Neoadjuvant concurrent chemoradiotherapy followed by transanal total mesorectal excision assisted by single-port laparoscopic surgery for low-lying rectal adenocarcinoma: a single center study.

PURPOSE: To assess the feasibility and short-term outcomes of neoadjuvant chemoradiotherapy (CCRT) followed by transanal total mesorectal excision assisted by single-port laparoscopic surgery (TaTME-SPLS) for low-lying rectal adenocarcinoma. METHODS AND MATERIALS: A total of 23 patients with clinical stage II-III low-lying (from anal verge 0-8 cm) rectal adenocarcinoma who underwent neoadjuvant CCRT followed by TaTME-SPLS consecutively from December 2015 to December 2018, were enrolled into our study. Chi-squared testing and Student's t testing were used to make parametric comparisons, and Fisher's exact test or the Mann-Whitney U test were used to make nonparametric comparisons. RESULTS: Conversion rate in patients who underwent neoadjuvant CCRT followed by TaTME-SPLS was only 4%. The mean operation time was 366 min and the inter-sphincter resection (ISR) was done for 14 patients (60%). The mean number of lymph nodes harvested was 15. There was no surgical mortality, but the 30-day morbidity rate was 21% (5 patients were Clavien-Dindo I-II). Pathological complete response was 21.74% with 100% organ preservation and 100% clear distal margin after neoadjuvant CCRT followed by TaTME-SPLS. CONCLUSION: TaTME-SPLS would be highly successful in lymph node negative and low T stage of low-lying rectal cancer patients who had pathological complete remission or high percentage of partial remission after neoadjuvant CCRT.

Identification of INFG/STAT1/NOTCH3 as γ-Mangostin's potential targets for overcoming doxorubicin resistance and reducing cancer-associated fibroblasts in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer characterized by drug resistance and distant metastasis. Cancer stem cells (CSCs) are considered a major contributor to TNBC's drug resistance. Thus targeting and eliminating CSCs have been vigorously researched. However, the precise targetable molecular networks responsible for CSC genesis remain unclear; this conundrum is mainly due to the high heterogeneity of the TNBC tumor microenvironment (TME). The cancer-associated fibroblasts (CAFs) are one of the most abundant cellular components of the TME. Emerging studies indicate that CAFs facilitate TNBC's progression by establishing a pro-tumor TME. Hence, identifying the molecular networks involved in CAF transformation and CAF-associated oncogenesis are essential areas to be explored. Through a bioinformatics approach, we identified INFG/STAT1/NOTCH3 as a molecular link between CSCs and CAF. DOX-resistant TNBC cell lines showed increased expression of INFG/STAT1/NOTCH3 and CD44 and were associated with increased self-renewal ability and CAF-transformative ability. Downregulation of STAT1 significantly reduced the tumorigenic properties of MDA-MB-231 and -468 cells and their CAF-transforming potential. Our molecular docking analysis suggested that gamma mangostin (gMG), a xanthone, formed complexes with INFG/STAT1/NOTCH3 better than celecoxib. We then demonstrated that gMG treatment reduced the tumorigenic properties similarly observed in STAT1-knocked down conditions. Finally, we utilized a DOX-resistant TNBC tumoroid-bearing mouse model to demonstrate that gMG treatment significantly delayed tumor growth, reduced CAF generation, and improved DOX sensitivity. Further investigations are warranted for clinical translation.

Preclinical Evaluation of a Novel Small Molecule LCC-21 to Suppress Colorectal Cancer Malignancy by Inhibiting Angiogenic and Metastatic Signatures.

