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Supplementary Data from Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor–Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002)

Purpose:There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy.Patients and Methods:We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses.Results:A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0–44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7–21.7)] in the ET group and 14.8 months (12.8–16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71–1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group.Conclusions:Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.

Depression is a serious mental illness, mainly characterized as large mood swings and sleep, diet, and cognitive function disorders. NLPR3, one of the inflammasomes that can be activated by a variety of stimuli to promote the maturation and secretion of pro-inflammatory cytokines, has been considered to be involved in the pathophysiology of depression. In this study, the putative role of CY-09, a selective and direct inhibitor of NLRP3, was evaluated in the lipopolysaccharide (LPS)-induced mice. The results of the study indicated that CY-09 significantly decreased the levels of NLRP3 in the hippocampus of LPS-induced mice. In addition, CY-09 increased the sucrose preference and shortened the immobility time in LPS-induced mice, suggesting the antidepressant-like effects of inhibiting NLRP3 inflammasome. Biochemical analysis showed that LPS significantly activated the NLRP3/ASC/cytokine signaling pathway and caused microglial activation, while CY-09 prevented the changes. Moreover, CY-09 increased the brain-derived neurotrophic factor (BDNF) only in microglia but not in the whole hippocampus. Meanwhile, CY-09 did not promote neurogenesis in the hippocampus of LPS mice. In conclusion, the results of the study showed that the antidepressant-like effects of NLRP3 inhibitor CY-09 were mediated by alleviating neuroinflammation in microglia and independent of the neurotrophic function in the hippocampus.

Aims: The addition of extended capecitabine after standard neo/adjuvant chemotherapy shows controversial results in triple-negative breast cancer (TNBC) patients between SYSUCC-001 trial and CIBOMA trial. Patients presents different responses to diverse regimens, and different dose strengths also affect their prognosis. Hence, we tried to investigate whether the benefit from SYSUCC-001 is effected by the strength of previous adjuvant chemotherapy. Methods: We reviewed the neo/adjuvant chemotherapy regimens, dose divide by body surface area, etc. of TNBC patients in SYSUCC-001 trial. Their therapeutic dose were classified into consistent and inconsistent with CIBOMA trial. Besides, we stratified patients into the strong regimen arm (A/EC-T and TA/EC) and medium regimen arm (A/EC, TA/E, CMF, FA/EC, FA/EC-T, and TC) according to their specific neo/adjuvant treatment.Subsequently, we compared differences in baseline characteristics between the strong and medium regimen arms, and further investigated the impact of therapeutic regimens and dose on the survival outcome of TNBC patients in SYSUCC-001 trial(the median follow-up is 61months, interquartile range, 44-82months). Results: A total of 434 TNBC patients were included in this study. Among them, patients who used strong chemotherapy regimen accounted for about 76.74%, and those who used medium regimen accounted for 23.26%. About 32.3% and 52.2% patients received the standard doses of anthracyclines and taxanes separately according to minimum acceptable regimens for chemotherapy in CIBOMA trial. In our analysis we found the dose strength did not affect the DFS in the observe group. However, the standard dose of taxanes improved the DFS in capecitabine group [HR, 2.04 (1.02 - 4.06)]. The interaction analysis showed that the strength of treatment regimenand anthracycline dose did not affect DFS. Whereas, subgroup analysis showed TNBC patients with standard dose of taxanes significantly benefited from capecitabine (P = 0.014). In addition, the standard dose of taxanes could improve DFS. Conclusions: The strength of neo/adjuvant chemotherapy does not affect the curative effect of capecitabine maintenance chemotherapy. The benefits of the SYSUCC-001 study are mainly from one-year capecitabine administration. Moreover, the standard dose of chemotherapy especially taxanes is a positive factor for the effect of capecitabine treatment. So in some special condition, such as patients can’t endure the side effect of the chemotherapy, we’d better reduce the dose of anthracycline not the taxanes.

Li Wang,1,&ast; Yu-Ling Zhang,2,&ast; Chang Jiang,1,&ast; Fang-Fang Duan,1 Zhong-Yu Yuan,1 Jia-Jia Huang,1 Xi-Wen Bi1 1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Endocrinology, Jiangxi Provincial People’s Hospital, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xi-Wen Bi; Jia-Jia Huang, Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China, Email bixw@sysucc.org.cn; huangjiaj@sysucc.org.cnBackground: The value of the lymphocyte-to-C-reactive protein (CRP) ratio (LCR) in early breast cancer (BC) is unclear. We explored the correlation between the LCR and survival of patients with early BC and established effective LCR-based prognostic signatures for predicting prognosis.Methods: In this retrospective study, we randomized 623 patients with early-stage BC diagnosed in December 2010 to October 2012 at the Sun Yat-sen University Cancer Center to training and verification datasets. The median follow-up of all patients was 109 months. The survival differences were calculated by Kaplan–Meier method using the Log rank test. For overall survival (OS) and disease-free survival (DFS), the independent factors in the training dataset were identified using univariate and multivariate Cox analyses, in which two-tailed P-values < 0.05 were considered statistically significant. Based on this, we respectively constructed novel signatures for survival prediction and validated the efficiency of signatures through the concordance index (C-index), calibration and receiver operating characteristic (ROC) curves in both datasets.Results: The LCR, lymphatic vessel invasion (LVI), progesterone receptor (PR) status, and Ki67 index were independent prognostic factors of OS. And the LCR and LVI are associated to DFS too. High LCR was associated with better OS and DFS. We constructed the prediction signatures based on those independent prognostic factors and calculated the risk scores. Patients in the training dataset with higher risk scores had significantly worse prognosis (P < 0.001). The signature had excellent discrimination capacity, with an OS C-index of 0.785 [95% confidence interval (CI): 0.713– 0.857] and 0.750 (95% CI: 0.669– 0.832) in the training and verification datasets, respectively. The time–ROC curves also suggest accurate prediction by the signature.Conclusion: The LCR was a significant prognostic predictor of OS and DFS in early BC. The LCR-based prognostic signatures could be a useful tool for individualized therapeutic guidance.Keywords: survival, nomogram, early breast cancer, LCR

