Unraveling the Adhesion Behavior of Different Cell Lines on Biomimetic PEDOT Interfaces: The Role of Surface Morphology and Antifouling Properties.

The poly(3,4-ethylenedioxythiophene) (PEDOT) interface, renowned for its biocompatibility and intrinsic conductivity, holds substantial potential in biosensing and cellular modulation. Through strategic functionalization, PEDOT derivatives can be adaptable for multifaceted applications. Notably, integrating phosphorylcholine (PC) groups into PEDOT, mimicking the hydrophilic headgroups from cell membranes, confers exceptional antifouling properties on the coating. This study systematically investigated biomolecule interactions with distinct forms of PEDOT, incorporating variations in surface modifications and structure. Zwitterionic PEDOT-PC was electropolymerized on smooth and nanostructured surfaces using various feeding ratios in electrolytes to finely control the antifouling properties of the interface. Precise electropolymerization conditions governed the attainment of smooth and nanostructured filamentous surfaces. The study employed a quartz crystal microbalance with dissipation (QCM-D) to assess protein binding behavior. Bovine serum albumin (BSA), lysozyme (LYZ), cytochrome c (cyt c), and fibronectin (FN) were used to evaluate their binding affinities for PEDOT films. FN, a pivotal extracellular matrix component, was included for connecting to cell adhesion behavior. Furthermore, the cellular adhesion behaviors on PEDOT interfaces were evaluated. Three cell lines─MG-63 osteosarcoma, HeLa cervical cancer, and fibroblast NIH/3T3 were examined. The presence of PC moieties significantly altered the adhesive response, including the number of attached cells, their morphologies, and nucleus shrinkage. MG-63 cells exhibited the highest tolerance for PC moieties. A feeding ratio of PEDOT-PC exceeding 70% resulted in cell apoptosis. This study contributes to understanding biomolecule adsorption on PEDOT surfaces of diverse morphologies and degrees of the antifouling moiety. Meanwhile, it also sheds light on the responses of various cell types.

Prognostic value of interim CT-based peritumoral and intratumoral radiomics in laryngeal and hypopharyngeal cancer patients undergoing definitive radiotherapy.

BACKGROUND AND PURPOSE: We aimed to investigate the prognostic value of peritumoral and intratumoral computed tomography (CT)-based radiomics during the course of radiotherapy (RT) in patients with laryngeal and hypopharyngeal cancer (LHC). MATERIALS AND METHODS: A total of 92 eligible patients were 1:1 randomly assigned into training and validation cohorts. Pre-RT and mid-RT radiomic features were extracted from pre-treatment and interim CT. LASSO-Cox regression was used for feature selection and model construction. Time-dependent area under the receiver operating curve (AUC) analysis was applied to evaluate the models' prognostic performances. Risk stratification ability on overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method and Cox regression. The associations between radiomics and clinical parameters as well as circulating lymphocyte counts were also evaluated. RESULTS: The mid-RT peritumoral (AUC: 0.77) and intratumoral (AUC: 0.79) radiomic models yielded better performance for predicting OS than the pre-RT intratumoral model (AUC: 0.62) in validation cohort. This was confirmed by Kaplan-Meier analysis, in which risk stratification depended on the mid-RT peritumoral (p = 0.009) and intratumoral (p = 0.003) radiomics could be improved for OS, in comparison to the pre-RT intratumoral radiomics (p = 0.199). Multivariate analysis identified mid-RT peritumoral and intratumoral radiomic models as independent prognostic factors for both OS and PFS. Mid-RT peritumoral and intratumoral radiomics were correlated with treatment-related lymphopenia. CONCLUSION: Mid-RT peritumoral and intratumoral radiomic models are promising image biomarkers that could have clinical utility for predicting OS and PFS in patients with LHC treated with RT.

GRAIL gene knockout mice protect against aging-related and noise-induced hearing loss.

