Factors affecting high-grade hepatotoxicity of tyrosine kinase inhibitors in cancer patients: a multi-center observational study.

PURPOSE: Although several studies have examined tyrosine kinase inhibitor (TKI)-induced hepatotoxicity, the majority of patients in those studies displayed low-grade (grade I-II) hepatotoxicity. The purpose of this study was to investigate factors affecting high-grade (grade III-IV) hepatotoxicity of TKIs. METHODS: This multi-center, retrospective study used individual patient data from five studies that examined factors affecting hepatotoxicity by TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib). Odds ratio (OR) and adjusted OR (AOR) were estimated from univariate and multivariate analyses, respectively. RESULTS: Data from 1279 patients treated with TKIs were analyzed. The rate of patients who experienced high-grade hepatotoxicity after TKI administration was 5.5%. In multivariable analysis, H2 blockers and CYP3A4 inducers increased high-grade hepatotoxicity 2.2- (95% CI 1.255-3.944) and 3.3-fold (95% CI 1.260-8.698), respectively. Patients with liver metastasis revealed a 3.4-fold (95% CI 1.561-7.466) higher risk of high-grade hepatotoxicity. Among underlying malignancies, pancreatic cancer and other cancers including acute lymphoblastic leukemia increased the risk of high-grade hepatotoxicity by 2.6- and 24.3-fold, respectively, whereas breast cancer decreased the risk (AOR 0.3, 95% CI 0.106-0.852), compared to non-small cell lung cancer. In patients who administrated TKIs which form reactive metabolites, use of CYP3A4 inducers and liver metastasis increased incidence of high-grade hepatotoxicity by 3.0- and 2.3-fold, respectively. In patients with EGFR mutation, exon 19 deletion and use of proton pump inhibitors were risk factors for high-grade hepatotoxicity in addition to liver metastasis and use of H2 blockers. CONCLUSION: The use of H2 blockers, presence of liver metastasis, and CYP3A4 inducers were associated with high-grade hepatotoxicity of TKIs. In subgroup analyses, presence of exon 19 deletion, and/or proton pump inhibitors, was additional risk factors for high-grade hepatotoxicity in special patients and use of specific TKIs. Close liver function monitoring is recommended, especially in patients with liver metastasis or using H2 blockers or CYP3A4 inducers.

Effects of pharmacist interventions on reducing prescribing errors of investigational drugs in oncology clinical trials.

OBJECTIVES: This study aimed to investigate the effectiveness of pharmacist intervention in reducing and preventing prescribing errors of investigational drugs for cancer patients. MATERIALS AND METHODS: A retrospective study was conducted during two periods: a baseline period from December 2015 to June 2016 and an intervention period from July 2016 to February 2017. The investigational drug service (IDS) pharmacists performed active interventions during the intervention period. RESULTS: Among 12,387 investigational drug orders, 395 (6.1%) prescribing errors were detected in 6477 orders at the baseline period, and 278 errors (4.7%) were detected in 5,910 orders at the intervention period. To identify factors that affect prescribing errors, three models were constructed for the multivariate analysis. Among factors affecting prescribing errors, sponsor initiated trial (SIT) was the strongest factor (AOR: 4.16, 95% CI: 3.31-5.23). Pharmacist intervention reduced prescribing errors by at least 25% in all constructed models after adjusting for confounding variables. Prescribing errors were 1.3 times higher when dealing with intravenous medications than when dealing with oral medications. There were 60% fewer prescribing errors in the blinded study than in the open study. SIT and multi-center/multi-nation studies had 4.2 and 2.4 times more frequent prescribing errors than in investigator-initiated trials (IIT) and single-center/single-nation studies, respectively. Fewer errors occurred in phase 2 and trials covering both phase 1 and phase 2 (phase 1/2) than in phase 3 trials. CONCLUSIONS: The IDS pharmacist intervention in cancer clinical trials was associated with significant reductions in prescribing errors and may lead to increased medication safety.

Risk factors associated with the incidence and time to onset of lapatinib-induced hepatotoxicity.