Background The clinical implication of plasma ESR1 mutations in the estrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who had progressed after prior aromatase inhibitor (AI)-based therapy remains controversial. We conducted the first meta-analysis to investigate the prognostic significance and predictive role of plasma ESR1 mutations in MBC patients with prior exposure to AI therapy. Materials and methods We searched PubMed, Embase, and Cochrane Library databases for eligible studies. Meta-analysis was conducted to calculate combined hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). Subgroup and sensitivity analyses were also performed. Results This study enrolled a total of 1,530 patients with ER-positive MBC cases from six articles, including 429 ESR1 mutation carriers (28.04%). Meta-analysis demonstrated that plasma ESR1 mutation carriers had significantly worse PFS (HR: 1.40, 95% CI: 1.17-1.66; P

Background: To investigate the role of Programmed death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in tumor recurrence and metastasis of Chinese patients suffering from triple negative breast cancer (TNBC). Methods: PD-L1 immunohistochemistry was performed on 215 TNBCs. Also, the prevalence of TILs correlated the expression of PD-L1 and TILs with clinical outcomes. Kaplan-Meier and the model analyses of univariate Cox proportional hazards were utilized to compare the survival of patients with positive PD-L1 expression with those with negative PD-L1 expression. Results: The median follow-up time was 67.7 months (range: 7-159 months). PD-L1-positive breast cancer patients had significantly longer disease-free survival (DFS) and Overall survival (OS) compared with PD-L1-negative patients (P=0.046; P=0.019) in TNBC. The presence of increased stromal lymphocytic infiltrates (STILs) was significantly associated with overall survival (P=0.026). The model analysis of univariate Cox proportional hazards showed that PD-L1 and STILs were independent prognostic factors for tumor prognosis. Conclusions: Our study found that high levels of PD-L1 could be expressed in TNBC, which was correlated with the prevalence of TILs.

// Qiong-Xia Zhang 1, 2, * , Rui Gao 1, * , Jin Xiang 3 , Zhong-Yu Yuan 1 , Yuan-Min Qian 1, 4 , Min Yan 1 , Zi-Feng Wang 1 , Quentin Liu 1 , Hai-Dong Zhao 1 and Chang-Hong Liu 1 1 Sun Yat-Sen University Cancer Center, The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, China 2 Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510060, China 3 Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China 4 Department of Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510060, China * These authors have contributed equally to this work Correspondence to: Quentin Liu, email: liuq9@mail.sysu.edu.cn Chang-Hong Liu, email: 17709870870@163.com Hai-Dong Zhao, email: z.hddl@hotmail.com Keywords: Bora, prognosis, cancer, biomarker Received: November 10, 2016 Accepted: February 28, 2017 Published: March 28, 2017 ABSTRACT Cell cycle protein Bora has been identified to integrate the functions of three major mitotic kinases: Cyclin-dependent kinase-1, Polo-like kinase-1, and Aurora A kinase. Overexpression of Bora disrupts spindle assembly and causes genomic instability. However, the clinical relevance of Bora in cancer remains unclear. In this study, we examined the expression of Bora and its association with clinical characteristics in breast ( n = 538), lung ( n = 144) and gastric ( n = 77) adenocarcinomas. We found that Bora was overexpressed in primary breast cancer tissues compared to paired non-cancerous tissues. Bora overexpression was observed at a higher proportion in triple-negative breast cancer (TNBC, 77.63%) compared with non-TNBC subtypes (42.76%, P < 0.0001). Kaplan-Meier survival analysis indicated that Bora overexpression was associated with unfavourable overall survival (OS, P < 0.0001) and disease-free survival (DFS, P = 0.007) in breast cancer. In addition, Bora subclassified patients with distinct clinical outcomes in both stages (II/III) and subtypes (HR+, HER2+) of breast cancer. Consistently, Bora was associated with adverse prognosis in lung ( P = 0.005 for OS and DFS P = 0.001 for DFS) and gastric adenocarcinomas ( P < 0.0001 for OS, and P < 0.0001 for DFS). Moreover, Bora was positively correlated with proliferation index Ki67 in breast and gastric cancer ( P < 0.001, P = 0.005, respectively). Multivariate analyses further revealed that Bora was an independent prognostic parameter for OS and DFS in all three types of adenocarcinomas. In conclusion, our findings demonstrated that Bora was overexpressed and served as an independent biomarker for poor prognosis in multiple adenocarcinomas.

