Comparison of initial and sequential salvage brain-directed treatment in patients with 1-4 vs. 5-10 brain metastases from breast cancer (KROG 16-12).

PURPOSE: We aimed to compare the initial and salvage brain-directed treatment and overall survival (OS) between patients with 1-4 brain metastases (BMs) and those with 5-10 from breast cancer (BC). We also organized a decision tree to select the initial whole-brain radiotherapy (WBRT) for these patients. METHODS: Between 2008 and 2014, 471 patients were diagnosed with 1-10 BMs. They were divided into two groups based on the number of BM: 1-4 BMs (n = 337) and 5-10 BMs (n = 134). Median follow-up duration was 14.0 months. RESULTS: Stereotactic radiosurgery (SRS)/fractionated stereotactic radiotherapy (FSRT) was the most common treatment modality (n = 120, 36%) in the 1-4 BMs group. In contrast, 80% (n = 107) of patients with 5-10 BMs were treated with WBRT. The median OS of the entire cohort, 1-4 BMs, and 5-10 BMs was 18.0, 20.9, and 13.9 months, respectively. In the multivariate analysis, the number of BM and WBRT were not associated with OS, whereas triple-negative BC and extracranial metastasis decreased OS. Physicians determined the initial WBRT based on four variables in the following order: number and location of BM, primary tumor control, and performance status. Salvage brain-directed treatment (n = 184), mainly SRS/FSRT (n = 109, 59%), prolonged OS by a median of 14.3 months. CONCLUSION: The initial brain-directed treatment differed notably according to the number of BM, which was chosen based on four clinical factors. In patients with ≤ 10 BMs, the number of BM and WBRT did not affect OS. The major salvage brain-directed treatment modality was SRS/FSRT and increased OS.

Disparities in awareness of the HPV vaccine and HPV-associated cancers among racial/ethnic minority populations: 2018 HINTS.

OBJECTIVES: Human papillomavirus (HPV) is a common virus that currently infects nearly 80 million people in the United States (U.S.) and can lead to cancer. HPV vaccination provides safe, effective, and lasting protection against HPV infections. Nevertheless, vaccination rates remain suboptimal. The purpose of this study was to examine the relationship between sociodemographic characteristics, HPV and HPV vaccine awareness, and knowledge of HPV-associated cancers among U.S. adults. DESIGN: Using responses from 3504 U.S. adults (aged 18 years and older) from the Health Information National Trends Survey 5 Cycle 2 (January-May 2018), we performed descriptive analysis to assess the level of awareness of HPV and HPV vaccines and knowledge of HPV-associated cancer. Multivariable regression analysis (including race, gender, age, level of education, marital status, number of children younger than 18) was conducted with weighted analysis. RESULTS: About 62% of respondents had heard of HPV and HPV vaccine. Asians had a lower level of awareness than non-Hispanic Whites of HPV (36.4% vs. 66.1%) and HPV vaccine (48.7% vs. 67.1%). Multivariable analysis showed that race/ethnicity was associated with outcomes, with Asians being less likely to have heard about HPV (aOR = 0.17, 95% CI: 0.07-0.38) and non-Hispanic Blacks (aOR = 0.57, 95% CI: 0.35-0.91) and Hispanics (aOR = 0.54, 95% CI: 0.36-0.80) being less likely to have heard of the HPV vaccine than non-Hispanic Whites. In addition, gender, age, marital status, and education were associated with awareness of HPV and the HPV vaccine; in particular, individuals who were female, younger (18-45), married, and more highly educated were more likely to have heard of HPV and HPV vaccine. CONCLUSION: Results highlight disparities in HPV and HPV vaccine awareness among racial/ethnic minority populations. Future interventions and legislation should target racial/ethnic minority populations to foster improvements in HPV vaccine uptake and reduce disparities in HPV-associated cancers.

Developing an Attention Assessment Tool for Individuals With Autism Spectrum Disorder Using Timbre, Rhythm, and Pitch.

