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Globally, there are over half a million new patients with head and neck squamous cell carcinomas (HNSCC) every year. The current therapeutic approaches to HNSCC are surgery and adjuvant radiotherapy. These approaches carry a high incidence of metastasis or recurrence from HNSCC cells' radioresistance. Recent studies have revealed that a combination with radiosensitizers can be used to improve the radioresistance in HNSCC; however, few agents are approved as radiosensitizers. The constitutive activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a vitally oncogenic type of signaling that promotes tumorigenesis, metastasis, and radiotherapy resistance in HNSCC. Pharmacological targeting of PI3K/AKT/mTOR signaling pathway is considered a promising strategy of radiosensitization in HNSCC. In this review, we summarize the oncogenic significance of PI3K/AKT/mTOR signaling in HNSCC with radiotherapy resistance and highlight the therapeutic potential of small molecule inhibitors against PI3K/AKT/mTOR signaling for the radiosensitization in HNSCC treatment. It provides a mechanistic framework for the development of new drugs for radiosensitization in HNSCC radiotherapy via targeting PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The incidence of follicular lymphoma (FL) in Taiwan has not been well investigated since its inclusion as a histological subtype in the Taiwan Cancer Registry in 2008. The purpose of this study was to describe the incidence patterns of FL in Taiwan and compare the trends with those in other racial groups in the United States. Materials and methods: We conducted an epidemiological study using population-based data from the Taiwan Cancer Registry, Ministry of Health and Welfare, and the 18 Surveillance, Epidemiology, and End Results (SEER) registries to evaluate the FL incidence from 2008 to 2017. We calculated the annual percent change (APC) to describe the trends in the incidence of FL in subpopulations defined by race and sex over time. Results: The annual age-adjusted incidence rate of FL in Taiwan increased significantly from 0.59 per 100,000 persons in 2008 to 0.82 per 100,000 persons in 2017, with an APC of 3.2. By contrast, the incidence rate in whites in the United States during the same period decreased from 3.42 to 2.74 per 100,000 persons, with an APC of −2.1. We found no significant change for the blacks (APC, −1.5%), Hispanics (APC, −0.7%), and Asians or Pacific Islanders (APC, +0.7%). The temporal trend was similar between the males and females. The relative frequency of FL among the incident non-Hodgkin lymphoma (NHL) cases also increased significantly in Taiwan from 7.64% in 2008 to 11.11% in 2017 (APC = 3.8). The relative frequency of FL among the incident NHL cases in the whites decreased from 2008 to 2012 (APC, −3.8%) and then stabilized after 2012 (APC, −0.2%). By contrast, little change in relative frequency of FL among the incident NHL cases was observed in the blacks, Hispanics, and APIs between 2008 and 2017. Conclusion: We found increases in the incidence of FL and the relative frequency of FL among the incident NHL cases in both males and females in Taiwan from 2008 to 2017. The FL incidence rates were unchanged for all races and sex groups in the United States, except for the decreases in the whites. [ABSTRACT FROM AUTHOR]

The curdlan gel is a natural material produced by bacteria. It utilizes chemical cross-linking reactions to form a 3D porous composite hydrogel, increasing its porosity and water content, and improving its mechanical properties. It can be used in tissue repair and regenerative medicine. Curdlan-Poly(vinyl alcohol) (PVA) composite hydrogel can rapidly swell within 1 min due to its porous structure. Compression tests confirmed that it still maintains its original mechanical strength, even after five repeated freeze-thaw (FT) processes, making it suitable for long-term cryopreservation. The purpose of this study is to transplant umbilical cord mesenchymal stem cells (UC-MSCs) on Curdlan-PVA composite hydrogel and observe the chondrocytes on the material. The results of using 4′,6-diamidino-2-phenylindole (DAPI), hematoxylin and eosin (H&E), calcein-acetoxymethyl ester (calcein AM), and Collagen type II–Fluorescein isothiocyanate (FITC) staining, confirmed that UC-MSCs can attach and differentiate into chondrocytes on 3D Curdlan-PVA composite hydrogel. [Display omitted] [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have been reported to directly alter the virus life cycle and virus–host interactions, and so are considered promising molecules for controlling virus infection. In the present study, we observed that miR‐155 time‐dependently downregulated upon dengue virus (DENV) infection. In contrast, exogenous overexpression of miR‐155 appeared to limit viral replication in vitro, suggesting that the low levels of miR‐155 would be beneficial for DENV replication. In vivo, overexpression of miR‐155 protected ICR suckling mice from the life‐threatening effects of DENV infection and reduced virus propagation. Further investigation revealed that the anti‐DENV activity of miR‐155 was due to target Bach1, resulting in the induction of the heme oxygenase‐1 (HO‐1)‐mediated inhibition of DENV NS2B/NS3 protease activity, ultimately leading to induction of antiviral interferon responses, including interferon‐induced protein kinase R (PKR), 2′‐5′‐oligoadenylate synthetase 1 (OAS1), OAS2, and OAS3 expression, against DENV replication. Collectively, our results provide a promising new strategy to manage DENV infection by modulation of miR‐155 expression. [ABSTRACT FROM AUTHOR]

Objectives: To assess the impact of age on the survival of patients with head and neck squamous cell carcinoma (HNSCC) using different statistical methods. Design: A retrospective population‐based study. Setting: Surveillance, Epidemiology, and End Results database. Subjects and methods: A total of 28 639 patients with newly diagnosed HNSCC were enrolled between 1 January 2007 and 31 December 2013. The effect of age on 5‐year disease‐specific survival was calculated using a Kaplan‐Meier method and compared using log‐rank tests. A Cox proportional hazards model was used for a multivariate analysis. A classification and regression tree (CART) analysis that partitioned patients with significantly different Kaplan‐Meier curves was introduced to identify the important cancer‐related parameters influencing survival. Results: Uni‐ and multivariate analyses indicated that patients who were older than 60 years had poorer 5‐year disease‐specific survival regardless of tumour subsite and tumor‐node‐metastasis (TNM) stage. However, the CART analysis determined that age played only a minor role in survival after comparing with other prognosticators. The relative importance of age using the Gini index was as follows: 3.21% for oral cancer, 8.32% for oropharyngeal cancer, 2.56% for hypopharyngeal cancer and 16.51% for laryngeal cancer. Conclusions: Different to traditional statistical methods, the CART analysis which was used to identify homogeneous populations revealed that the impact of age varied for different patient groups according to the presence or absence of other prognosticators. This important information could help to guide our clinical decisions and future researches. [ABSTRACT FROM AUTHOR]

Prunella vulgaris (PV) is a traditional Chinese medicine that has been used clinically for centuries in Asian countries to treat herpetic keratitis. In previous studies, PV was shown to suppress TPA-induced activation of MMP-9 and inhibit cell invasion and migration in hepatoma cell lines. However, the detailed molecular mechanism underlying these effects is still unclear. In this study, we investigated the mechanisms underlying PV-mediated inhibition of 12- O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (Huh-7 and HA22T). PV suppressed VEGF and MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-B (NF-B) activity. PV suppressed TPA-induced AP-1 activity by inhibiting phosphorylation of the extracellular signal-related kinase (ERK), downregulating p38 signaling pathways, and suppressing TPA-induced inhibition of NF-B nuclear translocation through IB. PV suppressed TPA-induced activation of ERK/phosphatidylinositol-3-kinase/Akt upstream of NF-B and AP-1. These data suggest that PV modifies the metastatic microenvironment of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways. PV thus may have the therapeutic potential to inhibit the migration and invasion of HCC and act as potential agent for systemic therapies. [ABSTRACT FROM AUTHOR]

