O6-methylguanine-DNA methyltransferase modulates cisplatin-induced DNA double-strand breaks by targeting the homologous recombination pathway in nasopharyngeal carcinoma.

BACKGROUND: The homologous recombination (HR) pathway is involved in DNA damage response (DDR), which is crucial to cancer cell survival after treatment with DNA damage agents. O6-methylguanine DNA methyltransferase (MGMT) is associated with cisplatin (CDDP) resistance in cancer cells; however, the underlying mechanisms remain unclear. Here, we explored the interactions between MGMT and the HR pathway in CDDP-activated DDR and their clinical implications in nasopharyngeal carcinoma (NPC). METHODS: Human NPC cells were assessed using loss-of-function approaches in vitro. The expression correlations between MGMT and major proteins of the HR pathway were analyzed through Western blotting, quantitative real-time PCR, and bioinformatic analysis by using a public database. The physical interactions between MGMT and HR proteins were studied using co-immunoprecipitation and immunofluorescence analyses. Cell comet tails and γ-H2AX expression levels were examined to evaluate double-strand break (DSB) formation. Established immunofluorescence and reporter analyses were conducted to measure HR activity. Xenograft and cell viability studies were used to assess the therapeutic potential of MGMT inhibition in combination with CDDP and poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. RESULTS: Among major proteins of the HR pathway, MGMT suppression inhibited CDDP-induced RAD51 expression. Bioinformatic analyses showed a positive correlation between MGMT and RAD51 expression in patients with NPC. Moreover, MGMT physically interacted with BRCA1 and regulated CDDP-induced BRCA1 phosphorylation (ser 988). In functional assays, MGMT inhibition increased CDDP-induced DSB formation through attenuation of HR activity. NPC xenograft studies demonstrated that MGMT inhibition combined with CDDP treatment reduced tumor size and downregulated RAD51 expression and BRCA1 phosphorylation. Furthermore, MGMT suppression increased PARP inhibitor-induced cell death and DSB formation in NPC cells. CONCLUSION: MGMT is crucial in the activation of the HR pathway and regulates DDR in NPC cells treated with CDDP and PARP inhibitor. Thus, MGMT is a promising therapeutic target for cancer treatments involving HR-associated DDR.

High FRMD3 expression is prognostic for worse survival in rectal cancer patients treated with CCRT.

BACKGROUND: Rectal cancer patients can conceivably obtain relief from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before resection, but the stratification of risk and clinical outcomes remains challenging. Therefore, identifying effective predictive biomarkers offers clinicians the opportunity to individually tailor early interventions, which would help optimize therapy. METHODS: Using a public rectal cancer transcriptome dataset (GSE35452), we focused on cytoskeletal protein binding (GO: 0008092)-related genes and identified FERM domain containing 3 (FRMD3) as the most significant differentially expressed gene associated with CCRT resistance. We gathered 172 tumor samples from rectal cancer patients treated with neoadjuvant CCRT accompanied by curative resection and estimated the expression level of FRMD3 using immunohistochemistry. RESULTS: The results revealed that high FRMD3 immunoexpression was remarkably associated with advanced pre-CCRT and post-CCRT tumor status (p = 0.004 and p < 0.001), pre-CCRT and post-CCRT lymph node metastasis (both p < 0.001), more perineurial invasion (p = 0.023), and a smaller extent of tumor regression (p = 0.018). High FRMD3 immunoexpression was remarkably correlated with inferior disease-specific survival (DSS) (p = 0.0001), local recurrence-free survival (LRFS) (p = 0.0003), and metastasis-free survival (MeFS) (p = 0.0023) at the univariate level. Furthermore, in multivariate analysis, high FRMD3 immunoexpression remained independently predictive of inferior DSS (p = 0.002), LRFS (p = 0.005), and MeFS (p = 0.015). CONCLUSION: These results suggest that high FRMD3 expression is related to advanced clinicopathological features and inferior therapeutic responses in rectal cancer patients treated with CCRT, validating the promising prognostic value of FRMD3 expression.

High EREG Expression Is Predictive of Better Outcomes in Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy.