BACKGROUND: Music is regarded as a beneficial tool for assessing the clinical symptoms and communication skills in individuals with autism spectrum disorder (ASD) or autism. The present study developed a music-based attention test (MAT) for individuals with autism using music parameters and the algorithm of the comprehensive attention test (CAT). METHODS: We recruited 51 autistic individuals and 50 neurotypical individuals to participate in the CAT, MAT, and social intelligence tests. The reliability and validity of the MAT were assessed using exploratory factor analysis, concurrent validity, and criterion-related validity. RESULTS: The MAT had sound internal consistency (high Cronbach's α = 0.948). In addition, the MAT had suitable concurrent validity in the correlation between CAT and MAT, as well as good criterion validity when attention was measured using the MAT and was compared between autistic individuals and neurotypical individuals. Attention evaluated using the MAT was associated with the social quotient in individuals with autism. CONCLUSIONS: The MAT could be a relevant tool for gauging attention in individuals with ASD. Furthermore, attention determined using the MAT may be correlated with social quotient in autistic individuals. Future studies should consider that using music in the field of attention could improve the social quotient of individuals with autism.

Bamboo Shoot and Artemisia capillaris Extract Mixture Ameliorates Dextran Sodium Sulfate-Induced Colitis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract and is characterized by recurrent chronic inflammation and mucosal damage of the gastrointestinal tract. Recent studies have demonstrated that bamboo shoot (BS) and Artemisia capillaris (AC) extracts enhance anti-inflammatory effects in various disease models. However, it is uncertain whether there is a synergistic protective effect of BS and AC in dextran sodium sulfate (DSS)-induced colitis. In the current study, we tested the combined effects of BS and AC extracts (BA) on colitis using in vivo and in vitro models. Compared with control mice, oral administration of DSS exacerbated colon length and increased the disease activity index (DAI) and histological damage. In DSS-induced colitis, treatment with BA significantly alleviated DSS-induced symptoms such as colon shortening, DAI, histological damage, and colonic pro-inflammatory marker expression compared to single extracts (BS or AC) treatment. Furthermore, we found BA treatment attenuated the ROS generation, F-actin formation, and RhoA activity compared with the single extract (BS or AC) treatment in DSS-treated cell lines. Collectively, these findings suggest that BA treatment has a positive synergistic protective effect on colonic inflammation compared with single extracts, it may be a highly effective complementary natural extract mixture for the prevention or treatment of IBD.

A comparison of the influencing factors of chronic pain and quality of life between older Koreans and Korean-Americans with chronic pain: a correlational study.

BACKGROUND: Chronic pain is one of the most common health problems for older adults worldwide and is likely to result in lower quality of life. Living in a different culture may also influence chronic pain and quality of life in older adults. The purpose of this study was to explore how multifaceted elements affect chronic pain and quality of life in older Koreans living in Korea and in older Korean-Americans (KAs) living in the USA. METHODS: We conducted a secondary data analysis of data from 270 adults aged 65 years or over (138 Koreans and 132 KAs). We compared the effects of multifaceted elements on pain and quality of life by testing structural equation models (SEMs) for each group, using a maximum likelihood estimation and bootstrapping. RESULTS: SEMs for both Korean and KAs showed that age and depressive symptoms directly affected quality of life. The number of comorbidities and depressive symptoms had mediating effects on quality of life through chronic pain in both groups. In older Koreans only, perceived financial status directly affected quality of life. In older KAs only, sleep quality indirectly affected quality of life through chronic pain. CONCLUSION: The data showed that multimorbidity and depressive symptoms play critical roles for explaining chronic pain in older Koreans and KAs and ultimately negatively influence quality of life. Future intervention program to improve quality of life in older adults with chronic pain should consider the different cultural aspects affecting quality of life for Koreans and KAs.

Prevalence and correlates of depression among South Korean older adults living in relative poverty.

This secondary analysis of the Tailored Health Visiting Service Program examined depression prevalence and associated factors among 1181 community-dwelling, South Korean older adults (range: 65 to 99 years) who live in relative poverty. Depression was assessed using the Geriatric Depression Scale short form. Generalized linear models with Poisson family and log link functions were employed to identify factors associated with depression. The overall depression prevalence was 46.3%, with most subjects mildly depressed. Better self-rated health and healthy activities were associated with lower depression prevalence, while having a disability was associated with higher prevalence. The factors identified in this study should be considered in community mental health interventions for older adults, especially those who experience economic disadvantage.

New brain metastases after whole-brain radiotherapy of initial brain metastases in breast cancer patients: the significance of molecular subtypes (KROG 16-12).