The association of chronic hepatitis B virus (HBV) infection with end-stage renal disease (ESRD) is unclear. To help clarify this we conducted a nationwide cohort study to measure the association by analyzing the claims data from the Taiwan National Health Insurance Research Database with ICD-9 codes used to identify diseases. We identified 17,758 adults who had chronic HBV infection and had not taken nucleos(t)ide analogs from 1999 to 2010 and randomly selected 71,032 matched controls without HBV in the same data set. The risk of ESRD was compared between these two cohorts. Cumulative incidences and hazard ratios were calculated after adjusting for competing mortality. The risk of ESRD was significantly higher in the HBV cohort (12-year cumulative incidence, 1.9%) than in the non-HBV cohort (0.49%) with a significant adjusted hazard ratio of 3.85. Multivariable stratified analysis further verified significant associations of ESRD with HBV in men of any age and women under the age of 60 years, but no significant association in women aged ⩾60 years. Thus, a large national cohort study indicates that untreated chronic HBV infection is associated with increased risk of ESRD. Hence, high-risk HBV-infected patients should have targeted monitoring for the development of ESRD. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Bcr-Abl fusion protein activates tyrosine kinase, resulting in the proliferation of leukemia cells, especially chronic myeloid leukemia (CML) cells. Imatinib (IM) effectively targets Bcr-Abl tyrosine kinase, but development of resistance to IM occurs with varying frequency. Methods: Elucidation of the common regulatory pathway upstream of Bcr-Abl in IM-sensitive and IM-resistant CML cells is important for developing novel therapeutics against CML. Results: This study demonstrated that IM preferentially inhibited the viability and Bcr-Abl expression in IM-sensitive K562 (K562) cells, but not in Bcr-Abl overexpressing IM-resistant K562 (K562R) cells. Both K562 and K562R cells expressed Shh preproprotein, cleaved Shh C-terminal and N-terminal peptides, as well as mRNA level of major Shh signaling molecules, including sonic hedgehog (Shh), patched (PTCH), smoothened (Smo) and Gli-1. Moreover, Gli-1 translocation into nucleus was evident in these two cell lines, suggesting that both K562 and K562R cells possess activated and major components of the Shh signaling pathway. Silencing of Gli-1 by interference RNA was accompanied by inhibition of Bcr-Abl protein expression. Pharmacological suppression of Bcr-Abl expression was restored by the Smo agonist purmorpharmine. Treatment of Shh peptide in both K562 and K562R cells not only increased Shh and Gli-1 expression, but also up-regulated Bcr-Abl expression. Resveratrol, a known Bcr-Abl inhibitor, reduced Gli-1 activation and inhibited the viability of CML cells. Conclusions: Shh signaling may regulate Bcr-Abl expression in human chronic myeloid leukemia cells. Novel compounds inhibiting both Shh signaling and Bcr-Abl expression, such as resveratrol, may have potential to be effective agents against CML independent of IM resistance. [Copyright &y& Elsevier]

Abstract: This paper describes the synthesis and characterization of difunctional epoxyacrylate oligomers from the reaction of diglycidyl ether of bisphenol-A (DGEBA) and acrylic acid (AA) in the presence of triphenyl phosphine as catalyst. The reaction was investigated in situ by using Fourier transform-infrared spectroscopy in the temperature range of 60–120°C, and demonstrated to be an addition esterification between the epoxide group and the carboxyl group. The specific rate constants calculated from the second-order kinetics obeyed Arrhenius law very well, and from which the activation energy was found to be 63.9kJmol−1. Moreover, various batches of respective epoxyacrylates, EA25 to EA100, were prepared by changing the equivalent ratio of carboxyl/epoxide from 0.25 to 1.0 in the feed under a temperature profile of 100°C for 2h and another 2h at 120°C. The epoxide conversions, acid values and epoxide equivalent weights of the produced EA25 to EA100 were all measured. The analysis by gel permeation chromatography revealed that the EA25 to EA75 consisted of unreacted DGEBA, monoacrylate-terminated epoxyacrylate and bisacrylate-terminated epoxyacrylate; while the EA100 was composed of only latter two. Increasing the initial carboxyl/epoxide equivalent ratio increased the epoxide conversion and the amount of bisacrylate-terminated epoxyacrylate. Yet, with an initial carboxyl/epoxide equivalent ratio of 0.5, the EA50 produced the maximum proportion (∼72%) of monoacrylate-terminated epoxyacrylate, which had one terminal double bond for UV-cure and one epoxide end group for thermo-cure. This dual-curable epoxyacrylate thus can be used as an adhesive sealant for LCD production. [Copyright &y& Elsevier]

Abstract: Background: The discovery of molecular biomarkers is crucial to the diagnosis of head and neck squamous cell cancer (HNSCC). Methods: Proteins from pre-surgery serum samples of patients with HNSCC and healthy individuals were analyzed by 2-dimensional gel electrophoresis (2-DE) using a 17 cm-long immobilized pH gradient gel strip (large gel). The differentially expressed protein spots were detected by statistical analysis. Because 2 haptoglobin (Hp) α chains were found to be differentially expressed, the genotypic distribution of Hp α chains in patients and healthy individuals was assayed by polymerase chain reaction. The protein expression levels of Hp α chains in individuals carrying different Hp alleles were analyzed by 2-DE with a small gel. Results: Two isoforms of haptoglobin α2 chain (Hp α2) in patients'' sera were found from 2-DE analysis to be up-regulated, while the isoforms of haptoglobin α1 chain (Hp α1) were significantly down-regulated. Apolipoprotein AII and 2 isoforms of apolipoprotein CII were also differentially expressed in the sera of patients with HNSCC. The Hp α2 chain was significantly up-regulated in the patients carrying at least one haptoglobin 2 allele, according to the spot intensities from scanned images of small-gel 2-DE. Conclusions: The expression pattern of seven differentially expressed polypeptides and the up-regulation of Hp α2 in individuals with the Hp 2 allele are potential biomarkers. [Copyright &y& Elsevier]

Conclusion. A weekly regimen of cisplatin 30 mg/m2 as concurrent chemoradiation (CCRT) was effective in elderly nasopharyngeal carcinoma (NPC) patients, with acceptable and reversible acute toxicity following CCRT therapy. Objectives. The purpose of this retrospective study was to evaluate the efficacy, toxicity, and tolerability of a multi-modal treatment strategy in elderly NPC patients. Subsequent systemic adjuvant chemotherapy was administered to achieve systemic control. Patients and methods. From December 2002 to December 2006, 26 NPC patients over 60 years of age who had stage IIB to IV NPC were evaluated in this retrospective analysis. The CCRT chemotherapy protocol consisted of eight weekly doses of cisplatin 30 mg/m2 administered in an outpatient setting. Adjuvant systemic chemotherapy consisted of four monthly cycles of cisplatin (20 mg/m2/day) plus 5-fluorouracil (1000 mg/m2/day) for 5 consecutive days. Study end points included treatment outcome, compliance, and toxicity. Results. The 2-year overall survival, disease-free survival, local control, and distant metastasis-free rate were 87%, 73%, 92%, and 76%, respectively. Over 80% of patients were able to take more than six doses of weekly cisplatin during CCRT; however, nearly half of the patients had grade 3 hematological toxicity during adjuvant therapy requiring treatment modification or cessation of further adjuvant therapy. [ABSTRACT FROM AUTHOR]

Surgery for acute mesenteric infarction (AMI) is associated with high mortality. This study aimed to generate a mortality prediction model to predict the 30-day mortality of surgery for AMI. We included patients ≥18 years who received bowel resection in treating AMI and randomly divided into the derivation and validation groups. After multivariable analysis, the 'Surgery for acute mesenteric infarction mortality score' (SAMIMS) system was generated and was including age >62-year-old (3 points), hemodialysis (2 points), congestive heart failure (1 point), peptic ulcer disease (1 point), diabetes (1 point), cerebrovascular disease (1 point), and severe liver disease (4 points). The 30-day-mortality rates in the derivation group were 4.4%, 13.4%, 24.5%, and 32.5% among very low (0 point), low (1–3 point(s)), intermediate (4–6 points), and high (7–13 points)-risk patients. Compared to the very-low-risk group, the low-risk (OR = 3.332), intermediate-risk (OR = 7.004), and high-risk groups (OR = 10.410, p < 0.001) exhibited higher odds of 30-day mortality. We identified similar results in the validation group. The areas under the ROC curve were 0.677 and 0.696 in the derivation and validation groups. Our prediction model, SAMIMS, allowed for the stratification of the patients' 30-day-mortality risk of surgery for acute mesenteric infarction. [ABSTRACT FROM AUTHOR]

