Association of body composition with survival and inflammatory responses in patients with non-metastatic nasopharyngeal cancer.

OBJECTIVES: It is unknown whether or not the body composition is correlated with the prognosis and inflammatory response in patients with nasopharyngeal cancer (NPC). MATERIALS AND METHODS: This cohort included 1767 patients with NPC. Visceral, subcutaneous and intra muscular adipose tissues (VAT, SAT and IMAT), and skeletal muscle index were quantified with computed tomography. We used the optimal stratification to select cut points for VAT, SAT and IMAT. We defined sarcopenia according to a widely used cut-point. The primary endpoint was overall survival (OS). The association between body composition and inflammatory response was also examined. RESULTS: Low VAT, SAT, IMAT and sarcopenia were observed in 260 (14.7%), 451 (25.5%), 773 (43.7%) and 683 (38.7%) patients, respectively. Low VAT (P < 0.001, hazard ratio [HR], 1.884; 95% confidence interval [CI], 1.436-2.473,) and SAT (P = 0.022, HR, 1.334, 95%CI, 1.043-1.706) were both associated worse survival. IMAT and sarcopenia were not with prognostic value. In multivariate analysis, we found the prognostic value of the VAT (HR: 1.544, 95% CI: 1.128-2.114; P = 0.007) was independent of T stage, N stage, disease stage, lactic dehydrogenase, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), the systemic immune-inflammation index (SII), EBV-DNA and body mass index. We observed higher NLR (P = 0.028) and PLR (P < 0.001) in patients with low SAT. Both low VAT (P = 0.009) and SAT (P = 0.005) were associated with decreased stromal lymphocyte infiltrating intensity. CONCLUSIONS: Among body composition parameters, VAT was an independent prognostic factor, especially in patients with locally advanced NPC.

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer.

BACKGROUND: Differences between the features of primary cancer and matched metastatic cancer have recently drawn attention in research. This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). METHODS: Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. RESULTS: A total of 369 patients were included. Of the 46 patients with MSI-high primary tumors, 37 (80.4%) also had MSI-high metastatic tumors, whereas 9 (19.6%) had microsatellite stable (MSS) metastatic tumors. A high concordance was found in patients with liver, lung, or distant lymph node metastases. Interestingly, the discrepancy was more likely to be limited to peritoneal (5/20) or ovarian (4/4) metastasis (chi-square test, P<.001). These organ-specific features were also found in the pooled analysis. Along with the change of MSI-high in primary cancer to MSS in metastatic cancer, lymphocyte infiltration decreased significantly (P=.008). However, the change did not influence survival; the median overall survival of MSI-high and MSS metastatic tumors was 21.3 and 21.6 months, respectively (P=.774). The discrepancy rate was 1.6% for patients with proficient MMR primary tumors. CONCLUSIONS: For patients with dMMR primary tumors, the concordance of MSI and MMR status in primary CRC and corresponding metastatic cancer is potentially organ-specific. High concordance is found in liver, lung, and distant lymph node metastases, whereas discrepancy is more likely to occur in peritoneal or ovarian metastasis. Rebiopsy to evaluate MSI-high/dMMR status might be needed during the course of anti-PD-1 therapy in cases of peritoneal or ovarian metastasis.

Systemic neutrophil lymphocyte ratio and mismatch repair status in colorectal cancer patients: correlation and prognostic value.