BACKGROUND/AIM: A great proportion of patients with rectal cancer initially present with locally advanced disease and can potentially benefit from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before surgery. However, risk and clinical outcome stratification remain a great challenge. We aimed to find the potential biomarker to predict the effect of neoadjuvant CCRT on rectal cancer. METHODS: We identified epiregulin (EREG) as the most significant predictive marker for neoadjuvant CCRT response from the published rectal cancer transcriptome data set GSE35452. We collected 172 biopsy specimens from rectal cancer patients who received neoadjuvant CCRT followed by radical proctectomy, performed EREG immunohistochemistry, and analyzed the H-scores. We further examined the correlations between the expression level of EREG and clinicopathological features, tumor regression grade, and survival, including disease-specific survival (DSS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MeFS). RESULTS: High EREG expression was significantly related to early pretreatment (pre-Tx) and posttreatment (post-Tx) tumor status (T1, T2, p = 0.047 and p < 0.001), pre-Tx and post-Tx negative nodal status (N0, p < 0.001 and p = 0.004), less vascular and perineurial invasion (p = 0.015 and p = 0.023), and higher tumor regression grade (p < 0.001). In the survival analysis, high EREG expression was significantly associated with better DSS (p < 0.0001), LRFS (p = 0.0004), and MeFS (p < 0.0001). In the multivariate analysis, high EREG expression remained prognostically significant for better DSS (p = 0.003; hazard ratio: 5.599). CONCLUSION: These data suggest that EREG is a potential predictive marker and therapeutic target in rectal cancer patients receiving neoadjuvant CCRT.

Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy.

Neoadjuvant concurrent chemoradiotherapy (CCRT), followed by radical proctectomy, is the standard treatment for locally advanced rectal cancer. However, a poor response and therapeutic resistance continue to occur despite this treatment. In this study, we analyzed the microarray datasets (GSE68204) of rectal cancer from the Gene Expression Omnibus database, and identified CHD4 as one of the most significantly up-regulated genes among all subunits of the nucleosome remodeling and histone deacetylation (NuRD) complex, in non-responders to CCRT, among locally advanced rectal cancer (LARC) patients. We confirmed the predictive and prognostic significance of CHD4 expression in CCRT treatment, and its correlation with other clinicopathological features, such as tumor regression grade (TRG), therapeutic response, and patient survival. This was carried out by immunohistochemical studies on endoscopic biopsy tissues from 172 rectal cancer patients, receiving neoadjuvant concurrent chemoradiotherapy (CCRT). A high expression of CHD4 was significantly associated with pre-treatment tumor status (p < 0.001) and lymph node metastasis (p < 0.001), post-treatment tumor status (p < 0.001), and lymph node metastasis (p < 0.001), vascular invasion (p = 0.042), and tumor regression grade (p = 0.001). A high expression of CHD4 could also predict poor disease-specific survival and metastasis-free survival (log-rank test, p = 0.0373 and p < 0.0001, respectively). In multivariate Cox proportional-hazards regression analysis, CHD4 overexpression was an independent factor of poor prognosis for metastasis-free survival (HR, 4.575; 95% CI, 1.717-12.192; p = 0.002). By in vitro studies, based on cell line models, we also demonstrated that, the overexpression of CHD4 induced radio-resistance in microsatellite instability-high (MSI-H) colorectal cells (CRCs). On the contrary, the knockdown of CHD4 enhanced radiosensitivity in microsatellite stable (MSS) CRCs. Altogether, we have identified CHD4 as an important regulator of radio-resistance in both MSI-H and MSS CRC cell lines.

The impact of young age on the prognosis for colorectal cancer: a population-based study in Taiwan.

