Comparison of the Efficacy, Safety, and Quality of Life of Pegylated Liposomal Doxorubicin-Cyclophosphamide versus Epirubicin-Cyclophosphamide in Patients with Early-Stage HER2-Negative Breast Cancer: A Prospective, Randomized, Multicenter, Phase II Study.

INTRODUCTION: This multicenter, phase II randomized, non-inferiority study reports from the first prospective two-armed randomized control trial that compared the efficacy, safety, and quality of life (QoL) of pegylated liposomal doxorubicin (PLD)-based and epirubicin-based as adjuvant chemotherapy for stage I-II human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: Patients with stage I/II HER2-negative breast cancer received PLD (37.5 mg/m2, Q3W, 5 cycles, LC arm) plus cyclophosphamide (600 mg/m2) or epirubicin (90 mg/m2, Q3W, 4 cycles, EC arm) plus cyclophosphamide (600 mg/m2). Randomization was stratified by lymph node and ER and PR status. The primary endpoint was disease-free survival (DFS), and secondary endpoints were overall survival (OS), safety profiles, and QoL. QoL was assessed using the EORTC-QLQ-C30 and QLQ-BR23 questionnaires. RESULTS: A total of 256 patients were assigned to LC (n = 148) and EC (n = 108). There was no difference in 5-year DFS and OS rate between the two groups. LC-based adjuvant regimens had significantly less alopecia and low-grade 3-4 hematologic adverse events (AEs). Significantly improved QoL was observed in the LC arm during and after treatment for symptoms including fatigue, nausea and vomiting, and systemic therapy side effects. CONCLUSION: Comparable efficacy and safety between adjuvant PLD and epirubicin for stage I-II HER2-negative breast cancer was observed. There was no difference in the 5-year DFS and OS rates between the two treatment arms. However, low-grade 3-4 AEs and a trend of favorable QoL symptom scales were observed in the LC arm, suggesting that PLD-containing regimen could become a new standard treatment for early-stage HER2-negative breast cancer patients.

Overexpression of malic enzyme is involved in breast cancer growth and is correlated with poor prognosis.

Malic enzyme (ME) genes are key functional metabolic enzymes playing a crucial role in carcinogenesis. However, the detailed effects of ME gene expression on breast cancer progression remain unclear. Here, our results revealed ME1 expression was significantly upregulated in breast cancer, especially in patients with oestrogen receptor/progesterone receptor-negative and human epidermal growth factor receptor 2-positive breast cancer. Furthermore, upregulation of ME1 was significantly associated with more advanced pathological stages (p < 0.001), pT stage (p < 0.001) and tumour grade (p < 0.001). Kaplan-Meier analysis revealed ME1 upregulation was associated with poor disease-specific survival (DSS: p = 0.002) and disease-free survival (DFS: p = 0.003). Multivariate Cox regression analysis revealed ME1 upregulation was significantly correlated with poor DSS (adjusted hazard ratio [AHR] = 1.65; 95% CI: 1.08-2.52; p = 0.021) and DFS (AHR, 1.57; 95% CI: 1.03-2.41; p = 0.038). Stratification analysis indicated ME1 upregulation was significantly associated with poor DSS (p = 0.039) and DFS (p = 0.038) in patients with non-triple-negative breast cancer (TNBC). However, ME1 expression did not affect the DSS of patients with TNBC. Biological function analysis revealed ME1 knockdown could significantly suppress the growth of breast cancer cells and influence its migration ability. Furthermore, the infiltration of immune cells was significantly reduced when they were co-cultured with breast cancer cells with ME1 knockdown. In summary, ME1 plays an oncogenic role in the growth of breast cancer; it may serve as a potential biomarker of progression and constitute a therapeutic target in patients with breast cancer.

Breast Cancer Surgery 10-Year Survival Prediction by Machine Learning: A Large Prospective Cohort Study.

