Automated identification and quantification of metastatic brain tumors and perilesional edema based on a deep learning neural network.

PURPOSE: This paper presents a deep learning model for use in the automated segmentation of metastatic brain tumors and associated perilesional edema. METHODS: The model was trained using Gamma Knife surgical data (90 MRI sets from 46 patients), including the initial treatment plan and follow-up images (T1-weighted contrast-enhanced (T1cWI) and T2-weighted images (T2WI)) manually annotated by neurosurgeons to indicate the target tumor and edema regions. A mask region-based convolutional neural network was used to extract brain parenchyma, after which the DeepMedic 3D convolutional neural network was in the segmentation of tumors and edemas. RESULTS: Five-fold cross-validation demonstrated the efficacy of the brain parenchyma extraction model, achieving a Dice similarity coefficient of 96.4%. The segmentation models used for metastatic tumors and brain edema achieved Dice similarity coefficients of 71.6% and 85.1%, respectively. This study also presents an intuitive graphical user interface to facilitate the use of these models in clinical analysis. CONCLUSION: This paper introduces a deep learning model for the automated segmentation and quantification of brain metastatic tumors and perilesional edema trained using only T1cWI and T2WI. This technique could facilitate further research on metastatic tumors and perilesional edema as well as other intracranial lesions.

Association of radiation dose to cardiac substructures with major ischaemic events following breast cancer radiotherapy.

BACKGROUND AND AIMS: Patients with left-sided breast cancer receive a higher mean heart dose (MHD) after radiotherapy, with subsequent risk of ischaemic heart disease. However, the optimum dosimetric predictor among cardiac substructures has not yet been determined. METHODS AND RESULTS: This study retrospectively reviewed 2158 women with breast cancer receiving adjuvant radiotherapy. The primary endpoint was a major ischaemic event. The dose-volume parameters of each delineated cardiac substructure were calculated. The risk factors for major ischaemic events and the association between MHD and major ischaemic events were analysed by Cox regression. The optimum dose-volume predictors among cardiac substructures were explored in multivariable models by comparing performance metrics of each model. At a median follow-up of 7.9 years (interquartile range 5.6-10.8 years), 89 patients developed major ischaemic events. The cumulative incidence rate of major ischaemic events was significantly higher in left-sided disease (P = 0.044). Overall, MHD increased the risk of major ischaemic events by 6.2% per Gy (hazard ratio 1.062, 95% confidence interval 1.01-1.12; P = 0.012). The model containing the volume of the left ventricle receiving 25 Gy (LV V25) with the cut-point of 4% presented with the best goodness of fit and discrimination performance in left-sided breast cancer. Age, chronic kidney disease, and hyperlipidaemia were also significant risk factors. CONCLUSION: Risk of major ischaemic events exist in the era of modern radiotherapy. LV V25 ≥ 4% appeared to be the optimum parameter and was superior to MHD in predicting major ischaemic events. This dose constraint could aid in achieving better heart protection in breast cancer radiotherapy, though a further validation study is warranted.

Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017.

In principle, approval of a modified-release (MR) drug product is based on evidence from pharmacokinetic (PK) and/or pharmacodynamic studies and clinical efficacy/safety studies. The purpose of this survey is (i) to explore the number of new drug applications (NDAs) of MR drug products, approved by the FDA, employ the PK study as a bridge to already-approved immediate-release drug products without conducting their own clinical efficacy/safety studies; and (ii) to understand the type of PK studies are required for such NDAs. To this end, we surveyed the approved records of MR drug products from 2008 to 2017 from the Drug@FDA website, and filtered pertinent information from FDA's assessment reports. A total of five out of 79 products were found. A single dose PK study was conducted to investigate the underlying drug release mechanisms in four of these products. For these products, the applicants also performed multiple dose PK equivalence studies, but the PK parameters used to support the equivalence were different among studies. Information regarding the exposure-response relationship was available for all selected products, which is fundamental for such cases. Although the difference in PK curve shapes is recognized as being critical for the clinical effectiveness, this evaluation was not performed in all selected cases, as indicated in FDA's assessment reports.

Epigenetic Modification and Differentiation Induction of Malignant Glioma Cells by Oligo-Fucoidan.