BACKGROUND: The impact of age as a prognostic factor for patients with colorectal cancer (CRC) remains controversial, possibly due to heterogeneity between studies in terms of patient numbers, percentage of patients undergoing curative resection, percentage of patients receiving neoadjuvant therapy, or failure to adjust for potential confounding factors. This study used colorectal cancer survival data from the Taiwan Cancer Registry database in order to comprehensively analyze age as a prognostic factor. METHODS: Survival data were analyzed for 62 060 CRC patients diagnosed with adenocarcinoma, mucinous adenocarcinoma, or signet-ring cell carcinoma of the colon and rectum between 1998 and 2005. The rates of all-cause mortality and CRC-related mortality were determined using Kaplan-Meier analysis, and the log-rank test was used to compare differences in survival between different age groups. The crude and adjusted hazard ratios for all-cause and CRC-related mortalities were calculated according to the estimates from the univariable and multivariable Cox proportional hazard models. RESULTS: Patients in the ≤40 and the 41-50 age groups had a higher proportion of mucinous adenocarcinoma (P < 0.001) and signet-ring cell carcinoma (P < 0.001) compared to the older age groups. After adjusting for gender, histology, and tumor site, patients in the ≤40 age group had a poorer overall survival (OS) and cancer-specific survival compared to patients in the 41-50 and 51-60, and 61-70 age groups (P < 0.001), but a better OS and cancer-specific survival compared to patients in the 71-80 and >80 age groups (P < 0.001). CONCLUSIONS: Our study indicated that age is an important consideration while determining the clinical management of CRC patients.

Trends in the use of maintenance immunosuppressive drugs among liver transplant recipients in Taiwan: a nationwide population-based study.

PURPOSE: During the past two decades, many novel immunosuppressive drugs have been approved for transplant recipients. Trends in the use of maintenance immunosuppressants after liver transplantation in Asia are unclear. Thus, we aimed to analyze the prescription trends in maintenance immunosuppressive drugs among liver transplant recipients in Taiwan and compare the results with the trends reported from western countries. METHODS: We conducted a retrospective nationwide population-based study utilizing the National Health Insurance Research Database (NHIRD) to analyze the prescribing patterns of immunosuppressants used in Taiwanese liver transplant recipients from 2000 to 2009. RESULTS: A total of 1686 liver transplant patients and their prescriptions of immunosuppressants were analyzed. The 5-year survival rate of liver transplant recipients was 79.6%. In 2009, the major immunosuppressive therapy among liver transplant recipients was a dual-drug regimen with tacrolimus and mycophenolic acid (57.3%). Among the calcineurin inhibitors (CNI), the use of cyclosporine decreased from 58.9% to 12.5%, while the use of tacrolimus notably increased from 23.3% to 77.5%. The use of azathioprine decreased from 21.3% to 0.4%, while the use of mycophenolic acid increased from 56.1% to 76.5%. Among the mammalian target of rapamycin (mTOR) inhibitors, sirolimus was approved in 2002, and its use increased to 8.7% in 2009. In the first 3 months after liver transplantation, a total of 17 different regimens were used in 2009, compared with seven regimens in 2000. CONCLUSIONS: Although the CNI-based combination obviously remains the major regimen, our results reveal a trend toward individualized immunosuppressive regimens among Taiwanese liver transplant recipients. Copyright © 2016 John Wiley & Sons, Ltd.

Prescription trends of immunosuppressive drugs in post-heart transplant recipients in Taiwan, 2000-2009.

PURPOSE: Significantly increasing heart transplantations have been performed in Taiwan in the past decades, but the trends of maintenance immunosuppression for heart transplant recipients have not been well known. In this study, we aimed to explore the trends of maintenance immunosuppressive therapy and common complications for heart transplant recipients. METHODS: We retrospectively analyzed ambulatory prescriptions in 488 heart transplant recipients for the period 2000-2009. Patient complications after heart transplantation were also identified. RESULTS: The annual number of new heart transplant recipients ranged from 18 to 68. The 5-year survival rate was 77.9%. The total number of regimens was 10 in 2000, and increased to 28 in 2009. Most prescriptions were immunosuppressive combinations (95.5%-89.5%). The majority of immunosuppressive regimens were a triple regimen: cyclosporine, mycophenolic acid and corticosteroid in 2009. Cyclosporine was a predominant calcineurin inhibitor with a decreasing trend from 73.9% to 59.1%, whereas the use of tacrolimus significantly increased from 11.9% to 38.4%. Mycophenolic acid was the most frequently used antimetabolite (60.1%-80.3%), while the use of azathioprine was reduced (21.6%-2.3%). From 2008, the launch of everolimus initiated a new era in the utilization of mammalian target of rapamycin inhibitors for maintenance immunosuppression. CONCLUSIONS: Cyclosporine remained the most frequently used calcineurin inhibitors, and tacrolimus increased gradually. Mycophenolic acid was the most popular antimetabolite rather than azathioprine. The rapidly increased everolimus combined regimen may change the patterns of maintenance immunosuppression. The increasing number of combination therapies indicates an active role of everolimus and a tendency of complex tailored individual therapies.