Simple Summary: The demand for multitarget-directed anticancer agents has been steadily increasing, as cancer remains a leading cause of death worldwide. Dyrk and Clk kinases play crucial roles in cancer cell division and survival. Our study presents novel Dyrk1/Dyrk1B/Clk1 inhibitors, developed by modifying our previous class of Clk1 inhibitors. These potent new inhibitors successfully halted the division of cancer cells without impacting normal cells. Additionally, we examined the effect of these compounds on the cell cycle to identify the specific phase affected. Finally, our compounds demonstrated the ability to activate pathways that induce cell death in cancer cells. Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds 12 and 17 emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds 12 and 17 displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound 17 retained cells in the G2/M phase and induced apoptosis. Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics. [ABSTRACT FROM AUTHOR]

Background: Liver metastases from breast cancer are associated with poor prognosis, and treatment options are usually restricted to palliative systemic therapy. The impact of liver resection on metastasis remains controversial. The aim of this study is to investigate whether liver resection can offer better survival outcomes in cases of isolated liver metastases from breast cancer. Methods: We conducted a nationwide cohort study using a claims dataset from Taiwan's National Health Insurance Research Database (NHIRD). We identified all patients with breast cancer (diagnostic code ICD-9: 174.x) from the Registry for Catastrophic Illness Patient Database (RCIPD) of the NHIRD who underwent mastectomy between January 1, 2000, and December 31, 2008. Patients with other malignancies (history, initially, or during follow-up), those with a history of metastasis prior to or at initial admission for mastectomy, and those without liver metastases were excluded. Patients with other metastases between mastectomy and liver metastasis and those who died at first admission for liver resection were also excluded. All patients were followed up until December 31, 2013, or withdraw from the database because of death. Results: Data were analyzed for 1,116 patients who fulfilled the inclusion criteria (resection group: 89; non-resection group: 1,027). There were no differences in age, Charlson Comorbidity Index, or major coexisting diseases except renal disease between two groups. Kaplan–Meier analysis demonstrated that the liver resection group had significantly better overall survival (OS) than the non-resection group. (1-year: 96.6% vs. 52.3%, 2-year: 86.8% vs. 35.4%, 3-year: 72.3% vs. 25.2%, 5-year: 51.6% vs. 16.9%, respectively, p<0.001). Cox analysis revealed that the liver resection group exhibited a significant improvement in patient survival (hazard ratio [HR] = 0.321, 95% confidence interval [CI]: 0.234–0.440, p<0.001). Conclusion: These findings indicate that liver resection may offer better survival benefit in patients with breast cancer who develop new liver metastases post mastectomy. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. Method: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. Result: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. Conclusions: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer. [ABSTRACT FROM AUTHOR]

Objective: Haptoglobin (Hp) is an acute-phase protein secreted by the liver; its concentration increases rapidly during infection, inflammation, and tumor formation. It has been reported that the level of Hp α alleles is altered in the serum of patients with head and neck squamous cell carcinoma (HNSCC), and the cellular level of Hp is strongly associated with the recurrence rate of HNSCC in patients. In the present study, the regulated mechanism of Hp expression was explored.Materials and Methods: We first identified the genetic polymorphism of Hp by PCR. The expression of Hp isoforms was determined through Western Blotting analysis. With the JAK specific inhibitors, the clear regulation mechanism was explored.Results: We observed that Hp exhibited variant polymorphisms in different cells. We found that interleukin-6 (IL-6) induced the expressions of Hp α2 in FaDu cells, and Hp α1 in SCC4 cells. Furthermore, the phosphorylated level of STAT3 was elevated with IL-6 treatment. Janus-associated kinase 2 (JAK-2) inhibitor, WP1066, reduced the phosphorylation of STAT3 after IL-6 induction, leading to the downregulation of Hp expression.Conclusions: The expression of Hp was increased via IL-6 induction through the activation of the transcription factor STAT3 in HNSCC cells. [ABSTRACT FROM AUTHOR]

A continuous increase in follicular lymphoma has been observed in Taiwan, Japan, and South Korea over the last few decades. This study aimed to evaluate the difference in incidence trends of follicular lymphoma in Taiwan, Japan, and South Korea between 2001 and 2019. The data for the Taiwanese populations was obtained from the Taiwan Cancer Registry Database, and those for the Japanese and Korean population were retrieved from the Japan National Cancer Registry and some additional reports, both of which included population-based cancer registry data, from Japan and Korea. Follicular lymphoma accounted for 4231 cases from 2002–2019 in Taiwan, 3744 cases from 2001–2008 and 49,731 cases from 2014–2019 in Japan; and 1365 cases from 2001–2012 and 1244 cases from 2011–2016 in South Korea. The annual percentage change for each time period was 3.49% (95% confidence interval: 2.75–4.24%) in Taiwan, 12.66% (95% confidence interval [CI]: 9.59–15.81%) and 4.95% (95% CI: 2.14–7.84%) in Japan, and 5.72% (95% CI: 2.79–8.73%) and 7.93% (95% CI: −1.63–18.42%) in South Korea. Our study confirms that the increasing trends of follicular lymphoma incidence in Taiwan and Japan have been remarkable in recent years, especially the rapid increase in Japan between 2014 and 2019; however, there was no significant in-crease from 2011 to 2015 in South Korea. [ABSTRACT FROM AUTHOR]

Purpose: Radiation/chemoradiotherapy-induced carotid stenosis and cerebrovascular events in patients with nasopharyngeal carcinoma (NPC) can cause severe disability and even death. This study aimed to estimate the risk of ischemic stroke in this patient population over more than 10 years of follow-up. Methods and Materials: The study cohorts consisted of all patients hospitalized with a principal diagnosis of NPC (n = 1094), whereas patients hospitalized for an appendectomy during 1997 and 1998 (n = 4376) acted as the control group and surrogate for the general population. Cox proportional hazard model was performed as a means of comparing the stroke-free survival rate between the two cohorts after adjusting for possible confounding and risk factors. Results: Of the 292 patients with ischemic strokes, 62 (5.7%) were from the NPC cohort and 230 (5.3%) were from the control group. NPC patients ages 35–54 had a 1.66 times (95% CI, 1.16–2.86; p = 0.009) higher risk of ischemic stroke after adjusting for patient characteristics, comorbidities, geographic region, urbanization level of residence, and socioeconomic status. There was no statistical difference in ischemic stroke risk between the NPC patients and appendectomy patients ages 55–64 years (hazard ratio = 0.87; 95% CI, 0.56–1.33; p = 0.524) after adjusting for other factors. Conclusions: Young NPC patients carry a higher risk for ischemic stroke than the general population. Besides regular examinations of carotid duplex, different irradiation strategies or using new technique of radiotherapy, such as intensity modulated radiation therapy or volumetric modulated arc therapy, should be considered in young NPC patients. [Copyright &y& Elsevier]

Accumulating evidence has shown the adverse effect of long-term hyperaldosteronism on cardiovascular morbidity that is independent of blood pressure. However, the diagnosis of primary aldosteronism (PA) remains a challenge for patients who present with subtle or atypical features or have chronic kidney disease (CKD). SPECT/CT has proven valuable in the diagnosis of a number of conditions. The aim of this study was to determine the usefulness of I-131 NP-59 SPECT/CT in patients with atypical presentations of PA and in those with CKD. The records of 15 patients with PA were retrospectively analyzed. NP-59 SPECT/CT was able to identify adrenal lesion(s) in CKD patients with suspected PA. Patients using NP-59 SPECT/CT imaging, compared with those not performing this procedure, significantly featured nearly normal serum potassium levels, normal aldosterone-renin ratio, and smaller adrenal size on CT and pathological examination and tended to feature stage 1 hypertension and non-suppressed plasma renin activity. These findings show that noninvasive NP-59 SPECT/CT is a useful tool for diagnosis in patients with subclinical or atypical features of PA and those with CKD. [ABSTRACT FROM AUTHOR]

