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Purpose Although the use of regorafenib plus nivolumab demonstrates promising outcomes in patients with refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC), other studies failed to observe such an effect. In addition, a comparison between regorafenib combined with programmed cell death protein 1 (PD-1) antibodies and regorafenib monotherapy has rarely been reported. The aim of this study was to assess whether regorafenib combined with a PD-1 antibody is superior to regorafenib monotherapy as third-line treatment for MSS mCRC. Methods Patients with MSS mCRC who received regorafenib combined with a PD-1 antibody or regorafenib monotherapy as third-line treatment were eligible for inclusion. Results In total, 179 patients were enrolled, of which 95 administered regorafenib combined with a PD-1 antibody and 84 administered regorafenib monotherapy. Overall, patients who administered regorafenib combined with a PD-1 antibody had similar progression-free survival (PFS) outcomes as those on regorafenib monotherapy (median PFS was 2.4 months and 1.9 months, respectively, P = 0.086). The administration of regorafenib combined with a PD-1 antibody showed significantly longer PFS than regorafenib monotherapy in both male (5.2 months vs. 2.4 months, P = 0.001) and female (3.9 months vs. 1.8 months, P = 0.037) patients without liver metastasis. Unexpectedly, female patients with liver metastasis who administered regorafenib combined with a PD-1 antibody showed inferior PFS outcomes than those who administered regorafenib monotherapy (1.8 months vs. 2.0 months, P = 0.030). Conclusion Liver metastasis and gender were predictors of survival benefit following the addition of a PD-1 antibody to regorafenib in patients with MSS mCRC.

Supplementary Figures + Supplementary Datas

Purpose:Immune checkpoint blockade (ICB) therapy induces durable tumor regressions in a minority of patients with cancer. In this study, we aimed to identify kinase inhibitors that were capable of increasing the antimelanoma immunity.Experimental Design:Flow cytometry–based screening was performed to identify kinase inhibitors that can block the IFNγ-induced PD-L1 expression in melanoma cells. The pharmacologic activities of regorafenib alone or in combination with immunotherapy in vitro and in vivo were determined. The mechanisms of regorafenib were explored and analyzed in melanoma patients treated with or without anti–PD-1 using The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.Results:Through screening of a kinase inhibitor library, we found approximately 20 agents that caused more than half reduction of cell surface PD-L1 level, and regorafenib was one of the most potent agents. Furthermore, our results showed that regorafenib, in vitro and in vivo, strongly promoted the antitumor efficacy when combined with IFNγ or ICB. By targeting the RET–Src axis, regorafenib potently inhibited JAK1/2–STAT1 and MAPK signaling and subsequently attenuated the IFNγ-induced PD-L1 and IDO1 expression without affecting MHC-I expression much. Moreover, RET and Src co-high expression was an independent unfavorable prognosis factor in melanoma patients with or without ICB through inhibiting the antitumor immune response.Conclusions:Our data unveiled a new mechanism of alleviating IFNγ-induced PD-L1 and IDO1 expression and provided a rationale to explore a novel combination of ICB with regorafenib clinically, especially in melanoma with RET/Src axis activation.

To assess the prognostic value of the systemic inflammation response index (SIRI) combined with plasma load of Epstein-Barr virus (EBV) DNA in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC).A total of 205 consecutive patients with CALANPC were enrolled. We used recursive partitioning analysis (RPA) to classify patients into various risk groups, with a primary endpoint of overall survival (OS).Elevated SIRI (≥1.53) and EBV DNA (≥4000 copy/ml) were significantly associated with inferior OS in CALANPC. RPA categorized patients into low- and high-risk groups based on prognostic factors. Survival curves showed excellent discrimination in OS (95.3% vs 77.6%; p 0.001) between the low- and high-risk groups. A significant improvement was confirmed using the prognostic methods for conventional TNM staging systems (p 0.05).The combination of SIRI with EBV DNA provided a more detailed understanding of patient risks, and enhanced risk discrimination in CALANPC.

Purpose To quantify and predict the survival benefits of cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC). Materials and Methods Patients with CA-LANPC who received first-line neoadjuvant chemotherapy (NAC) followed by concurrent chemoradiotherapy (CCRT) between September 2007 and April 2018 were evaluated. Recursive partitioning analyses (RPAs) helped identify the ideal thresholds of CC-CCD on disease-free survival (DFS). We then developed a web-based predictive model to quantify the survival benefit of CC-CCD for CA-LANPC. Results In total, 139 patients were eligible for the analysis. The median CC-CCD was 162 mg/m2 (IQR, 138-194 mg/m2). The optimum cut-off point of CC-CCD was 160 mg/m2 for DFS. Hence, we selected 160 mg/m2 as the cut-off to classify CA-LANPC into either high or low CC-CCD groups for survival analysis. The 5-year DFS rates were 91.6% in the high (≥160 mg/m2) CC-CCD group and 77.8% in the low ( Conclusions We built a predictive model to quantify the survival benefit of CC-CCD for CA-LANPC treated with NAC plus CCRT. This tool may improve individual treatment consultations and facilitate evidence-based decision-making.