Drugs cheaper than threepenny: the market of extremely low-priced drugs within the National Health Insurance in Taiwan.

While most drug policy researches paid attention to the financial impact of expensive drugs, the market situation of low-priced drugs in a country was seldom analyzed. We used the nationally representative claims datasets to explore the status within the National Health Insurance (NHI) in Taiwan. In 2007, a total of 12,443 distinct drug items had been prescribed 853,250,147 times with total expenditure of 105,216,950,198 new Taiwan dollars (NTD). Among them, 7,366 oral drug items accounted for 701,353,383 prescribed items and 68,133,988,960 NTD. Besides, 2,887 items (39.2% of oral drug items) belonged to cheap drugs with the unit price ≤ 1 NTD (about 0.03 of US dollar). While the top one item among all oral drugs had already a market share of 5.0%, 30 items 30.3% and 107 items 50.0%, the cheap drugs with aggregate 332,893,462 prescribed items (47.5% of all prescribed oral drug items) only accounted for 2,750,725,433 NTD (4.0% of expenditure for oral drugs and 2.6% of total drug expenditure). The drug market of Taiwan's NHI was abundant in cheap drugs. The unreasonably low prices of drugs might not guarantee the quality of pharmaceutical care and the sustainability of a healthy pharmaceutical industry in the long run.

Urban-rural disparity of generics prescription in Taiwan: the example of dihydropyridine derivatives.

The aim of the current study was to investigate the urban-rural disparity of prescribing generics, which were usually cheaper than branded drugs, within the universal health insurance system in Taiwan. Data sources were the cohort datasets of National Health Insurance Research Database with claims data in 2010. The generic prescribing ratios of dihydropyridine (DHP) derivatives (the proportion of DHP prescribed as generics to all prescribed DHP) of medical facilities were examined against the urbanization levels of the clinic location. Among the total 21,606,914 defined daily doses of DHP, 35.7% belonged to generics. The aggregate generic prescribing ratio rose from 6.7% at academic medical centers to 15.3% at regional hospitals, 29.4% at community hospital, and 66.1% at physician clinics. Among physician clinics, the generic prescribing ratio in urban areas was 63.9 ± 41.0% (mean ± standard deviation), lower than that in suburban (69.6 ± 38.7%) and in rural (74.1% ± 35.3%). After adjusting the related factors in the linear regression model, generic prescribing ratios of suburban and rural clinics were significantly higher than those of urban clinics (ß = 0.043 and 0.077; P = 0.024 and 0.008, resp.). The generic prescribing ratio of the most popular antihypertensive agents at a clinic was reversely associated with the urbanization level.

Longitudinal Risk Analysis of Second Primary Cancer after Curative Treatment in Patients with Rectal Cancer.

Predicting and improving the response of rectal cancer to second primary cancers (SPCs) remains an active and challenging field of clinical research. Identifying predictive risk factors for SPCs will help guide more personalized treatment strategies. In this study, we propose that experience data be used as evidence to support patient-oriented decision-making. The proposed model consists of two main components: a pipeline for extraction and classification and a clinical risk assessment. The study includes 4402 patient datasets, including 395 SPC patients, collected from three cancer registry databases at three medical centers; based on literature reviews and discussion with clinical experts, 10 predictive variables were considered risk factors for SPCs. The proposed extraction and classification pipelines that classified patients according to importance were age at diagnosis, chemotherapy, smoking behavior, combined stage group, and sex, as has been proven in previous studies. The C5 method had the highest predicted AUC (84.88%). In addition, the proposed model was associated with a classification pipeline that showed an acceptable testing accuracy of 80.85%, a recall of 79.97%, a specificity of 88.12%, a precision of 85.79%, and an F1 score of 79.88%. Our results indicate that chemotherapy is the most important prognostic risk factor for SPCs in rectal cancer survivors. Furthermore, our decision tree for clinical risk assessment illuminates the possibility of assessing the effectiveness of a combination of these risk factors. This proposed model may provide an essential evaluation and longitudinal change for personalized treatment of rectal cancer survivors in the future.