Colorectal cancer (CRC) is one of the most common cancers, and it frequently metastasizes to the liver and lymph nodes. Despite major advances in treatment modalities, CRC remains a poorly characterized biological malignancy, with high reported cases of deaths globally. Moreover, cancer stem cells (CSCs) and their microenvironment have been widely shown to promote colon cancer development, progression, and metastasis. Therefore, an understanding of the underlying mechanisms that contribute to the maintenance of CSCs and their markers in CRC is crucial in efforts to treat cancer metastasis and develop specific therapeutic targets for augmenting current standard treatments. Herein, we applied computational simulations using bioinformatics to identify potential theranostic markers for CRC. We identified the overexpression of vascular endothelial growth factor-α (VEGFA)/ß-catenin/matrix metalloproteinase (MMP)-7/Cluster of Differentiation 44 (CD44) in CRC to be associated with cancer progression, stemness, resistance to therapy, metastasis, and poor clinical outcomes. To further investigate, we explored in silico molecular docking, which revealed potential inhibitory activities of LCC-21 as a potential multitarget small molecule for VEGF-A/CTNNB1/MMP7/CD44 oncogenic signatures, with the highest binding affinities displayed. We validated these finding in vitro and demonstrated that LCC-21 inhibited colony and sphere formation, migration, and invasion, and these results were further confirmed by a Western blot analysis in HCT116 and DLD-1 cells. Thus, the inhibitory effects of LCC-21 on these angiogenic and onco-immunogenic signatures could be of translational relevance as potential CRC biomarkers for early diagnosis.

Multiomics Study of a Novel Naturally Derived Small Molecule, NSC772864, as a Potential Inhibitor of Proto-Oncogenes Regulating Cell Cycle Progression in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most prevalent malignant tumors, and it contributes to high numbers of deaths globally. Although advances in understanding CRC molecular mechanisms have shed significant light on its pathogenicity, current treatment options, including combined chemotherapy and molecular-targeted agents, are still limited due to resistance, with almost 25% of patients developing distant metastasis. Therefore, identifying novel biomarkers for early diagnosis is crucial, as they will also influence strategies for new targeted therapies. The proto-oncogene, c-Met, a tyrosine kinase that promotes cell proliferation, motility, and invasion; c-MYC, a transcription factor associated with the modulation of the cell cycle, proliferation, apoptosis; and cyclin D1 (CCND1), an essential regulatory protein in the cell cycle, all play crucial roles in cancer progression. In the present study, we explored computational simulations through bioinformatics analysis and identified the overexpression of c-Met/GSK3ß/MYC/CCND1 oncogenic signatures that were associated with cancer progression, drug resistance, metastasis, and poor clinical outcomes in CRC. We further demonstrated the anticancer activities of our newly synthesized quinoline-derived compound, NSC772864, against panels of the National Cancer Institute's human CRC cell lines. The compound exhibited cytotoxic activities against various CRC cell lines. Using target prediction tools, we found that c-Met/GSK3ß/MYC/CCND1 were target genes for the NSC772864 compound. Subsequently, we performed in silico molecular docking to investigate protein-ligand interactions and discovered that NSC772864 exhibited higher binding affinities with these oncogenes compared to FDA-approved drugs. These findings strongly suggest that NSC772864 is a novel and potential antiCRC agent.

Single-incision robotic colectomy versus single-incision laparoscopic colectomy: A matched case control study.

BACKGROUND: Single incision laparoscopic colectomy (SILC) and single incision robotic colectomy (SIRC) are both advanced minimally invasive operative techniques. However, studies comparing these two surgical methods have not been published. The purpose of this study is to compare and evaluate the short-term outcomes of SIRC with those of SILC. METHODS: A total of 21 consecutive patients underwent SIRC and 136 consecutive patients underwent SILC in separate institutes between January 2013 and December 2019. We used retrospective cohort matching to analyze these patients. RESULTS: Prior to matching, patients who underwent SIRC had a lower percentage of American Society of Anesthesiologists (ASA) grades III-IV (5% vs. 19%, P = 0.11) compared with patients who underwent SILC. The SIRC group revealed a higher proportion of sigmoid colon lesions and anterior resections than the SILC group (61% vs. 45%, P = 0.16). After 1:4 cohort matching, 21 patients were enrolled in the SIRC group and 84 patients were enrolled in the SILC group. No statistically significant difference in terms of operative time (SIRC: 185 ± 46 min, SILC: 208 ± 53 min; P = 0.51), estimated blood loss (SIRC: 12 ± 22 ml, SILC: 85 ± 234 ml; P = 0.12), and complications (SIRC: 4.7%, SIRC: 7.1%; P = 0.31) was observed between these groups. Length of postoperative hospital stay (SIRC: 8.3 ± 1.7 days, SILC: 9.3 ± 6.5; P = 0.10) and number of harvested lymph nodes (SIRC: 21.3 ± 10.3, SILC: 21.3 ± 9.5; P = 0.77) were also similar between the two groups. In subgroup analysis, numbers of harvested lymph node is less in SIRC than SILC (SIRC: 18.1 ± 4.7 vs. SILC: 18.9 ± 8.1, P = 0.04) in anterior resection. CONCLUSION: SIRC and SILC are safe and feasible procedures with similar surgical and pathological outcomes for right- and left-side colectomy.