PURPOSE: To identify the risk factors leading to new brain metastases (BM) following brain-directed treatment for initial BM resulting from breast cancer (BC). METHODS: In this multi-institutional study, 538 BC patients with available follow-up imaging after brain-directed treatment for initial BM were analyzed. Tumor molecular subtypes were classified as follows: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-, n = 136), HER2-positive (HER2+, n = 253), or triple-negative BC (TNBC, n = 149). RESULTS: In 37.4% of patients, new BM emerged at a median of 10.5 months after brain-directed treatment for initial BM. The 1-year actuarial rate of new BM for HR+/HER2-, HER2+, and TNBC were 51.9%, 44.0%, and 69.6%, respectively (p = 0.008). Initial whole-brain radiotherapy (WBRT) reduced new BM rates (22.5% reduction at 1 year, p < 0.001) according to molecular subtype (HR+/HER2-, 42% reduction at 1 year, p < 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis revealed an increased risk of new BM for the following factors: shorter intervals between primary BC diagnoses and BM (p = 0.031); TNBC (relative to HR+/HER2-) (p = 0.016); presence of extracranial metastases (p = 0.019); number of BM (>4) (p < 0.001); and BM in both tentorial regions (p = 0.045). Anti-HER2 therapy in HER2+ patients (p = 0.013) and initial use of WBRT (p < 0.001) significantly lowered new BM development. CONCLUSIONS: Tumor molecular subtypes were associated with both rates of new BM development and the effectiveness of initial WBRT. Anti-HER2 therapy in HER2+ patients significantly lowered new BM occurrence.

Prognostic effects of cytokine levels on patients treated with taxane and zoledronic acid for metastatic breast cancer in bone (BEAT-ZO) (KCSG BR 10-13).

Advanced breast cancer frequently metastasizes to the skeleton causing major mobility issues and hazards to quality of life. To manage osteolytic bone metastasis, bone-modifying agents and chemotherapy are recommended as the standard of care. Here, we investigated serologic biomarkers that might be associated with prognosis in breast cancer patients treated with zoledronic acid (ZA) and taxane-based chemotherapy. We collected serum samples from breast cancer patients with bone metastasis who received taxane plus ZA as palliative treatment. Fourteen biomarkers of angiogenesis, immunogenicity, and apoptosis were assessed, and the correlation between serum cytokine levels and patient's prognosis was statistically analyzed. Sixty-six patients were enrolled, and samples from 40 patients were analyzed after laboratory quality control. Patients with low baseline PDGF-AA, high IFN-γ, low MCP-2, low TGF-ß1, and low TNF-α were significantly associated with longer progression-free survival (PFS). Decreasing VEGF and TNF-α and increasing FGF-2 and PDGF-AA in the early treatment phase indicated longer PFS. In univariate and multivariate analyses, low TGF-ß1 and TNF-α and high IFN-γ at baseline were associated with a significantly low hazard ratio for disease progression. Further, we designed a risk score with TGF-ß1, TNF-α, and IFN-γ levels, which could prognosticate patients for PFS. In conclusion, serum cytokine level, such as TGF-ß1, TNF-α, and IFN-γ, could be a potential prognostic biomarker for breast cancer patients with bone metastasis treated with ZA and taxane-based chemotherapy.

Racial/Ethnic Disparities in Patient-Provider Communication and the Role of E-Health Use.

Although the health care industry has strived to address racial/ethnic disparities in health communication, several gaps remain. Previous findings suggest that communication technology might help narrow the gaps; however, they do not provide a comprehensive picture of how or why. To answer these questions, we examined the potential role of communication technology in mitigating the racial/ethnic disparities in patient-provider communication. Data analysis of the 2018 Health Information National Trends Survey (N= 3,504) revealed that the levels of perceived quality of communication with health care providers were lower among Asians and Hispanics than non-Hispanic Whites while no difference emerged between Blacks and non-Hispanic Whites. Although the adoption of communication technology was relatively high across minority groups, its use appeared to play different roles in different racial/ethnic populations. The Internet and patient portals showed no particular associations with patient-provider communication except for Black Internet users, who reported poorer experiences with patient-provider communication than non-users. Among Asians and Hispanics, social media and mobile communication appeared to play different roles in impacting communication experiences with health care providers. The findings suggest that communication technologies need to be strategically utilized and tailored to better meet the communication needs of racial/ethnic minorities.