REG3A overexpression functions as a negative predictive and prognostic biomarker in rectal cancer patients receiving CCRT.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is suggested before resection surgery in the control of rectal cancer. Unfortunately, treatment outcomes are widely variable and highly patient-specific. Notably, rectal cancer patients with distant metastasis generally have a much lower survival rate. Accordingly, a better understanding of the genetic background of patient cohorts can aid in predicting CCRT efficacy and clinical outcomes for rectal cancer before distant metastasis. METHODS: A published transcriptome dataset (GSE35452) (n=46) was utilized to distinguish prospective genes concerning the response to CCRT. We recruited 172 rectal cancer patients, and the samples were collected during surgical resection after CCRT. Immunohistochemical (IHC) staining was performed to evaluate the expression level of regenerating family member 3 alpha (REG3A). Pearson's chi-squared test appraised the relevance of REG3A protein expression to clinicopathological parameters. The Kaplan-Meier method was utilized to generate survival curves, and the log-rank test was performed to compare the survival distributions between two given groups. RESULTS: Employing a transcriptome dataset (GSE35452) and focusing on the inflammatory response (GO: 0006954), we recognized that REG3A is the most significantly upregulated gene among CCRT nonresponders (log2 ratio=1.2472, p=0.0079). Following IHC validation, high immunoexpression of REG3A was considerably linked to advanced post-CCRT tumor status (p<0.001), post-CCRT lymph node metastasis (p=0.042), vascular invasion (p=0.028), and low-grade tumor regression (p=0.009). In the multivariate analysis, high immunoexpression of REG3A was independently correlated with poor disease-specific survival (DSS) (p=0.004) and metastasis-free survival (MeFS) (p=0.045). The results of the bioinformatic analysis also supported the idea that REG3A overexpression is implicated in rectal carcinogenesis. CONCLUSION: In the current study, we demonstrated that REG3A overexpression is correlated with poor CCRT effectiveness and inferior patient survival in rectal cancer. The predictive and prognostic utility of REG3A expression may direct patient stratification and decision-making more accurately for those patients.

Predictive value of FCGBP expression for treatment response and survival in rectal cancer patients undergoing chemoradiotherapy.

Despite neoadjuvant chemoradiotherapy (CRT) being the established standard for treating advanced rectal cancer, clinical outcomes remain suboptimal, necessitating the identification of predictive biomarkers for improved treatment decisions. Previous studies have hinted at the oncogenic properties of the Fc fragment of IgG binding protein (FCGBP) in various cancers; however, its clinical significance in rectal cancer remains unclear. In this study, we first conducted an analysis of a public transcriptome comprising 46 rectal cancer patients. Focusing on cell adhesion during data mining, we identified FCGBP as the most upregulated gene associated with CRT resistance. Subsequently, we assessed FCGBP immunointensity using immunohistochemical staining on 343 rectal cancer tissue blocks. Elevated FCGBP immunointensity correlated with lymph node involvement before treatment (p = 0.001), tumor invasion, and lymph node involvement after treatment (both p < 0.001), vascular invasion (p = 0.001), perineural invasion (p = 0.041), and reduced tumor regression (p < 0.001). Univariate analysis revealed a significant association between high FCGBP immunoexpression and inferior disease-specific survival, local recurrence-free survival, and metastasis-free survival (all p ≤ 0.0002). Furthermore, high FCGBP immunoexpression independently emerged as an unfavorable prognostic factor for all three survival outcomes in the multivariate analysis (all p ≤ 0.025). Enriched pathway analysis substantiated the role of FCGBP in conferring resistance to radiation. In summary, our findings suggest that elevated FCGBP immunoexpression in rectal cancer significantly correlates with a poor response to CRT and diminished patient survival. FCGBP holds promise as a valuable prognostic biomarker for rectal cancer patients undergoing CRT.

Role for gender in colorectal cancer risk: a Taiwan population-based study.