To assess the feasibility of adjusting radiation dose (RD) in childhood NPC with favorable tumor response after neoadjuvant chemotherapy (NAC).Using an NPC-specific database, children and adolescents (≤18 years) with locoregionally advanced NPC (CA-LANPC) were retrospectively analyzed. Enrolled patients were those who received favorable tumor response after 2-4 cycles of NAC followed by concurrent chemoradiotherapy. Survival outcomes and treatment-related toxicities were compared for the standard RD on primary tumors (PT-RDA total of 132 patients were included, and the median follow-up time was 75.2 months (IQR, 53.2-98.7 months) for the entire cohort. The PT-RDChemoradiotherapy with RD at levels of 60-65.9 Gy may be a reasonable strategy for CA-LANPC with favorable tumor response after NAC.

Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death–inducing (ICD-inducing) drugs available that can kill cancer cells, enhance tumor immunogenicity, increase in vivo immune infiltration, and thereby boost a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immunostimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still being investigated. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and a T cell activation assay. We showed that teniposide, a DNA topoisomerase II inhibitor, could induce high-mobility group box 1 (HMGB1) release and type I IFN signaling in tumor cells and that teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling, including NF-κB activation and stimulator of IFN genes–dependent (STING-dependent) type I IFN signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 in multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity and enabled a potential chemoimmunotherapeutic approach to potentiating the therapeutic efficacy of anti-PD1 immunotherapy.

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, PP=.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.

Purpose: Immune checkpoint blockade (ICB) therapy induces durable tumor regressions in a minority of patients with cancer. In this study, we aimed to identify kinase inhibitors that were capable of increasing the antimelanoma immunity. Experimental Design: Flow cytometry–based screening was performed to identify kinase inhibitors that can block the IFNγ-induced PD-L1 expression in melanoma cells. The pharmacologic activities of regorafenib alone or in combination with immunotherapy in vitro and in vivo were determined. The mechanisms of regorafenib were explored and analyzed in melanoma patients treated with or without anti–PD-1 using The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. Results: Through screening of a kinase inhibitor library, we found approximately 20 agents that caused more than half reduction of cell surface PD-L1 level, and regorafenib was one of the most potent agents. Furthermore, our results showed that regorafenib, in vitro and in vivo, strongly promoted the antitumor efficacy when combined with IFNγ or ICB. By targeting the RET–Src axis, regorafenib potently inhibited JAK1/2–STAT1 and MAPK signaling and subsequently attenuated the IFNγ-induced PD-L1 and IDO1 expression without affecting MHC-I expression much. Moreover, RET and Src co-high expression was an independent unfavorable prognosis factor in melanoma patients with or without ICB through inhibiting the antitumor immune response. Conclusions: Our data unveiled a new mechanism of alleviating IFNγ-induced PD-L1 and IDO1 expression and provided a rationale to explore a novel combination of ICB with regorafenib clinically, especially in melanoma with RET/Src axis activation.

Adding neoadjuvant chemotherapy (NAC) to concurrent chemoradiotherapy (CCRT) is the main strategy in treatment of children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC). Yet, an optimal number of NAC cycles remains unknown. We aimed to optimize the NAC cycle and potentially contribute to clinical decision making for the individual treatment of CA-LANPC.Utilizing an NPC-specific database through an acknowledged big-data information system at our center, we identified 143 CA-LANPC treated with NAC followed by CCRT between September 2007 through April 2018. Recursive partitioning analysis (RPA) was performed to categorize the patients and predict disease-free survival (DFS). The clinical benefits of NAC cycles (two cycles vs three cycles) were assessed in each risk group.Independent factors derived from multivariable analysis to predict DFS were T stage (T1-3 vs T4) and plasma Epstein-Barr virus (EBV) DNA ( 4000 vs ≥ 4000 copies/mL) for risk stratification. Consequently, 87 (61%) participants were classified as low-risk group (T1-3 with low or high EBV DNA, and T4 with low EBV DNA) and the other 56 patients (39%) were classified as a high-risk group (T4 with high EBV DNA) through RPA, and corresponding 5-year DFS rates of 91.9% and 71.2%, respectively (p = 0.001). Among the high-risk group, patients receiving three cycles of NAC had statistically significant improvement in 5-year DFS over those who received two cycles of NAC (86.7% vs 59.1%; p = 0.020), while the survival benefit of three cycles NAC for low-risk groups were not observed (94.7% vs 89.7%; p = 0.652).We found three cycles of NAC with CCRT was a positive prognostic indicator for improved DFS for the high-risk group among CA-LANPC. However, whether low-risk patients could benefit from three cycles NAC needs further study.