PURPOSE: Although lapatinib-induced hepatotoxicity can cause severe clinical complications in patients, the factors affecting hepatotoxicity have rarely been investigated. The purpose of this study was to investigate risk factors for hepatotoxicity and time to lapatinib-induced hepatotoxicity. METHODS: This retrospective study was performed on metastatic breast cancer patients treated with lapatinib. Various factors were evaluated for hepatotoxicity and time to hepatotoxicity, including sex, age, body weight, height, body surface area, underlying disease, smoking history, start dose of lapatinib, status of liver metastasis, and concomitant drugs. RESULTS: Among 159 patients, the percentage of patients with hepatotoxicity after lapatinib initiation was 57.9% (n = 92). Multivariate analysis showed that concomitant use of H2 blockers increased the incidence of hepatotoxicity by 2.3-fold. Patients who received CYP3A4 inducers had 3.1 times higher risk of hepatotoxicity incidence; the attributable risks of H2 blockers and CYP3A4 inducers were 56.7% and 68.1%, respectively. Use of H2 blockers increased the hazard of time to hepatotoxicity by 1.8-fold compared to non-use of H2 blockers. CONCLUSIONS: Our study demonstrated that concomitant use of H2 blockers and CYP3A4 inducers was associated with lapatinib-induced hepatotoxicity. Close liver function monitoring is recommended, especially in patients receiving H2 blockers or CYP3A4 inducers.

Amomum cardamomum L. ethyl acetate fraction protects against carbon tetrachloride-induced liver injury via an antioxidant mechanism in rats.

BACKGROUND: Medicinal herb-derived drug development has become important in the relief of liver pathology. Amomun cardamomum is traditionally used therapeutically in Korea to treat various human ailments including dyspepsia, hiccupping, and vomiting. We investigated to assess the protective effect of A. cardamomum on carbon tetrachloride (CCl4)-induced liver damage through antioxidant activity in hepatic tissues of Sprague-Dawley rats. METHODS: Antioxidant properties of different fractions from A. cardamomum from ethanol extracts were evaluated by an in vitro free radical scavenging systems. The protective effect of the ethyl acetate fraction from A. cardamomum (EAAC) against CCl4-induced cytotoxicity was determined by a cell viability assay using HepG2 hepatocarcinoma cells. In vivo study, the influence of EAAC concentrations of 100 and 200 mg/kg following CCl4-induced hepatic injury was assessed. Serum levels of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and alkaline phosphatase (ALP) were determined, as was lipid peroxidation (malondialdehyde, MDA). Effect of EAAC on liver detoxification enzymes including superoxide dismutase (SOD), total glutathione (GSH), and glutathione S-transferase (GST) activity was measured in rat liver homogenates. Liver cytochrome P450 (CYP2E1) expression level was determined by quantification of mRNA. RESULTS: Phytochemical analysis of A. cardamomum indicated that EAAC was enriched in total polyphenol and total flavonoid. Most of the tannins were confined to the hexane fraction. Hepatoprotective properties of EAAC were evident, with significantly reduced serum levels of GOT, GPT, and ALP compared with the control group. Improved hepatic antioxidant status was evident by increased SOD, GSH, and GST enzymes in rat liver tissue. Liver lipid peroxidation induced by CCl4 was apparent by increased intracellular MDA level. EAAC suppressed lipid peroxidation as evidenced by the significant decrease in MDA production. Expression of CYP2E1 was also significantly decreased at the higher concentration of EAAC, indicating the hepatoprotective efficacy of EAAC on acute liver damage. CONCLUSION: These results indicated that EAAC has a significant hepatoprotective activity on CCl4-induced acute hepatic injury in rats, which might be derived from its antioxidant properties and CYP2E1 downregulation.

Phenotype difference between familial and sporadic ankylosing spondylitis in Korean patients.

