Gene Expression Profiles Accurately Predict Outcome Following Liver Resection in Patients with Metastatic Colorectal Cancer

Purpose

The aim of this study was to build a molecular prognostic model based on gene signatures for patients with completely resected hepatic metastases from colorectal cancer (MCRC).

Methods

Using the Illumina HumanHT-12 gene chip, RNA samples from the liver metastases of 96 patients who underwent R0 liver resection were analyzed. Patients were randomly assigned to a training (n = 60) and test (n = 36) set. The genes associated with disease-specific survival (DSS) and liver-recurrence-free survival (LRFS) were identified by Cox-regression and selected to construct a molecular risk score (MRS) using the supervised principle component method on the training set. The MRS was then evaluated in the independent test set.

Results

Nineteen and 115 genes were selected to construct the MRS for DSS and LRFS, respectively. Each MRS was validated in the test set; 3-year DSS/LRFS rates were 42/32% and 79/80% for patients with high and low MRS, respectively (p = 0.007 for DSS and p = 0.046 for LRFS). In a multivariate model controlling for a previously validated clinical risk score (CRS), the MRS remained a significant predictor of DSS (p = 0.001) and LRFS (p = 0.03). When CRS and MRS were combined, the patients were discriminated better with 3-year DSS/LRFS rates of 90/89% in the low risk group (both risk scores low) vs 42/26% in the high risk group (both risk scores high), respectively (p = 0.002/0.004 for DSS/LRFS).

Conclusion

MRS based on gene expression profiling has high prognostic value and is independent of CRS. This finding provides a potential strategy for better risk-stratification of patients with liver MCRC.     

Genetic Diversity of the KIR/HLA System and Outcome of Patients with Metastatic Colorectal Cancer Treated with Chemotherapy

Objective

To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).

Methods

A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.

Results

For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.

Conclusion

This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.     

Tissue MicroRNAs as Predictors of Outcome in Patients with Metastatic Colorectal Cancer Treated with First Line Capecitabine and Oxaliplatin with or without Bevacizumab

Purpose

We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC).

Experimental Design

Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs.

Results

In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts.

Conclusions

We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.     

Impact of Pre-Treatment Lactate Dehydrogenase Levels on Prognosis and Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer

Background

To investigate the impact of pre-treatment lactate dehydrogenase (LDH) levels on the outcome of patients with metastatic colorectal cancer treated with first-line chemotherapy with or without the anti-VEGF monoclonal antibody, bevacizumab, in a phase III prospective multicentre randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial.

Methods

Three hundred and seventy patients enrolled onto the ITACa first-line trial were considered for this study, 176 receiving chemotherapy (either FOLFIRI or FOLFOX) plus bevacizumab and 194 receiving chemotherapy only. Pre-treatment LDH levels were evaluated to identify a potential correlation with progression-free survival (PFS), overall survival (OS) and objective response rate.

Results

Information on pre-treatment LDH levels was available for 344 patients. High LDH levels were predictive of a lower median PFS (8.1 months vs. 9.2 months, p< 0.0001) and median OS (16.1 months vs. 25.2 months, p< 0.0001) in the overall population. In the chemotherapy plus bevacizumab group, median PFS was 9.1 and 9.8 months in patients with high LDH and low LDH, respectively (p= 0.073), whereas in the chemotherapy-only arm it was 6.9 and 9.1 months, respectively (p < 0.0001). In patients with high LDH, the addition of bevacizumab to chemotherapy led to a reduction in the rate of progressive disease (16.4 vs. 30.5%, p= 0.081) and to a prolonged PFS (p= 0.028).

Conclusion

A high LDH value was confirmed as a marker of poor prognosis. Bevacizumab reduced the progressive disease rate and improved PFS in the high-LDH subgroup, making serum LDH a potentially effective an easily available and marker to select patients who benefit from bevacizumab.