Background We aim to investigate the prognostic value of weight loss during radiotherapy (RT) among patients with nasopharyngeal carcinoma (NPC). Methods A total of 1149 NPC patients who received radical RT were retrospectively analyzed. Patients’ weight were measured at initiation of RT (WPre-RT) and every week during RT (WRT1,2,3,4,5,6,7). Percentage of weight loss (PWL) at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT (RT-PWL1,2,3,4,5,6,7) were calculated using the following equation: (WPre-RT –WRT1,2,3,4,5,6,7)/WPre-RT × 100%. The optimal threshold of RT-PWL7 was determined by recursive partitioning analyses (RPAs). Our endpoints included disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS). Results The median RT-PWLs were 0, 0, 1.5, 2.9, 4.1, 5.5, 6.6% at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT, respectively. RT-PWL7 optimal threshold with respect to DFS was 5.3% based on RPAs. Therefore, a consistent threshold of 5% ( ≥5%) was selected to classify NPC patients into low RT-PWL7 and high RT-PWL7 groups for survival analysis. Compared to high RT-PWL7 (≥5%), patients with low RT-PWL7 (P P = 0.007). However, no difference was observed between LRRFS groups (91.7% vs 94.3%; P = 0.173). In multivariate analysis, high RT-PWL7 was an independent risk factor for DFS (HR, 1.56; 95%CI, 1.19-2.03; P = 0.001), OS (HR, 1.54; 95%CI, 1.11-2.15; P = 0.011), and DMFS (HR, 1.47; 95%CI, 1.03-2.10; P = 0.033) in patients with NPC. In addition, treatment strategy, plasma Epstein-Barr virus DNA, and N stage were associated with weight loss. Conclusions High RT-PWL7 was significantly associated with decreased DFS, OS, and DMFS for NPC patients. Clinicians should continuously inform patients on the health impact of minimizing RT-PWL7 under 5% during radiotherapy.

Background: We investigated the dynamic variation and prognostic value of weight loss among nasopharyngeal carcinoma (NPC) patients. Methods: 1149 newly diagnosed NPC patients receiving radical radiotherapy (RT) were retrospectively analyzed. Patients’ weights were measured at initiation of RT and every week during RT. Recursive partitioning analyses (RPAs) were utilized to determine cut-off value for rate of weight loss (RWL). To assess predictive value of RWL survival analysis was performed. Disease-free survival (DFS) was our primary endpoint. Secondary endpoints included locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS).Results: RWLs were 0%, 0%, -1.54%, -2.86%, -4.11%, -5.98%, -6.56% at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT, respectively. RWL optimal threshold with respect to DFS was 5.3% based on RPAs. Thus, a consistent threshold of -5% (>-5% versus ≤-5%) was selected to classify NPC patients into low RWL and high RWL groups for survival analysis. Compared to high RWL (≤-5%), patients with low RWL (>-5%) had significantly better ten-year DFS (78.6% versus 61.2%; P< 0.001), OS (86.6% versus 70.1%; P< 0.001), and DMFS (88.5% versus 80.2%; P = 0.007). However, no difference was observed between LRRFS groups (91.7% versus 94.3%; P= 0.173). In multivariate analysis, RWL ≤-5% was an independent risk factor for DFS (HR, 1.56; 95% CI, 1.19-2.03; P= 0.001), OS (HR, 1.54; 95% CI, 1.11-2.15; P= 0.011) and DMFS (HR, 1.47; 95% CI, 1.03-2.10; P= 0.033) in patients with NPC. Additionally, chemotherapy and old age were attributed to the development of high RWL.Conclusions: Weight loss during RT was significantly associated with decreased survival among NPC patients. Clinicians should continuously inform patients on the health impact of minimizing weight loss under 5%.

// Lin Yang 1, 2, 3, * , Wenzhuo He 1, 2, 3, * , Qiong Yang 4, * , Pengfei Kong 1, 2, 3 , Qiankun Xie 1, 2, 3 , Chang Jiang 1, 2, 3 , Bei Zhang 1, 2, 3 and Liang Ping Xia 1, 2, 3 1 Sun Yat-Sen University Cancer Center, Guangzhou, China 2 State Key Laboratory of Oncology in Southern China, Guangzhou, China 3 Collaborative Innovation Center for Cancer Medicine, Guangzhou, China 4 Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China * These authors contributed equally to this work and share the first authorship Correspondence to: Liang Ping Xia, email: xialp@sysucc.org.cn Bei Zhang, email: zhangbei@sysucc.org.cn Keywords: primary tumor location, mismatch repair, survival, adjuvant chemotherapy, colon cancer Received: August 14, 2017 Accepted: September 22, 2017 Published: October 12, 2017 ABSTRACT Background: Current opinions on the benefits of adjuvant chemotherapy for stage II colon cancer are divided and reformative election of these patients is required. We examined whether the primary tumor location based on mismatch repair status and other risk factors could better inform the current guideline. Materials and Methods: A total of 673 consecutive patients with stage II colon cancer were included in the analysis. Differences in the common clinicopathological factors between left-sided colon cancer and right-sided colon cancer were analyzed using Fisher’s exact analysis. Kaplan–Meier analysis was used to distinguish the survival difference by primary tumor location and/or MMR status. Results: RCC had a shorter overall survival ( P = 0.001) and Disease-free survival ( P = 0.050) than LCC but was associated with survival benefit from adjuvant chemotherapy ( P = 0.001 and P = 0.011 for OS and DFS, respectively). Mismatch repair-proficient had a shorter OS ( P = 0.036) and disease free survival ( P = 0.034) than mismatch-repair deficient but chemotherapy improved the OS ( P = 0.007). When the primary tumor location and MMR status were combined, the PMMR/RCC was the only subgroup that could benefit from adjuvant chemotherapy ( P < 0.001 and P = 0.002 for OS and DFS, respectively). Other tumors such as DMMR/RCC, DMMR/LCC, and PMMR/LCC did not benefit. Conclusions: The observed survival benefits in PMMR/RCC patients treated with adjuvant chemotherapy will allow better selection of patients for chemotherapy who are in stage II.