Effect of pathologic stages on postmastectomy radiation therapy in breast cancer receiving neoadjuvant chemotherapy and total mastectomy: A Cancer Database Analysis.

PURPOSE: To use pathologic indicators to determine which patients benefit from postmastectomy radiation therapy (PMRT) for breast cancer after neoadjuvant chemotherapy (NACT) and total mastectomy (TM). PATIENTS AND METHODS: We enrolled 4236 patients with breast invasive ductal carcinoma who received NACT followed by TM. Cox regression analysis was used to calculate hazard ratios (HRs) and confidence intervals; independent predictors were controlled for or stratified in the analysis. RESULTS: After multivariate Cox regression analyses, the adjusted HRs derived for PMRT for all-cause mortality were 0.65 (0.52-0.81, P < 0.0001) and 0.58 (0.47-0.71, P < 0.0001) in postchemotherapy pathologic tumor stages T2-4 (ypT3-4) and postchemotherapy pathologic nodal stages N2-3 (ypN2-3), respectively. Moreover, adjusted HRs derived for PMRT with all-cause mortality were 0.51 (0.38-0.69, P < 0.0001), 0.60 (0.40-0.88, P = 0.0096), and 0.64 (0.48-0.86, P = 0.0024) in pathological stages IIIA, IIIB, and IIIC, respectively. Additionally, the PMRT group showed significant locoregional control irrespective of the pathologic response, even ypT0, ypN0, or pathological complete response (pCR), compared with the No-PMRT group. The multivariate analysis showed no statistical differences between the PMRT and No-PMRT groups for distant metastasis-free survival in any pathologic response of ypT0-4, ypN0-3, and pathologic American Joint Committee on Cancer stages pCR to IIIC. CONCLUSION: For patients with breast cancer ypT3-4, ypN2-3, or pathologic stages IIIA-IIIC receiving NACT and TM, benefit from PMRT if it is associated with OS benefits, regardless of the clinical stage of the disease. Compared with No-PMRT, PMRT improved locoregional recurrence-free survival, even pCR, in patients with breast cancer receiving NACT and TM.

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers might be associated with lung adenocarcinoma risk: a nationwide population-based nested case-control study.

OBJECTIVES: To analyze the association of the use of different doses of angiotensin II receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) independently with lung cancer risk and to evaluate the lung cancer type that may be related to ARB or ACEI use. PATIENTS AND METHODS: A nationwide population-based nested case-control study was conducted using Taiwan National Health Insurance Research Database linked to the Taiwan Cancer Registry database between January 1, 2000, and December 31, 2016. The cumulative defined daily dose (DDD) was estimated. We divided all users of ACEI or ARB into three categories based on the DDD of ACEI or ARB: low dose, middle dose, and high dose. RESULTS: We identified 16,091 patients with newly diagnosed lung cancer, and 80,455 controls with hypertension were selected. Univariate and multivariate conditional logistic regressions showed that the independent risk factor for lung cancer was high-dose (≥ 1095 DDD) ARB use (adjusted odds ratio [OR]: 1.069, 95% confidence interval [CI]: 1.02-1.12, P = 0.003). An increase in lung adenocarcinoma (ADC) risk was associated with middle-dose (adjusted OR: 1.073, 95% CI: 1.01-1.14, P = 0.025) to high-dose (adjusted OR: 1.106, 95% CI: 1.05-1.17, P < 0.001) ARB use and high-dose ACEI use (adjusted OR: 1.095, 95% CI: 1.01-1.19, P = 0.033). No association was observed between different ARB or ACEI dose levels and the risk of lung squamous cell carcinoma and small-cell lung carcinoma. CONCLUSIONS: Our results suggest that the use of both ACEI and ARB at a high cumulative dose is associated with the risk of lung ADC.