Clustered occurrences of ankylosing spondylitis (AS) in family have been noticed. We evaluated patients with AS confirmed by the modified New York criteria for familial history of AS (one or more first to third degree relatives). The clinical characteristics and the recurrence risks (number of AS patients/number of familial members) of the familial AS compared to sporadic AS were investigated. Out of a total of 204 AS patients, 38 patients (18.6%) reported that they had a familial history of AS. The recurrence risks in the familial AS patients for first, second and third degree family members were 14.5%, 5.2%, and 4.4% respectively. Erythrocyte sedimentation rate (ESR) (22.6 ± 22.2 vs 35.4 ± 34.4, P=0.029) and C-reactive protein (CRP) (1.24 ± 1.7 vs 2.43 ± 3.3, P=0.003) at diagnosis, body mass index (21.9 ± 2.7 vs 23.7 ± 3.3, P=0.002) and frequency of oligoarthritis (13.2% vs 33.7%, P=0.021) were significantly lower in the familial form. The presence of HLA-B27 (97.4% vs 83.1%, P=0.044) was significantly higher in familial AS. In conclusion, Korean familial AS patients show a lower frequency of oligoarthritis, lower BMI, lower ESR and CRP at diagnosis and higher presence of HLA-B27.

Development and application of a home-based exercise program for patients with cardiovascular disease: a feasibility study.

BACKGROUND: Cardiac rehabilitation (CR) is recommended for patients with cardiovascular disease. However, the participation and completion rates for hospital-based CR are low, and home-based CR has been suggested as an alternative. This study aimed to develop a home-based CR program and assess the feasibility of the program over a 6-week period in patients with left ventricular dysfunction or a history of myocardial infarction. METHODS: This feasibility study consisted of two phases. The initial phase (Study 1) focused on developing the home-based exercise protocol. Systematic approaches to developing evidence-based home-based exercise intervention were implemented including systematic review, patient surveys, and expert consensus. Study 2 aimed to evaluate the feasibility of a 6-week home-based CR program that was based on the results of Study 1. Study 2 included two exercise education sessions and four telephone counseling sessions. During this stage of the exercise program, the participants exercised on two separate days and their experiences while performing the aerobic and resistance exercises were surveyed. Eight participants participated in Study 1 and 16 participated in Study 2. RESULTS: Participants expressed overall satisfaction with the exercise program in Study 1. Heart rate increased in response to exercise, but this did not correspond with perceived exertion. The aim of the home-based CR exercise program was for participants to achieve exercise goals (≥150 min/week of aerobic type exercises as well as at least twice weekly resistance exercise using own body weights). We aimed to increase compliance and adherence to the home-based CR program. In Study 2, 13 out of 16 participants (81.3%) completed the 6-week home-based CR program, with a participation rate of 100% in both exercise education and phone counseling sessions. Adherence to the home-based exercise protocol was 83.1% and no serious adverse events were observed. At the beginning of the study, only three out of 13 participants (23.1%) met the requirements for both aerobic and resistance exercises, but at the end of the 6-week program, 10 out of 13 participants (76.9%) fulfilled the requirements. CONCLUSION: The exercise program developed in this study was safe and feasible, and the 6-week home-based CR program was feasible for patients with cardiovascular disease without any reported adverse effects.

High impacts of cultivar and home-cooking practice on the content of free myo-inositol, a bioavailable health-promoting cyclitol, in sweet potato.

Free myo-inositol is a bioavailable form of a cyclitol having various health-promoting activities. The impact of cultivar and home-cooking practice on the content of free myo-inositol in sweet potatoes (12 cultivars grown in 2 different locations) was studied. A GC-MS/MS method following in situ trimethylsilylation was established and validated to determine free myo-inositol. The established analytical method was sensitive, precise, and accurate. It was found that free myo-inositol content in sweet potato varied greatly (sevenfolds) with cultivar, ranging from 377.1 to 2628.3 mg/kg dw. A cultivar Poongwon-mi was found to be an exceptionally rich source of free myo-inositol (2628.3 mg/kg dw). Home-cooking practice markedly increased free myo-inositol content (maximum 240%). Baking showed the highest impact on the increase in free myo-inositol, followed by steaming, microwave cooking, and boiling, in decreasing order. This represents the first report of the remarkably high impact of cultivar and home-cooking practice on the free myo-inositol content in sweet potato. PRACTICAL APPLICATION: The free myo-inositol content in sweet potato varied greatly with the cultivars. Poongwon-mi contained a surprisingly high content of free myo-inositol. Home-cooking dramatically increased the free myo-inositol content.

A Risk Scoring System Utilizing Machine Learning Methods for Hepatotoxicity Prediction One Year After the Initiation of Tyrosine Kinase Inhibitors.