Background: This study was designed to investigate the prognostic role of the MMP-7-181 A/G gene polymorphism in patients with gastric cancer and to correlate the genotype with clinicopathological features. Methods: The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the MMP-7-181 A/G gene polymorphism, and prognostic analyses were performed to elucidate the prognostic role of the gene polymorphism. Results: The MMP-7-181 A/A genotype was detected in 83.8% (176/210) of cases, A/G genotype in 16.2% (34/210) of cases and G/G genotype in 0% (0/210) of cases. The MMP-7-181 A/G polymorphism was closely correlated with lymph node metastasis (P=0.037). A/G genotype carriers exhibit lymph node metastasis more frequently than A/A genotype carriers. The MMP-7-181 A/G polymorphism was also strongly correlated with vascular invasion (P=0.003), and A/G genotype carriers show an increase in vascular invasion over A/A genotype carriers. The 5-year overall survival rates of A/A genotype carriers and A/G genotype carriers were 59.56% and 33.33%, respectively. The discrepancy was significant (P=0.0164). The prognosis of A/G genotype carriers was significantly worse than that of A/A genotype carriers. Multivariate survival analysis by Cox regression model confirmed that the MMP-7-181 A/G genotype was an independent prognostic factor of gastric cancer (HR =2.10; 95% CI: 1.09–4.05; P=0.027). Conclusions: The MMP-7-181 A/G genotype was closely correlated with malignant biological behaviors and prognosis of gastric cancer. The MMP-7-181 A/G genotype may serve as valuable prognostic indicator of gastric cancer.

Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N6-methyladenosine (m6A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N6-methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease.

High body mass index (BMI) greater than 25 kg/m2 has a complex relationship with cancers. The aim of this systematic review and meta-analysis is to explore controversy over whether BMI is correlated with outcomes including survival and immunotherapy-related adverse events (irAEs) in cancer patients treated with immunotherapy. We searched PubMed, Embase, Web of Science, and The Cochrane Library for relevant studies published up to June 2020. Title/abstract screening, full-text review, data extraction, and quality assessment were performed independently. Subgroup analysis was based on sex, treatment lines, the status of programmed death-ligand 1 (PD-L1), and tumor types. Sensitivity analysis was performed by synthesizing studies that adjusted for certain covariates or studies with good quality. Statistical heterogeneity was evaluated by the I2 value. Meta-analysis was performed with hazard ratio (HR) / odds ratio (OR) and 95% confidence intervals (CIs) as the effect measures. Twenty studies were included for survival and irAEs analyses. Patients with high BMI who underwent immunotherapy had longer overall survival (OS) (pooled hazard ratio, pHR = 0.71 [95% CI: 0.59–0.85]) and progression-free survival (PFS) (pHR = 0.76 [95% CI: 0.65–0.88]) than those with low BMI; at the same time, high-BMI patients had increased irAEs (OR = 2.54 [95% CI: 1.12–5.79]). In general, high BMI was correlated with improved OS and PFS in patients treated with immunotherapy along with a high risk of irAEs. However, discrepant findings from subgroup analyses urgently call for further analysis.

Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N6-methyladenosine (m6A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N6-methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease., Liver metastasis of colorectal cancer leads to poor prognosis. Here the authors report that an N6-methyladenosine modified circular RNA is upregulated in colorectal cancer and promotes liver metastasis by enhancing the stability of HMGA2 mRNA.

Background Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ with respect to their biology and genomic patterns, but inflammatory index variation did not fully investigate. This study aimed to examine the difference of inflammatory indexes and its value between RCC and LCC. Methods The differences of common clinicopathologic factors, inflammatory indexes including PLR (Platelet lymphocyte ratio) between LCC and RCC were analyzed in the training cohort with logistic regression model, subsequently, confirmed in validation cohort. Kaplan-Meier analysis was applied for the analysis of the survival difference distinguished by the PLR and the Nonparametric Test was adopted to demonstrate the difference of PLR variation with the standard TNM classification between RCC and LCC. Results A total of 1846 CRC patients entered the study, 744 (40.3%) patients were RCC, 1102 (59.7%) were LCC. The patients’ number in both cohorts was 923. It was found that LCC patients in the training cohort significantly to be with higher CEA, adenocarcinoma, early UICC/AJCC stage, p-MMR (mismatch-repair proficient), and lower PLR, and the later four features were confirm in validation cohort. Higher PLR, the unique inflammatory index, was significantly associated with poorer OS in LCC cohort (P = 0.002) and was elevated with the TNM stage in the LCC patients (P