BACKGROUND: Hearing loss is a global health issue and its etiopathologies involve complex molecular pathways. The ubiquitin-proteasome system has been reported to be associated with cochlear development and hearing loss. The gene related to anergy in lymphocytes ( GRAIL ), as an E3 ubiquitin ligase, has not, as yet, been examined in aging-related and noise-induced hearing loss mice models. METHODS: This study used wild-type (WT) and GRAIL knockout (KO) mice to examine cochlear hair cells and synaptic ribbons using immunofluorescence staining. The hearing in WT and KO mice was detected using auditory brainstem response. Gene expression patterns were compared using RNA-sequencing to identify potential targets during the pathogenesis of noise-induced hearing loss in WT and KO mice. RESULTS: At the 12-month follow-up, GRAIL KO mice had significantly less elevation in threshold level and immunofluorescence staining showed less loss of outer hair cells and synaptic ribbons in the hook region compared with GRAIL WT mice. At days 1, 14, and 28 after noise exposure, GRAIL KO mice had significantly less elevation in threshold level than WT mice. After noise exposure, GRAIL KO mice showed less loss of outer hair cells in the cochlear hook and basal regions compared with WT mice. Moreover, immunofluorescence staining showed less loss of synaptic ribbons in the hook regions of GRAIL KO mice than of WT mice. RNA-seq analysis results showed significant differences in C-C motif chemokine ligand 19 ( CCL19 ), C-C motif chemokine ligand 21 ( CCL21 ), interleukin 25 ( IL25 ), glutathione peroxidase 6 ( GPX6 ), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 ( NOX1 ) genes after noise exposure. CONCLUSION: The present data demonstrated that GRAIL deficiency protects against aging-related and noise-induced hearing loss. The mechanism involved needs to be further clarified from the potential association with synaptic modulation, inflammation, and oxidative stress.

Genetic Authentication of the Medicinal Plant Portulaca oleracea Using a Quick, Precise, and Sensitive Isothermal DNA Amplification Assay.

Portulaca oleracea (PO) is a commonly known medicinal crop that is an important ingredient for traditional Chinese medicine (TCM) due to its use as a vegetable in the diet. PO has been recorded to be frequently adulterated by other related species in the market of herbal plants, distorting the PO plant identity. Thus, identification of the botanical origin of PO is a crucial step before pharmaceutical or functional food application. In this research, a quick assay named "loop-mediated isothermal amplification (LAMP)" was built for the specific and sensitive authentication of PO DNA. On the basis of the divergences in the internal transcribed spacer 2 (ITS2) sequence between PO and its adulterant species, the LAMP primers were designed and verified their specificity, sensitivity, and application for the PO DNA authentication. The detection limit of the LAMP assay for PO DNA identification specifically was 100 fg under isothermal conditions at 63 °C for 30 min. In addition, different heat-processed PO samples can be applied for use in PO authentication in the LAMP assay. These samples of PO were more susceptible to the effect of steaming in authentication by PCR than boiling and drying treatment. Furthermore, commercial PO samples pursued from herbal markets were used to display their applicability of the developed LAMP analysis for PO postharvest authentication, and the investigation found that approximately 68.4% of PO specimens in the marketplace of herbal remedies were adulterated. In summary, the specific, sensitive, and rapid LAMP assay for PO authentication was first successfully developed herein, and its practical application for the inspection of adulteration in PO samples from the herbal market was shown. This LAMP assay created in this study will be useful to authenticate the botanical origin of PO and its commercial products.

Engineering Superaerophobic Electrodes Using Hydrophilic PEDOT and Colloidal Lithography for Enhanced Bubble Release and Efficient Hydrogen Evolution Reaction.

The efficient removal of gas bubbles is essential to reduce the reaction overpotential and improve the electrode stability in the hydrogen evolution reaction (HER). To address this challenge, the current study combines hydrophilic functionalized poly(3,4-ethylenedioxythiophene) (PEDOT) with colloidal lithography to create superaerophobic electrode surfaces. The fabrication process involves the use of polystyrene (PS) beads with varying sizes (100, 200, and 500 nm) as hard templates and the electropolymerization of EDOTs with hydroxymethyl (EDOT-OH) and sulfonate (EDOT-SuNa) functional groups. The surface properties and HER performances of the electrodes are investigated. The electrode modified with poly(EDOT-SuNa) and 200 nm PS beads (SuNa/Ni/Au-200) exhibits the best hydrophilicity with a water contact angle of 37°. Moreover, the overpotential required at -10 mA cm-2 is substantially reduced from -388 mV (flat Ni/Au) to -273 mV (SuNa/Ni/Au-200). This approach is further applied to commercially available nickel foam electrodes, showing improved HER activity and electrode stability. These results highlight the potential for promoting catalytic efficiency by constructing a superaerophobic electrode surface.