Objective: Several comorbid measures have been developed and demonstrated the predictive ability for cancer mortality. We conducted a retrospective study on oral squamous cell carcinoma (OSCC) patients to compare the Charlson comorbidity index score (CCIS) to the Elixhauser comorbidity index score (ECIS).Methods: Newly diagnosed OSCC patients (n=232) post major surgery with or without adjuvant therapy were identified from the cancer registry database between 2006 and 2011. Comorbidities present prior to the cancer diagnosis were obtained and adapted to the CCIS and ECIS. The prevalence of comorbid conditions and the influence on disease-specific survival (DSS) rate were calculated and analyzed by Cox regression model. The discriminatory ability of these two comorbid measures was evaluated by using the adjusted hazard ratio and Akaike information criterion (AIC) in a multivariate regression model. The prediction accuracy was assessed using Harrell's c-statistic.Results: Most of the patients (93.5%) were male with a mean age of 54 ± 11 years and 77 of them (33.1%) had at least one comorbid condition. The ECIS was associated DSS, with an additional 10% increased risk observed for mortality for each increased score (HR, 1.10; 95% confidence interval [CI], 1.03-1.18) after adjusting with pathological risk features. However, the CCIS was not an independent prognostic factor for these patients. The ECIS increased discriminatory ability but the CCIS did not improve discrimination.Conclusions: Comorbid conditions significantly influenced the clinical outcomes of patient with OSCC post major surgery. A higher ECIS was associated with worse disease specific survival indicative of a valuable prognostic indicator. The ECIS may be considered in further clinical trials for a variety of cancers, including head and neck cancers. [ABSTRACT FROM AUTHOR]

In clinical practice, the Ishak Score system would be adopted to perform the evaluation of the grading and staging of hepatitis according to whether portal areas have fibrous expansion, bridging with other portal areas, or bridging with central veins. Based on these staging criteria, it is necessary to identify portal areas and central veins when performing the Ishak Score staging. The bile ducts have variant types and are very difficult to be detected under a single magnification, hence pathologists must observe bile ducts at different magnifications to obtain sufficient information. This pathologic examinations in routine clinical practice, however, would result in the labor intensive and expensive examination process. Therefore, the automatic quantitative analysis for pathologic examinations has had an increased demand and attracted significant attention recently. A multi-scale inputs of attention convolutional network is proposed in this study to simulate pathologists' examination procedure for observing bile ducts under different magnifications in liver biopsy. The proposed multi-scale attention network integrates cell-level information and adjacent structural feature information for bile duct segmentation. In addition, the attention mechanism of proposed model enables the network to focus the segmentation task on the input of high magnification, reducing the influence from low magnification input, but still helps to provide wider field of surrounding information. In comparison with existing models, including FCN, U-Net, SegNet, DeepLabv3 and DeepLabv3-plus, the experimental results demonstrated that the proposed model improved the segmentation performance on Masson bile duct segmentation task with 72.5% IOU and 84.1% F1-score. [ABSTRACT FROM AUTHOR]

Background: Many studies have reported excess cancer mortality in patients with mental illness. However, scant studies evaluated the differences in cancer treatment and its impact on survival rates among mentally ill patients. Oral cancer is one of the ten most common cancers in the world. We investigated differences in treatment type and survival rates between oral cancer patients with mental illness and without mental illness. Methods: Using the National Health Insurance (NHI) database, we compared the type of treatment and survival rates in 16687 oral cancer patients from 2002 to 2006. The utilization rate of surgery for oral cancer was compared between patients with mental illness and without mental illness using logistic regression. The Cox proportional hazards model was used for survival analysis. Results: Oral cancer patients with mental disorder conferred a grave prognosis, compared with patients without mental illness (hazard ratios [HR] = 1.58; 95% confidence interval [CI] = 1.30–1.93; P<0.001). After adjusting for patients’ characteristics and hospital characteristics, patients with mental illness were less likely to receive surgery with or without adjuvant therapy (odds ratio [OR] = 0.47; 95% CI = 0.34–0.65; P<0.001). In multivariate analysis, oral cancer patients with mental illness carried a 1.58-times risk of death (95% CI = 1.30–1.93; P<0.001). Conclusions: Oral cancer patients with mental illness were less likely to undergo surgery with or without adjuvant therapy than those without mental illness. Patients with mental illness have a poor prognosis compared to those without mental illness. To reduce disparities in physical health, public health strategies and welfare policies must continue to focus on this vulnerable group. [ABSTRACT FROM AUTHOR]

Coxsackievirus B3 (CVB3), one serotype of enteroviruses, can induce fatal myocarditis and hepatitis in neonates, but both treatment and vaccine are unavailable. Few reports tested antivirals to reduce CVB3. Several antivirals were developed against other enterovirus serotypes, but these antivirals failed in clinical trials due to side effects and drug resistance. Repurposing of clinical drugs targeting cellular factors, which enhance viral replication, may be another option. Parasite and cancer studies showed that the cellular protein kinase B (Akt) decreases interferon (IFN), apoptosis, and interleukin (IL)-6-induced STAT3 responses, which suppress CVB3 replication. Furthermore, miltefosine, the Akt inhibitor used in the clinic for parasite infections, enhances IL-6, IFN, and apoptosis responses in treated patients, suggesting that miltefosine could be the potential antiviral for CVB3. This study was therefore designated to test the antiviral effects of miltefosine against CVB3 in vitro and especially, in mice, as few studies test miltefosine in vitro , but not in vivo. In vitro results showed that miltefosine inhibited viral replication with enhanced activation of the cellular transcription factor, STAT3, which is reported to reduce CVB3 both in vitro and in mice. Notably, STAT3 knockdown abolished the anti-CVB3 activity of miltefosine in vitro. Mouse studies demonstrated that miltefosine pretreatment reduced CVB3 lethality of mice with decreased virus loads, organ damage, and apoptosis, but enhanced STAT3 activation. Miltefosine could be prophylaxis for CVB3 by targeting Akt to enhance STAT3 activation in the mechanism, which is independent of IFN responses and hardly reported in pathogen infections. • The cellular protein kinase B (Akt) can decreases IL-6-induced STAT3, IFN, and apoptosis, to suppress CVB3. • Miltefosine, the Akt inhibitor used in the clinic for parasite infections, enhances IL-6, IFN, and apoptosis in patients. • The antiviral activity of miltefosine has not been tested in animals. • Miltefosine reduces CVB3 lethality of mice with enhanced STAT3 activation. [ABSTRACT FROM AUTHOR]

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case–control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORshighest vs. lowest tertile > 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin. [ABSTRACT FROM AUTHOR]

Background: Oral cancer requires considerable utilization of healthcare services. Wide resection of the tumor and reconstruction with free flap are widely used. Due to high recurrence rate, close follow-up is mandatory. This study was conducted to explore the relationship between the healthcare expenditure of oncological surgery and one-year follow up and provider volume. Methods: From the National Health Insurance Research Database published by the Taiwanese National Health Research Institute, the authors selected a total of 1300 oral cancer patients who underwent tumor resection and free flap reconstruction in 2008. Hierarchical linear regression analysis was subsequently performed to explore the relationship between provider volume and expenditures of oncological surgery and one-year follow-up period. Emergency department (ED) visits and 30-day readmission rates were also analyzed. Results: The mean expenditure for oncological surgery was $11080±4645 (all costs are given in U.S. dollars) and $10129±9248 for one-year follow up. For oncological surgery expenditure, oral cancer patients treated by low-volume surgeons had an additional $845 than those in high-volume surgeons in mixed model. For one-year follow-up expenditure, patients in low-volume hospitals had an additional $3439 than those in high-volume hospitals; patient in low-volume surgeons and medium-volume surgeons incurred an additional expenditure of $2065 and $1811 than those in high-volume surgeons. Oral cancer patients treated in low-volume hospitals incurred higher risk of 30-day readmission rate (odds ratio, 6.6; 95% confidence interval, 1.6–27). Conclusions: After adjusting for physician, hospital, and patient characteristics, low-volume provider performing wide excision with reconstructive surgery in oral cancer patients incurred significantly higher expenditure for oncological surgery and one-year healthcare per patient than did others with higher volumes. Treatment strategies adapted by high-volume providers should be further analyzed. [ABSTRACT FROM AUTHOR]