Either cetuximab or bevacizumab can improve the survival of patients with metastastic colorectal cancer (mCRC) if administered combided with cytotoxic agents. However, the effect of two or more target agents in combination is uncertain in these patients. Here, we reported a patient with mCRC successfully treated by a combination of target agents after the failure of chemotherapy. The patient received palliative resection of primary tumor followed by 9 cycles of postoperative XELOX regimen, cytokine-induced killer cell (CIK)-based biotherapy, traditional Chinese medicine, particle implantation in the lung metastatic lesions. The tumor progressed 20 months after the standard treatments. Then, the regimen cetuximab, bevacizumab and cefitinib was applied. During the treatment with targeted agents, grade IV acne-like rash and relatively severe parionychia of the toes occurred. Both of them recovered smoothly. The PET-CT reexamination at 40 days after the target treatment showed that the metabolism of mediastinal lymph nodes basically recovered to a normal level. The combination of multiple targeted agents obtained a progression-free survival(PFS) of 11 months and the patient with a good quality of life during this period.

The changes in therapeutic strategies were determined and the efficacy of radical mastectomy (RM) and modified radical mastectomy (MRM) on Chinese male breast cancer (MBC) patients was compared. Seventy MBC patients, with a median age of 61 years, were enrolled. The characteristics of MBC were compared in cohort A (1969-1997) and cohort B (1998-2009), and the prognosis was compared between the RM and MRM groups. Infiltrating ductal carcinoma accounted for 81.4% of all cases; 93.7% were estrogen receptor (ER)/progesterone receptor (PR)-positive. More patients in cohort B accepted multidisciplinary treatment, MRM, adjuvant chemotherapy, and endocrine therapy than those in cohort A; however, the 5-year overall survival rates were similar in the two cohorts. The overall survival curves, locoregional recurrence rates, and systematic metastatic rates were similar in the RM and MRM groups. Currently, more MBC patients receive conservative surgery; MRM may be equally effective as RM for MBC.

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.

An elevated DNA-repair capacity in cancer cells leads to radiation resistance and severely limits the efficacy of radiation therapy. Activation of Akt is tightly associated with resistance to radiotherapy, and Mre11 protein has important role during the repair of DNA double-strand breaks (DSBs). In this report, our results showed that inhibition of Akt activity impaired the repair of DSBs in CNE2 cells, whereas activated Akt promoted the repair of DSBs in HeLa cells. Knockdown of Mre11 also impaired the process of DSB repair in both these two cell lines. More importantly, we found that Akt could regulate Mre11 expression. Inhibition of Akt activity by small interfering RNA or LY294002 efficiently downregulated the Mre11 expression in CNE2 cells, and transfection with myr-Akt plasmid in HeLa cells upregulated the Mre11 expression. In addition, luciferase reporter analysis revealed that Mre11 reporter activity increased after transfection with myr-Akt1 plasmids, and this myr-Akt1-induced transcriptional activity was blocked in the presence of LY294002. Further study showed GSK3β/β-catenin/LEF-1 pathway was involved in this regulation. Knockdown of β-catenin or LEF-1 led to the downregulation of Mre11, whereas overexpression of β-catenin led to upregulation of Mre11. The chromatin immunoprecipitation assay assay showed β-catenin/LEF-1 heterodimer could directly bind to the promoter of Mre11 in vivo. And the luciferase activity of the pGL3-Mre11 and pGL3-Lef increased in HeLa cells following β-catenin plasmid co-transfected, but was abolished when the LEF-1-binding conserved sequences of Mre11 promoter were mutated. These results together support Akt can upregulate the expression of Mre11 through GSK3β/ β-catenin/LEF pathway to elevate DSB-repair capacity in cancer cells.

BACKGROUND AND OBJECTIVE Male breast cancer (MBC) in China usually has been studied retrospectively with small sample size, and studies analyzing the prognostic factors are rare. This study was to investigate the prognostic factors of Chinese patients with MBC based on the data from a single institute with a relatively large sample. METHODS Clinical data of 72 patients with histopathologically confirmed MBC who received treatment at Sun Yat-sen University Cancer Center between January 1969 and March 2009, were collected. Kaplan-Meier, log-rank test and Cox regression model were used for statistical analysis. RESULTS The 5-year overall survival rate was 72.4%, and the survival rates for stage I, II, III, and IV were 100%, 74.2%, 57.2%, and 0%, respectively. Univariate analysis showed that the tumor size (P < 0.001), axillary lymph node status (P = 0.001), TNM stage (P = 0.001), operation model (with vs. without: P < 0.001; classic radical resection vs. modified radical resection, P = 0.336) and endocrine therapy(P = 0.02) significantly influenced the survival. Multivariate Cox regression showed that TNM stage (P = 0.035), operation model (P = 0.021) and endocrine therapy (P = 0.019) were independent prognostic factors for MBC. CONCLUSIONS Early diagnosis and comprehensive treatment strategy consisting of surgery and endocrine treatment is essential to improve the survival of the patients with MBC, and TNM stage, operation and endocrine treatment are the significant prognostic factors for MBC.