Purpose: Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is associated with increased local immune response as compared with mismatch repair-proficient (pMMR) CRC. We evaluated the relationship between MMR status and systemic inflammatory factors, including neutrophil lymphocyte ratio (NLR) and C-reactive protein (CRP). We also assessed the prognostic value of these parameters. Methods and materials: We analysed the relationship between MMR status (obtained by histochemical analysis), neutrophil and lymphocyte counts, NLR, and CRP level. The impact of systemic inflammatory factors on survival was also evaluated in dMMR and pMMR CRC patients. Results: A total of 1353 male and 892 female patients were eligible for analysis, of which, 253 patients (11.3%) were found to have dMMR status. Patients with dMMR status presented with increased neutrophil counts, and higher NLR and CRP levels in early stage CRC. In stage IV CRC patients, no correlation between MMR status and systemic inflammatory factors was found. Lymphocyte counts did not correlate with MMR status. High NLR was a prognostic factor for poor survival in pMMR CRC. However, NLR was not a prognostic factor in dMMR CRC. Conclusions: Our results suggest that dMMR CRC correlates with higher neutrophil count, NLR and CRP levels only in non-metastatic patients, and NLR has prognostic value only in pMMR CRC.

Association of low skeletal muscle index with increased systematic inflammatory responses and interferon γ-induced protein 10 levels in patients with colon cancer.

BACKGROUND: Skeletal muscle depletion is a prognostic factor in patients with cancer. Here, we evaluated the association between the skeletal muscle index (SMI) and local and systemic responses in patients with colon cancer. PATIENTS AND METHODS: We analyzed the relationships of the SMI with neutrophil, lymphocyte, monocyte, and platelet counts; the neutrophil-to-lymphocyte ratio; albumin levels; and C-reactive protein levels in a cohort of 561 patients, and with the circulating levels of 39 cytokines in a cohort of 125 patients. We also studied the association between the SMI and tumor local inflammatory response and the effect of SMI on survival. RESULTS: The median SMIs for male and female subjects were 44.1 and 34.2 cm2/m2, respectively. We observed positive correlations of the SMI with neutrophil (p=0.022), lymphocyte (p=0.001), and monocyte counts (p=0.003). A low SMI correlated significantly with an increased platelet count (p=0.017), decreased albumin level (p=0.006), neutrophil-to-lymphocyte ratio >3 (p=0.021), and an increased interferon γ-induced protein 10 level (IP-10, r = -0.276, p=0.002). The SMI did not correlate significantly with local inflammatory reactions or the C-reactive protein level. Finally, the SMI was a significant prognosticator in patients with stage III colon cancer (3-year disease-free survival rates: 35.1% for the low SMI arms versus 46.0% in the high SMI arms; HR =2.036; p=0.034). CONCLUSION: This study highlights the association of a low SMI with a high systematic inflammatory response and IP-10 levels. Furthermore, low SMI is a predictor of poor disease-free survival in patients with stage III colon cancer.

An increased number of negative lymph nodes is associated with a higher immune response and longer survival in colon cancer patients.

BACKGROUND: The purpose of the present study was to examine the relationship among the number of negative lymph nodes (LNs), the local and systemic immune response, and survival in patients with colon cancer. PATIENTS AND METHODS: One thousand one hundred and fifty-seven patients with colon cancer who underwent surgery at Sun Yat-sen University Cancer Center between 2009 and 2014 were included. We examined negative LNs in relation to the local and systemic immune response, including percentage carcinoma, neutrophil and lymphocyte infiltration, Crohn's-like reaction, neutrophil to lymphocyte ratio, platelets, and C-reactive protein (CRP). Disease-free survival and overall survival were also examined. We performed subgroup analysis based on the distribution of negative LNs. RESULTS: An increased number of negative LNs was associated with greater neutrophil invasion (p=0.001), more lymphocyte invasion (p=0.001), and more Crohn's-like reaction (p=0.001). No significant correlation was observed between negative LNs and the neutrophil to lymphocyte ratio. More than 12 negative LNs were associated with increased platelets and CRP levels. A higher number of negative LNs was independently associated with longer disease-free survival in stage I+II patients (p=0.004) and stage III patients (p=0.015), while negative LNs were also independent prognostic factors in stage IV patients (p=0.007). CONCLUSION: Our study suggests that negative LNs are indicators of the immune response and are associated with a better prognosis in patients with colon cancer.

Loss of LKB1 Expression Decreases the Survival and Promotes Laryngeal Cancer Metastasis.