Increased Expression of S100B and RAGE in a Mouse Model of Bile Duct Ligation-induced Liver Fibrosis.

BACKGROUND: Liver fibrosis is defined as the accumulation of the extracellular matrix and scar formation. The receptor for advanced glycation end products (RAGE) has been demonstrated to participate in fibrogenesis. S100B is a ligand of RAGE and exerts extracellular functions by inducing a series of signal transduction cascades. However, the involvement of S100B and RAGE in cholestasis-induced liver fibrosis remains unclear. In this study, we investigated S100B and RAGE expression during liver fibrosis in mice that underwent common bile duct ligation (BDL). METHODS: BDL was performed in 10-week-old male C57BL/6J mice with sham control (n = 26) and BDL (n = 26) groups. Expression levels of S100B, RAGE and fibrotic markers in the livers from both groups at week 1 and 3 after BDL were examined by western blot and quantitative real-time reverse transcription polymerase chain reaction analysis. Liver fibrotic changes were examined by histological and ultrastructural analysis. RESULTS: Histological staining with Sirius Red and the evaluation of the messenger RNA expression of fibrotic markers showed noticeable periportal fibrosis and bile duct proliferation. S100B was mainly present in bile duct epithelial cells, and its expression was upregulated in proportion to the ductular reaction during fibrogenesis by BDL. RAGE expression was also increased, and interestingly, triple immunofluorescence staining and transmission electron microscopy showed that both S100B and RAGE were expressed in proliferating bile duct epithelial cells and activated hepatic stellate cells (HSCs) of the BDL livers. In addition, in rat HSCs (HSC-T6), treatment with recombinant S100B protein significantly increased fibrotic markers in a dose-dependent manner, and RAGE small interfering RNA (siRNA) suppressed S100B-stimulated upregulation of fibrotic markers compared with cells treated with scramble siRNA and S100B. CONCLUSION: These findings suggest that the increased expression of S100B and RAGE and the interaction between S100B and RAGE may play an important role in ductular reaction and liver fibrosis induced by BDL.

Synergistic Anticancer Activity of N-Hydroxy-7-(2-Naphthylthio) Heptanomide, Sorafenib, and Radiation Therapy in Patient-Derived Anaplastic Thyroid Cancer Models.

Anaplastic thyroid cancer (ATC) is an undifferentiated and advanced form of thyroid cancer, accompanied with a high ratio of epigenetic adjustment, which occurs more than genetic mutations. In this study, we aimed to evaluate the synergistic anticancer effect (in vitro and in vivo) of the new combination of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) and sorafenib with radiation therapy in pre-clinical models of ATC. The ATC cell lines, YUMC-A1 and YUMC-A2, were isolated from the current patients who were treated with HNHA and sorafenib, either as monotherapy or combination therapy. Synergistic anticancer effect of the combination therapy on the intracellular signaling pathways and cell cycle was assessed via flow cytometry and immunoblot analysis. To examine tumor shrinkage activity in vivo, an ATC cell line-derived mouse xenograft model was used. Results showed that the combination therapy of HNHA and sorafenib with radiation promoted tumor suppression via caspase cleavage and cell cycle arrest in patient-derived ATC. In addition, the combination therapy of HNHA and sorafenib with radiation was more effective against ATC than therapy with HNHA or sorafenib with radiation. Thus, the combination of HNHA and sorafenib with radiation may be used as a novel curative approach for the treatment of ATC.

Intra-Ethnic Differences in Chronic Pain and the Associated Factors: An Exploratory, Comparative Design.