The giant cell tumor is considered to be a locally aggressive benign tumor and has a low tendency toward distant metastasis. They are primarily present in the long bone and are rare in the skull. The osteoclast-like giant cells do not demonstrate mitotic activity and contain large numbers of nuclei. Herein, we described a case of giant cell tumor in the temporal lobe. Heterogenous enhancement is shown on CT imaging in solid areas of tumor. The appearance intermediate to high signal intensity on T1-weighted and very low signal intensity on T2-weighted MR imaging were due to the presence of hemosiderin from prior hemorrhage. [Copyright &y& Elsevier]

Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are reported annually. Radiation therapy is an important treatment for oral squamous cell carcinoma (OSCC). The survival rate of patients with HNSCC remained low (50%) in decades because of radiation therapy failure caused by the radioresistance of HNSCC cells. This study aimed to identify PI3K inhibitors that can enhance radiosensitivity. Results showed that pan-Phosphoinositide 3-kinases (PI3K) inhibitor BKM120 and class I α-specific PI3K inhibitor BYL719 dose-dependently reduced the growth of OSCC cells but not that of radioresistant OML1-R cells. The combination treatment of BKM120 or BYL719 with radiation showed an enhanced inhibitory effect on OSCC cells and radioresistant OML1-R cells. Furthermore, the enhanced inhibitory effect of the combination treatment was confirmed in patient-derived OSCC cells. The triple combination treatment of mTOR inhibitor AZD2014 and BKM120 or AZD2014 and BYL719 with radiation showed a significantly enhanced inhibitory effect on radioresistant OML1-R cells. These results suggest that the PI3K inhibitors are potential therapeutic agents with radiosensitivity for patients with OSCC. [ABSTRACT FROM AUTHOR]

There is high risk of metastasis and recurrence in head and neck squamous cell carcinoma (HNSCC) patients, especially for patient who received definitive surgery and adjuvant radiotherapy. Aberrant activation of PI3K/AKT/mTOR signaling occurs in approximately 80% of HNSCC, which has been indicated to serve as prognostic biomarkers for patients suffer from recurrence or metastasis. Therefore, in this study, we focus on the relationship between the expression level of signaling factors in PI3K/AKT/mTOR pathway and recurrence tumor from HNSCC patients. A tissue microarray (TMA) was constructed from 54 cases of HNSCC patients who received definitive surgery and adjuvant radiotherapy, are followed more than 5 years, and with no previous malignancy and synchronous tumor. Slides were scored and dichotomized by two pathologists and scores. Based on the TMA block with IHC staining, the results showed that PI3K/AKT/mTOR signaling was highly activated both in recurrence and non-recurrence patients. Particularly, in the recurrence population, the results showed the low expression phospho-eukaryotic initiation factor 4E (p-eIF4E) or high expression eIF4E, phospho-eIF4E binding protein 1 (p-4EBP1), phospho-ribosomal protein S6 kinase beta-1 (p-S6K1) and phospho-40S ribosomal protein S6 (p-S6R) exhibited worse overall survival. The expression level of eIF4E and p-4EBP1 were significantly associated with tumor recurrence and recurrence-free survival. Furthermore, high expression level of eIF4E and p-4EBP1 had worse recurrence-free survival. In conclusion, the expression of eIF4E and p-4EBP1 should be considered as predictive biomarkers for the HNSCC patients. This may contribute to potential predictive biomarkers for HNSCC patient who receive adjuvant radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Activation of Ras oncogene in human tumors is associated with radiation-associated metastatic potential. Although ionizing radiation is one important method of cancer treatments, it has been shown to enhance matrix metalloproteinases (MMPs) activity and facilitates a more aggressive cancer phenotype. Our previous studies showed that andrographolide with lower dose rates of radiation could inhibit RAS-transformed cancer metastasis in vivo; however, the molecular mechanisms are not yet clear. In this study, we aimed to explore the anti-metastatic effect of andrographolide combined with radiation on Ras-transformed cells. Methods: RAS-transformed cells were treated with andrographolide in the presence or absence of irradiation (2–4 Gy) or angiotensin II to examine cell invasion. In vivo tumorigenesis assays were also performed. The MMP-2 activity was detected by using Gelatin zymography. Signal transduction of NF-κB subunit, p65 and phosphor-ERK 1/2, were examined by using Western blotting analysis. Results: Treatment with andrographolide inhibited migration of Ras-transformed cells. Andrographolide treatment with radiation significantly inhibited cancer metastasis in vivo. We found that andrographolide exhibited anti-migration and anti-invasive ability against cancer metastasis via inhibition of MMP2 activity rather than affected MMP-9 and EMT. In addition, combined andrographolide with radiation appeared to be more effective in reducing MMP-2 expression, and this effect was accompanied by suppression of ERK activation that inhibits cancer cell migration and invasion. Conclusions: These findings suggest that andrographolide enhances the anti-metastatic effect of radiation in Ras-transformed cells via suppression of ERK–mediated MMP-2 activity. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is one of the most common malignant neoplasms in Taiwan. Activation of the mTOR signaling pathway has been linked to decreased radiation responsiveness in human oral cancer, thus it limits efficacy of radiotherapy. To address this question, we investigated the effect of AZD2014, a novel small molecular ATP-competitive inhibitor of mTORC1 and mTORC2 kinase, as a radiosensitizer in primary OSCC and OSCC-derived cell line models. Methods: We isolated primary tumor cells from OSCC tissues and cell lines. AZD2014 was administered with and without ionizing radiation. The radiosensitizing effect of AZD2014 were then assessed using cell viability assays, clonogenic survival assays, and cell cycle analyses. Western blotting was used to detect protein expression. Results: Combination treatment with AZD2014 and irradiation resulted in significant reduction in OSCC cell line and primary OSCC cell colony formation due to the enhanced inhibition of AKT and both mTORC1 and mTORC2 activity. Pre-treatment with AZD2014 in irradiated oral cancer cells induced tumor cell cycle arrest at the G1 and G2/M phases, which led to disruption of cyclin D1-CDK4 and cyclin B1-CDC2 complexes. Moreover, AZD2014 synergized with radiation to promote both apoptosis and autophagy by increasing caspase-3 and LC3 in primary OSCC cells. Conclusions: These findings suggest that in irradiated OSCC cells, co-treatment with AZD2014, which targets mTORC1 and mTORC2 blockade, is an effective radiosensitizing strategy for oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Background: Identification of patients at risk of death from cancer surgery should aid in preoperative preparation. The purpose of this study is to assess and adjust the age-adjusted Charlson comorbidity index (ACCI) to identify cancer patients with increased risk of perioperative mortality. Methods: We identified 156,151 patients undergoing surgery for one of the ten common cancers between 2007 and 2011 in the Taiwan National Health Insurance Research Database. Half of the patients were randomly selected, and a multivariate logistic regression analysis was used to develop an adjusted-ACCI score for estimating the risk of 90-day mortality by variables from the original ACCI. The score was validated. The association between the score and perioperative mortality was analyzed. Results: The adjusted-ACCI score yield a better discrimination on mortality after cancer surgery than the original ACCI score, with c-statics of 0.75 versus 0.71. Over 80 years of age, 70–80 years, and renal disease had the strongest impact on mortality, hazard ratios 8.40, 3.63, and 3.09 (P < 0.001), respectively. The overall 90-day mortality rates in the entire cohort varied from 0.9%, 2.9%, 7.0%, and 13.2% in four risk groups stratifying by the adjusted-ACCI score; the adjusted hazard ratio for score 4–7, 8–11, and ≥ 12 was 2.84, 6.07, and 11.17 (P < 0.001), respectively, in 90-day mortality compared to score 0–3. Conclusions: The adjusted-ACCI score helps to identify patients with a higher risk of 90-day mortality after cancer surgery. It might be particularly helpful for preoperative evaluation of patients over 80 years of age. [ABSTRACT FROM AUTHOR]