// Tao Qin 1,* , Yin-duo Zeng 1,2,* , Ge Qin 1,* , Fei Xu 1,* , Jia-bin Lu 1 , Wen-feng Fang 1 , Cong Xue 1 , Jian-hua Zhan 1 , Xin-ke Zhang 1 , Qiu-fan Zheng 1 , Rou-jun Peng 1 , Zhong-yu Yuan 1 , Li Zhang 1 and Shu-sen Wang 1 1 Sun Yat-sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P. R. China 2 Sun Yat-sen University Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China * These authors have contributed equally to this work Correspondence to: Shu-sen Wang, email: // Li Zhang, email: // Zhong-yu Yuan, email: // Keywords : PD-L1, breast cancer, ER, PR, prognosis, nomogram Received : July 07, 2015 Accepted : August 22, 2015 Published : September 10, 2015 Abstract Background: To investigate the role of PD-L1 expression in tumor recurrence and metastasis in Chinese patients with breast cancer. Methods: Suitable tissue samples were available from 870 patients with breast cancer. Paraffin-embedded tumor sections were stained with PD-L1 antibody. The correlations between PD-L1 expression and clinical characteristics, ER/PR/HER2 status and survival parameters were analyzed. Kaplan-Meier and univariate Cox proportional hazards model analyses were used to compare the survival of patients with high PD-L1 expression and patients with no PD-L1 expression. Results: The median follow-up time was 98 months(range, 17–265 months).The positive rate of PD-L1 expression in breast cancer was 21.7% (189/870). PD-L1 high expression was inversely associated with larger tumor size, higher tumor grade, more positive lymph node number, as well as negative ER and PR status. PD-L1 expression was particularly higher in TNBC compared with non-TNBC, although no statistical significance was observed. Nomogram logistic regression results based on clinical and pathological features showed that the following factors were more likely associated with high PD-L1 expression: patient age younger than 35 years, larger tumor size, lymphovascular invasion and advanced stage. Our data indicated that patients with high PD-L1 expression had poor DFS, DMFS and overall survival compared with those with no PD-L1 expression. Univariate Cox proportional hazards model analysis showed that PD-L1 was an independent prognostic factor for tumor prognosis. Conclusions: PD-L1 expression is an important indicator of unfavorable prognosis in breast cancer patients.

NOP14, which is functionally conserved among eukaryotes, has been implicated in cancer development. Here, we show that NOP14 is poorly expressed in breast cancer cells and invasive breast cancer tissues. In vivo and in vitro studies indicated that NOP14 suppressed the tumorigenesis and metastasis of breast cancer cells. Further investigations revealed that NOP14 enhanced ERα expression and inhibited the Wnt/β-catenin pathway by up-regulating NRIP1 expression. Survival analysis indicated that low NOP14 expression was significantly associated with poor overall survival (P = 0.0006) and disease-free survival (P = 0.0007), suggesting that NOP14 is a potential prognostic factor in breast cancer. Taken together, our findings reveal that NOP14 may suppress breast cancer progression and provide new insights into the development of targeted therapeutic agents for breast cancer.

Foxp3⁺ regulatory T lymphocytes (Tregs) usually act as an immune suppressor and correlate with poorer survival in malignancies. This study aims to investigate the distribution and characterization of Foxp3(+) subset in peripheral blood mononuclear cells (PBMCs) and tumor tissues from extranodal NK/T cell lymphoma (ENKTL). Our study showed the percentage of Foxp3⁺ subset from PBMC was significantly higher than that of healthy individuals (P

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.

Pretreatment hematologic abnormalities have been reported to have prognostic value in patients with solid tumors. The aim of our study was to determine the prevalence of abnormalities in the hematologic profile in patients with colorectal cancer before treatment and to evaluate if such a profile could be used for prognostic evaluations. We identified all patients in Cancer Center of Sun Yat-Sen University who were diagnosed as colorectal cancers between May 2005 and August 2009. All subjects were investigated regarding levels of white blood cells, platelets, and hemoglobin concentration. Survival was compared by using the log-rank test on the Kaplan-Meier life table. Multivariate Cox regression analysis was used to evaluate if the pretreatment hematologic profile was independent prognostic factor. We identified 363 patients with colorectal cancer and 315 patients with benign diseases for the final analysis. The percentages of leukocytosis, anemia, and thrombocytosis were significantly higher in colorectal cancer patients than in patients with benign diseases. Univariate analysis showed that advanced tumor stages, leukocytosis, anemia, thrombocytosis, and low histological grade were all significantly associated with shorter survival. The multivariate Cox analysis revealed that low histological grade, tumor stage, pretreatment anemia, and thrombocytosis remained independent prognostic variables for survival. The cumulative effect of anemia and thrombocytosis yielded shorter survival. Anemia and thrombocytosis can be considered as useful prognostic markers in patients with colorectal cancer.