Background and objective Studies showed that cetuximab combined with chemotherapy was effective on advanced colorectal cancer (ACRC) in recent years, however, few reports based on large case cohort are available in China. This study was to analyze the efficacy of cetuximab combined with chemotherapy for 53 chinese patients with ACRC. Methods Clinical data of 53 patients with ACRC, treated with cetuximab combined with chemotherapy in Sun Yat-sen Cancer Center from March 2005 to April 2008, were analyzed for short-term efficacy and safety. The efficacy of the regimen used as first-line and non-first-line treatment was compared by Chi-square test; the effect of the regimen on prognosis was analyzed by multivariate Cox proportional hazards model. Results Of the 53 patients with colorectal adenocarcinoma, 40 were men and 13 were women, with a median age of 55 years. A total of 572 weeks (median, 8 weeks) of cetuximab treatment were completed. The overall response rate (RR) of the regimen was 39.6% and the disease control rate 66.0%. The disease control rates were similar when the regimen was used as first-line and non-first-line treatment (80.3% vs. 60.5%, P=0.177). For all 53 patients, clinical stage was an independent prognostic factor (P=0.002, OR>1). The most common Grade 3 to 4 adverse events included acne-like rash (7.5%), neutropenia (18.9%), and diarrhea (5.6%). No hypersensitive reaction or treatment-related death was observed. Only one patient discontinued treatment because of Grade 4 diarrhea and neutopenia. Conclusions Cetuximab combined with chemotherapy can achieve relatively high disease control rate for ACRC patients, with less adverse events. Whether cetuximab has better effect in first-line treatment than in non-first-line treatment needs further study.

Mitotic serine/threonine kinase Aurora-A (Aur-A) plays a critical role in regulating centrosome segregation and spindle assemble. Aur-A overexpression causes excessive centrosome duplication and abnormal spindle structure, leading to tumor malignant progression. Here, we investigated Aur-A expression in nasopharyngeal carcinoma (NPC) and the association between Aur-A and NPC invasiveness. We showed that overexpression of Aur-A in tumor tissues was correlated with cranial bone invasion and clinical stage in NPC patients. Suppression of Aur-A by either selective Aurora inhibitory VX-680 or small-interfering RNA caused G(2)/M arrest and apoptotic cell death in NPC CNE-2 cells. Significantly, inhibition of Aur-A suppressed CNE-2 cell invasion and restored membrane expression of epithelial markers, E-cadherin and beta-catenin, suggesting a reversed epithelial-mesenchymal transition process in cancer cells. In addition, we found that Aur-A-regulated epithelial-mesenchymal transition and invasion were mediated by mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, suppression of MAP kinase by small-interfering RNA or its upstream MEK1/2-selective inhibitor U0126 abrogated cell invasion enhanced by Aur-A overexpression. On the other hand, forced overexpression of constitutively active form of MEK1/2, MEK2DD, in CNE-2 cancer cells rescued cell invasive ability suppressed by VX-680-imposed Aur-A inhibition. Our results indicated that Aur-A acted through a downstream MAP kinase pathway to promote epithelial-mesenchymal transition and invasiveness in nasopharyngeal tumorigenesis. Small chemical inhibitor VX-680 may offer as a promising molecular targeting agent in human NPC.

We aimed to determine the prognostic values of 39 circulating cytokines in Chinese patients with metastatic colorectal cancer (CRC) and to develop a novel cytokine-based prognostic classifier (CBPC) for prognostic prediction. A total of 176 patients were divided into two cohorts based on the date of first-line chemotherapy. The first 99 cases were assigned to the training cohort, and the remaining 77 cases were assigned to the validation cohort. Thirty-nine cytokines were simultaneously analyzed in the patient serum samples using multiplex bead-based Luminex technology. We used support vector machine-based methods and Cox proportional hazards models to develop a CBPC from the training cohort, which we then validated using the second patient cohort. Univariate analysis showed that FGF-2, TGFα, Flt-3L, GM-CSF, INFα2, GRO, IL-10, MCP-3, MDC, sIL-2Rα, IL-2, IL-7, IL-8, MCP-1, MIP-1β, TNFα and VEGF were significant risk factors affecting the overall survival (OS) of both the training cohort and the validation cohort. We developed a CBPC to predict the OS of metastatic CRC patients using these 17 cytokines (sensitivity, 0.835; specificity, 0.800). In the validation cohort, the CBPC was found to have significant power in predicting the OS of metastatic CRC patients. Our study showed that there were significant associations between cytokine expression and prognosis of the patients with metastatic CRC. The CBPC that we developed includes multiple circulating cytokines and may serve as a novel screening tool for identifying metastatic CRC patients with a high risk of short OS. These high-risk individuals may also be suitable for cytokine-targeted therapies.