Background: After surgical resection of hepatocellular carcinoma (HCC), recurrence is common, especially in patients presenting with vascular invasion or multifocal disease after curative surgery. Consequently, we examined the expression pattern and prognostic value of miR-19b in samples from these patients.Methods: We performed a miRNA microarray to detect differential expression of microRNAs (miRNAs) in 5 paired samples of HCC and non-tumoral adjacent liver tissue and a quantitative real-time polymerase chain reaction (PCR) analysis to validate the results in 81 paired samples of HCC and adjacent non-tumoral liver tissues. We examined the associations of miR-19b expression with clinicopathological parameters and survival. MiR-19b was knocked down in Hep3B and an mRNA microarray was performed to detect the affected genes.Results: In both the miRNA microarray and real-time PCR, miR-19b was significantly overexpressed in the HCC tumor compared with adjacent non-tumor liver tissues (P < 0.001). The expression of miR-19b was significantly higher in patients who were disease-free 2 years after surgery (P < 0.001). High miR-19b expression levels were associated with higher α-fetoprotein levels (P = 0.017). In the log-rank test, high miR-19b was associated with better disease-free survival (median survival 37.107 vs. 11.357; P = 0.022). In Cox multivariate analysis, high miR-19b predicted better disease-free survival and overall survival (hazards ratio [HR] = 0.453, 95 % confidence interval [CI] = 0.245-0.845, P = 0.013; HR = 0.318, CI = 0.120-0.846, P = 0.022, respectively). N-myc downstream regulated 1 (NDRG1) was downregulated, while epithelial cell adhesion molecule (EPCAM), hypoxia-inducible factor 1-alpha (HIF1A), high-mobility group protein B2 (HMGB2), and mitogen activated protein kinase 14 (MAPK14) were upregulated when miR-19b was knocked down in Hep3B.Conclusions: The overexpression of miR-19b was significantly correlated with better disease-free and overall survival in patients with HCC presenting with vascular invasion or multifocal disease after curative surgery. MiR-19b may influence the expression of NDRG1, EPCAM, HMGB2, HIF1A, and MAPK14. [ABSTRACT FROM AUTHOR]

Background: The utility of lymph node ratio (LNR) in predicting outcomes has been reported previously. In current study, we further subgroup by LNR in subjects with lymph nodes metastasis of colorectal cancer, breast cancer, and head and neck cancer. Methods: Cancers with pathological lymph node metastasis (pN+) at time of diagnosis between 2004 and 2012 were identified from the cancer registry database of the Dalin Tzu Chi General Hospital. The Kaplan-Meier method with log-rank test and the Cox proportional hazards model were used to compare the disease-specific survival (DSS) rates for different LNR after adjusting for possible confounding risk factors. Results: A total of 431 cancer patients with pN+ were eligible in the current study: 149 patients with colorectal cancer; 141 patients with breast cancer; and 141 patients with head and neck cancer. High LNR was associated with poor DSS rates with the mean 24-45 months of follow-up period. In the multivariate analysis, high LNR was an independent poor prognostic factor in colorectal cancer (LNR ≥ 0.5; HR 4.10; p < 0.001), breast cancer (LNR ≥ 0.8; HR 5.75; p = 0.002), and head and neck cancer (LNR ≥ 0.4; HR 2.56; p = 0.005). Conclusion: High LNR exerts a significant role as a negative prognostic factor when comparing the traditional American Joint Committee on Cancer (AJCC) lymph nodes classification for major cancers. Therefore, LNR could be considered as an alternative and superior to, at least partially, traditional AJCC lymph nodes classification for cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Recent case reports suggest that zolpidem usage may be associated with infection events. The aim of this study was to determine the risk of infection events in patients with sleep disturbance taking zolpidem in a full 3-year follow-up study. Methods: A total of 17474 subjects with a diagnosis of sleep disturbance in 2002 and 2003 were identified, of whom 5882 had used zolpidem after recruitment. A Cox proportional hazard model was used to estimate the 3-year infection event-free rates for the patients using zolpidem and those not using zolpidem after adjusting for confounding factors. To maximize case ascertainment, only patients hospitalized for infection events were included. Results: A total of 646 patients had had infection events, 331 (5.63%) of whom had been taking zolpidem and 315 (2.71%) had not. Zolpidem usage increased the risk of infection events. After adjustments for gender, age, co-morbidities, and other medications, patients using zolpidem with cDDD 1-28, 29-84, and >84 had hazard ratios of 1.67 (95% CI, 1.32–2.11), 1.91 (95% CI, 1.47–2.49) and 1.62 (95% CI, 1.32–1.98) respectively, compared with patients who did not use zolpidem. Conclusions: Zolpidem increased the risk of infection events in sleep disturbance patients. This increased risk of infection should be explained to sleep disturbance patients, and prescriptions of zolpidem to chronic insomnia patients should be restricted. [Copyright &y& Elsevier]

The association of hepatitis C virus (HCV) infection with chronic kidney disease (CKD) remains widely debated. Here we quantify this association by analysis of data from the Taiwan National Health Insurance Research Database and ICD-9 codes to identify 9430 adults with newly diagnosed HCV (years 1999-2006) and randomly selected 37,720 matched non-HCV control individuals. The incidence rate and risk of incident CKD were evaluated through the end of 2010. The frequency of CKD was 1.66-fold higher in the HCV than the non-HCV cohort (5.46 compared with 3.43 per 1000 person-years), and the adjusted hazard ratio remained significant at 1.28 (95% confidence interval, 1.12-1.46). A multivariate analysis was used to determine the influence of HCV on CKD risk with regard to age, gender, follow-up duration, and comorbidities. The risk for CKD in HCV-infected individuals was higher with diabetes, hyperlipidemia, and cirrhosis (8.44; 3.70-19.23), followed by men <50 years (2.32; 1.49-3.61), all individuals <50 years (1.90; 1.33-2.73), men overall (1.44; 1.22-1.71), and individuals followed for ⩾6 years (1.35; 1.06-1.71); all with considerable significance. Thus, HCV infection is associated with an increased risk of CKD. Hence, high-risk HCV-infected individuals should be aggressively monitored for development of CKD. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the safety and efficacy of biweekly capecitabine in combination with oxaliplatin in previously untreated patients with locally advanced or metastatic gastric cancer. Methods: Patients received oral capecitabine 1,000 mg/m twice daily on days 1-10 plus oxaliplatin 85 mg/m as a 2-h intravenous infusion on day 1, every 2 weeks (XELOX). The primary endpoint was overall response rate. Secondary endpoints included progression-free survival, overall survival, and toxicity. Results: From March 2007 to October 2010, 46 patients were enrolled in this phase II study. The median age was 64 years (range 32-85). A total of 391 (median 7.5, range 1-29) cycles were delivered. Among the 41 patients evaluable for tumor response, 9 showed partial response and 25 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 22 % (95 % CI 10-42 %) and 20 % (95 % CI 9-34 %), respectively. In the ITT analysis, the progression-free survival and overall survival were 5.6 months (95 % CI 4.1-6.3 months) and 8.0 months (95 % CI 6.3-10.1 months), respectively. The most common hematological toxicities were thrombocytopenia (35 %) and leucopenia (34 %), whereas the most common non-hematological toxicities were neuropathy (35 %), fatigue (33 %), diarrhea (27 %), vomiting (26 %), and hand-foot syndrome (25 %). Major grade 3-4 toxicities were anemia (11 %), diarrhea (9 %), and hand-foot syndrome (7 %). No patient died of treatment-related toxicities. Conclusions: Although the biweekly XELOX regimen failed its primary response rate endpoint, it showed modest efficacy and an acceptable safety profile in the treatment of advanced gastric cancer. [ABSTRACT FROM AUTHOR]