Aim. Data from The Cancer Genome Atlas (TCGA) show that the ZNF703 gene amplifies and overexpresses in head and neck squamous cell carcinomas (HNSCC). However, the clinical relevance of this observation in HNSCC is unclear. The purpose of this study was to clarify the expression of ZNF703 protein and its prognostic effect on HNSCC.Methods. Two hundred ten HNSCC patients from Sun Yat-Sen University Cancer Center with complete survival follow-up were included in this study. Tumor samples from primary sites were collected. The expression of the ZNF703 protein was tested by immunohistochemistry (IHC).Results. The high expression of ZNF703 in HNSCC tumor tissues was significantly higher than that of the matched noncancerous tissues (48.6% versus 11.6%,P<0.001). ZNF703 overexpression was correlated with tumor position (laryngeal carcinoma) and recurrence (allP<0.05). Multivariate analysis revealed that ZNF703 protein overexpression was an independent prognostic factor (P=0.022, hazard ratio = 1.635, 95% CI 1.073–2.493) in HNSCC patients.Conclusion. ZNF703 overexpression is associated with adverse prognosis in HNSCC, which might be a novel biomarker of HNSCC.

Zhong-Yu Yuan,1–3,* Ting Dai,1,2,* Shu-Sen Wang,1–3 Rou-Jun Peng,1–3 Xing-Hua Li,1,2 Tao Qin,1–3 Li-Bing Song,1,2 Xi Wang1,2,41State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China; 2Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China; 3Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China; 4Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China *These authors contributed equally to this work Background: Patients with triple-negative breast cancer (TNBC) present a higher probability of distant metastasis and lack of effective targeted therapy. ETS translocation variant 4 (ETV4) is an ETS (E-26) transcription factor and has been associated with tumor metastasis. However, the clinical and functional significance of ETV4 in TNBC still remains unclear. Methods: A human tumor metastasis polymerase chain reaction array was used to profile differential expression of tumor metastasis-related genes in TNBC tissue. Real-time reverse transcription and Western blot analyses were performed to verify ETV4 expression in TNBC cells and tissue. Immunohistochemistry was used to detect expression of ETV4 protein in 135 TNBC tissue samples for association between ETV4 protein expression and clinical outcomes. Results: A total total of eight upregulated (CCL7, KISS1, MET, MMP7, NR4A3, ETV4, TIMP3, and TSHR) and three downregulated (ITGA7, SSTR, and MMP2) genes were identified between TNBC tissue and the luminal subtype of breast cancer tissue. ETV4 messenger ribonucleic acid was more than five-fold upregulated in TNBC tissue compared with the control tissue. ETV4 overexpression was found in 57.0% of 135 TNBC cases. Overexpression of ETV4 protein was associated with an advanced stage and a higher proportion of positive lymph node and lymphovascular invasion. Patients with an ETV4-overexpressed tumor had a significantly higher risk of developing distant metastasis (P

Even though ER-positive, HER2-negative breast tumors represent a subset of breast cancers with a better clinical outcome, approximately 12.7 % of patients in this subgroup ultimately develop cancer-related mortality. Recent studies had confirmed that hypoxia-induced autophagy-related gene Beclin 1 expression might be important for disease progression and be correlated with patient outcome in several tumors. Here, we examined the autophagic Beclin 1 and hypoxic HIF-1α levels in 378 ER-positive, HER2-negative breast cancer patients by immunohistochemistry using tissue microarray. We found that Beclin 1 was highly expressed in normal mammary gland epithelia. In contrast, it was either not expressed or only moderately expressed in 78.0 % of breast adenocarcinoma tissue. Compared to the subset overexpressing Beclin 1, the subset in which Beclin 1 levels were reduced had a poor 5-year overall survival rate (OS, 85.1 % vs. 94.1 %, P = 0.005) and a poor distant metastasis-free survival (DMFS, 79.1 % vs. 89.3 %, P = 0.037). Cox multivariate analysis confirmed that Beclin 1 was indeed an independent prognostic factor for OS and DMFS. Additionally, Beclin 1 positively correlated with HIF-1α expression (r = 0.206, P < 0.001). Importantly, among patients with HIF-1α overexpression, low levels of Beclin 1 predicted a worse OS. Our study confirmed that deficiency of Beclin 1 was a negative prognostic factor for OS and DMFS in ER-positive, HER2-negative breast cancer. The combination of Beclin 1 and HIF-1α refined the risk definition of the patient subset and provided a novel way to identify those with a high risk of relapse.

Purpose: This study aimed to assess possible interactive effects of coping styles and psychological stress on depression and anxiety symptoms in Chinese women shortly after diagnosis of breast cancer. Methods: Four hundred and one patients with breast cancer were face-to-face interviewed by trained research staff according to a standardized questionnaire including information on socio-demographic characteristics, psychological stress, coping styles, and anxiety and depressive symptoms. Interactive effects were assessed by hierarchical multiple regression analyses. Results: There were significant associations of the four domains of psychological stress with anxiety and depressive symptoms except for the relationship between "worrying about health being harmed" and depressive symptoms. "Abreaction coping behavior" and "escaping coping behavior" significantly increased the level of both anxiety and depressive symptoms; whereas an "active coping style" reswulted in significant decrease. The interaction of "active coping behavior" with "worrying about health being harmed" significantly increased the risk of the anxiety symptoms, while adopting "self-relaxing coping behavior" was associated with significant decrease. The interaction of "worry about daily life and social relationship being restricted" with "escaping coping behavior" significantly increased the risk of the depressive symptoms. Conclusions: The results of this study suggest that certain coping styles might moderate the association of psychological stress with anxiety and depressive symptoms in Chinese women with breast cancer.