Multidisciplinary team intervention associated with improved survival for patients with colorectal adenocarcinoma with liver or lung metastasis.

BACKGROUND AND OBJECTIVES: To investigate whether multidisciplinary team (MDT) intervention is associated with improved survival for patients with colorectal adenocarcinoma with liver or lung metastasis (CRA-LLM). METHODS: We enrolled 161 consecutive patients with histologically confirmed CRA-LLM at Taipei Medical University-Wan Fang Hospital between January 2007 and December 2017. In total, 75 patients with CRA-LLM received MDT intervention, and 86 patients did not receive MDT intervention. To evaluate prognostic factors for overall death, we performed univariate and multivariate Cox regression analyses of the overall death rate in all patients. Overall survival rates were calculated using the Kaplan-Meier method, and Kaplan-Meier survival curves were compared using the log-rank test (P < .001). RESULTS: A multivariate Cox regression analysis of the overall death rate in patients with CRA-LLM showed that age ≤ 65 years, systemic chemotherapy, curative-intent treatments, and MDT intervention are strong prognostic factors. The adjusted hazard ratio of death risk for age ≤ 65 years, systemic chemotherapy, curative-intent treatments, and MDT intervention were 0.60 (95% confidence interval [CI], 0.40-0.92; P = .019), 0.19 (95% CI, 0.12-0.32; P = .001), 0.25 (95% CI, 0.13-0.50; P = .001), and 0.40 (95% CI, 0.25-0.65; P = .001), respectively. The 3-year overall survival rates in patients with CRA-LLM receiving MDT intervention and not receiving MDT intervention were 48.75% and 24.21%, respectively. CONCLUSION: MDT intervention is associated with improved survival for patients with CRA-LLM.

Tumor location is an independent predictive factor for distant metastasis and metastatic sites of rectal adenocarcinoma in patients receiving total mesorectal excision.

Background and Objectives: To evaluate the predictive factor for and patterns of distant metastasis in patients with rectal adenocarcinoma receiving total mesorectal excision (TME). Methods: We enrolled 217 consecutive patients who had histologically confirmed rectal adenocarcinoma and underwent surgery at Taipei Medical University- Wanfang Hospital between January 2000 and December 2014. TME was performed in all patients undergoing a sphincter-sparing procedure or abdominal perineal resection of rectal cancer. We performed univariate and multivariate Cox regression analyses of the distant metastasis rate in all patients to evaluate predictive factors. Overall survival (OS) rates were calculated using the Kaplan-Meier method, and Kaplan-Meier survival curves were compared using the log-rank test. Results: A multivariate Cox regression analysis of the distant metastasis rate in patients with rectal adenocarcinoma identified tumor locations and American Joint Committee on Cancer (AJCC) stages as prognostic risk factors. The adjusted hazard ratios (aHRs) of distant metastasis for the upper-third, middle-third, and AJCC stage I-II cancers were 0.08 (95% CI, 0.01-0.69; p = 0.021), 0.41 (95% CI, 0.15-0.99; p = 0.047), and 0.20 (95% CI, 0.10-0.66; p = 0.008), respectively. The 5-year lung metastasis rates among patients with upper-, middle-, and lower-third rectal cancers were 0%, 3.37%, and 13.33%, respectively (log-rank, p = 0.001), and the 5-year liver metastasis rates among patients with upper-, middle-, and lower-third rectal cancers were 2.12%, 9.10%, and 11.76%, respectively (log-rank, p = 0.096). The 5-year OS rates also differed with different rectal adenocarcinoma locations. The 5-year OS rates for upper, middle, and lower rectal cancers were 96%, 86%, and 64%, respectively (log-rank, p < 0.001). Conclusion: A poor OS rate and high lung or liver metastasis rate were observed in distal rectal adenocarcinoma. Longer intensive surveillance of the chest, abdomen, and pelvis after TME in distal rectal adenocarcinoma could be necessary.