Background: Given recent results indicating that diminished LKB1 expression in laryngeal cancer correlates with shorter survival. We aim to perform an analysis estimate the role of decreased liver kinase B1(LKB1) and in the prognostication of human laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study and evaluate the expression of LKB1 and p16INK4a (p16) in 208 clinical advanced-stage LSCC tissue samples by using immunohistochemistry. The specimens were received at Sun Yat-sen University Cancer Center (Guangzhou, China). To evaluate the independent prognostic relevance of LKB1, univariate and multivariate Cox regression models were used, overall survival (OS) and distant metastasis-free survival (DMFS) were compared using the Kaplan-Meier method. Results: Immunohistochemical analyses revealed that 80/208 (38.5%) of the LSCC tissue samples expressed high LKB1. Low LKB1 expression was associated with a significantly shorter OS and DMFS than high LKB1 expression (P = 0.041 and 0.028, respectively; log-rank test), and there was a poorer OS in the p16-positive than p16-negative group. In the subgroup stratified by p16 status, the shorter OS were also seen with low LKB1 expression. Multivariate survival analysis indicated that high LKB1 expression was an independent prognostic factor for OS (hazard ratio [HR]: 1.628, 95% confidence interval [CI]: 1.060-2.500, P = 0.026) and DMFS (HR: 2.182, 95% CI: 1.069-4.456, P = 0.032). Conclusions: Our data indicated that low expression of LKB1 was significantly associated with poor prognosis and it may represent a marker of tumor metastasis in patients with LSCC. When combined with p16, LKB1 was also of prognostic value.

DNA-dependent protein kinase catalytic subunit functions in metastasis and influences survival in advanced-stage laryngeal squamous cell carcinoma.

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is known to function in several types of cancer. In this study, we investigated the expression and clinicopathologic significance of DNA-PKcs in laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study of 208 patients with advanced-stage LSCC treated at Sun Yat-sen University Cancer Center, Guangzhou, China. We assessed DNA-PKcs and p16INK4a (p16) status using immunohistochemistry. We examined the association between DNA-PKcs expression and clinicopathologic features and survival outcomes. To evaluate the independent prognostic relevance of DNA-PKcs, we used univariate and multivariate Cox regression models. We estimated overall survival (OS) and distant metastasis-free survival (DMFS) using the Kaplan-Meier method. Results: Immunohistochemical analyses revealed that 163/208 (78.4%) of the LSCC tissue samples exhibited high DNA-PKcs expression. High DNA-PKcs expression was significantly associated with survival outcomes (P = 0.016) and distant metastasis (P = 0.02; chi-squared test). High DNA-PKcs expression was associated with a significantly shorter OS and DMFS than low DNA-PKcs expression (P = 0.029 and 0.033, respectively; log-rank test), and was associated with poor OS in the p16-positive subgroup (P = 0.047). Multivariate analysis identified DNA-PKcs as an independent prognostic indicator of OS and DMFS in all patients (P = 0.039 and 0.037, respectively). Conclusions: Our results suggest that patients with LSCC in whom DNA-PKcs expression is elevated have a higher incidence of distant metastasis and a poorer prognosis. DNA-PKcs may represent a marker of tumor progression in patients with p16-positive LSCC.

Primary Tumor Location as a Predictive Factor for First-line Bevacizumab Effectiveness in Metastatic Colorectal Cancer Patients.

Background: Published papers reported contradictory results about the correlation between bevacizumab effectiveness and primary tumor location of metastatic colorectal cancer (mCRC). Methods: 740 mCRC patients treated with chemotherapy (CT group) and 244 patients treated with bevacizumab plus chemotherapy as first-line setting (CT + B group) were included. Propensity score analyses were used for patients' stratification and matching. Kaplan-Meier curves with log-rank tests were used to detect different overall survival (OS). Results: Patients in CT + B group had similar OS comparing with CT group only when the primary tumor located at right-side colon (20.2 for CT + B versus 19.7 months for CT group, p = 0.269). For left-side colon and rectal cancer patients, significantly longer OS were observed in CT + B than CT group. Conclusion: Our data suggested only patients with left-side colon or rectal cancer could get survival benefit from the addition of bevacizumab to first-line chemotherapy.

