected by intraoperative exploration and differentiated between the two lobes using the Cantlie line. Results. Out of a total of 178 patients, 109 men and 69 women with 264 metastases were eligible for the study. The ratio of metastases in the right and left hemiliver was 3.6:1 for 35 right-sided primary tumors (p=0.002) compared with 2.1:1 for 143 left-sided primary tumors (p=NS). No significant differences were evident for the sub-analysis of involved liver segments. Conclusions. The results of our study support the existence of the “streaming” effect in the portal vein. Right-sided colon carcinomas predominantly involve the right hemiliver, while left-sided colon carcinomas involve the liver homogeneously, considering the size ratio of the right to left liver lobe, which is about 2:1. Knowledge of streaming may help us to understand the spread of abdominal malignancies and may provide a reference concerning the possible primary site depending on metastatic distribution in the liver.     

Resection margin influences the outcome of patients with bilobar colorectal liver metastases

AIM To evaluate the outcome of patients with bilobar colorectal liver metastases(CRLM) and identify clinicopathological variables that influenced survival.METHODS Patients with bilobar CRLM were identified from a prospectively maintained hepatobiliary database during the study period(January 2010-June 2014). Collated data included demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome. Down-staging therapy included Oxaliplatinor Irinotecan- based regimens, and Cetuximab was also used in patients that were K-RAS wild-type. Response to neo-adjuvant therapy was assessed at the multidisciplinary team meeting and considered for surgery if all macroscopic CRLM were resectable with a clear margin while preserving sufficient liver parenchyma.RESULTS Of the 136 patients included, thirty-two(23.5%) patients were considered inoperable and referred for palliative chemotherapy, and thirty-four(25%) patients underwent liver resection. Seventy(51.4%) patients underwent down-staging therapy, of which 37(52.8%) patients responded sufficiently to undergo liver resection. Patients that failed to respond to down-staging therapy(n = 33, 47.1%) were referred for palliative therapy. There was a significant difference in overall survival between the three groups(surgery vs down-staging therapy vs inoperable disease, P 0.001). All patients that underwent hepatic resection, including patients that had down-staging therapy, had a significantly better overall survival compared to patients that were inoperable(P 0.001). On univariate analysis, only resection margin significantly influenced disease-free survival(P = 0.017). On multi-variate analysis, R0 resection(P = 0.030) and female(P = 0.036) gender significantly influenced overall survival. CONCLUSION Patients undergoing liver resection with bilobar CRLM have a significantly better survival outcome. R0 resection is associated with improved disease-free and overall survival in this patient group.     

CCL20和CCR6与消化系统肿瘤的相关性研究

CCL20是一种CC亚族趋化因子,在与受体CCR6结合后直接参与树突状细胞、T细胞的定向迁移,在肿瘤免疫、自身免疫等方面发挥一定作用.近年来趋化因子及其受体在肿瘤免疫中的作用备受重视,本文就CCL20和CCR6在消化道肿瘤中的研究进展作一综述.     

Cryoablation of colorectal liver metastases: minimally invasive tumour control

Background: Freezing is used for in situ destruction (ablation) of liver tumours not eligible for resection. The procedure is typically done during laparotomy. The objective of this report was to study tumour control at the site of freezing and a minimally invasive approach to cryoablation of colorectal liver metastases. Methods: A prospective study of 19 patients was conducted between 1999 and 2003. Twenty‐five tumours were ablated during 24 procedures (i.e. 5 reablations). Sixteen procedures were performed percutaneously, 5 during laparotomy and 3 laparoscopically. Magnetic resonance imaging (MRI) was used for intraprocedural monitoring during most procedures. Nine patients had concomitant liver resections performed (5 during laparoscopy, 4 during laparotomy). Results: Out of 25 ablations, 18 (72%) were assumed adequate. Total ice‐ball volume during percutaneous procedures was median 62?cm ³ (range 32–114). Excellent imaging of the extent of freezing was achieved using MRI. Hospital stay for patients treated percutaneously was median 4 days (range 3–30). No perioperative mortality occurred. Tumour recurrence at the site of ablation occurred in 8 of 18 (44%) tumours adequately ablated. Actuarial 2‐year tumour‐free survival at site of ablation was 48%. At the time of analyses 12 out of 13 (92%) patients assumed to be adequately ablated were alive. Of all patients, 14 out of 19 (74%) survived. Conclusions: Short‐term tumour control can be achieved following cryoablation of colorectal liver metastases. A minimally invasive approach is feasible but the diameter of metastases considered for percutaneous cryoablation should not exceed 3?cm.