Malignant glioma (MG) is a poor prognostic brain tumor with inevitable recurrence after multimodality treatment. Searching for more effective treatment is urgently needed. Differentiation induction via epigenetic modification has been proposed as a potential anticancer strategy. Natural products are known as fruitful sources of epigenetic modifiers with wide safety margins. We thus explored the effects of oligo-fucoidan (OF) from brown seaweed on this notion in MG cells including Grade III U87MG cells and Grade IV glioblastoma multiforme (GBM)8401 cells and compared to the immortalized astrocyte SVGp12 cells. The results showed that OF markedly suppress the proliferation of MG cells and only slightly affected that of SVGp12 cells. OF inhibited the protein expressions of DNA methyltransferases 1, 3A and 3B (DNMT1, 3A and 3B) accompanied with obvious mRNA induction of differentiation markers (MBP, OLIG2, S100ß, GFAP, NeuN and MAP2) both in U87MG and GBM8401 cells. Accordingly, the methylation of p21, a DNMT3B target gene, was decreased by OF. In combination with the clinical DNMT inhibitor decitabine, OF could synergize the growth inhibition and MBP induction in U87MG cells. Appropriated clinical trials are warranted to evaluate this potential complementary approach for MG therapy after confirmation of the effects in vivo.

Treatment results and prognostic factors for intracranial nongerminomatous germ cell tumors: single institute experience.

PURPOSE: This study aimed to evaluate the treatment of intracranial nongerminomatous germ cell tumors (NGGCT) and to identify the prognostic factors for survival. METHODS: Thirty-nine patients with nondisseminated NGGCTs, excluding those with pure mature teratomas, were treated between January 1985 and December 2010. Twenty-four patients received gross total or partial removal, 11 had excision biopsies, and 4 had no surgery. Radiotherapy was given postoperatively or definitively with a median tumor bed dose of 54 Gy (range 30-54) with or without craniospinal irradiation. All patients received ten cycles of adjuvant chemotherapy, vinblastine, bleomycin, etoposide, and cisplatin after radiotherapy, except for one with mixed anaplastic astrocytoma component who received oral temozolomide. Survival and prognostic factors were estimated by the Kaplan-Meier method and log-rank tests, respectively. RESULTS: After a median follow-up of 77.7 months (range 14-336), the 6-year overall survival (OS) and progression-free survival (PFS) were 74.4 and 79.5 %, respectively. Inferior PFS was associated with lesions in the suprasellar region (p = 0.017), poor pathological features (p = 0.048), and with poor image (p < 0.0001) and tumor marker (TM) response (p = 0.003) to irradiation. Decreased OS was associated with lesions in the suprasellar region (p = 0.026) and with poor image (p < 0.0001) and TM response (p = 0.027) to irradiation. Neither the extent of surgery nor the radiation field was found to significantly influence survival. CONCLUSIONS: By our multimodality approach, patients achieved comparable outcomes. Other than poor pathological features, patients with poor responses to radiotherapy are prone to early recurrence and inferior survival. These patients should be focused for more intensive adjuvant treatment.

The effect of radiotherapy on patients with pathological stage IIB breast cancer after breast-conserving surgery or mastectomy: A cohort study.

BACKGROUND: Breast cancer is one of the most common cancers in women, and treatment options include surgery, systemic therapies, and radiotherapy (RT). While postoperative RT plays an important role in reducing local recurrence rates and improving survival outcomes, its exact impact on patients with pathological stage IIB breast cancers remains unidentified. METHODS: In this retrospective cohort study, patients with newly diagnosed pathological stage IIB breast cancer who underwent surgery and postoperative RT were included. The data were collected from medical records, and survival outcomes were assessed using the Kaplan-Meier method, log-rank tests, and Cox regression models. RESULTS: In total, 350 patients participated in this study. Overall survival, locoregional recurrence-free survival, event-free survival, and distant metastasis-free survival rates did not significantly differ between those who received RT and those who did not. Multivariate analyses revealed that patients who received anthracycline or taxane chemotherapy had better survival outcomes. CONCLUSION: Our findings demonstrated that postoperative RT had no significant effect on overall survival, locoregional recurrence, event-free survival, or distant metastasis rates in patients with pathological stage IIB breast cancer. However, anthracycline- and taxane-based chemotherapies were associated with improved outcomes. These findings demonstrated the complexities of treating such patient populations with multimodal therapies. Further research is needed to ensure optimal postoperative RT in patients with pathological stage IIB breast cancer. Clinicians must consider individual patient characteristics and incorporate comprehensive treatment approaches to ensure successful outcomes in this population.