Palliative primary tumor resection provides survival benefits for the patients with metastatic colorectal cancer and low circulating levels of dehydrogenase and carcinoembryonic antigen.

BACKGROUND: It remains controversial whether palliative primary tumor resection (PPTR) can provide survival benefits to the patients with metastatic colorectal cancer (mCRC) who have unresectable metastases. The aim of this study was to evaluate whether PPTR could improve the survival of patients with mCRC. METHODS: We conducted a retrospective study on consecutive mCRC patients with unresectable metastases who were diagnosed at Sun Yat-sen University Cancer Center in Guangzhou, Guangdong, China, between January 2005 and December 2012. Overall survival (OS) and progression-free survival (PFS) after first-line chemotherapy failure were compared between the PPTR and non-PPTR patient groups. RESULTS: A total of 387 patients were identified, including 254 who underwent PPTR and 133 who did not. The median OS of the PPTR and non-PPTR groups was 20.8 and 14.8 months (P < 0.001), respectively. The median PFS after first-line chemotherapy was 7.3 and 4.8 months (P < 0.001) in the PPTR and non-PPTR groups, respectively. A larger proportion of patients in the PPTR group (219 of 254, 86.2%) showed local progression compared with that of patients in the non-PPTR group (95 of 133, 71.4%; P < 0.001). Only patients with normal lactate dehydrogenase (LDH) levels and with carcinoembryonic antigen (CEA) levels <70 ng/mL benefited from PPTR (median OS, 22.2 months for the PPTR group and 16.2 months for the non-PPTR group; P < 0.001). CONCLUSIONS: For mCRC patients with unresectable metastases, PPTR can improve OS and PFS after first-line chemotherapy and decrease the incidence of new organ involvement. However, PPTR should be recommended only for patients with normal LDH levels and with CEA levels <70 ng/mL.

Positive expression of programmed death ligand-1 correlates with superior outcomes and might be a therapeutic target in primary pulmonary lymphoepithelioma-like carcinoma.

BACKGROUND: Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of non-small cell lung cancer (NSCLC), and no effective treatments have been defined for advanced disease. Programmed cell death-ligand 1 (PD-L1) is expressed in a group of cancers that may be suitable targets for specific immunotherapy. METHODS: This study investigated the expression and clinical value of PD-L1 in pulmonary LELC. Seventy-nine patients with pulmonary LELC were investigated. Paraffin-embedded tumor sections were stained with PD-L1 antibody. Correlations of PD-L1 expression with clinicopathologic parameters and outcomes were analyzed. RESULTS: Fifty patients (63.3%) were PD-L1 positive. The 3-year and 5-year progression-free survival (PFS) rate was 76.0% and 68.0%, respectively, and the 3-year and 5-year overall survival (OS) rate was 88.0% and 79.0%, respectively. Kaplan-Meier analysis revealed that patients with positive PD-L1 expression had longer PFS and OS than those with negative PD-L1 expression (P=0.019 and P=0.042, respectively). In a multivariate Cox regression model including age, tumor size, stage, and PD-L1 expression status, the latter three factors were found to be independent predictors of PFS (P=0.023, P=0.000, and P=0.009, respectively), but only stage was found to be an independent factor for OS (P=0.007), and PD-L1 expression status showed a trend to be independently correlated with OS (P=0.080). CONCLUSION: Our results showed that a large proportion of patients with pulmonary LELC had positive expression of PD-L1, supporting the potential use of anti-PD-1/PD-L1-targeted therapies in this distinct type of NSCLC.

Prognostic model built on blood-based biomarkers in patients with metastatic colorectal cancer.