Background: There is currently no method to predict tyrosine kinase inhibitor (TKI) -induced hepatotoxicity. The purpose of this study was to propose a risk scoring system for hepatotoxicity induced within one year of TKI administration using machine learning methods. Methods: This retrospective, multi-center study analyzed individual data of patients administered different types of TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib) selected in five previous studies. The odds ratio and adjusted odds ratio from univariate and multivariate analyses were calculated using a chi-squared test and logistic regression model. Machine learning methods, including five-fold cross-validated multivariate logistic regression, elastic net, and random forest were utilized to predict risk factors for the occurrence of hepatotoxicity. A risk scoring system was developed from the multivariate and machine learning analyses. Results: Data from 703 patients with grade II or higher hepatotoxicity within one year of TKI administration were evaluated. In a multivariable analysis, male and liver metastasis increased the risk of hepatotoxicity by 1.4-fold and 2.1-fold, respectively. The use of anticancer drugs increased the risk of hepatotoxicity by 6.0-fold. Patients administered H2 blockers or PPIs had a 1.5-fold increased risk of hepatotoxicity. The area under the receiver-operating curve (AUROC) values of machine learning methods ranged between 0.73-0.75. Based on multivariate and machine learning analyses, male (1 point), use of H2 blocker or PPI (1 point), presence of liver metastasis (2 points), and use of anticancer drugs (4 points) were integrated into the risk scoring system. From a training set, patients with 0, 1, 2-3, 4-7 point showed approximately 9.8%, 16.6%, 29.0% and 61.5% of risk of hepatotoxicity, respectively. The AUROC of the scoring system was 0.755 (95% CI, 0.706-0.804). Conclusion: Our scoring system may be helpful for patient assessment and clinical decisions when administering TKIs included in this study.

Feasibility of using dental putty-based custom molds for high-dose-rate brachytherapy of oral mucosal melanoma.

PURPOSE: To investigate the feasibility of using dental putty to fabricate custom molds for high-dose-rate (HDR) brachytherapy of oral mucosal melanoma. Practical guidelines of using dental putty for the custom mold fabrication are presented. METHODS: Dose measurements were performed using radiochromic films to understand the dosimetric characteristics of dental putty. The percentage depth dose (PDD) and profile curves were obtained using a single Co-60 source located on top of a cubic volume of the dental putty. Two custom molds were fabricated for a patient with mucosal melanoma lesions, which were spread throughout the right mandibular gingiva and soft palate regions. Furthermore, pretreatment dosimetry for both lesions was performed to evaluate the delivery quality of the resulting HDR brachytherapy plans and adjust the overall dose level. RESULTS: Prescribed doses for the two oral cavity regions were successfully delivered with a reasonable dose uniformity. Based on the measured single-source PDD curve, the maximum dose was observed at a depth of approximately 1 mm, which indicated steep dose gradients at depths ranging from 0 to 2 mm. Furthermore, a simulation with the measured single-source two-dimensional profile revealed that a source-to-source distance of 10 mm was appropriate to generate a uniform dose distribution at a source-to-surface distance of 5 mm. CONCLUSIONS: The use of a custom mold was found to be feasible for HDR brachytherapy while carefully considering the source-to-surface and source-to-source distances. Pretreatment delivery verification would be necessary when a uniform dose distribution is required.

Synthetic contrast-enhanced computed tomography generation using a deep convolutional neural network for cardiac substructure delineation in breast cancer radiation therapy: a feasibility study.