Long-term outcomes of frontline intensification in primary CNS lymphoma: A real-world single-center experience.

BACKGROUND: Frontline intensification (including consolidative whole-brain radiotherapy or high-dose chemotherapy with autologous stem-cell transplantation after induction therapy) has been proposed to treat primary central nervous system lymphoma (PCNSL). However, no prospective randomized trials have answered whether frontline intensification can offer a survival benefit to PCNSL patients. We aim to clarify the outcomes and survival influence of frontline intensification on real-world patients with different risk-stratified PCNSLs. METHODS: Between January 2003 and December 2016, 110 PCNSL adults were retrospectively included, and 76 patients achieved at least PR after induction therapy, including 38 patients who received frontline intensification. The median follow-up with the 31 survivors was 7.52 years. RESULTS: Of the 38 induction-completed patients who had not received frontline intensification, 95% achieved post-induction therapy CR/CRu; however, all inevitably recurred. In the 38 who received frontline intensification, CR/CRu improved from 45% (pre-frontline intensification) to 84% (post-frontline intensification), and they achieved significantly better PFS (non-reach vs. 522 days, p < 0.001) and OS (non-reach vs. 899 days, p < 0.001). Additionally, patients had similar PFS and OS rates when receiving HDC-ASCT and/or WBRT as frontline intensification. Frontline intensification significantly improved PFS and OS survival in higher-risk patients (intermediate/high IELSG risk, MSKCC group 2/3, or Nottingham/Barcelona score ≥ 2 points) but did not improve OS in lower-risk patients. Among the 38 patients who received frontline intensification, two had treatment-related mortality; 14 recurred after frontline intensification. MTX-based chemotherapy was the main salvage modality, and the median OS was 295 days after recurrence. Progressive disease and infection (especially pneumonia) are two major causes of mortality in patients who receive frontline intensification. CONCLUSIONS: When achieving CR/CRu/PR after induction chemotherapy, frontline intensification should be adopted to improve PFS and OS in real-world PCNSL patients, especially higher-risk patients.

Development of a specific and sensitive diagnostic PCR for rapid molecular authentication of the medicinal plant Portulaca oleracea.

Adulteration by Bacopa monnieri (BM) in Portulaca oleracea (PO) plants frequently occurs; it decreases the efficacy of traditional Chinese medicine (TCM) and leads to fraud in the herbal marketplace. In this study, a diagnostic PCR assay was established for the rapid authentication of PO and BM in the herbal market. The sequence divergences in internal transcribed spacer 2 (ITS2) between PO and its adulterant species were used to design diagnostic PCR primers. The specific designed primer sets were evaluated and show that the diagnostic PCR assay can be used to verify the authenticity of PO and BM. The detection limits of the primer set for PO and BM identification were 10 pg and 1 pg, respectively. The reactivity of diagnostic PCR was 0.1% PO genomic DNA and 0.01% BM genomic DNA in the test sample during DNA amplification. In addition, multiplex PCR (mPCR) for PO and BM identification was also established. The samples were more susceptible to the effect of steaming in authentication by singleplex PCR and mPCR than boiling and drying treatment. Furthermore, commercial samples from the market were used to demonstrate the applicability of the developed diagnostic PCR for PO authentication and diagnose BM adulteration, and the investigation found that approximately 72.2% (13/18) of PO plants in the herbal market were adulterated. In conclusion, the diagnostic PCR assay was successfully developed and its specificity, sensitivity and reactivity for PO and BM authentication were proven. These developed PCR-based molecular methods can be applied as an identification tool for PO authenticity and can be practically applied for inspection of BM adulteration in the herbal market in the future.

Adjuvant Chemoradiotherapy Associated with Improved Overall Survival in Resected Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy in Intensity-Modulated Radiotherapy Era.