BACKGROUND: We had previously showed that the neutrophil lymphocyte ratio (NLR), γ-glutamyl transpeptidase (GGT) and carcinoembryonic antigen (CEA) are prognostic factors for metastatic colorectal cancer (mCRC) patients. In this study we developed a prognostic model based on these three indices. MATERIALS AND METHODS: A total of 243 patients who were initially diagnosed as mCRC between 2005 and 2010 in the Sun Yat-sen University Cancer Center were studied. The endpoint was overall survival (OS). RESULTS: NLR>3, elevated GGT and elevated CEA were confirmed as independent risk factors which could predict poor prognosis. Patients could be divided into three groups according to the number of risk factors they had. Those with two or three were defined as the high risk group, individuals with one risk factor as the modest risk group and patients without risk factor as the low risk group. The OS values for these three groups were 16.2 months (2.80~68.8), 24.2 months (4.07~79.0), and 37.2 months (12.6~87.8), respectively (p<0.001). CONCLUSIONS: We developed a simple but useful model based on NLR, GGT and CEA to provide prognostic information to clinical practice in highly selected mCRC patients. Further prospective and multi-center studies are warranted to test our model.

Efficacy of taxane-based regimens in a first-line setting for recurrent and/or metastatic Chinese patients with esophageal cancer.

OBJECTIVE: To compare the efficacy of taxane-based regimens in the first line setting retrospectively in Chinese patients with recurrent and/or metastatic esophageal cancer. METHODS: We analyzed 102 recurrent and/or metastatic esophageal cancer patients who received taxanes-based regimens in a first-line setting from January 2009 to December 2013. Sixteen (15.7%) patients were administered Nab-PTX based chemotherapy and 86 patients (84.3%) received paclitaxel (PTX) or docetaxel (DTX) based chemotherapy. Patients in the PTX/DTX group could be further divided into TP (71 patients) and TPF (15 patients) groups. RESULTS: The objective response rate (ORR) of all patients was 20.6%, and the disease control rate (DCR) was 67.6%. The median overall survival (OS) was 10.5 months (95% CI 10.1-16.4) and the median progression-free survival (PFS) was 6.04 months (95% CI 5.09-7.91). The DCR was higher in the TPF group than the TP group (93.3% vs. 59.1%; p = 0.015 ). There were no significant differences in ORR, OS, and PFS among Nab-PTX, TPF and TP groups. CONCLUSIONS: The three regimens of Nab-PTX based, TP and TPF proved active in a first line setting of Chinese patients with recurrent and/or metastatic esophageal cancer, and should thus be regarded as alternative treatments.

Clinical activity of adjuvant cytokine-induced killer cell immunotherapy in patients with post-mastectomy triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is a high risk form of this disease, even after surgery, due to the absence of targets for hormone treatment and anti-Her-2 therapy. Chemotherapy is the main therapeutic strategy for such patients with breast cancer, although the outcome is often unsatisfactory. Thus, the development of combination adjuvant therapies is essential for improved prognosis in patients with TNBC. In this study, we investigated the efficacy of a sequential combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for patients with post-mastectomy TNBC. EXPERIMENTAL DESIGN: From 2008 to 2012, 90 patients with post-mastectomy TNBC were included in this retrospective study: 45 cases received chemotherapy alone or with sequential radiotherapy; a further 45 cases received chemotherapy with/without radiotherapy and sequential CIK infusion. RESULTS: Survival analysis showed significantly higher disease-free survival (DFS) and overall survival (OS) rates in the CIK treatment group compared with the control group (P = 0.0382, P = 0.0046, respectively; log-rank test). Multivariate survival analysis showed that CIK adjuvant treatment was an independent prognostic factor for OS of patients with TNBC. In subgroup analyses, CIK adjuvant treatment significantly increased the DFS rate of patients with pathologic grade 3, and significantly increased the OS rate of patients in N1, N2, N3, IIB, III TNM (tumor-node-metastasis) stages, and with pathologic grade 3. CONCLUSIONS: These data indicate that adjuvant CIK treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of patients with TNBC, particularly those with lymph node metastasis, advanced TNM stage, and poor pathologic grade. Clin Cancer Res; 20(11); 3003-11. ©2014 AACR.