Trial Registration

NCT01878422 ClinicalTrials.gov     

The Correlation Between Serum Chemokines and Clinical Outcome in Patients with Advanced Biliary Tract Cancer

BACKGROUND: Biliary tract cancers (BTCs) are known to have a dismal prognosis. A number of chemokines play important roles in the progress of BTCs. However, the serum levels of chemokines in BTCs have not yet been explored. METHODS: The sera of healthy donors (n = 8) and patients with BTCs who were enrolled in second line sunitinib trials (n = 27) were collected. The concentrations of three kinds of chemokines (CXCL5, CXCL8 and CXCL12) were measured using ELISA assay. The median concentrations of chemokines were compared between healthy donors and BTC patients and the role of chemokines as a prognostic biomarker was examined. RESULTS: BTC patients generally had higher serum levels of CXCL5 and CXCL12 compared to healthy donors. Patients with cholangiocarcinoma showed significantly higher levels of serum CXCL12 than patients with gallbladder cancer. In survival analysis, only CXCL12 level showed a prognostic impact on overall survival (median OS: 6.9 vs. 0.9 months in low CXCL12 vs. high CXCL12, respectively; P = .008). High CXCL5 levels were also correlated with poor survival without statistical insignificance (median OS: 6.2 vs. 2.0 months in low CXCL5 vs. high CXCL5, respectively; P = .070). CONCLUSIONS: There was a significant difference in OS according to the level of CXCL12, suggesting that serum CXCL12 levels may be a useful surrogate marker for clinical outcome in advanced BTCs.     

Clinical Efficacy of Chemotherapy Combined with Verapamil in Metastatic Colorectal Patients

In order to determine the clinical efficacy and adverse reactions of chemotherapy and verapamil infusion through a target artery to treat colorectal cancer patients with metastasis after failure with previous conventional treatments. Patients with metastatic colon cancer (n = 36) received an infusion of verapamil, interleukin-2, oxaliplatin (or hydroxy camptothecin or irinotecan hydrochloride), fluorouracil and calcium folinate through target artery using the Seldinger puncture technique. From the second day of infusion, the patients were treated with fluorouracil and calcium folinate via systematic intravenous injection for 2–3 days. Efficacy was evaluated after at least two treatment courses. The objective response including complete or partial response was 58.3% in the 36 patients; clinical benefit rate, evaluated by Karnofsky Performance Status score was 91.7%; by weight was 83.3%; by the amount of painkiller consumed was 80.6%. No patient experienced side effects associated with heart function. Post-treatment, the P–R period, Q–T period, QRS, and heart rate were not significantly different than before treatment. Liver function was significantly improved. Side effects of chemotherapy were minor in comparison to those observed with intravenous chemotherapy. Infusion of verapamil and chemotherapy directly into pelvic tumor tissue can increase treatment efficacy and has been shown to be a relatively safe technique.     

老年高血压患者颈动脉内膜中膜厚度与动态血压参数的相关性

目的:探究老年高血压患者颈动脉内膜中膜厚度(IMT)与动态血压参数间的相关关系,为老年高血压患者的临床治疗提供理论基础。方法:选取2015年1月至2016年1月在我院接受治疗的老年高血压患者204例,根据超声检查结果分为A、B、C三组,每组68例。24 h无创检测患者动态血压参数,包括24h平均收缩压(24h SBP),24 h平均舒张压(24h DBP)、白天平均收缩压(d SBP)、白天平均舒张压(d DBP)、夜间平均收缩压(n SBP)、夜间平均舒张压(n DBP),24h脉压(24h PP)及白天脉压(d PP)、夜间脉压(n PP),记录冠心病的发生率、杓型与非杓型高血压比例,利用Person相关性分析IMT与冠心病发生率及动态血压参数的相关性。结果:收缩压和脉压比较差异均有统计学意义(P0.05),其中B组、C组高于A组,C组高于B组,差异具有统计学意义(P0.05)。非杓型高血压在A组占54.41%,B组占60.29%,C组占79.41%,各组间差异有统计学意义(P0.05);A组、B组、C组冠心病发病率分别为41.18%、54.41%和91.18%,组间比较差异有统计学意义(P0.05)。IMT同冠心病发生率和24h SBP、d SBP、n SBP、24h PP、d PP、n PP呈正相关(r=0.876,0.448,0.378,0.476,0.443,0.491,0.438,P0.05)。结论:老年高血压患者收缩压,脉压升高以及非杓型高血压是造成颈动脉内膜中膜厚度增加的主要原因,同时,IMT与冠心病发病率和动态血压参数间呈正相关关系。     