BACKGROUND AND AIMS: Gender differences in the prognosis of colorectal cancer (CRC) remain controversial. The aim of this study was to complete a comprehensive analysis of gender differences in CRC survival derived from population registries in Taiwan. MATERIALS AND METHODS: We analyzed survival data for patients diagnosed with CRC between 1998 and 2005 derived from the Taiwan Cancer Registry database. During this time period, 65,113 patients were registered, and 62,060 patients were eligible. Gender differences in overall survival and cancer-specific survival were analyzed by use of the Kaplan-Meier method. We then modeled the risk in different genders by use of a multivariate proportional hazard (Cox) model adjusting for possible confounders of survival. RESULTS: The 5-year period overall and cancer-specific survivals were significantly higher in women than in men [51.84% (95% confidence interval (CI), 51.22-52.46) vs. 47.68% (95% CI, 47.14-48.22), log-rank p < 0.001; and 56.44% (95% CI, 55.82-57.07) vs. 53.47 % (95 % CI, 52.92-54.01), log-rank p < 0.001, respectively]. Subgroup analysis revealed higher overall and cancer-specific survivals in women between 50 and 80 years age and those with adenocarcinomas (p < 0.001). By use of Cox modeling, we noted a decreased hazard ratio (HR) for death from CRC in women compared with men (HR, 0.820-0.971), especially in the 50-80-year age group. All estimated HRs, after adjusting for age, tumor histology, and tumor site, had significant trends of a decreasing risk of death from CRC in women. CONCLUSIONS: Our findings suggest that overall and cancer-specific survival advantage was most evident in women between 50 and 80 years of age.

Punicalagin is cytotoxic to human colon cancer cells by modulating cell proliferation, apoptosis, and invasion.

Purpose: The purpose of this study was to explore the anticancer effect of punicalagin, an abundant bioactive tannin compound isolated from Punica granatum L., on three colon cancer cell lines, namely, HCT 116, HT-29, and LoVo.Research Design: Normal and colon cancer cells were treated with different concentrations of punicalagin for different periods. Data Collection and Analysis: Cell viability was measured with a CCK-8 assay. Programmed cell death and invasion were analyzed using an annexin V and cell death kit and a cell invasion analysis kit. The expression of active caspase-3, MMP-2, MMP-9, Snail, and Slug were measured by Western blot.Results: The results of the cell viability analysis showed that punicalagin was cytotoxic to colon cancer cells, but it was not to normal cells in a dose- and time-dependent manner. Additionally, punicalagin induced apoptosis in colon cancer cells (shown by the cumulative percentage of colorectal cancer cells in early and late apoptosis). It was found that caspase-3 activity increased following punicalagin treatment. Western blot results also showed that punicalagin increased the expression of activated caspase-3. In contrast, punicalagin inhibited the invasion of colon cancer cells. Further, treatment of colon cancer cells with punicalagin suppressed the expression of MMP-2, MMP-9, Snail, and Slug. Conclusions: These results showed that the activation of caspase-3 and the inhibition of MMP-2, MMP-9, Snail and Slug were involved in the effects of punicalagin on colon cancer cells.

NCAPG deregulation indicates poor patient survival and contributes to colorectal carcinogenesis.

Colorectal cancer (CRC) is one of the types of cancers with a high incidence and is ranked the 3rd among men and 2nd among women worldwide. The purpose of this study was to investigate the correlation between non-SMC condensin I complex subunit G (NCAPG) and the prognosis of CRC and its function in CRC cells. The expression of NCAPG in colorectal tissues and cells was detected by immunoblotting and immunohistochemistry. Kaplan-Meier analysis was used to analyze the correlation between NCAPG and CRC prognosis. RNAi technology was used to investigate how NCAPG inhibition affected the proliferation and migration of CRC cells. Overexpression of NCAPG was positively correlated with several clinicopathologic characteristics, including T stage (P = 0.0198), M stage (P = 0.0005), and TNM stage (P < 0.0001). Kaplan-Meier analysis showed that the overexpression of NCAPG was also negatively correlated with disease-free survival and overall survival. In the culture of CRC cells, the knockdown of NCAPG inhibited the proliferation, migration, and invasion of the cells. Meanwhile, it was also found that NCAPG knockdown could interfere with G2/M-G1 transition in the cell cycle, resulting in the inhibition of cell proliferation. The overexpression of NCAPG may serve as a candidate biomarker for CRC prognosis. NCAPG is also a potential therapeutic target for CRC.