Development of a Taiwan cancer-related fatigue cognition questionnaire: reliability and validity.

PURPOSE: We prospectively designed a Taiwan cancer-related fatigue cognition questionnaire, version 1.0 (TCRFCQ-V1.0), for Taiwanese patients with cancer and investigated the reliability and validity of this questionnaire. RESULTS: The completion rate of the TCRFCQ-V1.0 was high (97% of the patients completed all items), and the rate of missing data was low (0.2%-1.1% for each item). Moreover, the Cronbach alpha value was 0.889. We eliminated 5 items because their respective Cronbach alpha values were higher than the total mean value of Cronbach's alpha. Overall, the TCRFCQ-V1.0 had adequate Cronbach alpha coefficients (range, from 0.882 to 0.889). In addition, the results of Bartlett's test were significant (chi-squared, 2390.11; p < 0.001), indicating the appropriateness of factor analysis. Sampling adequacy was confirmed by the Kaiser-Meyer-Olkin statistic of 0.868. Through exploratory factor analysis, we identified 6 factors with eigenvalues of > 1, and the scree plot indicated no flattening factors. Overall, 28 items achieved a factor loading of ≥ 0.55. MATERIALS AND METHODS: We enrolled patients with cancer who were aged > 18 years, had received a pathological diagnosis of cancer, and had undergone cancer treatments such as surgery, chemotherapy, radiotherapy, or concurrent chemoradiotherapy at a single institute in Taiwan. Of the identified 167 eligible patients, 161 (96.4%) were approached. Of these patients, 6 (7.2%) declined to participate and 155 (92.8%) were interviewed. The initial 43 items in the TCRFCQ-V1.0 were assessed for ceiling and floor effects. CONCLUSIONS: The TCRFCQ-V1.0 is a reliable and valid instrument for measuring CRF cognition in Taiwanese patients with cancer.

A critical reappraisal for the value of tumor size as a prognostic variable in rectal adenocarcinoma.

Background and Objectives: To investigate critical prognostic factors for local recurrence in patients with rectal adenocarcinoma. Methods: We enrolled 221 consecutive patients who had histologically confirmed adenocarcinoma of the rectum and underwent surgery in our hospital between January 2000 and December 2014. Total mesorectal excision was performed in all patients undergoing a sphincter-sparing procedure or abdominal perineal resection of rectal cancer. To evaluate prognostic factors for local recurrence, we performed univariate and multivariate Cox regression analyses of the local recurrence rate in all patients. Overall survival rates were calculated using the Kaplan-Meier method, and Kaplan-Meier survival curves were compared using the log-rank test. Results: After the inclusion of only model variables of local recurrence with the highest or lowest univariate risk, a tumor size of <5 cm, a negative circumferential margin, well-to-moderately differentiated adenocarcinoma, low anterior resection, not receiving adjuvant RT, pathological T1-T3 stages, and upper- and middle-third rectal cancers were identified as strong prognostic factors with hazard ratios of 0.18, 0.20, 0.03, 0.01, 0.25, 0.18 and 0.18, respectively (95% confidence intervals [CIs], 0.06-0.58, 0.05-0.82, 0.03-0.38, 0.04-0.23, 0.05-0.64,0.09-0.70 and 0.06-0.54, respectively). After the multivariate Cox regression analysis of the local recurrence rate, a pathological tumor size of ≥5 cm was identified as the only prognostic risk factor (95% CI, 0.03-0.66; P = 0.013). The 5-year local recurrence rates among the patients having tumors measuring <5 cm and ≥5 cm in size were 1.40% and 23.00%, respectively (log-rank, P = 0.0001). The 5-year overall survival rates in the patients having tumors measuring <5 cm and ≥5 cm in size were 82.60% and 71.20%, respectively (log-rank, P = 0.001). Conclusion: A pathological tumor size of ≥5 cm is an independent prognostic factor for local recurrence in rectal adenocarcinoma.

Outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer with peritoneal metastasis.

In Taiwan, colorectal cancer with peritoneal carcinomatosis is considered a terminal condition. We examined the clinical outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) treatment for colorectal cancer with peritoneal carcinomatosis in Taiwan.We enrolled patients with colorectal cancer and peritoneal metastasis from Taipei Medical University, Wanfang Hospital between January 1999 and December 2014. Of the enrolled patients, 3 had mucinous-type tumors. In total, we enrolled 31 patients who underwent a total of 33 procedures. Of the 31 patients, 2 received the HIPEC procedure twice. Cytoreductive surgery was performed followed by HIPEC. The hazard ratios of death following cytoreductive surgery and HIPEC were calculated using the Cox proportional hazards model.The 2- and 5-year overall survival rates of these patients following cytoreductive surgery and HIPEC were 57% and 38%, respectively. The completeness of cytoreduction (CC) scores were CC-0, CC-1, CC-2, and CC-3 in 18 (54.5%), 3 (9%), 7 (21.2%), and 5 (15.2%) patients, respectively. The mean peritoneal cancer index (PCI) was 16.20, and the mean postoperative PCI (PPCI) was 4.6. The major risk factors for death in these patients were a total PCI score > 20, total PPCI score > 0, and CC score ≥ 2 (P = 0.022, 0.031, and 0.0001, respectively; log-rank test). Multivariate analysis revealed that the total PPCI score was the strongest predictor of death following cytoreductive surgery and HIPEC in these patients.In Taiwan, performing cytoreductive surgery and administering HIPEC for treating colorectal cancer with peritoneal metastasis are feasible and resulted in long-term survival. In addition, the total PPCI score was related to poor prognosis following cytoreductive surgery and HIPEC in patients with colorectal cancer and peritoneal metastasis.

The outcomes of therapeutic decision in lower 3rd rectal cancer patients.

To investigate the outcomes of the selective neoadjuvant concurrent chemoradiotherapy (CCRT) in lower 3rd rectal cancer patients in different groups (with or without neoadjuvant CCRT), especially in survival rate, local recurrence rate, and sphincter preservation rate.From January 1999 to December 2012, 69 consecutive patients who had histologically proven adenocarcinoma of lower 3rd rectum, defined preoperatively as lower tumor margin within 7 cm from the anal verge as measured by rigid sigmoidoscopy, received total mesorectum excision (TME). Our inclusion criteria of neoadjuvant CCRT are lower 3rd rectal cancer, stage II/III, and large (diameter >5 cm or >1/2 of circumference). Neoadjuvant concurrent CCRT had begun to apply lower 3rd rectal cancer patients or not. The radiation techniques of neoadjuvant CCRT for lower 3rd rectal cancer patients were all conventional fraction intensity modulated radiotherapy (IMRT) and concurrent fluoropyrimidine chemotherapy.Five-year overall survival rate, disease-free survival rate, and local recurrence rate for lower 3rd rectal cancer patients in group I were 51%, 45%, and 25%, respectively. On the contrary, 5-year overall survival rate, disease-free survival rate, and local recurrence rate for lower rectal cancer patients in group II were 70%, 70%, and 3%, respectively. The 5-year sphincter sparing rate was increased from 38.2% to 100% after the beginning of neoadjuvant CCRT. Analyzing local recurrence, overall survival rate, disease-specific survival rate, and sphincter sparing rate in group II were statistically significant superior to group I.Five-year overall survival rate, disease-free survival rate, and sphincter sparing rate for lower 3rd rectal cancer patients were improved after the addition of neoadjuvant CCRT. No unacceptable toxicity was noted after conventional fraction IMRT and concurrent fluoropyrimidine chemotherapy. Our study showed neoadjuvant CCRT could be valuable for lower 3rd rectal cancer patients.