Background and Purpose: A high risk of stroke occurrence has been reported in several types of irradiated cancer patients. However, clinical data are lacking in irradiated lung cancer patients. The present study intended to explore a risk level of ischemic stroke occurrence in irradiated lung cancer patients. Methods: A nationwide population-based database obtained from the Taiwan National Health Insurance was analyzed. Between 2003 and 2006, we recruited 560 resected lung cancer patients into two study groups: surgery-plus-irradiation (n = 112) and surgery-alone (n = 448). Patients treated with chemotherapy were excluded. Propensity score match was used for pairing cases with a ratio of 1∶4. Two-year ischemic-stroke-free survival was defined as the primary endpoint. Results: Three observations supported a high risk of ischemic stroke occurrence in patients with postoperative irradiation when compared with those patients with surgery alone: first, a high incidence per 1,000 person-year (22.3 versus 11.2, 1.99 folds); second, a low two-year ischemic-stroke-free survival rate (92.2% versus 98.1%, P = 0.019); and third, a high adjusted hazard ratio (HR, 4.19; 95% CI, 1.44–12.22; P = 0.009). More notably, the highest risk of ischemic stroke occurrence was found in irradiated patients who had diabetes mellitus (HR, 34.74; 95% CI, 6.35->100; P<0.0001). Conclusions: A high incidence of ischemic stroke was observed in irradiated lung cancer patients, especially in those with diabetes mellitus. For these patients, close clinical surveillance and strict diabetes control should be considered. Further studies to define detail biological mechanisms are encouraged. [ABSTRACT FROM AUTHOR]

Background: The relationship between individual and neighborhood socioeconomic status (SES) and mortality rates in patients with nasopharyngeal carcinoma (NPC) is unknown. This population-based study aimed to examine the association between SES and survival of patients with NPC in Taiwan. Materials and Methods: A population-based follow-up study was conducted of 4691 patients diagnosed with NPC between 2002 and 2006. Each patient was traced to death or for 5 years. Individual SES was defined by enrollee job category. Neighborhood SES was based on household income dichotomized into advantaged and disadvantaged areas. Cox proportional hazards model was used to compare the death-free survival rates between the different SES groups after adjusting for possible confounding factors and risk factors. Results: In NPC patients below the age of 65 years, 5-year overall survival rates were worst for those with low individual SES living in disadvantaged neighborhoods. After adjusting for patient characteristics (age, gender, Charlson Comorbidity Index Score), NPC patients with low individual SES residing in disadvantaged neighborhoods were found to have a 2-fold higher risk of mortality than patients with high individual SES residing in advantaged neighborhoods. We found no significant difference in mortality rates between different SES groups in NPC patients aged 65 and above. Conclusions: Our findings indicate that NPC patients with low individual SES who live in disadvantaged neighborhoods have the higher risk of mortality than their more privileged counterparts. Public health strategies and welfare policies would be well advised to try to offset the inequalities in health care and pay more attention to addressing the needs of this vulnerable group. [ABSTRACT FROM AUTHOR]

Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 (10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39 , which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC 50 = 56.4 nM) against the KM12 human colorectal cancer cell line. 39 also displayed good AUC and oral bioavailability (F = 27%), excellent in vivo efficacy (TGI = 64%) in a KM12 xenograft model, and broad-spectrum anti -TRK mutant potency (IC 50 = 3.74–151.4 nM), especially in the double-mutant TRKA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II TRK inhibitor. [Display omitted] • A next-generation orally selective type II TRK inhibitor was discovered. • Twenty-nine quinazoline-based analogues were designed and synthesized. • Property-driven strategy guided lead-to-candidate optimization. • 39 is a potent TRK inhibitor against both wild-type and mutant TRKs. • 39 demonstrated antitumor effectiveness in KM-12 xenograft model. [ABSTRACT FROM AUTHOR]

Objective: Lymph node yield is recommended as a benchmark of quality care in colorectal cancer. The objective of this study was to evaluate the impact of various factors upon lymph node yield and to identify independent factors associated with lymph node harvest. Materials and Methods: The records of 162 patients with Stage I to Stage III colorectal cancers seen in one institution were reviewed. These patients underwent radical surgery as definitive therapy; high-risk patients then received adjuvant treatment. Pathologic and demographic data were recorded and analyzed. The subgroup analysis of lymph node yields was determined using a t-test and analysis of variants. Linear regression model and multivariable analysis were used to perform potential confounding and predicting variables. Results: Five variables had significant association with lymph node yield after adjustment for other factors in a multiple linear regression model. These variables were: tumor size, surgical method, specimen length, and individual surgeon and pathologist. The model with these five significant variables interpreted 44.4% of the variation. Conclusions: Patients, tumor characteristics and surgical variables all influence the number of lymph nodes retrieved. Physicians are the main gatekeepers. Adequate training and optimized guidelines could greatly improve the quality of lymph node yields. [ABSTRACT FROM AUTHOR]

Summary: Objectives: In resected buccal cancer patients, an unexpected close surgical margin has been observed to correlate with poor clinical outcomes. However, close surgical margin alone does not independently guide post-operative therapies, revealing a clinical debate. Hence, the present study intended to explore epigenetic-based bio-predictors for further stratifying this debating patient population. Materials and methods: Between 2000 and 2008, we retrospectively recruited 44 resected buccal cancer patients with a close surgical margin of⩽5mm. All patients had post-operative radiotherapy. Genomic DNA was extracted from tumor-enrich areas that contained cancer cells of>70%. Methylation-specific PCR was performed to detect promoter methylation of four tumor suppressor genes, including RASSF1A, DAPK, IRF8, and SFRP1. Post-irradiation locoregional control was defined as the primary end point. Results: There were 40 males and 4 females, with a median age of 53.5years (range, 32–82years). Multivariate analysis identified two independent predictors for locoregional recurrence: very close margin of⩽1 mm (HR: 4.96; 95% CI, 1.63–15.09; P =0.018) and promoter hypermethylation of DAPK (HR: 2.83; 95% CI, 1.05–7.63; P =0.042). The highest risk of locoregional recurrence was observed in patients with both of the two factors (HR, 8.05; 95% CI, 2.56–25.82; P =0.002) when compared with patients with none. Shorter disease-free survival, but not overall survival, was also observed. Conclusion: More aggressive managements should be considered in resected buccal cancer patients with both very close margin and DAPK promoter hypermethylation rather than post-operative observation or radiotherapy alone. [ABSTRACT FROM AUTHOR]