PURPOSE: To describe and compare the levels of pain severity and pain interference, pain catastrophizing, and associated factors between elderly Koreans living in South Korea and Korean Americans living in the United States with chronic pain. METHODS: An exploratory, comparative design was used for this study. A total of 270 individuals (138 Koreans living in South Korea and 132 Korean Americans living in the United States), aged more than 65 years, with self-reported chronic pain, and defined as at least 3 months of persistent musculoskeletal pain, is included. Outcome variables were pain severity, pain interference, and pain catastrophizing. Multivariate linear regression was conducted to examine factors associated with the outcome variables. RESULTS: In multivariate analysis, Korean Americans had higher levels of pain severity and pain catastrophizing than Koreans. Depressive symptoms, sleep quality, and health-related quality of life were significant factors for pain severity, pain interference, and pain catastrophizing for both groups. Among those factors, health-related quality of life was the most significant factor for predicting pain severity and pain interference, whereas depressive symptoms were the most significant factor for predicting pain catastrophizing for both groups. CONCLUSIONS: Intra-ethnic differences in pain severity and pain catastrophizing were found between elderly Koreans living in South Korea and Korean Americans living in the United States. CLINICAL RELEVANCE: Because unfamiliar sociocultural and environmental factors may influence the pain responses, cultural differences and language barriers should be taken into account in pain research and management strategies for Asian immigrants in the United States. Psychological factors, including depressive symptoms, sleep quality, and health-related quality of life, should also be considered in chronic pain management for both elderly Koreans and Korean Americans.

Mortality reduction with physical activity in patients with and without cardiovascular disease.

AIMS: Physical activity has been shown to reduce mortality in a dose-response fashion. Current guidelines recommend 500-1000 metabolic equivalent task (MET)-min per week of regular physical activity. This study aimed to compare the impact of leisure-time physical activity on mortality in primary versus secondary cardiovascular prevention. METHODS AND RESULTS: This study included a total of 131 558 and 310 240 subjects with and without cardiovascular disease (CVD), respectively, from a population-based cohort. Leisure-time physical activity was measured by self-report questionnaires. The study subjects were followed-up for a median of 5.9 years, and the main study outcome was all-cause mortality. There was an inverse relationship between the physical activity level and the mortality risk in both groups. The benefit in the secondary prevention group was shown to be greater than that in the primary prevention group: every 500 MET-min/week increase in physical activity resulted in a 14% and 7% risk reduction in mortality in the secondary and primary prevention groups, respectively (interaction P < 0.001). In addition, while individuals without CVD benefited the most between 1 and 500 MET-min/week of physical activity, the benefit in those with CVD continued above 500 - 1000 MET-min/week. The adjusted mortality risk of individuals with CVD who performed a high level of physical activity (≥1000 MET-min/week) was shown to be comparable to or lower than that of their counterparts without CVD. CONCLUSION: Individuals with CVD may benefit from physical activity to a greater extent than do healthy subjects without CVD.

RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity.

Scrapie infection, which converts cellular prion protein (PrPC) into the pathological and infectious isoform (PrPSc), leads to neuronal cell death, glial cell activation and PrPSc accumulation. Previous studies reported that PrPC regulates RhoA/Rho-associated kinase (ROCK) signaling and that connexin 43 (Cx43) expression is upregulated in in vitro and in vivo prion-infected models. However, whether there is a link between RhoA/ROCK and Cx43 in prion disease pathogenesis is uncertain. Here, we investigated the role of RhoA/ROCK signaling and Cx43 in prion diseases using in vitro and in vivo models. Scrapie infection induced RhoA activation, accompanied by increased phosphorylation of LIM kinase 1/2 (LIMK1/2) at Thr508/Thr505 and cofilin at Ser3 and reduced phosphorylation of RhoA at Ser188 in hippocampal neuronal cells and brains of mice. Scrapie infection-induced RhoA activation also resulted in PrPSc accumulation followed by a reduction in the interaction between RhoA and p190RhoGAP (a GTPase-activating protein). Interestingly, scrapie infection significantly enhanced the interaction between RhoA and Cx43. Moreover, RhoA and Cx43 colocalization was more visible in both the membrane and cytoplasm of scrapie-infected hippocampal neuronal cells than in controls. Finally, RhoA and ROCK inhibition reduced PrPSc accumulation and the RhoA/Cx43 interaction, leading to decreased Cx43 hemichannel activity in scrapie-infected hippocampal neuronal cells. These findings suggest that RhoA/ROCK regulates Cx43 activity, which may have an important role in the pathogenesis of prion disease.

Statistical correlation of ecotoxicity and water quality parameters in slaughterhouse wastewater.