Cyclooxygenase-2 expression in the endometrium at the end of 2 years' continuous combined hormone replacement therapy.

OBJECTIVE: To evaluate the change of endometrial histology and the expression of cyclooxygenase-2 (Cox-2) in the endometrium after continuous combined hormone replacement therapy (HRT). METHODS: Forty-five postmenopausal women were recruited. All participants received 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone (MPA) daily for 2 years. Endometrial biopsy was performed twice, before medication (baseline) and after 2 years of HRT, respectively. Immunohistochemistry was used to detect the presence of Cox-2 expression. RESULTS: More atrophic and weak secretory features of endometrium were noted after the 2-year HRT. Endometrial hyperplasia and carcinoma were not found and immunohistochemistry results revealed that Cox-2 was not expressed in the endometrium. CONCLUSION: Cox-2, known to play an important role in the tumorigenesis of cancer, was not stained in endometrium tissue after hormonal induction and more endometrium atrophy was noted after the 2-year HRT. From the results, it is noted that continuous combined HRT may be a relatively safe and appropriate regimen for long-term use in postmenopausal women.

Epidermal growth factor stimulates nuclear factor-κB activation and heme oxygenase-1 expression via c-Src, NADPH oxidase, PI3K, and Akt in human colon cancer cells.

Previous report showed that epidermal growth factor (EGF) promotes tumor progression. Several studies demonstrated that growth factors can induce heme oxygenase (HO)-1 expression, protect against cellular injury and cancer cell proliferation. In this study, we investigated the involvement of the c-Src, NADPH oxidase, reactive oxygen species (ROS), PI3K/Akt, and NF-κB signaling pathways in EGF-induced HO-1 expression in human HT-29 colon cancer cells. Treatment of HT-29 cells with EGF caused HO-1 to be expressed in concentration- and time-dependent manners. Treatment of HT-29 cells with AG1478 (an EGF receptor (EGFR) inhibitor), small interfering RNA of EGFR (EGFR siRNA), a dominant negative mutant of c-Src (c-Src DN), DPI (an NADPH oxidase inhibitor), glutathione (an ROS inhibitor), LY294002 (a PI3K inhibitor), and an Akt DN inhibited EGF-induced HO-1 expression. Stimulation of cells with EGF caused an increase in c-Src phosphorylation at Tyr406 in a time-dependent manner. Treatment of HT-29 cells with EGF induced an increase in p47(phox) translocation from the cytosol to membranes. The EGF-induced ROS production was inhibited by DPI. Stimulation of cells with EGF resulted in an increase in Akt phosphorylation at Ser473, which was inhibited by c-Src DN, DPI, and LY 294002. Moreover, treatment of HT-29 cells with a dominant negative mutant of IκB (IκBαM) inhibited EGF-induced HO-1 expression. Stimulation of cells with EGF induced p65 translocation from the cytosol to nuclei. Treatment of HT-29 cells with EGF induced an increase in κB-luciferase activity, which was inhibited by a c-Src DN, LY 294002, and an Akt DN. Furthermore, EGF-induced colon cancer cell proliferation was inhibited by Sn(IV)protoporphyrin-IX (snPP, an HO-1 inhibitor). Taken together, these results suggest that the c-Src, NADPH oxidase, PI3K, and Akt signaling pathways play important roles in EGF-induced NF-κB activation and HO-1 expression in HT-29 cells. Moreover, overexpression of HO-1 mediates EGF-induced colon cancer cell proliferation.

Neutrophil elastase as a diagnostic marker and therapeutic target in colorectal cancers.