The aim of the present study was to assess the association of psychological stress and social support with anxiety and depressive symptoms in Chinese newly diagnosed breast cancer patients.Four hundred and one patients with breast cancer were recruited. Their demographic characteristics, psychological stress and social support were determined with a structured questionnaire, and their anxiety and depressive symptoms were assessed with the Hospital Anxiety and Depression Scale.Psychological stressors caused by breast cancer diagnosed originated from five major sources, as determined by factor analysis. These included "Worrying about health being harmed, " "Fear of decline of physical function, " "Fear of work being harmed, " "Worry about daily life and social relationship being restricted, " and "Fear of family being harmed. " Hierarchical linear regression analysis indicated that, after adjusting for gender, age, marital status, educational level, and duration of illness, solid social support can alleviate such symptoms.The results of this study suggest that there are strong associations between patients' needs and psychological distress with newly diagnosed breast cancer. Social support might affect these associations in Chinese women with breast cancer.

The clinical significance of bilateral breast cancer is unclear and its influence on prognosis is controversial. We compared the characteristics and prognosis of bilateral breast cancer and unilateral breast cancer.Our study included 4,183 patients with breast cancer who were treated at Sun Yat-sen University Cancer Center between January 1, 2000, and December 31, 2007. Bilateral breast cancer was categorized as synchronous (within 3 months) or metachronous (diagnosed after 3 months of first cancer). SPSS was used for data analysis.106 (2.5%) and 31 (0.7%) patients were diagnosed with metachronous and synchronous bilateral cancer. Women with bilateral cancer had more frequent postmenopause, HER-2 negativity, and advanced disease than in patients with unilateral cancer. Young age at diagnosis, invasive lobular carcinoma, ER/PR negativity, HER-2 positivity, radiation, large tumor size (T5 cm), and stage III disease of the first cancer were risk factors for contralateral cancer. The 5-year disease-free survival and overall survival rates were 76 and 83% for unilateral cancer, while 32 and 72% for bilateral cancer (P = 0.000 for both).Bilateral cancer was associated with shorter disease-free survival and overall survival than unilateral cancer. The prognosis of metachronous bilateral cancer, especially those diagnosed within 2 years after the first cancer was significantly worse than synchronous bilateral cancer.

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.

In this paper, an adaptive predictive control algorithm was presented for a class nonlinear system. Linear equation between increment output and input of nonlinear system was acquired by differential mean value theorem and time-variable parameters were identified by leakage recursive least squares algorithm. On the basis of fact, recursive state-space equations were used as predictive model and controller was designed by Linear predictive control theroy. The example of simulation results has shown the method's validity.

To investigate the clinical characteristics and prognosis of patients with different subtypes of breast cancer: basaloid, HER-2 and luminal types, and try to find the evidence of individualized treatment for the patients.1280 histologically and immunohistochemically proven patients with resectable breast cancer were treated, and the clinical data including characteristics, relapse and survival of the patients with different subtypes of breast cancer were analyzed retrospectively.Of the 1280 breast cancer patients, basaloid, HER-2 and luminal types accounted for 20.9%, 23.2% and 55.9%, respectively. Basaloid type was more likely to be found in younger patients frequently with a family history of breast cancer. HER-2 type usually had a tumor of larger size with more advanced stage disease and more metastatic lymph nodes. Luminal type was likely to occur in aged patients with an earlier stage disease. The recurrence rates in basaloid, HER-2 and luminal types were 25.0%, 27.9% and 11.7%, respectively. Patients with basaloid or HER-2 type were found to have a significantly higher recurrence rate than the patients with luminal type breast cancer (P0.001), but no significant difference was observed between the basaloid and HER-2 types. However, patients with basaloid type breast cancer were more likely to develop lung metastasis than HER-2 type (13.4% vs. 7.1%, P = 0.017). Up to December 2006, the 5-year disease-free survival (DFS) rates for patients with basaloid, HER-2 and luminal types were 72.2%, 68.2% and 86.2% (P0.001), respectively. The overall 5-yr survival (OS) rates of the three groups were 88.6%, 83.8% and 95.8% (P0.001) , respectively. Of the patients with luminal type breast cancer, HER2-negative patients had a higher DFS (86.2% vs 57.0%, P0.001) and OS (95.8% vs 87.7%, P = 0.0001) compared with those with HER2-positive. The results of Multivariate Cox Regression showed that tumor size and lymph node state were the most important factors influencing the prognosis.Each subtype of breast cancer has somewhat its own specific clinical features in terms of recurrence pattern and prognosis, therefore, individualized treatment regimen may be required.