BACKGROUND: Adjuvant radiation therapy improves the overall survival and loco-regional control in patients with breast cancer. However, radiation-induced heart disease, which occurs after treatment from incidental radiation exposure to the cardiac organ, is an emerging challenge. This study aimed to generate synthetic contrast-enhanced computed tomography (SCECT) from non-contrast CT (NCT) using deep learning (DL) and investigate its role in contouring cardiac substructures. We also aimed to determine its applicability for a retrospective study on the substructure volume-dose relationship for predicting radiation-induced heart disease. METHODS: We prepared NCT-CECT cardiac scan pairs of 59 patients. Of these, 35, 4, and 20 pairs were used for training, validation, and testing, respectively. We adopted conditional generative adversarial network as a framework to generate SCECT. SCECT was validated in the following three stages: (1) The similarity between SCECT and CECT was evaluated; (2) Manual contouring was performed on SCECT and CECT with sufficient intervals and based on this, the geometric similarity of cardiac substructures was measured between them; (3) The treatment plan was quantitatively analyzed based on the contours of SCECT and CECT. RESULTS: While the mean values (± standard deviation) of the mean absolute error, peak signal-to-noise ratio, and structural similarity index measure between SCECT and CECT were 20.66 ± 5.29, 21.57 ± 1.85, and 0.77 ± 0.06, those were 23.95 ± 6.98, 20.67 ± 2.34, and 0.76 ± 0.07 between NCT and CECT, respectively. The Dice similarity coefficients and mean surface distance between the contours of SCECT and CECT were 0.81 ± 0.06 and 2.44 ± 0.72, respectively. The dosimetry analysis displayed error rates of 0.13 ± 0.27 Gy and 0.71 ± 1.34% for the mean heart dose and V5Gy, respectively. CONCLUSION: Our findings displayed the feasibility of SCECT generation from NCT and its potential for cardiac substructure delineation in patients who underwent breast radiation therapy.

Heart-Sparing Capability and Positional Reproducibility of Continuous Positive Airway Pressure in Left-Sided Breast Radiation Therapy.

PURPOSE: Our purpose was to investigate the interfraction and intrafraction reproducibility and practical applicability of continuous positive airway pressure (CPAP) for left breast volumetric modulated arc therapy (VMAT). METHODS AND MATERIALS: Interfraction reproducibility of the position of the heart was evaluated by measuring the heart-to-target distance on 20 planning computed tomography (CT) and 300 daily cone beam CT of 20 patients with left breast cancer treated with a 15-fraction VMAT. The dosimetric metrics of the whole heart and its substructures were compared between CPAP and free-breathing based VMAT plans. Intrafraction reproducibility was evaluated by measuring the motions of the breast target and diaphragm in 4-dimensional CT of 20 female patients with nonbreast cancer. Lastly, we analyzed the CPAP compliance data of 237 consecutive patients with left-sided breast cancer with and without internal mammary node irradiation (IMNI). RESULTS: The heart position was reproducible as evidenced by an absolute average heart-to-target distance error of 2.0 ± 2.0 mm. Compared with free-breathing, CPAP significantly reduced the mean heart dose and the dose to the left ventricle and left anterior descending artery. The average intrafraction position variation of the breast target was 0.5 ± 0.5, 2.5 ± 2.0, and 1.8 ± 1.4 mm in the mediolateral, craniocaudal, and anteroposterior directions, respectively. CPAP was successfully applied in 221 patients (93%), with a mean heart dose of 1.6 ± 0.7 Gy (IMNI: 2.0 Gy and no IMNI: 1.1 Gy). CONCLUSIONS: CPAP has adequate heart-sparing capability and sufficient reproducibility in VMAT for left-sided breast cancer treatment, with a high compliance rate. Thus, CPAP is applicable in routine practice for left-sided breast cancer radiation therapy.

Clinical features and treatment outcomes of resected large cell neuroendocrine carcinoma of the lung.

PURPOSE: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a high-grade lung neuroendocrine tumor with a poor prognosis, similar to small cell lung cancer (SCLC). However, it remains unclear whether to treat LCNEC as non-small-cell lung cancer (NSCLC) or as SCLC. We reviewed our experiences to suggest appropriate treatment strategy for resected pulmonary LCNEC. MATERIALS AND METHODS: Forty-four patients were treated for pathologically diagnosed pulmonary LCNEC during 2005‒2018. We considered curative surgery first in early-stage or some locally advanced tumors, unless medically inoperable. Adjuvant treatments were decided considering patient's clinical and pathological features. After excluding two stage I tumors with radiotherapy alone and three stage III tumors with upfront chemotherapy, we analyzed 39 patients with stage I‒III pulmonary LCNEC, who underwent curative resection first. RESULTS: Adjuvant chemotherapy (NSCLC-based 91%, SCLC-based 9%) was performed in 62%, and adjuvant radiotherapy was done in three patients for pN2 or positive margin. None received prophylactic cranial irradiation (PCI). With a median follow-up of 30 months, the 2- and 5-year overall survival (OS) rates were 68% and 51%, and the 2- and 5-year recurrence-free survival (RFS) rates were 49% and 43%, respectively. Aged ≥67 years and SCLC-mixed pathology were significant poor prognostic factors for OS or RFS (p < 0.05). Among 17 recurrences, regional failures were most common (n = 6), and there were five brain metastases. CONCLUSIONS: Surgery and adjuvant treatment (without PCI) could achieve favorable outcomes in pulmonary LCNEC, which was more similar to NSCLC, although some factors worsened the prognosis. The importance of intensified adjuvant therapies with multidisciplinary approach remains high.