IL-17A promotes immune cell recruitment in human esophageal cancers and the infiltrating dendritic cells represent a positive prognostic marker for patient survival.

We previously reported that tumor-infiltrating interleukin (IL)-17A-producing cells play a protective role in human esophageal squamous cell carcinoma (ESCC). However, the potential mechanisms involved remain unclear. In the present study, we investigated the effects of IL-17A on immune cell recruitment and function in ESCC. In vitro chemotaxis assays using the ESCC cell lines EC109 and KYSE30 demonstrated that although IL-17A showed no significant direct effects on the migration of T cells, natural killer (NK) cells as well as dendritic cells (DCs), it could induce ESCC tumor cells to produce inflammatory chemokines, for example, CXCL9, CXCL10 and CCL2, CCL20, which are associated with the migration of T cells, NK cells, and DCs, respectively. In addition, IL-17A enhanced the cytotoxic effects of NK cells against tumor cells by augmenting the expression of cytotoxic molecules, for example, tumor necrosis factor-α, interferon-γ, Perforin, and Granzyme B and activation receptors, for example, NKp46, NKp44, NTB-A, and NKG2D on NK cells. Furthermore, immunohistochemical analysis revealed that the density of IL-17A-producing cells was positively and significantly associated with the density of CD1a DCs in tumor tissues. With the analyses of 181 ESCC patients, we found a correlation of higher number of tumor-infiltrating CD1a DCs with significantly improved overall survival of patients with ESCC. This study provides further understanding of the roles of Th17 cells in ESCC, which may contribute to the development of novel cancer immunotherapy strategies.

The efficacy of cytokine-induced killer cell infusion as an adjuvant therapy for postoperative hepatocellular carcinoma patients.

BACKGROUND: Even after surgery, hepatocellular carcinoma (HCC) has poor prognosis; adjuvant therapy is needed to improve effectively the outcome of HCC patients. We evaluated the efficacy of cytokine-induced killer (CIK) cell infusion as an adjuvant therapy for postoperative HCC patients. METHODS: A total of 410 patients were studied retrospectively (January 2002 to January 2007): 206 received surgery alone; 204 received surgery and at least four cycles of CIK cell transfusion (CIK group). Kaplan-Meier and Cox regression analyses were used to explore differences in OS between two groups. RESULTS: The CIK group overall survival rates were significantly higher than that of the surgery-alone group (log-rank test; p = 0.0007). Multivariate survival analysis showed that CIK cell treatment was an independent prognostic factor. In subgroup analysis, patients who received ≥8 cycles of CIK cell transfusion exhibited significantly better survival than the <8 cycle group (p = 0.0272). There was no significant difference in overall survival in patients with ≤5-cm tumors between the CIK and surgery-alone groups (p = 0.7567). However, in patients with >5-cm tumors, the CIK group displayed significantly better overall survival than the surgery-alone group (p = 0.0002). CONCLUSIONS: Postoperative immunotherapy with CIK cell transfusion may be an effective adjuvant treatment for improving the outcomes of HCC patients; >8 cycles of CIK cell transfusion may ensure that patients derive maximal benefits. Moreover, patients with large tumors might benefit more from CIK cell adjuvant treatment than patients with small tumors.

Decreased expression of Beclin 1 correlates closely with Bcl-xL expression and poor prognosis of ovarian carcinoma.