Machine learning algorithms have proven to be effective for predicting survival after surgery, but their use for predicting 10-year survival after breast cancer surgery has not yet been discussed. This study compares the accuracy of predicting 10-year survival after breast cancer surgery in the following five models: a deep neural network (DNN), K nearest neighbor (KNN), support vector machine (SVM), naive Bayes classifier (NBC) and Cox regression (COX), and to optimize the weighting of significant predictors. The subjects recruited for this study were breast cancer patients who had received breast cancer surgery (ICD-9 cm 174-174.9) at one of three southern Taiwan medical centers during the 3-year period from June 2007, to June 2010. The registry data for the patients were randomly allocated to three datasets, one for training (n = 824), one for testing (n = 177), and one for validation (n = 177). Prediction performance comparisons revealed that all performance indices for the DNN model were significantly (p < 0.001) higher than in the other forecasting models. Notably, the best predictor of 10-year survival after breast cancer surgery was the preoperative Physical Component Summary score on the SF-36. The next best predictors were the preoperative Mental Component Summary score on the SF-36, postoperative recurrence, and tumor stage. The deep-learning DNN model is the most clinically useful method to predict and to identify risk factors for 10-year survival after breast cancer surgery. Future research should explore designs for two-level or multi-level models that provide information on the contextual effects of the risk factors on breast cancer survival.

Machine Learning Algorithms to Predict Recurrence within 10 Years after Breast Cancer Surgery: A Prospective Cohort Study.

No studies have discussed machine learning algorithms to predict recurrence within 10 years after breast cancer surgery. This study purposed to compare the accuracy of forecasting models to predict recurrence within 10 years after breast cancer surgery and to identify significant predictors of recurrence. Registry data for breast cancer surgery patients were allocated to a training dataset (n = 798) for model development, a testing dataset (n = 171) for internal validation, and a validating dataset (n = 171) for external validation. Global sensitivity analysis was then performed to evaluate the significance of the selected predictors. Demographic characteristics, clinical characteristics, quality of care, and preoperative quality of life were significantly associated with recurrence within 10 years after breast cancer surgery (p < 0.05). Artificial neural networks had the highest prediction performance indices. Additionally, the surgeon volume was the best predictor of recurrence within 10 years after breast cancer surgery, followed by hospital volume and tumor stage. Accurate recurrence within 10 years prediction by machine learning algorithms may improve precision in managing patients after breast cancer surgery and improve understanding of risk factors for recurrence within 10 years after breast cancer surgery.

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.

PURPOSE: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 in patients with metastatic breast cancer: phase II randomized, placebo-controlled study.

PURPOSE: This randomized, double-blind, placebo-controlled, parallel-group, phase II trial assessed the efficacy and safety of adagloxad simolenin (OBI-822; a Globo H epitope covalently linked to keyhole limpet hemocyanin (KLH)) with adjuvant OBI-821 in metastatic breast cancer (MBC). METHODS: At 40 sites in Taiwan, USA, Korea, India, and Hong Kong, patients with MBC of any molecular subtype and ≤2 prior progressive disease events with stable/responding disease after the last anticancer regimen were randomized (2:1) to adagloxad simolenin (AS/OBI-821) or placebo, subcutaneously for nine doses with low-dose cyclophosphamide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, correlation of clinical outcome with humoral immune response and Globo H expression, and safety. RESULTS: Of 349 patients randomized, 348 received study drug. Patients with the following breast cancer subtypes were included: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (70.4%), triple negative (12.9%), and HER2+ (16.7%), similarly distributed between treatment arms. Median PFS was 7.6 months (95% CI: 6.5-10.9) with AS/OBI-821 (n=224) and 9.2 months (95% CI: 7.3-11.3) with placebo (n=124) (HR=0.96; 95% CI: 0.74-1.25; p=0.77), with no difference by breast cancer subtype. AS/OBI-821 recipients with anti-Globo H IgG titer ≥1:160 had significantly longer median PFS (11.1 months (95% CI: 9.3-17.6)) versus those with titers <1:160 (5.5 months (95% CI: 3.7-5.6); HR=0.52; p<0.0001) and placebo recipients (HR=0.71; p=0.03). Anti-KLH immune responses were similar at week 40 between AS/OBI-821 recipients with anti-Globo IgG titer ≥1:160 and those with anti-Globo IgG titer <1:160. The most common adverse events with AS/OBI-821 were grade 1 or 2 injection site reactions (56.7%; placebo, 8.9%) and fever (20.1%; placebo, 6.5%). CONCLUSION: AS/OBI-821 did not improve PFS in patients with previously treated MBC. However, humoral immune response to Globo H correlated with improved PFS in AS/OBI-821 recipients, leading the way to further marker-driven studies. Treatment was well tolerated.NCT01516307.

Aberrant DNA Hypermethylation Silenced LncRNA Expression in Gastric Cancer.