Triple-negative breast cancer is defined by a lack of expression of estrogen receptor, progesterone receptor, and HER2/neu, and considered to be a clinicopathologic entity with aggressive behaviors and poor prognosis. No satisfactory treatment is available. This study was to analyze the clinical characteristics and prognostic factors of the patients with triple-negative breast cancer.Clinical data of 1,280 patients with histopathologically confirmed resectable breast cancer, treated at Cancer Center of Sun Yat-sen University from Jan. 2000 to Dec. 2004, were analyzed. Of the 1,280 patients, 305 (23.8%) were confirmed to be triple-negative breast cancer. The clinical characteristics, recurrence and survival of the patients were summarized.Triple-negative breast cancer was commonly seen in young patients, with large masses, a high proportion of lymph node metastasis and familial history of breast cancer at diagnosis. By Jun. 2007, the median time of follow-up was 52 months (range, 28-89 months). Of the 1,280 patients, 234 had local recurrence and metastasis, and 94 died. There was no significant difference in local recurrence between triple-negative and non-triple-negative breast cancer patients. However, the occurrence rates of lung metastasis (HR= 4.41, P0.001) and liver metastasis (HR=2.13, P=0.006) were significantly higher in triple-negative breast cancer patients than in non-triple-negative breast cancer patients. The 5-year disease-free and overall survival rates were significantly lower in triple-negative breast cancer patients than in non-triple-negative breast cancer patients (73.7% vs. 80.8%, P=0.025; 88.5% vs. 92.8%,P=0.010). Multivariate Cox regression analysis showed that tumor size and lymph node state were prognostic factors of triple-negative breast cancer patients.Nearly one fourth of breast cancer patients in China are triple-negative breast cancer patients. These patients are usually young, with large masses, lymph node metastasis, and family history of breast cancer. Lung metastasis and liver metastasis may be the main reason of poor prognosis of triple-negative breast cancer.

Few treatment options are available for metastatic breast cancer with resistance to both anthracycline-and taxane-based chemotherapy regimens. Docetaxel combined capecitabine (DC regimen) is approved as a new active regimen for metastatic breast cancer. This study was to explore the efficacy of DC regimen on metastatic breast cancer, and evaluate its safety.A total of 31 metastatic breast cancer patients received DC regimen during each 3-week chemotherapy cycle. All patients received oral administration of capecitabine (1250 mg/m(2)) twice daily, within 30 min after meal on day 1 to Day 14, and infusion of docetaxel (75 mg/m(2)) on the first day of each 3-week cycle. All patients received prophylactic therapy with oral dexamethasone (8 mg) twice daily on 3 successive days.A total of 116 cycles of DC regimen were administered, with a median of 3.7 cycles. The objective response rate was 41.9%, with a complete remission (CR) rate of 9.6%. The most frequent treatment-related adverse events were fatigue, leukopenia, nausea, vomiting, hand-foot syndrome, and stomatitis. The median follow-up was 10.8 months (range 2-23 months). Two patients were died of tumor progression.The combination of docetaxel and capecitabine provides a well-tolerated and active chemotherapy regimen for metastatic breast cancer.

Purpose This study investigated the clinicopathological features of operable breast cancer lesions located in different hemispheres of the breast and determined related survival outcomes. Methods Data from 5,330 patients with invasive ductal carcinoma were retrospectively analyzed based on tumor location. Results The median follow-up time was 68 months (range, 18-176 months). Patients with breast cancer located in the outer hemisphere of the breast had lesions with more advanced nodal stages and more frequently received adjuvant chemotherapy than patients with breast cancer in the inner hemisphere. The 5-year disease-free survival (DFS) rates of patients with tumors located in outer versus inner hemispheres were 81.5% and 77.0%, respectively (p=0.004); the overall survival (OS) rates were 90.7% and 88.8%, respectively (p

The majority of small cell carcinoma occurs in the lung. Extrapulmonary small cell carcinoma (ESCC) has been recognized as a clinicopathologic entity distinct from small cell carcinoma of the lung. The study was to investigate the clinical characteristics, therapy, and prognosis of ESCC.The medical records, from Jan. 1985 to Dec. 2005, of 53 patients with pathologically proved ESCC were analyzed retrospectively.Of the 53 patients, 39 were men and 14 were women, with the median age of 53 years (range, 27-76 years). Of the 53 cases of ESCC, 33 (62.3%) were detected in the esophagus, 5 in the cervix, 4 in the larynx, 3 in the pharynx, 2 in the upper sinus, 2 in the rectum and sublingual gland, 1 in the thyroid gland, 1 in the pleura, and 1 in the liver. Forty patients (75.5%) had limited disease (LD) and 13 (24.5%) had extensive disease (ED). Patients with ED mostly received platinum-based chemotherapy, for which the response rate was 69.2%. Patients with LD were treated with a variety of therapeutic modalities: 7 were treated with surgery plus radiochemotherapy, 3 with surgery plus radiotherapy, 18 with surgery plus chemotherapy, 6 with radiotherapy plus chemotherapy, 4 with radiotherapy alone, and 2 with chemotherapy alone. The median survival time (MST) was 20 months for all patients, and the 1-and 3-year survival rates were 41.3% and 31.4%. MST for patients with ED and LD were 15 months and 26 months, respectively, and 1-and 3-year survival rates were 51.1% vs. 14.4%, and 42.5% vs. 0% (P=0.017 ).ESCC is identified in various sites, with the most common primary site being the esophagus. Multimodality therapy has become increasingly used for the majority of patients with LD-ESCC. Combination chemotherapy has been a major treatment for patients with ED-ESCC. Generally, the prognosis of LD-ESCC is significantly superior to ED-ESCC.