We aimed to determine the prognostic values of 39 circulating cytokines in Chinese patients with metastatic colorectal cancer (CRC) and to develop a novel cytokine-based prognostic classifier (CBPC) for prognostic prediction. A total of 176 patients were divided into two cohorts based on the date of first-line chemotherapy. The first 99 cases were assigned to the training cohort, and the remaining 77 cases were assigned to the validation cohort. Thirty-nine cytokines were simultaneously analyzed in the patient serum samples using multiplex bead-based Luminex technology. We used support vector machine-based methods and Cox proportional hazards models to develop a CBPC from the training cohort, which we then validated using the second patient cohort. Univariate analysis showed that FGF-2, TGFα, Flt-3L, GM-CSF, INFα2, GRO, IL-10, MCP-3, MDC, sIL-2Rα, IL-2, IL-7, IL-8, MCP-1, MIP-1β, TNFα and VEGF were significant risk factors affecting the overall survival (OS) of both the training cohort and the validation cohort. We developed a CBPC to predict the OS of metastatic CRC patients using these 17 cytokines (sensitivity, 0.835; specificity, 0.800). In the validation cohort, the CBPC was found to have significant power in predicting the OS of metastatic CRC patients. Our study showed that there were significant associations between cytokine expression and prognosis of the patients with metastatic CRC. The CBPC that we developed includes multiple circulating cytokines and may serve as a novel screening tool for identifying metastatic CRC patients with a high risk of short OS. These high-risk individuals may also be suitable for cytokine-targeted therapies.

AIM: To investigate the utility of Beclin-1 and LC3, two autophagy-related proteins, in predicting the cetuximab efficacy in advanced colorectal cancer (ACRC). METHODS: The data of 85 patients with ACRC treated at the Sun Yat-sen University Cancer Center from March 1, 2005 to December 31, 2008 were studied, including 45 cases treated with cetuximab-containing chemotherapy and 40 cases treated with non-cetuximab-containing chemotherapy. Beclin-1 and LC3 expression was evaluated by immunohistochemistry, and KRAS status was evaluated by polymerase chain reaction. RESULTS: Beclin-1 and LC3 expression in ACRC was significantly correlated (r = 0.44, P < 0.01); however, LC3 was more highly expressed in cancerous tissues than in normal tissues (Z = -2.63, P < 0.01). In the cetuximab-containing chemotherapy group, patients with low LC3 expression had higher objective response rates (ORRs) than those with high LC3 expression (52.9% vs 17.9%, P = 0.01), and patients with low Beclin-1 expression had a longer median progression-free survival (PFS) than their counterparts with higher Beclin-1 expression (9.0 mo vs 3.0 mo, P = 0.01). However, neither of these predictive relationships was detected in the group treated with non-cetuximab-containing chemotherapy. Patients with wild-type KRAS had higher ORRs (42.3% vs 9.1%, P = 0.049) and disease control rates (DCRs) (73.1% vs 36.4%, P = 0.035), and longer median PFS (5.5 mo vs 2.5 mo, P = 0.02) than those with mutant KRAS in the cetuximab-containing chemotherapy group. Neither Beclin-1 (P = 0.52) nor LC3 (P = 0.32) expression was significantly correlated with KRAS status. CONCLUSION: Patients with low Beclin-1 expression had a longer PFS than those with high Beclin-1 expression, and patients with low LC3 expression had a higher ORR in ACRC patients treated with cetuximab-containing chemotherapy.

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 2nd 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 2nd 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 [2nd progression-free survival (PFS)] and the second endpoint [overall survival (OS)] were compared among the 2nd TKI and chemotherapy groups as well as their subgroups. Results (1) Twenty-one patients were treated with 2nd 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) [2nd PFS (P=0.833) and OS (P=0.369)] between the 2nd TKI and chemotherapy groups. (2) In the 2nd TKI group, 9 patients exhibited PFS≥7 months. The initial TKI treatment group exhibited a longer 2nd PFS than the other 12 patients with an initial PFS

Background Autophagy is a dynamic catabolic process characterized by the formation of double membrane vacuoles termed autophagosomes. LC3, a homologue of yeast Atg8, takes part in autophagosome formation, but the exact regulation mechanism of LC3 still needs to be elucidated. Methods Ceramide-induced autophagy was determined by detecting LC3 expression with Western blotting and confocal microscopy in human nasopharyngeal carcinoma cell lines CNE2 and SUNE1. The activation of JNK pathway was assessed by Western blotting for phospho-specific forms of JNK and c-Jun. The JNK activity specific inhibitor, SP600125, and siRNA directed against JNK were used to block JNK/c-Jun pathway. ChIP and luciferase reporter analysis were applied to determine whether c-Jun was involved in the regulation of LC3 transcription. Results Ceramide-treated cells exhibited the characteristics of autophagy and JNK pathway activation. Inhibition of JNK pathway could block the ceramide-induced autophagy and the up-regulation of LC3 expression. Transcription factor c-Jun was involved in LC3 transcription regulation in response to ceramide treatment. Conclusions Ceramide could induce autophagy in human nasopharyngeal carcinoma cells, and activation of JNK pathway was involved in ceramide-induced autophagy and LC3 expression.