Efficacy of therapeutic play for pediatric brain tumor patients during external beam radiotherapy.

OBJECTIVE: External beam radiotherapy (EBRT) is frequently used to improve disease control for pediatric brain tumor patients. However, to facilitate the radiotherapy (RT) procedure, "forced" type interventions including conscious sedation or general anesthesia are frequently used to manage patients' fear and anxiety. The aim of this study was to investigate the effects of therapeutic play (TP) in reducing anxiety for pediatric brain tumor patients treated by EBRT. METHODS: Between April 1st and September 30th, 2009, 19 young brain tumor patients, aged 3-15 years and recommended for RT, were recruited: ten to a control group and nine to the study intervention group. The study group was introduced with TP during EBRT. The Beck Youth Anxiety Inventory and the Faces Anxiety Scale were used to evaluate patients' psychological levels of anxiety. The heart rate variability and salivary cortisol concentrations were used to indicate the patients' physical levels of anxiety. Both the psychological and physiological tests were administered to all subjects before and after the RT procedure. RESULTS: The study group had significantly lower anxiety scores and expressed fewer negative emotions than did the control group before EBRT. CONCLUSIONS: TP can not only improve the quality of medical services but can also reduce costs and staffing demands. In addition, it can help lower young patients' anxiety and fear during medical procedures. As a result, it further decreases the potential negative impacts of hospitalization on these young patients.

Effectiveness of Stereotactic Ablative Radiotherapy for Systemic Therapy Respondents with Inoperable Pulmonary Oligometastases and Oligoprogression.

Stereotactic ablative radiotherapy (SABR) may improve survival in patients with inoperable pulmonary oligometastases. However, the impact of pulmonary oligometastatic status after systemic therapy on SABR outcomes remains unclear. Hence, we investigated the outcomes of SABR in 45 patients with 77 lung tumors and the prognostic value of pulmonary oligoprogression. Eligibility criteria were pulmonary oligometastases (defined as ≤5 metastatic lung tumors), controlled extrapulmonary disease (EPD) after front-line systemic therapy, SABR as primary local treatment for inoperable pulmonary metastases, and consecutive imaging follow-up. Oligometastatic lung tumor was classified into controlled or oligoprogressive status. Overall survival (OS), in-field progression-free survival (IFPFS), out-field progression-free survival (OFPFS), and prognostic variables were evaluated. With 21.8 months median follow-up, the median OS, IFPFS, and OFPFS were 28.3, not reached, and 6.5 months, respectively. Two-year OS, IFPFS, and OFPFS rates were 56.0%, 74.2%, and 17.3%, respectively. Oligoprogressive status (p = 0.003), disease-free interval < 24 months (p = 0.041), and biologically effective dose (BED10) < 100 Gy (p = 0.006) were independently associated with inferior OS. BED10 ≥ 100 Gy (p = 0.029) was independently correlated with longer IFPFS. Oligoprogressive status (p = 0.017) and EPD (p = 0.019) were significantly associated with inferior OFPFS. Grade ≥ 2 radiation pneumonitis occurred in four (8.9%) patients. Conclusively, SABR with BED10 ≥ 100 Gy could provide substantial in-field tumor control and longer OS for systemic therapy respondents with inoperable pulmonary oligometastases. Oligoprogressive lung tumors exhibited a higher risk of out-field treatment failure and shorter OS. Hence, systemic therapy should be tailored for patients with oligoprogression to reduce the risk of out-field treatment failure. However, in the absence of effective systemic therapy, SABR is a reasonable alternative to reduce resistant tumor burden.

Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

Wafer-scale nanocracks enable single-molecule detection and on-site analysis.