BACKGROUND: The prognosis of patients with resected esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy is particularly poor in those who were staged as ypT3/T4 and/or ypN+. This study investigated whether adjuvant chemoradiotherapy was associated with improved clinical outcomes in these patients. METHODS: we identified patients with esophageal squamous cell carcinoma who were staged as ypT3/T4 and/or ypN+ after being treated with neoadjuvant chemoradiotherapy followed by esophagectomy between the years 2013 and 2019. Patients were divided into two groups based on whether they received adjuvant chemoradiotherapy. The Kaplan-Meier method and Cox regression modeling were performed for survival analyses and multivariable analysis, respectively. RESULTS: 76 eligible patients were included in the analyses. The median follow-up for the study cohort was 43.4 months. On Kaplan-Meier analyses of the overall population, adjuvant chemoradiotherapy was associated with significantly improved median overall survival (31.7 months vs. 16.3 months, p = 0.036). On Kaplan-Meier analyses of the 35 matched pairs generated by propensity score matching, adjuvant chemoradiotherapy was associated with significantly longer median overall survival (31.7 months vs. 14.3 months; p = 0.004) and median recurrence-free survival (18.9 months vs. 11.7 months; p = 0.020). In multivariable analysis, adjuvant chemoradiotherapy was independently associated with a 60% reduction in mortality (p = 0.003) and a 48% reduction in risk of recurrence (p = 0.035) after adjusting for putative confounders. In addition, microscopic positive resection margin and Mandard tumor regression grade 3-4 were independently associated with increased mortality and risk of recurrence. While a greater number of lymph nodes dissected was independently associated with significantly improved overall survival, the number of positive lymph nodes was independently associated with significantly worse overall survival and a trend (p = 0.058) towards worse recurrence-free survival. CONCLUSIONS: This study demonstrated that adjuvant CRT was independently associated with a significantly improved survival and lower risk of recurrence than observation in esophageal squamous cell carcinoma patients staged as ypT3 and/or ypN+ after receiving neoadjuvant chemoradiotherapy and radical surgery. The results of this study have implications for the design of future clinical trials and may improve treatment outcomes of patients in this setting who cannot afford or are without access to adjuvant nivolumab.

Effectiveness of entecavir vs tenofovir disoproxil fumarate for functional cure of chronic hepatitis B in an international cohort.

INTRODUCTION: Both entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line therapies for chronic hepatitis B (CHB), but their comparative effectiveness with regards to hepatitis B surface antigen (HBsAg) seroclearance remains unclear. METHODS: This international multicenter cohort study enrolled 7697 treatment-naïve CHB patients (median age 50 years; male 66.75%) initiated on either ETV (n = 5430) or TDF (n = 2267) without baseline malignancy or immunosuppression from 23 centers across 10 countries or regions. Patients were observed for HBsAg seroclearance until death, loss to follow-up, or treatment discontinuation or switching. The incidences of HBsAg seroclearance were adjusted for competing mortality and compared between ETV and TDF cohorts with inverse probability of treatment weighting (IPTW) and also by multivariable regression analysis. RESULTS: The study population was followed up for a median duration of 56.1 months with 36,929 11 person-years of observation. HBsAg seroclearance occurred in 70 ETV-treated and 21 TDF-treated patients, yielding 8-year cumulative incidence of 1.69% (95% confidence interval [CI] 1.32-2.17) for ETV and 1.34% (95% CI 0.85-2.10%), for TDF (p = 0.58). In the IPTW analysis with the two study cohorts more balanced in background covariates, the age-adjusted hazard ratio (HR) of TDF versus ETV for HBsAg seroclearance was 0.91 (95% CI 0.50-1.64; p = 0.75). Furthermore, there was no significant difference between the two medications in the multivariable competing risk regression model (adjusted sub-distributional HR 0.92 for TDF vs. ETV; 95% CI 0.56-1.53; p = 0.76). CONCLUSIONS: ETV and TDF did not differ significantly in the incidence of HBsAg seroclearance, which rarely occurred with either regimen.

Adoptive transfer of IL-4 reprogrammed Tc17 cells elicits anti-tumour immunity through functional plasticity.