To study the efficacy and safety of cetuximab combined with chemotherapy for patients with advanced colorectal cancer (ACRC) and unclear K-ras status.Clinical data of 102 ACRC patients, treated by cetuximab combined with chemotherapy in Sun Yat-sen Cancer Center from March 2005 to December 2008, were collected. The cumulative survival rate, objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) of the cases were calculated. The difference in ORR, DCR, PFS and oval survival (OS) between the regimens used as first-line and non-first-line treatment, and between the regimens including oxaliplatin and irinotecan were compared.The overall ORR of cetuximab plus chemotherapy was 43.1%, DCR 73.5%, median PFS 4.0 months, OS 28.5 months, and the 1-year, 3-year, and 5-year survival rate was 89.2%, 50.9% and 27.5%, respectively. The differences in ORR (50.0% vs. 40.0%, P = 0.344), DCR (78.1% vs. 72.9%, P = 0.571) and OS (51.0 months vs. 35.0 months, P = 0.396) between the regimens as first line and as non-first line treatment were not statistically significant. However, the PFS of the regimen as first-line was longer than that as non-first-line treatment (PFS 5.5 months vs. 3.0 months, P = 0.001). The differences in ORR (54.2% vs. 40.0%, P = 0.223), DCR (79.2% vs. 74.7%, P = 0.654), PFS (5.0 months vs. 3.0 months, P = 0.726) and OS (36.0 months vs. 40.0 months, P = 0.759) between cetuximab plus oxliplatin and irinotecan were not statistically significant. The most common side effects of cetuximab plus chemotherapy were acneiform eruption (80.4%, grade 3-4 in 9.8%), neutropenia (66.7%, grade 3-4 in 18.6%), and diarrhea (19.6%, grade 3-4 in 5.9%). No treatment-related death was recorded.Patients with advanced colorectal cancer and unclear K-ras treated by cetuximab combined with chemotherapy have good ORR and OS, and the regimen is safe with less adverse events for them. There is no significant difference between the efficacies of regimens as first line and as non-first line treatment, and between cetuximab plus oxliplatin and cetuximab plus irinotecan regimens.

To summarize our experiences with the treatment of non-small cell lung cancer (NSCLC) with cetuximab and compare the therapeutic effects of cetuximab applied in the first line and non-first line settings.From October 1, 2006 to December 31, 2009, 16 NSCLC patients were treated with cetuximab combined with standard chemotherapy in Sun Yat-sen University Cancer Center. The short-term efficacy of the therapeutic protocols were analyzed.A total of 115 cycles of cetuximab treatment were administered in these patients with a median of 6 cycles (7.5 in the first line setting and 2 in non-first line setting). In the 10 patients with cetuximab treatment in the first line setting, the ORR was 40.0% (4/10), DCR was 80.0% (8/10), median TTP was 6.5 months (2-19), and median OS was 8.5 months (2-48); in the non-first line setting, these indices were 33.3% (2/6), 33.3% (2/6), 3.5 months (3-4) and 18 months (4-28), respectively. Both ORR and DCR were similar between the first and non-first line settings (P=0.790, P=0.062). Ten of the patients (62.5%) developed acne-like rash within 3 weeks, who had an ORR of 60% (6/10) and DCR of 90% (9/10); the ORR and DCR in patients without acne-like rash were both 10.4% (1/6), showing no significant difference in ORR (P=0.080) but a significant difference in DCR between the two groups (P=0.003). No treatment-associated death or cetuximab-associated discontinuation occurred. Altogether 11 patients (68.8%) developed acne-like rash, which occurred within 3 weeks in 10 cases. Seven patients showed side effects associated with the chemotherapy.Cetuximab combined with standard chemotherapy is a good option for Chinese patients with NSCLC and the current data support the application of cetuximab in the first line setting.

It is not clear if there is a difference in prognosis between male breast cancer (MBC) and female breast cancer (FBC) patients. The aim of this study was to compare the prognosis of MBC and FBC patients in China and the prognosis of MBC and their corresponding postmenopausal FBC patients.Thirty-five MBC patients who were treated at the Sun Yat-sen University Cancer Center between 1969 and 2004 were enrolled in the study. Seventy FBC patients who were matched with the MBC patients for TNM stage, year of diagnosis, and age at diagnosis were simultaneously enrolled in the study. A second group comprising 18 MBC patients and their corresponding 36 matched postmenopausal FBC patients were also enrolled. The whole group and the postmenopausal groups were compared for five- and ten-year survivals.All the factors that could potentially affect prognosis were comparable among the groups except more FBC than MBC patients underwent endocrine therapy and a modified radical mastectomy. The 5- and 10-year survivals in the whole group were 81.6% and 60.3% for men and 90.7% and 73.5% for women (P = 0.02). The 5- and 10-year survival in the postmenopausal group was 82.5% and 100% for men and 66.0% and 85.9% for women (P = 0.159).Chinese FBC patients had a better prognosis than Chinese MBC patients. However, MBC patients and their corresponding postmenopausal FBC patients had a similar prognosis.