Impact of Diabetes on Oncologic Outcome of Colorectal Cancer Patients: Colon vs. Rectal Cancer

Background

To evaluate the impact of diabetes on outcomes in colorectal cancer patients and to examine whether this association varies by the location of tumor (colon vs. rectum).

Patients and methods

This study includes 4,131 stage I-III colorectal cancer patients, treated between 1995 and 2007 (12.5% diabetic, 53% colon, 47% rectal) in South Korea. Cox proportional hazards modeling was used to determine the prognostic influence of DM on survival endpoints.

Results

Colorectal cancer patients with DM had significantly worse disease-free survival (DFS) [hazard ratio (HR) 1.17, 95% confidence interval (CI): 1.00–1.37] compared with patients without DM. When considering colon and rectal cancer independently, DM was significantly associated with worse overall survival (OS) (HR: 1.46, 95% CI: 1.11–1.92), DFS (HR: 1.45, 95% CI: 1.15–1.84) and recurrence-free survival (RFS) (HR: 1.32, 95% CI: 0.98–1.76) in colon cancer patients. No association for OS, DFS or RFS was observed in rectal cancer patients. There was significant interaction of location of tumor (colon vs. rectal cancer) with DM on OS (P = 0.009) and DFS (P = 0.007).

Conclusions

This study suggests that DM negatively impacts survival outcomes of patients with colon cancer but not rectal cancer.     

Immunomodulatory Effects in a Phase II Study of Lenalidomide Combined with Cetuximab in Refractory KRAS-Mutant Metastatic Colorectal Cancer Patients

This study assessed the immunomodulatory effects in previously treated KRAS-mutant metastatic colorectal cancer patients participating in a phase II multicenter, open-label clinical trial receiving lenalidomide alone or lenalidomide plus cetuximab. The main findings show the T cell immunostimulatory properties of lenalidomide as the drug induced a decrease in the percentage CD45RA⁺ naïve T cells 3-fold while increasing the percentage HLA-DR⁺ activated T helper cells and percentage total CD45RO⁺ CD8⁺ memory T cytotoxic cells, 2.6- and 2.1-fold respectively (p<0.0001). In addition, lenalidomide decreased the percentage of circulating CD19⁺ B cells 2.6-fold (p<0.0001). Lenalidomide increased a modest, yet significant, 1.4-fold change in the percentage of circulating natural killer cells. Our findings indicate that lenalidomide significantly activates T cells, suggestive of an immunotherapeutic role for this drug in settings of maintenance therapy and tumor immunity. Furthermore, reported for the first time is the effect of lenalidomide in combination with cetuximab on T cell function, including increases in circulating naïve and central memory T cells. In summary, lenalidomide and cetuximab have significant effects on circulating immune cells in patients with colorectal carcinoma.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01032291","term_id":"NCT01032291"}}NCT01032291     

Mutational Analysis of Circulating Tumor Cells from Colorectal Cancer Patients and Correlation with Primary Tumor Tissue