BACKGROUND/AIM: Long noncoding RNAs (lncRNAs) are noncoding transcripts that are >200 nucleotides in length. However, the biological functions and regulation mechanisms of lncRNAs in gastric carcinogenesis remain unknown. MATERIALS AND METHODS: The expression levels of Linc00472 were analyzed by real-time PCR. The DNA methylation status was assessed using Combined Bisulfite Restriction Analysis (COBRA). The biological role of Linc00472 was assessed in AGS cells with Linc00472 overexpression. RESULTS: Using the next-generation sequencing approach, we identified DNA methylation-associated lncRNAs in gastric cancer cells. Among them, the expression level of Linc00472 significantly decreased in gastric cancer tissues compared to adjacent normal tissues. Furthermore, we observed a more frequent hypermethylation of CpG islands upstream of Linc00472 in gastric cancer tissues. Ectopic Linc00472 expression could significantly inhibit gastric cancer cell growth and migration. CONCLUSION: Epigenetically regulated Linc00472 expression plays a crucial role in modulating gastric cancer cell growth and motility.

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells.

Background: Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), which lack molecular markers for diagnosis and therapy. Cancer cells activate chemoresistant pathways and lead to therapeutic failure for patients with TNBC. Several kinases have been identified as chemoresistant genes. However, the involvement of kinases in the chemoresistance in TNBC cells is not fully understood. Methods: We employed a kinome siRNA library to screen whether targeting any kinases could increase the chemosensitivity of TNBC cell lines. The effects of kinase on cell viability in various breast cancer cells were validated with ATP level and colony formation. Protein expression and phosphorylation were determined by immunoblotting. The Cancer Genome Atlas (TCGA) dataset was collected to analyze the correlation of Src expression with prognosis of TNBC patients. Results: Primary screening and validation for the initial hits showed that Src kinase was a potential doxorubicin-resistant kinase in the TNBC cell lines MDA-MB-231 and Hs578T. Both siRNA against Src and the Src inhibitor dasatinib enhanced the cytotoxic effects of doxorubicin in TNBC cells. Moreover, phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), downstream effectors of Src, were accordingly decreased in Src-silenced or -inhibited TNBC cells. Additionally, TCGA data analysis indicated that Src expression levels in tumor tissues were higher than those in tumor-adjacent normal tissues in patients with TNBC. High co-expression level of Src and STAT3 was also significantly correlated with poor prognosis in patients. Conclusion: Our results showed that Src-STAT3 axis might be involved in chemoresistance of TNBC cells.

Hepatic Arterial Infusion Chemotherapy Is a Feasible Treatment Option for Breast Cancer with Liver-predominant Metastatic Disease.

BACKGROUND: Patients with liver metastasis from breast cancer (LMBC) are usually offered systemic therapy. However, for those with progressive liver disease and limited extra-hepatic conditions, local liver management becomes an option. Herein we present our experience with hepatic arterial infusion chemotherapy (HAIC). PATIENTS AND METHODS: From 1999 to 2018, 42 patients with LMBC, who had progressive liver metastasis after systemic therapy, were treated with HAIC. A catheter was placed angiographically into the hepatic artery and remained there for 5 consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5-fluorouracil, folinic acid, and cisplatin. This treatment was repeated at monthly intervals. The medical records were reviewed and analyzed for hepatic tumor response, progression-free survival, overall survival and adverse effects. RESULTS: Complete response was observed in two patients (5%), partial response in 18 patients (43%) and stable disease in eight patients (19%). Fourteen patients (33%) had progressive disease after HAIC. The median progression-free survival and overall survival were 8.4 and 19.3 months, respectively. There was no death related to HAIC. The patients with response to the treatment had a significant survival benefit (p<0.005). CONCLUSION: HAIC can be an option for those with progressive liver disease who are heavily pretreated while their extra-hepatic conditions are minimal or stable.

Extracellular Matrix-receptor Interaction Signaling Genes Associated with Inferior Breast Cancer Survival.