Dosimetric Comparison of Radiation Techniques for Comprehensive Regional Nodal Radiation Therapy for Left-Sided Breast Cancer: A Treatment Planning Study.

PURPOSE: How modern cardiac sparing techniques and beam delivery systems using advanced x-ray and proton beam therapy (PBT) can reduce incidental radiation exposure doses to cardiac and pulmonary organs individually or in any combination is poorly investigated. METHODS: Among 15 patients with left-sided breast cancer, partial wide tangential 3D-conformal radiotherapy (3DCRT) delivered in conventional fractionation (CF) or hypofractionated (HF) schedules; PBT delivered in a CF schedule; and volumetric modulated arc therapy (VMAT) delivered in an HF schedule, each under continuous positive airway pressure (CPAP) and free-breathing (FB) conditions, were examined. Target volume coverage and doses to organs-at-risk (OARs) were calculated for each technique. Outcomes were compared with one-way analysis of variance and the Bonferroni test, with p-values <0.05 considered significant. RESULTS: Target volume coverage was within acceptable levels in all interventions, except for the internal mammary lymph node D95 (99% in PBT, 90% in VMAT-CPAP, 84% in VMAT-FB, and 74% in 3DCRT). The mean heart dose (MHD) was the lowest in PBT (<1 Gy) and VMAT-CPAP (2.2 Gy) and the highest in 3DCRT with CF/FB (7.8 Gy), respectively. The mean lung dose (MLD) was the highest in 3DCRT-CF-FB (20 Gy) and the lowest in both VMAT-HF-CPAP and PBT (approximately 5-6 Gy). VMAT-HF-CPAP and PBT delivered a comparable maximum dose to the left ascending artery (7.2 and 6.13 Gy, respectively). CONCLUSIONS: Both proton and VMAT in combination with CPAP can minimize the radiation exposure to heart and lung with optimal target coverage in regional RT for left-sided breast cancer. The clinical relevance of these differences is yet to be elucidated. Continued efforts are needed to minimize radiation exposures during RT treatment to maximize its therapeutic index.

Development of a tablet PC-based portable device for colorimetric determination of assays including COVID-19 and other pathogenic microorganisms.

There has been a strong and urgent demand to diagnose community transmission-driven coronavirus disease 2019 (COVID-19) after it crossed borders. A large number of rapid and accurate tests and diagnoses are required at drive-through test stations, community clinics and hospitals. Isothermal amplification technology, such as loop-mediated isothermal amplification (LAMP) and recombinase polymerase amplification (RPA), provides excellent alternatives for resource limited test environments. LAMP has been shown to be comparable with polymerase chain reaction (PCR) and can be performed in less than 30 min by non-laboratory staff without ribonucleic acid (RNA) extractions commonly associated with PCR. LAMP tests on assays with SARS-CoV-2 and other pathogenic microorganisms, such as Dengue, Malaria, and Influenza viruses and Helicobacter pylori show color changes allowing test results to be interpreted by the color change of the assays. However, visual inspection of a large number of assays is prone to human error and manual record keeping makes test result tracking for an epidemiologic investigation very difficult and inefficient. The epidemiologic investigation is an essential part of the fight against community transmission-driven viruses. We have developed a very accurate and reliable, human error free, tablet PC-based portable device for colorimetric determination of assays including SARS-CoV-2 and other pathogenic microorganisms.

Treatment outcome of anaplastic ependymoma under the age of 3 treated by intensity-modulated radiotherapy.