Toxicities and their severities vary among advanced gastric cancer patients when they receive the same regimen containing continuous infusion of 5-fluorouracil (5-FU). Dihydropyrimidine dehydrogenase (DPD) is the key rate-limiting enzymes which is closely related to toxicities of 5-FU in chemotherapy. This study was to explore the relationship between activity of DPD and concentration of 5-FU, and their correlation to adverse events among advanced gastric cancer patients treated with the same regimen containing 5-FU continuous infusion.Patients received the same regimen (intravenous injection of paclitaxel 75 mg/m(2), leucovorin 200 mg/m(2) and 5-FU 375 mg/m(2), continuous infusion of 5-FU 2.5 g/m2 for 46 hours every two weeks). The peripheral blood was collected from 36 patients with advanced gastric cancer before and after chemotherapy to detect the activity of DPD and concentration of 5-FU by high-performance liquid chromatography (HPLC). Adverse events were assessed every cycle.Serum activity of DPD revealed a unimodel distribution, which globally fits to a guassian distribution (range 1.56-6.01). Mean and median DPD activity values were 2.38 and 2.13, respectively. No total DPD deficiency was found in the patients. The concentration of 5-FU varied from 179.2 microg/L to 1 589.2 microg/L, which demonstrated normality distribution after a logarithmic transformation was applied. The DPD activity was inversely correlated with 5-FU concentration (r=-0.376, P=0.024). The patients with low activity of DPD were more frequently suffering from severe diarrhea, mucositis, and myelosuppression. And high level of 5-FU concentration led to the increase of adverse events.Pre-chemotherapy DPD activity and 5-FU concentration during chemotherapy vary among gastric cancer patients, which may help to prevent severe toxicities during the treatment.

Multidrug resistance is one of the main causes of treatment failure of chemotherapy. Reversal agents may be used to reverse drug-resistance. To date, no appropriate reversal agent is used clinically. This study was to evaluate reverse effect of genetically modified adenovirus H101 on drug-resistance of A549/DDP cells to cisplatin (DDP), and to explore its mechanisms.Lung adenocarcinoma cell line A549 and its DDP-resistant cell line A549/DDP were treated with DDP and H101. Reverse effect of H101 on drug-resistance of A549/DDP to DDP was tested by MTT assay. The levels of cellular multidrug resistant protein 1 (MRP1), glutathione-S-transferase (GST), and topoisomerase-II (TOPO-II) were detected by flow cytometry (FCM). The level of intracellular glutathione (GSH) was measured by fluorescence-Coomassie light blue method. The intracellular concentration of platinum was measured by atomic absorption spectrometry.The resistance index of A549/DDP cells to DDP was 14.3. After infection of H101, the 50% inhibitory concentration (IC(50)) of DDP to A549/DDP cells reduced from 352.4 micromol/L to 61.6 micromol/L by 5.7 folds. Protein levels of GST and TOPO-II were higher in A549/DDP cells than in A549 cells, which were markedly decreased in A549/DDP cells after infection of H101. No MRP1 protein was detected in both A549 cells and A549/DDP cells. Intracellular amount of GSH in A549/DDP cells was 2 times higher than that in A549 cells, which was significantly decreased after infection of H101. The concentration of platinum in A549 cells was 3 times higher than that in A549/DDP cells. After infection of H101, the concentration of platinum in A549 cells had no significant change, but that in A549/DDP cells was significantly increased.H101 may reverse drug-resistance of A549/DDP cells to DDP through down-regulating GST and TOPO-IIand increasing intracellular cumulation of platinum.

The effect of adenovirus, a kind of oncolytic virus and a kind of carrier in gene therapy, depends on the expression of Coxsackie and adenovirus receptor (CAR) on cell surface to a large degree. This study was to evaluate relationship of CAR expression to infectivity and efficacy of adenovirus.Pathologic specimens from 29 patients in a clinical trial of genetically modified adenovirus (H101) were collected. Expression of CAR in cancer tissues was detected by immuohistochemistry. Expression of CAR on cancer cell membrane was detected by flow cytometry (FCM). Inhibitory effect of H101 on cells was assessed by MTT assay.Positive rate of CAR was significantly higher in patients achieved complete remission (CR) or partial remission (PR) than in patients had stable disease (SD) or progressive disease (PD) [70.0% (7/10) vs. 31.6% (6/19), P=0.048]. CAR expression on different cells was different, and the amount of CAR was positively related to virus infectivity, presented as the inhibitory rate of H101-infected cells (r=0.986).The expression of CAR closely relates to antitumor activity and efficacy of adenovirus. Also, the efficacy of adenovirus is higher on cancers with increased CAR expression than on those with decreased CAR expression.