BACKGROUND/AIM: Breast cancer is a common type of cancer in women, and metastasis frequently leads to therapy failure. Using next-generation sequencing (NGS), we aspired to identify the optimal differentially expressed genes (DEGs) for use as prognostic biomarkers for breast cancer. MATERIALS AND METHODS: NGS was used to determine transcriptome profiles in breast cancer tissues and their corresponding adjacent normal tissues from three patients with breast cancer. RESULTS: Herein, 15 DEGs (fold change >4 and <0.25) involved in extracellular matrix (ECM)-receptor interaction signaling were identified through NGS. Among them, our data indicated that high HMMR expression levels were correlated with a poor pathological stage (p<0.001) and large tumor size (p<0.001), whereas high COL6A6 and Reelin (RELN) expression levels were significantly correlated with an early pathological stage (COL6A6: p=0.003 and RELN: p<0.001). Multivariate analysis revealed that high HMMR and SDC1 expression levels were significantly correlated with poor overall survival (OS; HMMR: adjusted hazard ratio [aHR] 1.93, 95% confidence interval [CI]=1.10-3.41, p=0.023; SDC1: [aHR] 2.47, 95%CI=1.28-4.77, p=0.007) for breast cancer. Combined, the effects of HMMR and SDC1 showed a significant correlation with poor OS for patients with breast cancer (high expression for both HMMR and SDC1: [aHR] 3.29, 95%CI=1.52-7.12, p=0.003). CONCLUSION: These findings suggest that HMMR and SDC1 involved in the ECM-receptor interaction signaling pathway could act as effective independent prognostic biomarkers for breast ductal carcinoma.

Comprehensive identification of microRNA arm selection preference in lung cancer: miR-324-5p and -3p serve oncogenic functions in lung cancer.

MicroRNA (miRNA/miR) dysfunction is a hallmark of lung cancer, and results in the dysregulation of tumor suppressors and oncogenes during lung cancer progression. Selection of the 5p and 3p arms of miRNA is a mechanism that improves the modulation of miRNA biological functions and complicates the regulatory network in human types of cancer. However, the involvement of arm selection preference of miRNA in lung cancer remains unclear. In the present study, changes in miRNA arm selection preference were comprehensively identified in lung cancer and corresponding adjacent normal tissues by analyzing The Cancer Genome Atlas. Arm selection was revealed to be consistent in the majority of miRNAs in lung cancer. Only a few miRNAs had significantly altered arm selection preference in lung cancer. Among these, the biological functions of the individual arms of miR-324 were investigated further. The data revealed that miR-324-5p and -3p were significantly overexpressed in lung cancer cells. Ectopic expression of miR-324-5p significantly promoted cell proliferation and invasion in lung cancer cells, while miR-324-3p overexpression significantly increased cell proliferation but did not alter the invasion of lung cancer cells. In conclusion, the arm selection preference of miRNA may be an additional mechanism through which biological functions are modulated. The results of the present study provide a novel insight into the underlying mechanisms of lung cancer and may direct research into future therapies.

Isocitrate dehydrogenase 1-snail axis dysfunction significantly correlates with breast cancer prognosis and regulates cell invasion ability.

BACKGROUND: The isocitrate dehydrogenase (IDH) gene family expresses key functional metabolic enzymes in the Krebs cycle and mediates the epigenetic reprogramming, which serves as an important biomarker of breast cancer. However, the expression levels of the IDH protein and their biological function in human breast cancer remain largely unknown. METHODS: In this study, the clinical impact of IDH1 expression on the progression and prognosis of breast cancer was evaluated using immunohistochemistry assay (IHC) of the corresponding tumor-adjacent normal, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tissues from 309 patients with breast ductal carcinoma. The relationship between microRNA (miRNA) and IDH1 were examined by a bioinformatics approach, western blot and reporter assay. The biological functions of IDH1 were examined in breast cancer cells with IDH1 knockdown, including proliferation, migration and invasion. RESULTS: The present findings revealed that the mRNA and protein expression levels of IDH1 were both significantly lower in breast cancer tissues than in adjacent normal tissues. A low expression level of IDH1 in breast cancer significantly correlated with advanced stage (p = 0.012), lymph node metastasis (p = 0.018), and poor disease-specific survival (DSS) (adjusted hazard ratio (AHR), 1.57, 95% confidence interval (CI), 1.08-2.30; p = 0.02). Furthermore, oncogenic miR-32 and miR-92b were identified to suppress IDH1 expression, leading to the inhibition of cell migration and invasion. We further explored whether reduced expression of IDH1 significantly increases snail expression by activating HIFα (hypoxia-inducible factor-1 alpha) and NFκB (nuclear factor kappa B) signaling. Multivariate Cox regression analysis revealed that the combination of low IDH1 and high snail expression could be an independent risk factor for shorter DSS (AHR, 2.34; 95% CI, 1.32-4.16; p = 0.004) and shorter disease-free survival (AHR, 2.50; 95% CI, 1.39-4.50; p = 0.002) in patients with breast cancer. CONCLUSION: Our findings revealed that a IDH1low/Snailhigh molecular signature could serve as an independent biomarker for poor prognosis in breast cancer.