Circulating tumor cells (CTCs) provide a non-invasive accessible source of tumor material from patients with cancer. The cellular heterogeneity within CTC populations is of great clinical importance regarding the increasing number of adjuvant treatment options for patients with metastatic carcinomas, in order to eliminate residual disease. Moreover, the molecular profiling of these rare cells might lead to insight on disease progression and therapeutic strategies than simple CTCs counting. In the present study we investigated the feasibility to detect KRAS, BRAF, CD133 and Plastin3 (PLS3) mutations in an enriched CTCs cell suspension from patients with colorectal cancer, with the hypothesis that these genes` mutations are of great importance regarding the generation of CTCs subpopulations. Subsequently, we compared CTCs mutational status with that of the corresponding primary tumor, in order to access the possibility of tumor cells characterization without biopsy. CTCs were detected and isolated from blood drawn from 52 colorectal cancer (CRC) patients using a quantum-dot-labelled magnetic immunoassay method. Mutations were detected by PCR-RFLP or allele-specific PCR and confirmed by direct sequencing. In 52 patients, discordance between primary tumor and CTCs was 5.77% for KRAS, 3.85% for BRAF, 11.54% for CD133 rs3130, 7.69% for CD133 rs2286455 and 11.54% for PLS3 rs6643869 mutations. Our results support that DNA mutational analysis of CTCs may enable non-invasive, specific biomarker diagnostics and expand the scope of personalized medicine for cancer patients.     

lncRNA91H在结直肠癌患者中的表达及其与临床病理特征和预后的关系

目的:探讨长链非编码RNA(lncRNA)91H在结直肠癌(CRC)患者中的表达及其与临床病理特征和预后的关系。方法:抽取我院2010年1月到2012年1月行CRC根治性切除术患者组织标本80例(包括癌组织和癌旁组织),实时荧光定量PCR检测癌组织和癌旁组织中的lncRNA91H表达,设置干扰序列,噻唑蓝(MTT)测定细胞增殖率和流式细胞仪检测细胞凋亡率,COX分析lncRNA91H和预后关系。结果:癌组织lncRNA91H相对表达量为(1.83±0.14),癌旁组织为(0.36±0.07),差异具有统计学意义(P0.05);lncRNA91H表达在不同TNM分期、肿瘤转移以及浸润深度间差异均具有统计学意义(P0.05)。多因素COX分析显示,TNM分期、肿瘤转移、浸润深度、lncRNA91H表达是影响CRC预后独立危险因素(P0.05)。干扰序列作用于lncRNA91H表达后,培养24 h、48 h、96 h时lncRNA91H表达组吸光度(OD)均低于对照组,且随着培养时间的延长,两组OD均显著上升(P0.05);阴性对照组细胞凋亡率为(5.67±1.23)%,转染lncRNA91H细胞凋亡率为(25.37±0.89)%,差异具有统计学意义(P0.05)。结论:lncRNA91H可以作为CRC患者预后特异指标,并且与TNM分期、肿瘤转移以及浸润深度间等临床病理特征密切相关。     

Effect of Proteinuria and Glomerular Filtration Rate on Renal Outcome in Patients with Biopsy-Proven Benign Nephrosclerosis

Background

Reduced estimated glomerular filtration rate (eGFR) and proteinuria are risk factors for end-stage renal disease (ESRD), of which benign nephrosclerosis is a common cause. However, few biopsy-based studies have assessed these associations.

Methods

We performed retrospective cohort study of 182 Japanese patients who underwent renal biopsy from June 1985 through March 2014 and who were diagnosed with benign nephrosclerosis. Competing risk regression analyses were used to investigate the effect of eGFR and proteinuria levels at the time of renal biopsy on the risk for renal events (ESRD or a 50% decline in eGFR from baseline).

Results

During a median 5.8-year follow-up, 63 (34.6%) patients experienced renal events. The incidence of renal events increased with lower baseline eGFR and greater baseline proteinuria levels. After adjustment for baseline covariates, lower eGFR levels (subhazard ratios [SHRs], 1.30; 95% confidence interval [CI], 1.01–1.67, per 10 mL/min/1.73 m²) and higher proteinuria levels (SHR, 1.52; 95% CI, 1.23–1.87, per 1.0 g/day) at the time of renal biopsy were associated independently with higher risk for renal events. Lower levels of serum albumin (SHR, 2.07; 95% CI, 1.20–3.55 per 1.0 g/dL) were also associated with renal events. Patients with both eGFR <30 mL/min/1.73 m² and proteinuria ≥0.5 g/day had a 26.7-fold higher risk (95% CI, 3.97–179.4) of renal events than patients with both eGFR ≥60 mL/min/1.73 m² and proteinuria <0.5 g/day.