Prognostic Significance of DNA Topoisomerase II Alpha (TOP2A) in Cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a malignant tumor with an increasing incidence worldwide. Although radiation therapy has improved the therapeutic efficiency of CCA treatment, differential expression of genes among cholangiocarcinoma subtypes has been revealed through precise sequencing. However, no specific molecular therapeutic targets or biomarkers have been figured out for use in precision medicine, and the exact mechanism by which antitumorigenic effects occur is still unclear. Therefore, it is necessary to conduct further studies on the development and mechanisms associated with CCA. METHODS: We examined the clinical data and pathological features of patients with cholangiocarcinomas. We investigated the associations between DNA Topoisomerase II Alpha (TOP2A) expression and patient outcomes, such as metastasis-free survival (MFS) and disease-specific survival (DSS), as well as clinical characteristics and pathological results. RESULTS: TOP2A expression was shown to be upregulated in CCA tissue sections by immunohistochemistry staining and data mining. Moreover, we observed that the TOP2A expression correlated with clinical features, such as the primary tumor stage, histological variants, and patients with hepatitis. Furthermore, high expression of TOP2A was associated with worse survival outcomes in terms of the overall survival (p < 0.0001), disease-specific survival (p < 0.0001), and metastasis-free survival (p < 0.0001) compared with patients in the low TOP2A expression group. This indicates that a high level of TOP2A expression is related to an unfavorable prognosis. CONCLUSIONS: Our results show that TOP2A is highly expressed in CCA tissues, and its upregulation is correlated with the primary disease stage and poor prognosis significantly. Consequently, TOP2A is a prognostic biomarker and a novel therapeutic target for the treatment of CCA.

Ubiquitin-conjugating enzyme E2C (UBE2C) is a prognostic indicator for cholangiocarcinoma.

Cholangiocarcinoma is the most common malignant bile duct tumor in Southeast Asia. The special location of cholangiocarcinoma leads to it being difficult to diagnose. Currently, the progress in clinical prognosis outcomes remains abysmal owing to the lack of definitive diagnostic criteria. Therefore, uncovering the potential markers for cholangiocarcinoma is a pressing issue. Ubiquitin-conjugating enzyme E2 C (UBE2C) is a critical ubiquitination enzyme; it is involved in the tumorigenesis of various malignancies and affects the patient's prognosis. However, there is currently no relevant literature to indicate whether UBE2C is related to the clinical survival outcome of cholangiocarcinoma patients. In this report, we mined the published cholangiocarcinoma transcriptome data set (GSE26566), compared it with the ubiquitination-associated gene (GO:0016567), and identified that UBE2C was highly expressed in cholangiocarcinoma tumor tissue. Moreover, high expression of UBE2C was markedly correlated with surgical margin, primary tumor, histological variants, and histological grade. More specifically, high expression of UBE2C was negatively associated with overall survival, disease-specific survival, local recurrence-free survival, and metastasis-free survival in patients with cholangiocarcinoma. Our findings demonstrate that UBE2C may provide a potential therapeutic marker and prognostic factor for cholangiocarcinoma patients.

LAMC2 is a potential prognostic biomarker for cholangiocarcinoma.

Cholangiocarcinoma is a common malignancy with increasing incidence worldwide. Most patients are diagnosed at the advanced stage with poor survival rate. Laminin subunit γ2 (LAMC2) is a heparin binding-associated gene involved in tumorigenesis and has been implicated in the prognosis of various types of cancers. However, it is unclear whether expression of LAMC2 is associated with the clinical outcome of patients with cholangiocarcinoma. In the present study, the role and prognostic value of LAMC2 expression in patients with cholangiocarcinoma was investigated. Clinical information and pathological characteristics were analyzed and the association between LAMC2 expression and clinical characteristics, pathological findings and patient outcomes, including metastasis-free and disease-specific survival, were investigated. Data from 182 patients with cholangiocarcinoma were evaluated. High LAMC2 expression was associated with higher tumor stage (P<0.001), large duct type (P=0.024) and poor histological grade (P=0.002). Kaplan-Meier analysis showed high LAMC2 expression was associated with lower overall (P=0.003), disease-specific (P=0.0025), local recurrence-free (P<0.0001) and metastasis-free survival (P<0.0001). Moreover, multivariate analysis demonstrated that increased LAMC2 expression was a significant predictive risk factor for overall [hazard ratio (HR) 1.713; P=0.034], disease-specific (HR 2.011; P=0.039), local recurrence-free (HR 2.721; P<0.001) and metastasis-free survival (HR 3.117; P<0.001). Gene enrichment analysis using Gene Ontology showed that terms associated with LAMC2 upregulation were 'regulation of platelet-derived growth factor receptor-ßsignaling pathway' and 'platelet-derived growth factor receptor-ß signaling pathway'. The present study indicated that LAMC2 was upregulated in cholangiocarcinoma tumor tissue and had an inverse association with overall, disease-specific, local recurrence-free and metastasis-free survival in patients with cholangiocarcinoma. These results suggested that LAMC2 may serve as a potential biomarker for cholangiocarcinoma.