Ability of IL-17-producing CD8+ T cells (Tc17) to transform into cytotoxic anti-tumour effectors makes them a promising candidate for immune effector cell (IEC) therapy. However, key factors regulating Tc17 reprogramming remain poorly defined, hindering translation of Tc17-based IEC use from bench to bedside. We probed the effects of multiple cytokines and underlying signalling pathways on Tc17 cells and identified pivotal role for IL-4 and PI3K/AKT in promoting Tc17 transformation into cytotoxic IFN-γ-producing IECs, an effect dependent on Eomes expression. IL-4 not only triggered Tc17 cytotoxicity, but also induced cell expansion, which significantly improved the antitumour potential of Tc17 cells compared to that of IFN-γ-producing CD8+ T cells (Tc1) in a murine model. Furthermore, IL-4/AKT signalling drove the upregulation of the T-cell receptor-associated transmembrane adaptor 1 (Trat1) in Tc17 cells to promote IL-4-induced T-cell receptor stabilization and Tc17 cytotoxicity. Finally, we proposed a possible procedure to expand human Tc17 from peripheral blood of cancer patients, and confirmed the function of IL-4 in Tc17 reprogramming. Collectively, these results document a novel IL-4/AKT/Eomes/Trat1 axis that promotes expansion and transformation of Tc17 cells into cytotoxic effectors with a therapeutic potential. IL-4 priming of Tc17 cells should be further explored as a cell therapy engineering strategy to generate IECs to augment anti-tumour responses.

Efficacy of Postoperative Unilateral Neck Irradiation in Patients with Buccal Mucosa Squamous Carcinoma with Extranodal Extension: A Propensity Score Analysis.

Unilateral radiotherapy (RT) as a postoperative treatment for multiple ipsilateral lymph node (LN) metastases remains controversial. We investigated the efficacy of postoperative unilateral RT for buccal mucosa squamous cell carcinoma (BMSCC) with extranodal extensions (ENEs). We retrospectively reviewed the clinical records of 186 patients with ENE+ BMSCC who received postoperative RT during 1997-2016. Propensity score matching was used to establish comparable cohorts. The endpoints were contralateral nodal control (CLNC), overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), local control (LC), and regional control (RC). After matching, 123 patients were selected for analysis; 45 (36.6%) and 78 (63.4%) patients underwent unilateral and bilateral RT, respectively. The median follow-up was 36.27 months. The survival outcomes in the unilateral and bilateral RT groups were similar: 3-year CLNC (85.6% vs. 89.1%, p = 0.748), OS (53.2% vs. 57.4%, p = 0.229), DFS (46.5% vs. 48.6%, p = 0.515), DMFS (70.7% vs. 72.0%, p = 0.499), LC (78.0% vs. 75.6%, p = 0.692), and RC (79.9% vs. 76.2%, p = 0.465). On multivariable Cox regression analysis, unilateral and bilateral RT showed comparable outcomes; the number of ENEs ≥ 4 was the only significant prognostic factor for all clinical outcomes. Using decision tree analysis, we classified our patients to have a low, intermediate, or high risk of contralateral failure based on three factors: number of ENEs, margin status, and tumor stage. In conclusion, postoperative unilateral RT did not worsen outcomes in patients with ENE+ BMSCC in this cohort. The decision tree model may assist physicians in optimizing and tailoring radiation fields.

Psoralea corylifolia L. Ameliorates Collagen-Induced Arthritis by Reducing Proinflammatory Cytokines and Upregulating Myeloid-Derived Suppressor Cells.

Background: Rheumatoid arthritis is an autoimmune disease that may lead to severe complications. The fruit of Psoralea corylifolia L. (PCL) is widely used in traditional Chinese medicine as a well-known herbal treatment for orthopedic diseases. However, there is a lack of studies of its effects on rheumatoid arthritis. The purpose of the study was to investigate the effects and mechanisms of concentrated herbal granules of PCL on rheumatoid arthritis to provide some insights for future development of new drug for the treatment of rheumatoid arthritis. Methods: We used collagen-induced arthritis (CIA) DBA/1J mice as an experimental model to mimic human rheumatoid arthritis. The mice were immunized with collagen on days 0 and 21 and then orally administered 200 mg/kg/day PCL on days 22-49. Starch was used as a control. The mice were sacrificed on day 50. Clinical phenotypes, joint histopathology, and immunological profiles were measured. Results: Compared to the CIA or CIA + Starch group, the CIA + PCL group had significantly ameliorated clinical severity and decreased paw swelling. Histopathological analysis of the hind paws showed that PCL mitigated the erosion of cartilage and the proliferation of synovial tissues. There were significant differences in the levels of TNF-α, IL-6 and IL-17A, as measured by ELISA, and the percentages of CD4 + IL-17A+, CD4 + TNF-α+, CD4 + IFN-γ+ T cells. Furthermore, we also found that in mice treated with CIA + PCL, the percentage and number of bone marrow-derived suppressor cells (MDSCs; Gr1+ CD11b+) increased significantly. Conclusions: We provided evidence for the potential antiarthritic effects of PCL through the inhibition of inflammation and increase of MDSCs. These findings indicate that PCL may be a promising therapeutic herb for the treatment of rheumatoid arthritis.