Large-area surface-enhanced Raman spectroscopy (SERS) sensing platforms displaying ultrahigh sensitivity and signal uniformity have potentially enormous sensing applicability, but they are still challenging to prepare in a scalable manner. In this study, silver nanopaste (AgNPA) was employed to prepare a wafer-scale, ultrasensitive SERS substrate. The self-generated, high-density Ag nanocracks (NCKs) with small gaps could be created on Si wafers via a spin-coating process, and provided extremely abundant hotspots for SERS analyses with ultrahigh sensitivity-down to the level of single molecules (enhancement factor: ca. 1010; detection limit: ca. 10-18 M)-and great signal reproducibility (variation: ca. 3.6%). Moreover, the Ag NCK arrays demonstrated broad applicability and practicability for on-site detection when combined with a portable 785 Raman spectrometer. This method allowed the highly sensitive detection of a diverse range of analytes (benzo[a]pyrene, di-2-ethylhexyl phthalate, aflatoxins B1, zearalenone, ractopamine, salbutamol, sildenafil, thiram, dimethoate, and methamidophos). In particular, pesticides are used extensively in agricultural production. Unfortunately, they can affect the environment and human health as a result of acute toxicity. Therefore, the simultaneous label-free detection of three different pesticides was demonstrated. Finally, the SERS substrates are fabricated through a simple, efficient, and scalable process that offers new opportunities for mass production.

Selenium Yeast and Fish Oil Combination Diminishes Cancer Stem Cell Traits and Reverses Cisplatin Resistance in A549 Sphere Cells.

Cisplatin is a prevalent chemotherapeutic agent used for non-small cell lung cancer (NSCLC) that is difficult to treat by targeted therapy, but the emergence of resistance severely limits its efficacy. Thus, an effective strategy to combat cisplatin resistance is required. This study demonstrated that, at clinically achievable concentrations, the combination of selenium yeast (Se-Y) and fish oil (FO) could synergistically induce the apoptosis of cancer stem cell (CSC)-like A549 NSCLC sphere cells, accompanied by a reversal of their resistance to cisplatin. Compared to parental A549 cells, sphere cells have higher cisplatin resistance and possess elevated CSC markers (CD133 and ABCG2), epithelial-mesenchymal transition markers (anexelekto (AXL), vimentin, and N-cadherin), and cytoprotective endoplasmic reticulum (ER) stress marker (glucose-regulated protein 78) and increased oncogenic drivers, such as yes-associated protein, transcriptional coactivator with PDZ-binding motif, ß-catenin, and cyclooxygenase-2. In contrast, the proapoptotic ER stress marker CCAAT/enhancer-binding protein homologous protein and AMP-activated protein kinase (AMPK) activity were reduced in sphere cells. The Se-Y and FO combination synergistically counteracted the above molecular features of A549 sphere cells and diminished their elevated CSC-like side population. AMPK inhibition by compound C restored the side population proportion diminished by this nutrient combination. The results suggest that the Se-Y and FO combination can potentially improve the outcome of cisplatin-treated NSCLC with phenotypes such as A549 cells.

Microsatellite Instability, Epstein-Barr Virus, and Programmed Cell Death Ligand 1 as Predictive Markers for Immunotherapy in Gastric Cancer.

Immunotherapy benefits selected cases of gastric cancer (GC), but the correlation between biomarkers and prognosis is still unclear. Fifty-two patients with GC who underwent immunotherapy were enrolled from June 2016 to December 2020. Their clinical features and biomarkers-microsatellite instability-high (MSI-H), programmed cell death ligand 1 (PD-L1) combined positive score (CPS), and Epstein-Barr encoding region (EBER)-were analyzed. Eight patients had MSI-H, five patients had EBER, 29 patients had CPS ≥ 1, and 20 patients had no biomarker. The overall response rates (ORRs) of the MSI-H, EBER, PD-L1 CPS ≥ 1, and all-negative group were 75%, 60%, 44.8%, and 15%, respectively. Compared with that of the all-negative group, progression-free survival (PFS) was better in the MSI-H (p = 0.018), CPS ≥ 5 (p = 0.012), and CPS ≥ 10 (p = 0.006) groups, but not in the EBER (p = 0.2) and CPS ≥ 1 groups (p = 0.35). Ten patients had combined biomarkers, CPS ≥ 1 with either MSI-H or EBER. The ORRs were 66.7% for CPS ≥ 1 and MSI-H and 75% for CPS ≥ 1 and EBER. PFS was better in patients with combined biomarkers (p = 0.01). MSI-H, EBER, and CPS are useful biomarkers for predicting the efficacy of immunotherapy.

Outcomes of intracranial germinoma-A retrospective multinational Asian study on effect of clinical presentation and differential treatment strategies.