Prevention of Tamoxifen-related Nonalcoholic Fatty Liver Disease in Breast Cancer Patients.

BACKGROUND: Tamoxifen is commonly used to prevent breast cancer recurrence. Studies have confirmed the association between tamoxifen and nonalcoholic fatty liver disease (NAFLD), with the results indicating the need for aggressive management of this side effect. We assessed the potential risk factors for and identified the possible protective factors of tamoxifen-related fatty liver. MATERIALS AND METHODS: We enrolled patients with a history of breast cancer, aged 20 to 70 years, who had received with tamoxifen treatment within the past 5 years. We obtained the initial data and performed a follow-up blood test and ultrasound examination to compare the differences before and after tamoxifen treatment. The patients were divided into relatively normal and fatty liver groups. RESULTS: Of the 266 enrolled tamoxifen-treated patients, 143 (53.8%) and 123 (46.2%) were in the relatively normal and fatty liver groups, respectively. The initial body weight (57.6 ± 9.3 kg vs. 60.9 ± 10.3 kg; P = .006) and body mass index (BMI; 23.4 ± 3.8 kg/m2 vs. 25.0 ± 4.2 kg/m2; P < .001) were lower in the relatively normal group. An initial BMI of ≥ 22 kg/m2 was a potential risk factor for tamoxifen-related NAFLD (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.00-2.48; P = .048). In contrast, a weekly exercise duration of ≥ 150 minutes reduced the risk (HR, 0.47; 95% CI, 0.31-0.69; P < .001). CONCLUSION: The results from our study suggest that a BMI of ≥ 22 kg/m2 is a potential risk factor for tamoxifen-related fatty liver and exercise is a possible protective factor.

miR-105/93-3p promotes chemoresistance and circulating miR-105/93-3p acts as a diagnostic biomarker for triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Moreover, chemotherapy only produces 20-30% pathologic complete response. Because miRNAs are frequently dysregulated in breast cancer and have broad tissue effects, individual or combinations of circulating miRNAs may serve as ideal diagnostic, predictive or prognostic biomarkers, as well as therapeutic targets. Understanding the role and mechanism of dysregulated miRNAs in TNBC may help to develop novel diagnostic and prognostic strategy for TNBC patients. METHODS: The miRNA array profiles of 1299 breast cancer patients were collected from the Metabric database and subjected to analysis of the altered miRNAs between TNBC and non-TNBC. In Student's t-test and Kaplan-Meier analysis, four upregulated miRNAs correlated with poor survival in TNBC but not in non-TNBC. Four miRNAs were manipulated in multiple cell lines to investigate their functional role in carcinogenesis. From these results, we studied miR-105 and miR-93-3p in greater detail. The level of miR-105 and miR-93-3p were evaluated in 25 breast cancer tumor tissues. In addition, the diagnostic utility of circulating miR-105 and miR-93-3p were examined in 12 normal and 118 breast cancer plasma samples by ROC curve construction. RESULTS: miR-105 and miR-93-3p were upregulated and correlated with poor survival in TNBC patients. Both miR-105 and miR-93-3p were found to activate Wnt/ß-catenin signaling by downregulation of SFPR1. By this action, stemness, chemoresistance, and metastasis were promoted. Importantly, the combination of circulating miR-105/93-3p may serve as a powerful biomarker for TNBC, even in early-stage disease. CONCLUSIONS: miR-105/93-3p activates Wnt/ß-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells. Most importantly, combined circulating miR-105/93-3p levels represent a prime candidate for development into a diagnostic biomarker for both early- and late-stage TNBC.

An Analysis of Emergency Department Visits and the Survival Rate for Colorectal Cancer Patients: A Nationwide Population-based Study.