Background: Increased risk of ischemic stroke has been validated for several cancers, but limited study evaluated this risk in cervical cancer patients. Our study aimed to evaluate the risk of ischemic stroke in cervical cancer patients. Methods: The study analyzed data from the 2003 to 2008 National Health Insurance Research Database (NHIRD) provided by the National Health Research Institutes in Taiwan. Totally, 893 cervical cancer patients after radiotherapy and 1786 appendectomy patients were eligible. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the risk of ischemic stroke. Results: The 5-year cumulative risk of ischemic stroke was significantly higher for the cervical cancer group than for the control group (7.8% vs 5.1%; p <0.005). The risk of stroke was higher in younger (age <51 years) than in older (age =51 years) cervical cancer patients (HR = 2.73, p = 0.04; HR = 1.37, p = 0.07) and in patients with more than two comorbid risk factors (5 years cumulative stroke rate of two comorbidities: 15% compared to no comorbidities: 4%). Conclusions: These study demonstrated cervical cancer patients had a higher risk of ischemic stroke than the general population, especially in younger patients. Strategies to reduce this risk should be assessed. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine the influence of inflammation on acute phase protein and epithelial-mesenchymal transition (EMT) in buccal cancer. Methods: Western blotting was carried out to investigate the expression of haptoglobin and epithelial-mesenchymal transition in oral cancer cell lines with or without IL-6 stimulation. We studied patients with buccal cancer patients without distant metastasis at diagnosis. Correlation between cellular haptoglobin, EMT, and clinical characteristics of buccal cancer was analyzed to assess the prognostic value of cellular haptoglobin level and EMT. The relationship of haptoglobin, and EMT expression with survival was assessed using Cox proportional hazard models. Results: Western blotting analysis showed that increased haptoglobin protein was associated with overexpression of vimentin. Under IL-6 stimulation, overexpression of haptoglobin, EMT-associated motile phenotype was noted in OC2 cell lines. Overexpression of haptoglobin was also associated with an increased risk for locoregional recurrence [hazard ratio (HR) 1.04; p=0.011] after adjusting for age, gender, disease site, stage, and treatment modality. Conclusions: Increased cellular expression of haptoglobin is associated with EMT in oral cancer cell lines and this phenomenon could be exaggerated with IL-6. Cellular expression of haptoglobin is related to locoregional recurrence rate in buccal cancer patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: The outcome of peripheral blood stem cell (PBSC) harvest depends on mobilization and leukapheresis. Some poor harvests might not be directly related to poor mobilizations. STUDY DESIGN AND METHODS: We retrospectively analyzed the results of 793 consecutive healthy donors who underwent PBSC donation to evaluate the impact of low mean corpuscular volume (MCV) of red blood cells on the outcomes of hematopoietic stem cell mobilization and leukapheresis. RESULTS: The circulating CD34+ cells in peripheral blood after five doses of granulocyte-colony-stimulating factor injection were similar in donors with low MCV and those with normal MCV (68.0 × 106/L vs. 69.2 × 106/L, p = 0.38). The procedural settings were not different between the two groups. However, the apheresis outcome of donors with low MCV was significantly lower in total CD34+ cells, cell dose, apheresis yield, and collection efficiency than those with normal MCV (277.6 × 106 vs. 455.0 × 106; 4.9 × 106/kg vs. 8.2 × 106/kg; 16.9 × 106/L vs. 27.3 × 106/L; 0.285 vs. 0.388; all p < 0.0001). Similar results were noticed in subgroup analysis using the severity of microcytosis and Mentzer index for the donors with MCV of less than 80 fL. The collection efficiency was significantly correlated with the MCV (r = 0.30, p < 0.0001). CONCLUSION: Low MCV was associated with poor apheresis outcomes in PBSC donors. This effect is not related to poor mobilization of CD34+ cells into the peripheral blood. Further studies to elucidate the detailed mechanism and develop strategy to avoid poor harvest are necessary. [ABSTRACT FROM AUTHOR]

Summary: This population-based study investigated the relationship between individual and neighborhood socioeconomic status (SES) and oral cancer mortality. A population-based follow-up study was conducted of 3607 oral cancer patients (predominantly male) who were diagnosed between 2004 and 2005. Each patient was traced to death or for 2years. Individual SES was defined by enrollee category. Neighborhood SES was defined by income, and numbers of doctors, and neighborhoods were grouped into advantaged and disadvantaged areas. The Cox proportional hazards model was used to compare the death-free survival rate between the different SES groups after adjusting for possible confounding and risk factors. In oral cancer patients aged below 65years, death rates among those with low SES were highest in disadvantaged neighborhoods. After adjusting for patient characteristics (age, gender, Charlson Comorbidity Index Score, urbanization, and area of residence), tumor extent, treatment modalities (operation, adjuvant therapy), hospital characteristics (ownership, teaching level, caseload), and year of diagnosis, oral cancer patients with low individual SES in disadvantaged neighborhoods conferred a 1.46- to 1.64-fold higher risk for death, compared with patients with high individual SES in advantaged neighborhoods. No statistically significant difference was found in risk of death between different SES groups in patients aged 65 and above. Our findings indicate that oral cancer patients with low individual SES have the highest risk of mortality even under a universal health-care system. Public health strategies and welfare policies must continue to focus on this vulnerable group. [Copyright &y& Elsevier]

Background: Venous thromboembolism (VTE) is a life-threatening condition that occurs as a complication of cervical cancer. The aim of this study was to evaluate the incidence of VTE in cervical cancer patients during a 5-year follow-up. Methods: The study analyzed data deposited between 2003 and 2008 in the National Health Insurance Research Database (NHIRD), provided by the National Health Research Institutes in Taiwan. Totally, 1013 cervical cancer patients after treatment and 2026 appendectomy patients were eligible. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the VTE risk. Results: The 5-year cumulative risk for VTE was significantly higher in the cervical cancer group than in the control group (3.3% vs 0.3%, p<0.001). The hazard ratio for VTE was 10.14 times higher in the cervical cancer group than in the controls. The combined presence of more comorbidities was associated with a higher risk for VTE. Furthermore, cervical cancer patients without VTE had a significantly higher survival (75.3% vs 30.3%, p<0.001). Conclusions: The cumulative risk of VTE was significantly higher in cervical cancer patients, and these patients also had lower survival rates. Strategies to reduce these risks need to be examined. [ABSTRACT FROM AUTHOR]

Summary: Background: Chemo-radiotherapy-induced carotid stenosis and cerebrovascular events in head and neck cancer patients can cause severe disability and death. We aimed to estimate the risk of stroke in such patients over a six-year follow-up period. Patients and methods: The study cohort consisted of head and neck cancer patients (n =10,172). Cox proportional hazard model was used to compare the stroke-free survival rate between the patients treated with radiotherapy or chemotherapy, surgery alone, and surgery with adjuvant therapy after adjusting for possible confounding factors. Results: At the end of follow-up, 384 patients had strokes: 126 (4.3%) from the surgery alone group, 167 (3.8%) from the radiotherapy or chemotherapy group, and 91 (3.2%) from the surgery with adjuvant therapy (P =0.222). Head and neck cancer patients aged less than 55years treated with radiotherapy or chemotherapy conferred a 1.8-fold higher risk for stroke (95% CI, 1.22–2.56; P =0.003) after adjusting for patient characteristics, co-morbidities, geographic region, urbanization level, and socio-economic status. There was no statistical difference in stroke risk between different treatment modalities in head and neck cancer patients aged 55years and more. Conclusions: Young head and neck cancer patients treated with radiotherapy or chemotherapy have higher risks for stroke. Different treatment strategies should be considered in such patients. [Copyright &y& Elsevier]

Abstract: The aim of this study is to validate the clinical utility of the flow cytometric scoring system (FCSS), quantifying phenotypic aberrancies in the myelomonocytic lineages, in the diagnosis and prognosis for conventionally treated myelodysplastic syndromes (MDS) patients. The bone marrow samples from 56 consecutive newly diagnosed MDS patients were characterized by the FCSS and compared with findings in 27 non-MDS cytopenic patients. The FCSS scores were significantly higher in patients with MDS than those in the non-MDS control. A flow score of 2 or more allowed for a specificity of 100% with 75% sensitivity in distinguishing these two groups. The FCSS scores correlated directly with validated prognostic systems including WHO classification, International Prognostic Scoring System (IPSS), WHO-adjusted prognostic scoring system (WPSS) and transfusion dependency. The median survival of conventionally treated MDS patients was directly related to FCSS group; severe: 6months; moderate: 19months and normal/mild: not reached. The multivariate analyses suggested the FCSS risk categories were an independent prognostic factor after adjustment for sex, age (above or below 70years), IPSS or WPSS risk categories. These results confirm that quantifying aberrancies in the myelomonocytic lineage by FCSS is useful in MDS diagnosis and extends the prognostic utility for conventionally treated/untreated patients, especially among patients classified within the refractory cytopenia with multilineage dysplasia (RCMD) subgroup. [Copyright &y& Elsevier]