BACKGROUND: This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes. METHODS: A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken. RESULTS: From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had ß-human chorionic gonadotropin values <50 mIU/mL. The 5/10-year overall survival (OS) and recurrence-free survival (RFS) rates were 97.2%/96.2% and 89.9%/86.9%, respectively. RFS was predicted by the radiotherapy (RT) field, with focal RT having the worst outcome, whereas chemotherapy usage had no impact on survival. Among patients who received chemotherapy, response to chemotherapy did not predict survival outcomes. In M0 patients, primary basal ganglia tumors predicted a worse RFS. In patients with bifocal tumors, an extended field RT was associated with better outcomes. In multivariable analysis, only RT fields were associated with RFS. In relapsed patients, salvage rates were high at 85.7%. Additionally, patients who received salvage RT had a better outcome (91.6% vs. 66.7%). CONCLUSIONS: Survival outcomes of patients with germinoma were excellent. Thus, the focus of treatment for intracranial germinoma should be on survivorship. Further studies are warranted to find the optimal intensity and volume of radiation, including the role of chemotherapy in the survival of patients with intracranial germinomas, considering age, primary tumor location, and extent of disease.

The Irradiated Brain Volume Within 12 Gy Is a Predictor for Radiation-Induced Changes After Stereotactic Radiosurgery in Patients With Unruptured Cerebral Arteriovenous Malformations.

PURPOSE: Our purpose was to determine whether the coverage of brain parenchyma within the 12 Gy radiosurgical volume (V12) correlates with the development of radiation-induced changes (RICs) in patients with unruptured cerebral arteriovenous malformations (AVM) after undergoing stereotactic radiosurgery (SRS). METHODS AND MATERIALS: This study conducted regular follow-up examinations of 165 patients with unruptured AVMs who had previously undergone SRS. The RICs identified in T2-weighted magnetic resonance imaging (MRI) scans at any time point in the first 3 years after SRS were labeled "early RICs." The RICs identified in T2-weighted MRI scans at 5-year follow-up brain images were labeled "late RICs." Fully automated segmentation was used to analyze the MRI scans from these patients, whereupon the volume and proportion of brain parenchyma within the V12 was calculated. Logistic regression analysis was used to characterize the factors affecting the incidence of early and late RICs of any grade after SRS. RESULTS: The median duration of follow-up was 70 months (range, 36-222). Early RICs were identified in 124 of the 165 patients with the highest grades as followed: grade 1 (103 patients), grade 2 (19 patients), and grade 3 (2 patients). Only 103 patients had more than 5 years follow-up, and late RICs were identified in 70 of 103 patients. Seventeen of 70 patients with late RICs were symptomatic. The median volume and proportion of brain parenchyma within the V12 was 22.4 cm3 (range, 0.6-63.9) and 58.7% (range, 18.4-76.8). Univariate analysis revealed that AVM volume and the brain volume within the V12 were correlated with the incidence of both early and late RICs after SRS. Multivariable analysis revealed that only the brain volume within the V12 was significantly associated with the incidence of early and late RICs after SRS. CONCLUSIONS: In patients with unruptured AVM, the volume of brain parenchyma within the V12 was an important factor associated with the incidence of early and late RICs after SRS. Before SRS, meticulous radiosurgical planning to reduce brain parenchyma coverage within the V12 could reduce the risk of complications.

Effects of Erythropoietin Payment Policy on Cardiovascular Outcomes of Peritoneal Dialysis Patients: Observational Study.

BACKGROUND: The change in the reimbursement policy of erythropoietin administration to patients receiving peritoneal dialysis by the Taiwan National Health Insurance (NHI) system provided a natural experimental venue to examine whether cardiovascular risk differs when maintaining the hematocrit (Hct) level below or above 30%. OBJECTIVE: The aim of this study was to analyze the impact of loosening the erythropoietin payment criteria for peritoneal dialysis patients on their cardiovascular outcomes. METHODS: Two cohorts of incident peritoneal dialysis patients were identified according to the time before and after relaxation of the NHI's erythropoietin payment criteria, designated cohort 1 (n=1759) and cohort 2 (n=2981), respectively. The cohorts were matched according to propensity scores (1754 patients in each cohort) and then followed up for cardiovascular events, which were analyzed with Cox regressions. RESULTS: For the composite cardiovascular endpoint, patients in cohort 2 had a significantly lower risk than those in cohort 1. However, subgroup analysis showed that this risk reduction was observed only in patients with diabetes. CONCLUSIONS: After loosening erythropoietin payment criteria, reduced cardiovascular risks were observed, particularly for patients with diabetes. These results indicate that it is crucial to maintain an Hct level above 30% to reduce the cardiovascular risk in patients with diabetes undergoing peritoneal dialysis.