BACKGROUND: It has been suggested that autophagy-related Beclin 1 plays a critical role in the regulation of tumor development and/or progression, but its prognostic significance and relationship with Bcl-xL expression in ovarian carcinoma are unclear. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, the methods of Western blotting and immunohistochemistry (IHC) were utilized to investigate the expression status of Beclin 1 and Bcl-xL in fresh ovarian tissues and paraffin-embedded epithelial ovarian tumor tissues. Decreased expression of Beclin 1 was examined by IHC in 8.3% of normal ovaries, in 15.4% of cystadenomas, in 20.0% of borderline tumors, and in 55.6% of ovarian carcinomas, respectively. In ovarian carcinomas, decreased expression of Beclin 1 was correlated closely with ascending histological grade, later pT/pN/pM status and/or advanced clinical stage (P<0.05). In univariate survival analysis, a highly significant association between low-expressed Beclin 1 and shortened patient survival was evaluated in ovarian carcinoma patients (P<0.01), and Beclin 1 expression was an independent prognostic factor as evidenced by multivariate analysis (P = 0.013). In addition, decreased expression of Beclin 1 was inversely correlated with altered expression of Bcl-xL in ovarian carcinoma cohort, and combined analysis further showed that the low Beclin 1/high Bcl-xL group had the lowest survival rate. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that Beclin 1 expression, as examined by IHC, could be served as an additional tool in identifying ovarian carcinoma patients at risk of tumor progression, and predicting patient survival in ovarian carcinomas with increased expression of Bcl-xL.

BIRB796, the inhibitor of p38 mitogen-activated protein kinase, enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cells.

ATP-binding-cassette family membrane proteins play an important role in multidrug resistance. In this study, we investigated BIRB796, an orally active inhibitor of p38 mitogen-activated protein kinase, reversed MDR induced by ABCB1, ABCG2 and ABCC1. Our results showed that BIRB796 could reverse ABCB1-mediated MDR in both the drug selected and transfected ABCB1-overexpressing cell models, but did not enhance the efficacy of substrate-chemotherapeutical agents in ABCC1 or ABCG2 overexpression cells and their parental sensitive cells. Furthermore, BIRB796 increased the intracellular accumulation of the ABCB1 substrates, such as rhodamine 123 and doxorubicin. Moreover, BIRB796 bidirectionally mediated the ATPase activity of ABCB1, stimulating at low concentration, inhibiting at high concentration. However, BIRB796 did not alter the expression of ABCB1 both at protein and mRNA level. The down-regulation of p38 by siRNA neither affected the expression of ABCB1 nor the cytotoxic effect of paclitaxel on KBV200. The binding model of BIRB796 within the large cavity of the transmembrane region of ABCB1 may form the basis for future lead optimization studies. Importantly, BIRB796 also enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBV200 cell xenografts in nude mice. Overall, we conclude that BIRB796 reverses ABCB1-mediated MDR by directly inhibiting its transport function. These findings may be useful for cancer combinational therapy with BIRB796 in the clinic.

The tumor-log odds of positive lymph nodes-metastasis staging system, a promising new staging system for gastric cancer after D2 resection in China.

BACKGROUND: In this study, we established a hypothetical tumor-lodds-metastasis (TLM) and tumor-ratio-metastasis (TRM) staging system. Moreover, we compared them with the 7(th) edition of American Joint Committee on Cancer tumor-nodes-metastasis (AJCC TNM) staging system in gastric cancer patients after D2 resection. METHODS: A total of 1000 gastric carcinoma patients receiving treatment in our center were selected for the analysis. Finally, 730 patients who received D2 resection were retrospectively studied. Patients were staged using the TLM, TRM and the 7(th) edition AJCC TNM system. Survival analysis was performed with a Cox regression model. We used two parameters to compare the TNM, TRM and TLM staging system, the -2log likelihood and the hazard ratio. RESULTS: The cut points of lymph node ratio (LNR) were set as 0, 0-0.3, 0.3-0.6, 0.6-1.0. And for the log odds of positive lymph nodes (LODDS), the cut points were established as≤-0.5, -0.5-0, 0-0.5, >0.5. There were significant differences in survival among patients in different LODDS classifications for each pN or LNR groups. When stratified by the LODDS classifications, the prognosis was highly homologous between those in the according pN or LNR classifications. Multivariate analysis showed that TLM staging system was better than the TRM or TNM system for the prognostic evaluation. CONCLUSIONS: The TLM system was superior to the TRM or TNM system for prognostic assessment of gastric adenocarcinoma patients after D2 resection.