PURPOSE: Intensity-modulated radiotherapy (IMRT) allows for more precise treatment, reducing unwanted radiation to nearby structures. We investigated the safety and feasibility of IMRT for anaplastic ependymoma patients below 3 years of age. MATERIALS AND METHODS: A total of 9 anaplastic ependymoma patients below 3 years of age, who received IMRT between October 2011 and December 2017 were retrospectively reviewed. The median equivalent dose in 2 Gy fractions was 52.0 Gy (range, 48.0 to 60.0 Gy). Treatment outcomes and neurologic morbidities were reviewed in detail. RESULTS: The median patient age was 20.9 months (range, 12.1 to 31.2 months). All patients underwent surgery. The rates of 5-year overall survival, freedom from local recurrence, and progression-free survival were 40.6%, 53.3%, and 26.7%, respectively. Of the 9 patients, 5 experienced recurrences (3 had local recurrence, 1 had both local recurrence and cerebrospinal fluid [CSF] seeding, and 1 had CSF seeding alone). Five patients died because of disease progression. Assessment of neurologic morbidity revealed motor dysfunction in 3 patients, all of whom presented with hydrocephalus at initial diagnosis because of the location of the tumor and already had neurologic deficits before radiotherapy (RT). CONCLUSION: Neurologic morbidity is not caused by RT alone but may result from mass effects of the tumor and surgical sequelae. Administration of IMRT to anaplastic ependymoma patients below 3 years of age yielded encouraging local control and tolerable morbidities. High-precision modern RT such as IMRT can be considered for very young patients with anaplastic ependymoma.

Differential involvement of GABA system in mediating behavioral and neurochemical effect of acupuncture in ethanol-withdrawn rats.

In our previous study we demonstrated that acupuncture at Shenmen (HT7) points suppressed a decrease of accumbal dopamine (DA) release in ethanol-withdrawn rats. Furthermore, here we found that it inhibited behavioral withdrawal signs of ethanol. In an effort to better understand the mechanisms underlying this inhibition, the potential role of GABA receptor system in acupuncture was investigated. Male Sprague-Dawley rats were treated with 3g/kg/day of ethanol (20%, w/v) or saline by intraperitoneal injection for 21 days. Following 48 or 72h of ethanol withdrawal, acupuncture was applied at bilateral HT7 for 1min. The selective GABA(A) antagonist bicuculline and the selective GABA(B) antagonist SCH 50911 were injected intraperitoneally 20min before acupuncture, respectively. Importantly, suppressive effects of acupuncture on DA deficiency were completely abolished by SCH 50911, but not by bicuculline, whereas ameliorating effects of acupuncture on ethanol withdrawal syndrome were completely blocked either by SCH 50911 or bicuculline. These results suggest that acupuncture at specific acupoint HT7 may normalize the DA release in the mesolimbic system and attenuate withdrawal syndrome through the GABA(B) receptor system in ethanol-withdrawn rats.

Suppression of mast cell-mediated allergic reaction by Amomum xanthiodes.

The mast cell-mediated immediate-type allergic reaction is involved in many allergic diseases such as asthma, allergic rhinitis and sinusitis. Stimulation of mast cells starts the process of degranulation resulting in release of mediators such as histamine and an array of inflammatory cytokines. In this report, we investigated the effect of aqueous extract of Amomum xanthiodes (Zingiberaceae) (AXE) on the mast cell-mediated allergy model and studied its possible mechanisms of action. AXE inhibited compound 48/80-induced systemic reactions and serum histamine release in mice. AXE decreased immunoglobulin E (IgE)-mediated passive cutaneous anaphylaxis reaction. AXE reduced histamine release and intracellular calcium from rat peritoneal mast cells activated by compound 48/80. Furthermore, AXE decreased the activation of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase and c-jun N-terminal kinase, and downstream tumor necrosis factor (TNF)-alpha production in phorbol 12-myristate 13-acetate and calcium ionophore A23187-stimulated human mast cells. Our findings provide evidence that AXE inhibits mast cell-derived allergic reactions, and that intracellular calcium, TNF-alpha, and p38 MAPK are involved in these effects.

Factors for time to trastuzumab-induced cardiotoxicity in breast cancer patients.