Effectiveness of stereotactic ablative radiotherapy in patients with advanced hepatocellular carcinoma unsuitable for transarterial chemoembolization.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) can deliver tumoricidal doses and achieve long-term control in early hepatocellular carcinoma (HCC). However, limited studies have investigated the safety and effectiveness of SABR in patients with advanced diseases that is unsuitable for transarterial chemoembolization (TACE). METHODS: In this observational study, we reviewed the medical records of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease treated with linear accelerator-based SABR between 2008 and 2016. Their tumors were either refractory to TACE or TACE was contraindicated. Overall survival (OS), in-field progression-free survival (IFPFS), and out-field progression-free survival were calculated using Kaplan-Meier analysis. The Cox regression model was used to examine the effects of variables. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03) and whether patients developed radiation-induced liver disease (RILD) after SABR. RESULTS: This study included 32 patients. The mean maximal tumor diameter and tumor volumes were 4.7 cm and 135.9 ml, respectively. Patients received linear accelerator-based SABR with a median prescribed dose of 48 Gy (30-60 Gy) in three to six fractions. Based on the assessment of treatment response by using the Response Evaluation Criteria in Solid Tumors (version 1.1), 19% of patients achieved a complete response and 53% achieved a partial response. After a median follow-up of 18.1 months (4.0-65.9 months), 10, 19, and 9 patients experienced in-field failure, out-field hepatic recurrence, and extrahepatic metastases, respectively. The estimated 2-year OS and IFPFS rates were 54.4% and 62.7%, respectively. In a multivariate analysis, a pretreatment Cancer of the Liver Italian Program (CLIP) score of ⩾2 (p = 0.01) was a prognostic factor for shorter OS, and a biologically effective dose (BED) of < 85 Gy10 (p = 0.011) and a Child-Pugh score of ⩾6 (p = 0.014) were prognostic factors for inferior IFPFS. In this study five and eight patients developed classic and nonclassic RILD, respectively. CONCLUSIONS: SABR can serve as a salvage treatment for patients with HCC with BCLC stage C disease unsuitable for TACE, in particular, in those with a baseline CLIP score of ⩽1. A BED10 of ⩾85 Gy is an appropriate prescribed dose for tumor control. Because out-field relapse is the major cause of treatment failure, SABR in combination with novel systemic modalities should be investigated in future studies.

Chronic hepatitis ameliorates anaemia in haemodialysis patients.

BACKGROUND: Study for influence of chronic hepatitis (CH) on anaemia in haemodialysis (HD) patients remains inconclusive. We aim to characterize the red cell status between CH and hepatitis-free groups among the HD population. METHODS: We retrospectively analysed 80 chronic HD patients from Taipei Medical University Hospital with monthly sampled biochemical study between December 2004 and December 2005. Data classified according to the hepatitis-free, chronic hepatitis B and C groups were expressed as mean +/- standard deviation. Student's t-test and anova were used to determine the mean difference for continuous variables. RESULTS: Age, Kt/V, systolic or diastolic blood pressure, body mass index, total cholesterol and triglyceride were not different between CH and hepatitis-free groups. HD duration (P = 0.0002), aspartate (P < 0.0001), alanine aminotransferase (P < 0.0001), alkaline phosphatase (P = 0.04), haemoglobin (P = 0.0066) and haematocrit (P = 0.002) were significantly more elevated in the CH group demanding less erythropoietin dose than in the hepatitis-free group. CONCLUSION: Our study demonstrated that lessened anaemia was observed in CH, which demanded less erythropoietin dose.

Opposite Regulation of CHOP and GRP78 and Synergistic Apoptosis Induction by Selenium Yeast and Fish Oil via AMPK Activation in Lung Adenocarcinoma Cells.