Conclusions

Reduced eGFR and increased proteinuria as well as lower serum albumin at the time of renal biopsy are independent risk factors for renal events among patients with biopsy-proven benign nephrosclerosis.     

Impact of Serum Apolipoprotein A-I on Prognosis and Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer: a Propensity Score-Matched Analysis

PURPOSE: We aimed to investigate the role of apolipoprotein A-I (ApoA-I) as a predictor of prognosis and treatment efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy with or without bevacizumab. METHODS: We conducted a retrospective study on consecutive patients who were diagnosed with mCRC at Sun Yat-sen University Cancer Center. According to their pretreatment ApoA-I level, patients were divided into low– and high–ApoA-I groups. Propensity score-matched method was performed to balance baseline characteristics between two groups. Based on whether they accepted bevacizumab as a first-line therapy, patients were further divided into the chemo + bevacizumab group and the chemo group. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier method, log-rank test, and Cox regression. RESULTS: The optimal cutoff value for the ApoA-I level was determined to be 1.105 g/l. In the propensity-matched cohort of 508 patients, low ApoA-I was significantly associated with inferior OS (P < .001) and PFS (P < .001) than high ApoA-I. Multivariate analysis showed that ApoA-I level was an independent prognostic maker of OS (P < .001) and PFS (P = .001). PFS (P < .001) in either the high– or low–ApoA-I groups could be extended significantly after the administration of bevacizumab, and patients with a high ApoA-I level also had a better OS in the chemo + bevacizumab group than the chemo group (P = .049). CONCLUSIONS: Patients with a low ApoA-I level have poor prognoses, and they did not display an OS benefit from bevacizumab.     

EMAST Is Associated with a Poor Prognosis in Microsatellite Instable Metastatic Colorectal Cancer

Purpose

To determine the frequency and prognostic value of elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in metastatic colorectal cancer (mCRC) patients in relation to microsatellite instability (MSI) status and MSH3 protein expression.

Material and Methods

The frequency of EMAST was evaluated in mCRC patients with MSI tumors and microsatellite stable (MSS) tumors. A literature overview was performed to compare the frequency of EMAST in our study with existing data. Immunohistochemistry for MSH3 was compared with EMAST status. Outcome was studied in terms of overall survival (OS) of mCRC patients with MSI and MSS tumors.

Results

EMAST was evaluated in 89 patients with MSI tumors (including 39 patients with Lynch syndrome) and 94 patients with MSS tumors. EMAST was observed in 45.9% (84 out of 183) of patients, with an increased frequency in MSI tumors (79.8% versus 13.8%, p < 0.001). We found no correlation between EMAST and MSH3 protein expression. There was no effect of EMAST on prognosis in patients with MSS tumors, but patients with MSI / non-EMAST tumors had a significantly better prognosis than patients with MSI / EMAST tumors (OS: HR 3.22, 95% CI 1.25-8.30).

Conclusion

Frequency of EMAST was increased in mCRC patients with MSI tumors, compared to MSS tumors. Our data suggest that the presence of EMAST correlates with worse OS in these patients. There was no effect of EMAST on the prognosis of patients with MSS tumors. A limitation of our study is the small number of patients in our subgroup analysis.     

The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer

Background

Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC).

Methods

Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions.

Results

Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8–10.5) and 4.2 months (95% CI: 3.4–4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21–0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36–0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS.

Conclusion

The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC.

Trial Registration

ClinicalTrials.gov NCT01290926     

Clinical Implication of Anti-Angiogenic Effect of Regorafenib in Metastatic Colorectal Cancer

Background

Regorafenib induces distinct radiological changes that represent its anti-angiogenic effect. However, clinical implication of the changes is unclear.