Human Costars Family Protein ABRACL Modulates Actin Dynamics and Cell Migration and Associates with Tumorigenic Growth.

Regulation of cellular actin dynamics is pivotal in driving cell motility. During cancer development, cells migrate to invade and spread; therefore, dysregulation of actin regulators is often associated with cancer progression. Here we report the role of ABRACL, a human homolog of the Dictyostelium actin regulator Costars, in migration and tumorigenic growth of cancer cells. We found a correlation between ABRACL expression and the migratory ability of cancer cells. Cell staining revealed the colocalization of ABRACL and F-actin signals at the leading edge of migrating cells. Analysis of the relative F-/G-actin contents in cells lacking or overexpressing ABRACL suggested that ABRACL promotes cellular actin distribution to the polymerized fraction. Physical interaction between ABRACL and cofilin was supported by immunofluorescence staining and proximity ligation. Additionally, ABRACL hindered cofilin-simulated pyrene F-actin fluorescence decay in vitro, indicating a functional interplay. Lastly, analysis on a colorectal cancer cohort demonstrated that high ABRACL expression was associated with distant metastasis, and further exploration showed that depletion of ABRACL expression in colon cancer cells resulted in reduced cell proliferation and tumorigenic growth. Together, results suggest that ABRACL modulates actin dynamics through its interaction with cofilin and thereby regulates cancer cell migration and participates in cancer pathogenesis.

Conducting polymer-based sensors for food and drug analysis.

Conducting polymers (CPs) are a category of polymeric materials with conjugated main chains. The characteristic electrical and optical properties of CPs can be fine-tuned through controlling the doping states of CPs. Because of their long-term stability in water, CPs have been demonstrated as electroactive biointerfaces and electrode materials especially in aqueous environments. Serving as multifunctional interfaces and organic electrodes for the integration bioelectronics and devices, CPs have been studied and applied in various biological applications. This paper provides a review of conducting polymer-based electrochemical sensors, particularly those used in biological fields. General conducting polymers and derivatives and their main electrochemical sensing platforms with different design of devices are introduced. Cyclic voltammetry, differential pulse voltammetry, chronoamperometry, electrochemical impedance spectroscopy, and quartz crystal microbalance methods and their features are then explored as detection methods for the analysis of drugs and food. To enhance the sensitivity and lower the detection limit of sensing platforms, various CP-based nanocomposites have been designed and developed. Although the electrodes made of CP-based nanocomposites usually outperform those made of pristine CPs, more systematic studies are required to provide insights into the design of nanocomposite-based electrodes. More applications of CP-based sensors for advanced food and drug analyses are expected.

Oncological Outcomes After Hippocampus-Sparing Whole-Brain Radiotherapy in Cancer Patients With Newly Diagnosed Brain Oligometastases: A Single-Arm Prospective Observational Cohort Study in Taiwan.

BACKGROUND: Promisingly, the technique of hippocampus sparing during WBRT (HS-WBRT) might preserve NCFs. In this research, we examined oncological outcomes, with emphasis on neurologic/non-neurologic causes of death, CNS progression, and leptomeningeal disease (LMD) recurrence in cancer patients who underwent HS-WBRT. METHODS: One hundred and fourteen cancer patients with newly diagnosed brain oligometastases underwent HS-WBRT were consecutively enrolled. The cumulative incidence of cancer-specific deaths (neurologic or non-neurologic), LMD recurrence, and the composite endpoint of CNS progression (CNS-CE) as the first event were computed with a competing-risks approach to characterize the oncological outcomes after HS-WBRT. RESULTS: Patients with intact brain metastases had a significantly increased likelihood of dying from non-neurologic causes of death associated with early manifestation of progressive systemic disease (hazard ratio for non-neurologic death, 1.78; 95% CI, 1.08-2.95; p = 0.025; competing-risks Fine-Gray regression), which reciprocally rendered them unlikely to encounter LMD recurrence or any pattern of CNS progression (HR for CNS-CE as the first event, 0.13; 95% CI, 0.02-0.97; p = 0.047; competing-risks Fine-Gray regression). By contrast, patients with resection cavities post-craniotomy had reciprocally increased likelihood of CNS progression which might be associated with neurologic death eventually. CONCLUSIONS: Patterns of oncological endpoints including neurologic/non-neurologic death and cumulative incidence of CNS progression manifesting as LMD recurrence are clearly clarified and contrasted between patients with intact BMs and those with resection cavities, indicating they are clinically distinct subgroups. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT02504788, NCT03223675.