Selenium has been intensively studied for the use of cancer prevention and treatment. However, the clinical effects are still plausible. To enhance its efficacy, a combinational study of selenium yeast (SY) and fish oil (FO) was performed in A549, CL1-0, H1299, HCC827 lung adenocarcinoma (LADC) cells to investigate the enhancement in apoptosis induction and underlying mechanism. By sulforhodamine B staining, Western blot and flow cytometric assays, we found a synergism between SY and FO in growth inhibition and apoptosis induction of LADC cells. In contrast, the fetal lung fibroblast cells (MRC-5) were unsusceptible to this combination effect. FO synergized SY-induced apoptosis of A549 cells, accompanied with synergistic activation of AMP-activated protein kinase (AMPK) and reduction of Cyclooxygenase (COX)-2 and ß-catenin. Particularly, combining with FO not only enhanced the SY-elevated proapoptotic endoplasmic reticulum (ER) stress marker CCAAT/enhancer-binding protein homologous protein (CHOP), but also reduced the cytoprotective glucose regulated protein of molecular weight 78 kDa (GRP78). Consequently, the CHOP downstream targets such as phospho-JNK and death receptor 5 were also elevated, along with the cleavage of caspase-8, -3, and the ER stress-related caspase-4. Accordingly, inhibition of AMPK by compound C diminished the synergistic apoptosis induction, and elevated CHOP/GRP78 ratio by SY combined with FO. The AMPK-dependent synergism suggests the combination of SY and FO for chemoprevention and integrative treatment of LADC.

Induction of Forkhead Class box O3a and apoptosis by a standardized ginsenoside formulation, KG-135, is potentiated by autophagy blockade in A549 human lung cancer cells.

BACKGROUND: KG-135, a standardized formulation enriched with Rk1, Rg3, and Rg5 ginsenosides, has been shown to inhibit various types of cancer cells; however, the underlying mechanisms are not fully understood. In this study, we explored its effects in A549 human lung cancer cells to investigate the induction of Forkhead Class box O3a (FOXO3a) and autophagy. METHODS: Cell viability was determined by sulforhodamine B staining. Apoptosis and cell cycle distribution were analyzed using flow cytometry. The changes of protein levels were determined using Western blot analysis. Autophagy induction was monitored by the formation of acidic vesicular organelles stained with acridine orange. RESULTS: KG-135 effectively arrested the cells in G1 phase with limited apoptosis. Accordingly, a decrease of cyclin-dependent kinase-4, cyclin-dependent kinase-6, cyclin D1, and phospho-retinoblastoma protein, and an increase of p27 and p18 proteins were observed. Intriguingly, KG-135 increased the tumor suppressor FOXO3a and induced the accumulation of autophagy hallmark LC3-II and acidic vesicular organelles without an increase of the upstream marker Beclin-1. Unconventionally, the autophagy adaptor protein p62 (sequestosome 1) was increased rather than decreased. Blockade of autophagy by hydroxychloroquine dramatically potentiated KG-135-induced FOXO3a and its downstream (FasL) ligand accompanied by the cleavage of caspase-8. Meanwhile, the decrease of Bcl-2 and survivin, as well as the cleavage of caspase-9, were also drastically enhanced, resulting in massive apoptosis. CONCLUSION: Besides arresting the cells in G1 phase, KG-135 increased FOXO3a and induced an unconventional autophagy in A549 cells. Both the KG-135-activated extrinsic FOXO3a/FasL/caspase-8 and intrinsic caspase-9 apoptotic pathways were potentiated by blockade of autophagy. Combination of KG-135 and autophagy inhibitor may be a novel strategy as an integrative treatment for cancers.

Definitive Radiotherapy for Older Patients with Prostate Cancer: Experience of a Medical Center in Taiwan.

Whether age predicts treatment outcome of prostate cancer remains controversial. With the aging of the world population, properly understanding the effect of age may facilitate both treatment decision-making and defining the natural history of prostate cancer. Consecutive 581 patients with locally-confined adenocarcinoma of the prostate who received radical definitive radiotherapy(RT) (76-78 Gy) between 2004 and 2015 at a medical center in Taiwan were reviewed retrospectively. Median age was 78 years. The median follow-up was 66 months. The 5-year biochemical failure-free survival(BFFS), distant metastasis-free survival(DMFS), disease-specific survival(DSS), and overall survival(OS) rates were 84.9%, 93.8%, 97.8%, and 86.6%, respectively, for all patients. Comparing those above and below the age of 80, no difference in 5-year BFFS, DMFS, or DSS was found. Multivariate Cox regression analysis showed that tumor stage, Gleason score, initial PSA, and latency before RT were significant risk factors of BFFS. The latency before RT was significantly longer in the older group than in the under 80 group. Delay to start RT might explain the previous finding of inferior disease control in older patients in other studies. With the exception of OS, no other differences in outcomes or toxicities were observed in older patients.