Impact of Tumor Location on Survival in Patients With Colorectal Cancer: A Retrospective Cohort Study Based on Taiwan's Cancer Registry Database.

Background: Colorectal cancer is one of the leading cancers worldwide. This study aimed to investigate the mortality differences between 2 primary tumor locations, the proximal/distal colon and rectosigmoid junction (RSJ)/rectum, after adjusting for comorbidities. Methods: The Taiwan Cancer Registry linked with Taiwan's National Health Insurance Research Database was used to estimate the 5-year mortality rate among patients with colorectal cancer. A total of 73 769 individuals were enrolled in the study, which included 44 234 patients with proximal and distal colon cancers and 29 535 patients with RSJ and rectal cancers. Potential mortality risk was calculated using Cox regression analysis. Results: The mortality rates due to the location of the cancer in the proximal/distal colon and RSJ/rectum were 45.27% and 42.20%, respectively. After adjustment for age, sex, comorbidities, and clinical stages, the proximal/distal colon had a 1.03-fold higher 5-year overall mortality rate than RSJ/rectal cancer (95% confidence interval = 1.00-1.05). Proximal and distal colon cancers had a worse prognosis and survival than RSJ and rectal colon cancers in women and older patients (⩾70 years). Comorbidities had different effects on mortality in the proximal/distal colon and RSJ/rectum. Conclusions: Tumor location is associated with the prognosis of patients with colorectal cancer. It is important to treat patients beyond their cancer treatment, and to manage their comorbidities.

Upregulated Ubiquitin D is a Favorable Prognostic Indicator for Rectal Cancer Patients Undergoing Preoperative Concurrent Chemoradiotherapy.

Purpose: For locally advanced rectal cancer, neoadjuvant concurrent chemoradiotherapy (CCRT) allows tumor downstaging and makes curative radical proctectomy possible. However, we lack a genetic biomarker to predict cancer prognosis or treatment response. We investigated the association between ubiquitin D (UBD) expression and clinical outcomes in rectal cancer patients receiving CCRT. Patients and Methods: We analyzed the genes associated with the protein modification process (GO:0036211) and identified the UBD gene as the most relevant among the top 7 differentially expressed genes associated with CCRT resistance. We collected tissue specimens from 172 rectal cancer patients who had received CCRT followed by a curative proctectomy. We examine the relationship between UBD expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MeFS) and disease-specific survival. Results: Upregulated UBD expression was associated with lower pre-CCRT tumor T stage (P = 0.009), lower post-CCRT tumor T stage (P < 0.001), lower post-CCRT nodal stage (P < 0.001), less vascular invasion (P = 0.015), and better tumor regression (P < 0.001). Using univariate analysis, we found that high UBD expression was correlated with better disease-free survival (DFS) (P < 0.0001), local recurrence-free survival (LRFS) (P < 0.0001) and MeFS (P < 0.0001). Moreover, multivariate analysis demonstrated that high UBD expression was associated with superior DFS (P < 0.001), LRFS (P = 0.01), and MeFS (P = 0.004). Conclusion: UBD upregulation was linked to better clinical prognosis, favorable pathological features, and good treatment response in rectal cancer patients undergoing CCRT. These results suggest UBD is a biomarker for rectal cancer.