Prognostic significance of dynamic changes in lymphocyte-to-monocyte ratio in patients with head and neck cancer treated with radiotherapy: results from a large cohort study.

BACKGROUND AND PURPOSE: We sought to investigate whether dynamic changes in lymphocyte-to-monocyte ratio (LMR) occurring during the course of radiotherapy (RT) may have prognostic value in patients with head and neck cancer (HNC). MATERIALS AND METHODS: We retrospectively reviewed the clinical records of patients with HNC who underwent RT at our center between 2005 and 2013. Generalized estimating equations were used to longitudinally assess changes in LMR through the course of RT. Delta-LMR was calculated as the difference between LMR measured during treatment and baseline LMR values. Freedom from metastasis (FFM) and overall survival (OS) served as the main outcome measures. RESULTS: A total of 1431 patients with HNC were enrolled. After a median follow-up of 9 years, 636 (44.4%) patients died and 240 (16.8%) had distant metastases. Compared with patients with low delta-LMR at two weeks, those with high delta-LMR experienced less favorable outcomes (five-year OS: 73% versus 59%, respectively, p < 0.001; five-year FFM: 87% versus 80%, respectively, p = 0.015). Similar findings were observed for delta-LMR measured at four weeks (five-year OS: 72% versus 60%, p < 0.001; five-year FFM: 86% versus 79%, respectively, p = 0.002) and six weeks (five-year OS: 72% versus 57%, p < 0.001; five-year FFM: 87% versus 79%, respectively, p = 0.002). Multivariate analysis identified delta-LMR as an independent prognostic factor for both FFM and OS. CONCLUSION: Delta-LMR is a simple and inexpensive biomarker that may be clinically useful for predicting FFM and OS in patients with HNC treated with RT.

Prognostic significance of the preoperative systemic immune-inflammation index in patients with oral cavity squamous cell carcinoma treated with curative surgery and adjuvant therapy.

OBJECTIVES: To investigate the prognostic value of the preoperative systemic immune-inflammation index (SII) in patients with oral cavity squamous cell carcinoma (OC-SCC) treated with curative surgery followed by adjuvant radiotherapy (RT) or chemoradiotherapy (CCRT). MATERIALS AND METHODS: We retrospectively reviewed the clinical records of patients with OC-SCC who received surgery and postoperative adjuvant RT/CCRT between January 2005 and December 2012. Blood samples were drawn in the 2 weeks preceding surgery. SII was calculated by multiplying the absolute neutrophil and platelet counts, and then, divided by the absolute lymphocyte count, and its optimal cutoff value was identified using the Youden's index. The study endpoints included overall survival (OS), local control (LC), regional control (RC), and distant control (DC). RESULTS: The study sample consisted of 993 patients (58.8% of them treated with CCRT). The optimal cutoff value for SII was 810.6. A total of 347 (34.9%) study participants had high preoperative SII values. After allowance for potential confounders in multivariable analysis, high SII values were independently associated with less favorable DC (adjusted hazard ratio [HR] = 1.683, p = 0.001) and OS (adjusted HR = 1.466, p < 0.001). No independent association between SII and LC/RC was observed. CONCLUSION: Increased SII values predict poor DC and OS in patients with OC-SCC treated with curative resection and adjuvant RT/CCRT. Owing to the higher risk of systemic failure in this patient group, a thorough follow-up surveillance schedule may be advisable pending independent confirmation of our data.

Baseline Mac-2 Binding Protein Glycosylation Isomer Level Stratifies Risks of Hepatocellular Carcinoma in Chronic Hepatitis B Patients with Oral Antiviral Therapy.