Trastuzumab is a drug used for the treatment of metastatic breast cancer patients. Due to blockage of the human epidermal growth factor receptor 2 signaling in cardiac myocytes, cardiotoxicity has been observed. There are many studies that investigated risk factors for trastuzumab-induced cardiotoxicity, but no study has been published for factors on the time to cardiotoxicity. This study aimed to investigate the factors for the time to occur trastuzumab-induced cardiotoxicity. From January 2014 to December 2015, a retrospective study was performed with breast cancer patients who were treated with trastuzumab. Associations between presence of and time to cardiotoxicity and various factors were analyzed. Based on multivariate models, it was found that baseline left ventricular ejection fraction (LVEF) < 62.5% (AHR 5.96, 95% CI 2543-13.95) and anthracycline-based chemotherapy (AHR 7.90, 95% CI 1.05-59.71) were significant factors for time to cardiotoxicity after adjusting other confounding factors. Multivariate analysis also showed that BMI ≥ 23 kg/m2 and baseline LVEF value < 62.5% increased cardiotoxicity 3.0 and 6.6 times, respectively. Our study showed that BMI ≥ 23 kg/m2, LVEF < 62.5%, and anthracycline-based chemotherapy were associated with time to trastuzumab-induced cardiotoxicity. Thus, close monitoring of cardiac function is recommended especially for patients using the above risk factors.

Compound K attenuates stromal cell-derived growth factor 1 (SDF-1)-induced migration of C6 glioma cells.

BACKGROUND/OBJECTIVES: Stromal cell-derived growth factor 1 (SDF-1), also known as chemokine ligand 12, and chemokine receptor type 4 are involved in cancer cell migration. Compound K (CK), a metabolite of protopanaxadiol-type ginsenoside by gut microbiota, is reported to have therapeutic potential in cancer therapy. However, the inhibitory effect of CK on SDF-1 pathway-induced migration of glioma has not yet been established. MATERIALS/METHODS: Cytotoxicity of CK in C6 glioma cells was determined using an EZ-Cytox cell viability assay kit. Cell migration was tested using the wound healing and Boyden chamber assay. Phosphorylation levels of protein kinase C (PKC)α and extracellular signal-regulated kinase (ERK) were measured by western blot assay, and matrix metallopeptidases (MMP) were measured by gelatin-zymography analysis. RESULTS: CK significantly reduced the phosphorylation of PKCα and ERK1/2, expression of MMP9 and MMP2, and inhibited the migration of C6 glioma cells under SDF-1-stimulated conditions. CONCLUSIONS: CK is a cell migration inhibitor that inhibits C6 glioma cell migration by regulating its downstream signaling molecules including PKCα, ERK1/2, and MMPs.

Fruits extracts of Hovenia dulcis Thunb. suppresses lipopolysaccharide-stimulated inflammatory responses through nuclear factor-kappaB pathway in Raw 264.7 cells.

OBJECTIVE: To investigate the anti-inflammatory effects and the action mechanism of the fruits of Hovenia dulcis (H. dulcis) in lipopolysaccharide (LPS)-induced mouse macrophage Raw 264.7 cells. METHODS: The extract of H. dulcis fruits (EHDF) were extracted with 70% ethanol. Mouse macrophages were treated with different concentrations of EHDF in the presence and absence of LPS (1 µg/mL). To demonstrate the inflammatory mediators including nitric oxide, inducible nitric oxide synthase and cyclooxygenase (COX)-2 expression levels were analyzed by using in vitro assay systems. COX-derived pro-inflammatory cytokines including interleukin-1ß, tumor necrosis factor-α and prostaglandin E2 were determined using ELISA kits. Cell viability, heme oxygenase-1 expression, nuclear factor-kappaB and nuclear factor E2-related factors 2 translocation were also investigated. RESULTS: EHDF potently inhibited the LPS-stimulated nitric oxide, inducible nitric oxide synthase, COX-2, interleukin-1ß and tumor necrosis factor-α expression in a dose-dependent manner. EHDF suppressed the phosphorylation of inhibited kappaB-alpha and p65 nuclear translocation. Treatment of macrophage cells with EHDF alone induced the heme oxygenase-1 and nuclear translocation of nuclear factor E2-related factor 2. CONCLUSIONS: These results suggest that the ethanol extract of H. dulcis fruit exerts its anti-inflammatory effects by inhibiting inhibited kappaB-alpha phorylation and nuclear translocation of nuclear factor-kappaB.