Objective We examined the general characteristics, survival rate, and most common reasons for visiting the emergency department (ED) among colorectal cancer patients in Taiwan. We performed a population-based retrospective study and used data sourced from the National Health Insurance Research Database (NHIRD). Methods The colorectal cancer patient population, their diagnosis, and their medical management at the ED were identified using the Longitudinal Health Insurance Database 2000 (HV) codes and International Classification of Diseases, Ninth Revision, Clinical Modification system. We investigated their reasons for visiting the ED and the medications used there, analyzed their cumulative survival curves using the Kaplan-Meier method, and compared the survival curves with other colorectal cancer patients who had never visited the ED. Results Between 2000 and 2012, there were 6,532 ED visits by 3,347 colorectal patients, and the number per year increased gradually. The top three most common reasons for visiting ED were ill-defined conditions, abdominal pain, and intestinal obstruction. The overall survival rates of colorectal patients in the ED visit group at 3, 5, and 10 years, were 0.65, 0.56, and 0.47, respectively, without significant differences from the rates among colorectal cancer patients who did not visit the ED (p=0.2072). Conclusion We described the circumstances of ED visitation by colorectal cancer patients in Taiwan. Health care providers and researchers should pay more attention to improve medical care quality and investigate more details to predict the outcome among colorectal cancer patients.

Analysis of gallstone disease after gastric cancer surgery.

BACKGROUND: The incidence rate of newly developed gallstone disease after gastrectomy for gastric cancer is thought to be higher than that in the general population. However, the presentation and management of these gallstones remain under debate, and the role of prophylactic cholecystectomy remains questionable. METHODS: Data on adult patients who were diagnosed with gastric cancer and received gastrectomy between 2000 and 2011 were extracted from the Taiwan National Health Insurance Research Database. A patient was excluded if he or she had gallstone disease or received cholecystectomy before the index date. The incidence of newly developed gallstone disease and its subsequent management were recorded. Data were analyzed to evaluate the factors associated with gallstone development and treatment options. RESULTS: A total of 17,325 gastric cancer patients who underwent gastrectomy were eligible for analysis. During the follow-up period (mean 4.1 years; median, 2.9 years), 1280 (7.4%) patients developed gallstone disease and 560 (3.2%) patients subsequently underwent cholecystectomy. The in-hospital mortality for cholecystectomy was 1.8% (10/560). Development of gallstone disease was associated with older age, total gastrectomy, duodenal exclusion, diabetes, cirrhosis, and more comorbidities. Factors associated with the use of cholecystectomy to treat gallstone disease included younger age, fewer comorbidities, medical center admission, and presentation as cholecystitis. CONCLUSIONS: Although few patients required further gallbladder removal after gastrectomy for gastric malignancy, the increased mortality rate for subsequent cholecystectomy was worth noting. The decision to undergo prophylactic cholecystectomy might be individualized based upon patient characteristics and the surgeon's discretion.

Breast Cancer Incidence and Predictors of Surgical Outcome: a Nationwide Longitudinal Study in Taiwan.

AIMS: Despite the huge and growing global burden of patients who require breast cancer surgery, high-quality population-based studies of breast cancer trends and outcomes are scarce. The purpose of this study was to explore the incidence of breast cancer and predictors of hospital resource utilisation, mortality and recurrence in a nationwide population of patients who have received surgery. MATERIALS AND METHODS: This retrospective study analysed trends and outcomes in a Taiwan population of 77 971 patients after breast cancer surgery during 1996-2010. The Cox proportional hazards model was used for multivariate assessment of both mortality and recurrence predictors. RESULTS: The data analysis indicated that, during this period, the estimated mean hospital treatment cost and mean length of stay increased by 16.3% and 53.4%, respectively. The estimated mean overall survival time was 138.9 months (standard deviation 0.3 months) and the overall 1, 3, 5 and 10 year survival rates were 97.3, 89.2, 82.2 and 70.1%, respectively. The estimated mean overall recurrence time was 10.8 months (standard deviation 0.2 months) and the overall 1, 3, 5 and 10 year recurrence rates were 0.1, 18.8, 26.6 and 36.0%, respectively. Outcomes were significantly associated with age, Deyo-Charlson comorbidity index score, surgeon seniority, hospital volume, surgeon volume, surgery type, hospital level and baseline comorbidities (P<0.001). CONCLUSIONS: Analyses of these population-based data revealed simultaneous increases in the standard incidence of breast cancer surgery and its associated medical resource utilisation. Notably, healthcare providers and patients should recognise that both patient attributes and hospital attributes may affect breast cancer surgery outcomes.

Effect of thymol on Ca²âº homeostasis and viability in PC3 human prostate cancer cells.