BACKGROUND AND AIMS: Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel biomarker correlating with liver fibrosis stages. However, little is known about how it predicts risks of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long-term antiviral treatment. MATERIALS AND METHODS: The study contained 2 parts. The first part was to explore whether M2BPGi could be an HCC predictor in 899 CHB patients receiving long-term entecavir therapy. The second part was to validate the findings in an independent cohort of 384 on-treatment CHB patients with more severe liver disease. RESULTS: In the discovery cohort, there were 64 patients developing HCC within an average follow-up of 7.01 years. Our data showed that M2BPGi level was positively associated with HCC development. When stratifying the patients by an M2BPGi level of 1.73 (the third quartile), the high M2BPGi group was shown to have an increased HCC risk compared to the low M2BPGi group with hazard ratio of 5.80 (95% CI 3.50-9.60). Furthermore, we found that the M2BPGi level complements PAGE-B score, a well-validated HCC prediction model, to predict HCC development. Lastly, the cutoff was validated in the independent cohort, especially those with an intermediate PAGE-B score. CONCLUSIONS: In CHB patients receiving long-term antiviral treatment, serum M2BPGi level not only serves as an independent HCC predictor but also complements PAGE-B in stratifying HCC risks.

On-Treatment Changes in FIB-4 and 1-Year FIB-4 Values Help Identify Patients with Chronic Hepatitis B Receiving Entecavir Therapy Who Have the Lowest Risk of Hepatocellular Carcinoma.

Noninvasive fibrosis indices can help stratify the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogue (NA) therapy. We investigated the predictive performance of on-treatment changes in FIB-4 (△FIB-4) and 1-year FIB-4 values (FIB-4 12M) for HCC risk in patients with CHB receiving entecavir therapy. We included 1325 NA-naïve patients with CHB treated with entecavir, retrospectively, from January 2007 to August 2012. A combination of △FIB-4 and FIB-4 12M was used to stratify the cumulative risk of HCC into three subgroups each in the noncirrhotic and cirrhotic subgroups with p < 0.0001 by using the log-rank test (noncirrhotic: the highest risk (n = 88): FIB-4 12M ≥ 1.58/△FIB-4 ≥ 0 (hazard ratio (HR): 40.35; 95% confidence interval (CI): 5.107-318.7; p <0.0001) and cirrhotic: the highest risk (n = 89): FIB-4 12M ≥2.88/△FIB-4 ≥0 (HR: 9.576; 95% CI: 5.033-18.22; p < 0.0001)). Patients with noncirrhotic CHB treated with entecavir who had a FIB-4 12M < 1.58 or FIB-4 12M ≥ 1.58/△FIB-4 < 0 exhibited the lowest 5-year HCC risk (0.6%). A combination of on-treatment changes in FIB-4 and 1-year FIB-4 values may help identify patients with CHB receiving entecavir therapy with the lowest risk of HCC.

Partitioned Extracts of Bauhinia championii Induce G0/G1 Phase Arrest and Apoptosis in Human Colon Cancer Cells.

Bauhinia championii (Benth.) is one of the commonly used herbs in Taiwan. The stem of this plant has been used to treat epigastria pain and rheumatoid arthritis. However, the antitumor activities of this herb have never been reported. This study aims to investigate the mechanism of anticancer activity of the extracts from B. championii (BC). BC was fractionated with a series of organic solvents, including n-hexane (H), ethyl acetate (EA), 1-butanol (B), and water (W). We first investigated the effects of BC-H, BC-EA, BC-B and BC-W partitioned fraction on cell viability. In HCT 116 colon cancer cell lines, BC-EA showed the highest inhibition of cell viability and changed the morphology of cells. With dose- and time-dependent manners, BC-EA inhibited the proliferation of HCT 116 cells by inducing apoptosis and G0/G1 phase arrest of cell cycle. To determine the underlying mechanisms, down-regulated CDK2, Cyclin D, and Cyclin E and up-regulated p16, p21, and p53 may account for the cell cycle arrest, while the apoptotic effect of BC-EA may attribute to increased intracellular Ca2+, loss of mitochondria membrane potential (ΔΨm), increase of Bax, Bak, puma, and AIF, and decrease of Bcl-2. Furthermore, the inactivation of Ras signaling pathway by BC-EA also contributed to its apoptotic effect on HCT 116. Our study demonstrates that BC-EA not only inhibits cell growth but also induces apoptosis through inhibiting Ras signal pathway and increasing p53 expression levels. We suggest that BC-EA may be a new dietary supplement and a useful tool to search for therapeutic candidates against colon cancer.