Methods

Tumor attenuation as measured by Hounsfield units (HU) in contrast-enhanced computed tomography (CT) and cavitary changes of lung metastases were analyzed in association with treatment outcome of metastatic colorectal cancer patients (N = 80) treated with regorafenib in a prospective study.

Results

141 lesions in 72 patients were analyzed with HU. After 2 cycles of regorafenib, 87.5% of patients showed decrease of HU (Median change -23.9%, range -61.5%–20.7%). Lesional attenuation change was modestly associated with metabolic changes of 18-fluoro-deoxyglucose positron emission tomography-CT (Pearson’s r = 0.37, p = 0.002). Among 53 patients with lung metastases, 17 (32.1%) developed cavitary changes. There were no differences in disease control rate, progression-free survival, or overall survival according to the radiological changes. At the time of progressive disease (PD) according to RECIST 1.1, HU was lower than baseline in 86.0% (43/50) and cavitary change of lung metastasis persisted without refilling in 84.6% (11/13).

Conclusion

Regorafenib showed prominent anti-angiogenic effect in colorectal cancer, but the changes were not associated with treatment outcome. However, the anti-angiogenic effects persisted at the time of PD, which suggests that we may need to develop new treatment strategies.     

贝伐单抗二线治疗转移性结直肠癌的临床观察

目的:观察贝伐单抗二线治疗转移性结直肠癌患者的临床疗效和毒副反应。方法:回顾性分析2008年8月至2011年10月我院经组织病理学证实的转移性结直肠癌患者21例,一线治疗进展后,二线治疗方案中加用贝伐单抗,用法为5mg/kg,每2-3周1次,与化疗方案同步。化疗方案以奥沙利铂及伊立替康为基础,完成2-3周期治疗后评定疗效,观察毒副反应。结果:21例患者中PR1例,SD11例,PD9例,客观缓解率为4.8%,疾病控制率为57.1%,中位TTP为3.7个月。患者出现的不良反应有骨髓抑制、皮疹、恶心呕吐、腹泻、肝功能损害、神经毒性等,贝伐单抗所致高血压的发生率为14.3%(3/21),鼻衄发生率为4%(2/21)。结论:二线治疗中使用贝伐单抗,对一线治疗进展后的转移性结直肠癌疗效有限,毒副反应可耐受。     

Prognostic Significance of CD26 in Patients with Colorectal Cancer

Background

CD26, dipeptidyl peptidase IV, was discovered firstly as a membrane-associated peptidase on the surface of leukocyte. We previously demonstrated that a subpopulation of CD26⁺ cells were associated with the development of distant metastasis, enhanced invasiveness and chemoresistance in colorectal cancer (CRC). In order to understand the clinical impact of CD26, the expression was investigated in CRC patient''s specimens. This study investigated the prognostic significance of tumour CD26 expression in patients with CRC. Examination of CD26⁺ cells has significant clinical impact for the prediction of distant metastasis development in colorectal cancer, and could be used as a selection criterion for further therapy.

Methods

Tumour CD26 expression levels were studied by immunohistochemistry using Formalin-fixed paraffin embedded (FFPE) tissues in 143 patients with CRC. Tumour CD26 expression levels were correlated with clinicopathological features of the CRC patients. The prognostic significance of tumour tissue CD26 expression levels was assessed by univariate and multivariate analyses.

Result

CD26 expression levels in CRC patients with distant metastasis were significantly higher than those in non-metastatic. High expression levels of CD26 were significantly associated with advanced tumour staging. Patients with a high CD26 expression level had significantly worse overall survival than those with a lower level (p<0.001).

Conclusions

The expression of CD26 was positively associated with clinicopathological correlation such as TNM staging, degree of differentiation and development of metastasis. A high CD26 expression level is a predictor of poor outcome after resection of CRC. CD26 may be a useful prognostic marker in patients with CRC.