Thymol is a phenolic compound that affects physiology in different cell models. However, whether thymol affects Ca²âº homeostasis in prostate cancer cells is unknown. The action of this compound on cytosolic Ca²âº concentrations ([Ca²âº]i) and viability in PC3 human prostate cancer cells was explored. The results show that thymol at concentrations of 100-1500 µM caused [Ca²âº]i rises in a concentration-dependent manner. Removal of extracellular Ca²âº reduced thymol's effect by approximately 80%. Thymol-induced Ca²âº entry was confirmed by Mn²âº entry-induced quench of fura-2 fluorescence, and was inhibited by approximately 30% by Ca²âº entry modulators (nifedipine, econazole, SKF96365), and the protein kinase C (PKC) inhibitor GF109203X. In Ca²âº-free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin abolished thymol-induced [Ca²âº]i rises. Treatment with thymol also abolished thapsigargin-induced [Ca²âº]i rises. Thymol-induced Ca²âº release from the endoplasmic reticulum was abolished by the phospholipase C (PLC) inhibitor U73122. Thymol at 100-900 µM decreased cell viability, which was not reversed by pretreatment with the Ca²âº chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Together, in PC3 cells, thymol induced [Ca²âº]i rises by inducing PLC-dependent Ca²âº release from the endoplasmic reticulum and Ca²âº entry via PKC-sensitive store-operated Ca²âº channels and other unknown channels. Thymol also induced Ca²âº-dissociated cell death.

Do racial differences exist in the association between pregnancy-induced hypertension and breast cancer risk?

BACKGROUND: Previous studies investigating the relationship between pregnancy-induced hypertension (PIH) and breast cancer risk have yielded inconsistent results. Unlike numerous Western studies, studies have reported that PIH may be a risk factor for breast cancer in Western Asian women. To confirm these results, we designed a retrospective population-based cohort study to assess the relationship between PIH and subsequent risk for breast cancer in Taiwan. METHODS: Patients with newly diagnosed PIH were selected from the Taiwan National Health Insurance Research Database (NHIRD), and a 1:4 matched cohort of women without PIH based on age and the year of delivery was randomly selected from the same database as the comparison group. The incidence of new-onset breast cancer was assessed in both cohorts. RESULTS: Among the 23.3 million individuals registered in the NHIRD, 26,638 patients with PIH and 106,552 matched controls were identified. The incidence rate of breast cancer was higher in patients with PIH than in the matched controls (incidence rate ratio = 1.09, 95% confidence interval [CI] = 1.09-1.10, p < 0.0001). However, the Kaplan-Meier analysis revealed a similar cumulative incidence rate of breast cancer between the PIH and comparison cohorts (log-rank p = 0.4303). Moreover, results from a multivariate analysis indicated that PIH was not a statistically significant independent risk factor for breast cancer (adjusted hazard ratio = 1.10, 95% CI = 0.87-1.39, p = 0.4247). CONCLUSIONS: The present study demonstrated no significant temporal relationship between PIH and risk for subsequent breast cancer in Eastern Asian women.

CTMP, a predictive biomarker for trastuzumab resistance in HER2-enriched breast cancer patient.

Trastuzumab is regarded as the primary therapy for patients with HER2-enriched breast cancer, but the pathological complete response for advanced cases is less than 30%. The underlying mechanism of trastuzumab resistance remains unclear and there are currently no conclusive biomarkers for patient response to trastuzumab. Identifying predictive biomarkers for trastuzumab response may allow treatments to be individually tailored and optimized multi-target therapies may be developed. CTMP activates AKT signaling in breast cancer and over-activation of AKT has been reported to contribute to trastuzumab resistance. In this study, we examined samples from 369 patients to investigate the correlation between CTMP expression level and patient outcome. Elevated CTMP expression was correlated with adverse outcomes in HER2-enriched patients including overall and disease-free survival as well as trastuzumab resistance. Ectopic expression of varying levels of CTMP in SkBR3 cells dose-dependently attenuated trastuzumab-mediated growth inhibition through AKT activation. In addition, inhibition of AKT signaling by AKT inhibitor IV and Rapamycin reversed CTMP-mediated trastuzumab resistance. In clinical samples, the high expression of CTMP was showed in trastuzumab non-responders and positively correlated with AKT activity. Taken together, we demonstrated that CTMP promotes AKT activation resulting in trastuzumab resistance in patients with HER2-enriched breast cancer. High CTMP expression not only predicted poor prognosis, but may also predict resistance to trastuzumab in HER2-enriched patients. Therefore, CTMP expression may be considered as a prognostic biomarker in HER2-enriched breast cancer and high expression may indicate a utility for AKT-inhibition in these patients.