Gastrointestinal tract is the most common extranodal involvement site of non-Hodgkin's lymphoma (NHL). However, no standard treatment regimen has ever been established for primary gastric NHL (PGNHL). This paper was to summarize the clinical characteristics and treatment results of PGNHL patients.Records of 59 PGNHL patients, treated from Jan. 1980 to Jan. 2002 in Cancer Center of Sun Yat-sen University, were reviewed to summarize their clinical characteristics, and influence of treatment modality on their survival.Of the 59 PGNHL patients, 46 (78.0%) were in stage I/II. According to Working Formulation, most of them were in intermediate grade (46, 78.0%). The most common immune phenotype was B-cell lineage (46/49, 93.9%). These patients were treated with chemotherapy plus surgery (37,62.7%), chemotherapy alone (17,28.8%), and surgery alone (5,8.5%), respectively. The 2-, 5-, and 10-year survival rates of the 59 patients were 76.4%,63.7%, and 42.5%, respectively. For those patients in intermediate grade (including immunoblastic cell lymphoma), there was no significant difference in the 5-year survival rate between the patients received chemotherapy plus surgery and the patients received chemotherapy alone (52.5% vs. 57.1%).Chemotherapy-dominated modality is recommended for patients with PGNHL of intermediate or high grade. The effect of surgery on PGNHL needs to be confirmed by prospective randomized trial.

In recent years,great development have been made in cancer therapeutics with replication-competent viruses (oncolytic viruses), E1B deleted adenovirus is one of promising viruses. The current study was designed to evaluate the efficacy and toxicity of intratumoral H101, a E1B-deleted adenovirus, in combination with chemotherapy on patients with cancer.A total of 50 patients with malignant tumors in multiple centers clinical trial were treated with H101, 0.5ml 5x10(11) viral particle per day for 5 consecutive days every three weeks. Routine chemotherapy was performed at the same time. And the efficacy and toxicity were recorded.Among 46 valuable cases, the overall response rate was 30.4%. The response rate was 28.0% (14/50) among ITT population, including 3 complete response (CR) and 11 partial response (PR). The overall response rate of control lesion was 13.0%, including 1 case of CR and 5 cases of PR. Thus, the response rate in injected lesion is clearly higher than that in control lesion (P0.001). Main side effects were injection site pain (26.9%) and fever (30.2%). Grade 1 hepatic dysfunction was found in 4 patients, grade 2 in 1 patients, grade 4 in 1 patients. Grade 4 hematological toxicities were found in 4 patients.The study showed that the combination of genetically modified adenovirus (H101) and chemotherapy possessed some effect for treating the patients with refractory malignant tumors, and the toxicities were lower, well tolerated.

The side effects of glucocorticoid, for example inducing or sharpening diabetes, should be considered in treatment of non-Hodgkin's lymphoma (NHL) accompanied by diabetes mellitus with CHOP regimen[Adriamycin(doxorubicin)+cyclophosphamide+Oncovin(Vincristine)+prednisone]. The study was performed to compare the efficacy and toxicity of CHO (without prednisone) and standard CHOP regimen.From June 1991 to May 1999, 53 patients with histologically and immunohistochemically proven of intermediate-grade NHL accompanied by diabetes mellitus were analyzed retrospectively.Twenty-two patients received CHO regimen and thirty-one received CHOP regimen. Patients in both groups were well- matched with baseline disease characteristics (P0.05). In CHO group,the response rate was 81.8%;whereas in CHOP group,the response rate was 90.4%. The median survival of CHO group and CHOP group were 31 months and 33 months,respectively. The three-year survival rate and three-year disease- free survival rate in CHO group were 44.1% and 31.2% respectively versus 47.3% and 33.8% in CHOP group. For the side effects, there were differences between two groups except nausea and vomiting which were obvious in CHO group (P=0.015).CHO regimen may be selected in treatment of intermediate-grade NHL accompanied by diabetes mellitus. The efficacy and the toxicity of CHO regimen is similar to standard CHOP regimen. Whether it is true should be confirmed by well-controlled randomized clinical trials with more patients.

In recent years, great development has been made in cancer therapeutics with replication-competent viruses (oncolytic viruses). Genetically modified adenovirus is one of promising viruses. The current study was designed to evaluate the safety of intratumoral H101, an E1B deleted adenovirus.A total of 15 patients with malignant tumors were treated with H101 in a dose-escalation manner (from 5 x 10(7) VP to 1.5 x 10(12) VP per day for 5 consecutive days). Systemic examination was performed prior to injection. Physical signs (including weight, temperature, respiration,pulse, and blood pressure) and toxicity were observed and recorded carefully during treatment. Adenoviral DNA in plasma, urine, and swabs of oropharynx, swabs of the injection site from different time-point were determined by PCR.Evaluation of toxicity in all 15 cases was available. All patients tolerated well following intratumoral injection of H101. Dose limited toxicity (DLT) and serious adverse event (SAE) were not found in the course of treatment. Main side effects were injection site pain (60.0%) and fever (33.3%). Adenoviral DNA was undetectable in plasma, urine, and swabs of oropharynx, swabs of the injection site.This study showed that the toxicities of intratumoral injection of E1B deleted adenovirus (H101) were lower and tolerable. There is no evidence indicating the invasion. These results suggested that intratumorally injected H101 is safe.

Triple negative breast cancer (TNBC) acquires an unfavorable prognosis, emerging as a major challenge for the treatment of breast cancer. In the present study, 122 TNBC patients were subjected to analysis of Aurora-A (Aur-A) expression and survival prognosis. We found that Aur-A high expression was positively associated with initial clinical stage (P = 0.025), the proliferation marker Ki-67 (P = 0.001), and the recurrence rate of TNBC patients (P