Neutrophil elastase (NE), a serine protease secreted by neutrophils, contributes to the progression of cancers to enhance tumor invasion and metastasis. It has been well reported that the regions surrounding the colorectal cancerous tissues usually are decorated with increased accumulation or aggregation of neutrophils coupled with a higher deposition/expression of NE. Therefore, we hypothesized that an increased expressional level of NE in patients with colorectal cancer (CRC) may represent as one of putative biomarkers for CRC. The aim of this study was to evaluate and assure our hypothesis by measurements of the expressional level of NE in the sera and tissues from CRC patients. Moreover, we also proposed a potential therapeutic strategy by blocking enzymatic activity of NE using sivelestat to inhibit the progression of tumor developments. The infiltrated numbers of neutrophils from specimen tissues of CRC patients, and the secreted forms of NE in the sera were quantitatively measured and compared. To evaluate the serum NE as one of putative biomarkers of CRC patients, the receiver operating characteristic (ROC) curve was made to determine the cut-off value of NE in sera for assurance of CRC diagnosis. To evaluate NE as therapeutic target for CRC, sivelestat, a NE inhibitor, was used and administrated into the CRC xenografts. NE expression level coupled with tumor volume were measured and compared between the control and sivelestat-treated xenografts. We found that more infiltrated neutrophils and an increased NE expression were detected in the cancerous tissues compared to the normal tissues. The serum NE concentration in CRC patients was statistically higher than that in the healthy controls (0.56 ± 0.08 µg/ml vs. 0.22 ± 0.03 µg/ml) (p<0.05), indicating that serum NE can potentially be a putative marker of CRC. To characterize the role of NE in tumorigenesis, the NE activity was detected in HCT-15-xenografts using in vivo imaging system (IVIS). Compare to normal mice, the amounts of active NE in xenografts are significantly higher than normal control animals. In the therapeutic characterizing studies, we found that sivelestat can inhibit tumor growth in the HCT-15-induced xenografts. This study suggests that NE is not only as a putative diagnostic biomarker of CRC, but also a potential therapeutic target for patients suffered with CRC.

Waist to height ratio and elevated blood pressure among children in Taiwan.

OBJECTIVES: To study the association of waist to height ratio (WHtR) and elevated blood pressure (BP) in children. STUDY DESIGN: Cross-sectional study. SETTING: Six elementary schools in Taipei, Taiwan. PARTICIPANTS: All children aged 7 years at first grade. METHODS: We measured anthropometrics and BP during the regular health examinations among children. MAIN OUTCOME MEASURES: Elevated BP in children was defined as an average systolic BP or diastolic BP greater than or equal to the gender, age, and height-percentile-specific 95th percentile BP value. RESULTS: Among 2,334 eligible school children, the averages of systolic BP and diastolic BP increased with quartiles of WHtR. The prevalence of elevated BP in children among the first quartile of WHtR was 8.8% and increased to 31.2% among the fourth quartile of WHtR (P < 0.0001). Children among the first quartile of WHtR being reference, the adjusted odds ratio of elevated BP for children among the fourth quartile of WHtR was 3.10. The odds ratio of elevated BP with per 0.01 increase of WHtR was 1.11. CONCLUSIONS: WHtR, simple to measure, is an important factor associated with elevated BP in children.

Waist-to-Height Ratio and Elevated Blood Pressure Among Children in Taiwan.

Objectives: To study the association of waist-to-height ratio (WHtR) and elevated blood pressure (BP) in children. Study design: Cross-sectional study. Setting: Six elementary schools in Taipei, Taiwan. Participants: All children aged 7 years at first grade. Methods: We measured anthropometrics and BP during the regular health examinations among children. Main Outcome Measures: Elevated BP in children was defined as an average systolic BP or diastolic BP greater than or equal to the gender, age, and height-percentile-specific 95th percentile BP value. Results: Among 2,334 eligible school children, the averages of systolic BP and diastolic BP increased with quartiles of WHtR. The prevalence of elevated BP in children among the first quartile of WHtR was 8.8% and increased to 31.2% among the fourth quartile of WHtR (P < 0.0001). Children among the first quartile of WHtR being reference, the adjusted odds ratio of elevated BP for children among the fourth quartile of WHtR was 3.10. The odds ratio of elevated BP with per 0.01 increase of WHtR was 1.11. Conclusions: WHtR, simple to measure, is an important factor associated with elevated BP in children.