Initial Progression-Free Survival after Non-First Line TKIs Therapy Potentially Guides Immediate Treatment after Its Failure in Advanced Non-Small Cell Lung Cancer.

OBJECTIVE: The standard therapy after failure of the initial non-first line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in advanced non-small cell lung cancer (NSCLC) has not yet been established. The aim of the current study was to identify whether the 2(nd) TKI treatment or chemotherapy (paclitaxel-containing or non-paclitaxel regimen) is the appropriate treatment for patients with NSCLC based on the efficacy of the initial TKIs. METHODS: Seventy-two advanced NSCLC patients who had accepted 2(nd) TKIs or chemotherapy immediately after failure of the initial TKIs in non-first line setting from May 1, 2004 to January 31, 2010 at the Sun Yat-sen University Cancer Center were enrolled. The primary endpoint [2(nd) progression-free survival (PFS)] and the second endpoint [overall survival (OS)] were compared among the 2(nd) TKI and chemotherapy groups as well as their subgroups. RESULTS: (1) Twenty-one patients were treated with 2(nd) TKIs, and 51 patients were administered chemotherapy after failure of the initial non-first line TKI treatment. There was nonsignificant difference in the responses (P=0.900) [2(nd) PFS (P=0.833) and OS (P=0.369)] between the 2(nd) TKI and chemotherapy groups. (2) In the 2(nd) TKI group, 9 patients exhibited PFS≥7 months. The initial TKI treatment group exhibited a longer 2(nd) PFS than the other 12 patients with an initial PFS<7 months (7 months vs. 2 months, P=0.019). However, these groups had nonsignificantly different OS (P=0.369). (3) In the chemotherapy group, patients with PFS<5 months exhibited longer 2(nd) PFS than those with PFS ≥ 5 months in the initial TKI treatment (3 months vs. 2 months, P=0.039). (4) In the chemotherapy group, patients treated with paclitaxel-containing regimen showed longer 2(nd) PFS than those treated with non-paclitaxel regimen (5 months vs. 2.3 months, P=0.043). CONCLUSIONS: Patients with PFS≥7 months or <5 months under the initial TKI treatment potentially benefit from the 2(nd) TKI treatment or chemotherapy immediately after failure of the non-first line TKIs. The paclitaxel-containing regimen may improve the 2(nd) PFS. However, more patient samples are urgently needed to validate these findings.

Overexpression of SGLT1 and EGFR in colorectal cancer showing a correlation with the prognosis.

Na+-dependent glucose cotransporter (SGLT1), reported overexpression in tumor tissues while its clinical significance was not established, and epidermal growth factor receptor (EGFR) with potential relation to SGLT1 were studied in order to investigate their clinical significance in colorectal cancer (CRC). Eighty-five patients of CRC who received chemotherapy in Sun Yat-sen Cancer Center from March 1st 2005 to December 31st 2008 were enrolled. SGLT1 and EGFR expression in these cancer tissues and 28 normal tissues were tested by immunohistochemistry. (1) Expression of SGLT1 (P = 0.00) and EGFR (P = 0.01) in cancer tissues was higher than that in normal tissues. (2) Their expression related with clinical stage (P = 0.03 and P = 0.02), but not with other clinical characteristics. (3) For first-line chemotherapy, expression of SGLT1 (P = 0.06 and P = 0.21) and EGFR (P = 0.37 and P = 0.31) had no influence on objective response rate (ORR) and disease control rate (DCR). EGFR overexpression was associated with lower disease-free survival (P = 0.00) and overall survival (P = 0.01), while SGLT1 did not (P = 0.79 and P = 0.34). Conclusions Both SGLT1 and EGFR overexpression in CRC was related to higher clinical stages. SGLT1 had a potential impact on the ORR of first-line chemotherapy in CRC. EGFR was associated with prognosis, while SGLT1 did not.