The major causes of toxicity in slaughterhouse wastewater are identified by analyzing the relationship between representative pollutants and the acute toxicity of Daphnia magna. Experimental results demonstrate that organic matters are strongly associated with the acute toxicity. Among many organic pollutants, proteins and carbohydrates were found to be the main toxicity inducers that cause metabolic transformation of D. magna. Statistical correlation between biodegradable soluble organics and the acute toxicity further explains how principal pollutants play potential toxin roles. Also, this study verifies that the variations of biochemical oxygen demand over total chemical oxygen demand (BOD TCOD-1) as well as total organic carbon over total carbon (TOC TC-1) can be indirect indicators explaining the acute toxicity of D. magna because the removal of non-degradable and non-soluble organic matters is connected to the toxicity removal. Overall, these results provide how the acute toxicity of D. magna is attributed to pollutants and what is the potential source of threats to society in slaughterhouse wastewater.

Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. METHODS: This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0-2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival. FINDINGS: Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9-22), median progression-free survival was 20·1 months (95% CI 14·2-21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1-17·0) in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 [75%] of 92 vs 14 [16%] of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred. INTERPRETATION: Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen. FUNDING: Pfizer, Shinpoong, and Daewoong Korea and Takeda.

Randomised Phase 2 study of lapatinib and vinorelbine vs vinorelbine in patients with HER2 + metastatic breast cancer after lapatinib and trastuzumab treatment (KCSG BR11-16).

BACKGROUND: The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments. METHODS: A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks. RESULTS: The median number of previous anti-HER2 therapies was 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61-1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72-1.58). Toxicity profiles were similar in both arms and all were manageable. CONCLUSIONS: Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT01730677.

A phase II trial of S-1 and oxaliplatin in patients with advanced hepatocellular carcinoma.

BACKGROUND: Oxaliplatin is a platinum derivative that has shown efficacy in advanced hepatocellular carcinoma. S-1 is an oral fluoropyrimidine that has substituted for 5-fluorouracil in many cancers. This was a multicenter, open-label, single-arm phase II trial that evaluated the efficacy of S-1 and oxaliplatin (SOX) in advanced hepatocellular carcinoma. All patients included in the present study were systemic treatment-naïve. Prior treatment with sorafenib was allowed, but other treatments were not. METHODS: Patients received S-1 (40 mg/m2 twice daily from day 1-14) and oxaliplatin (130 mg/m2 on day 1) every 3 weeks. The primary end point was time to progression (TTP). Secondary end points included progression-free survival, overall survival (OS), response rate, and safety profile. RESULTS: Thirty six patients with advanced hepatocellular carcinoma were included in this study. The median TTP was 3.0 months (95% confidence interval (CI), 0.75-5.25), and the median OS was 10.3 months (95% CI, 6.4-14.3). Bone metastasis was associated with poorer TTP and OS. The efficacy of SOX was unaffected by prior sorafenib or locoregional therapy. The objective response rate was 13.9%. No grade 4 toxicity or death from adverse events occurred. The most common grade 3 toxicities were neutropenia (13.9%), thrombocytopenia (13.9%), and diarrhea (8.3%). CONCLUSIONS: Although this trial did not meet its primary end point, the SOX regimen showed comparable efficacy and safety to the 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen. As the SOX regimen is easier for patients, SOX may be a reasonable substitute for FOLFOX in hepatocellular carcinoma. TRIAL REGISTRATION: Clinicaltrials.gov NCT01429961 . Registered 7 September 2011.

A Mobile Game for Patients With Breast Cancer for Chemotherapy Self-Management and Quality-of-Life Improvement: Randomized Controlled Trial.

BACKGROUND: The application of game-based learning in clinical practice has shown potential advantages in previous studies. However, there have been little efforts to use smartphone-based mobile games in the management of adult patients with cancer. OBJECTIVE: The objective of our study was to evaluate if patient education using a mobile game may increase drug compliance, decrease physical side effects of chemotherapy, and improve psychological status in breast cancer patients. METHODS: A total of 76 patients with metastatic breast cancer who were planned to receive cytotoxic chemotherapy were enrolled in this trial. Study participants were randomly assigned to a mobile game play group (game group, n=36) or a conventional education group (control group, n=40) in a ratio of 1:1. The patients were unblinded and followed prospectively for 3 weeks. Outcome measures included time spent for education, compliance to medication, physical side effects, and psychological side effects including quality of life (QoL). RESULTS: Overall, 72 out of 76 patients completed the study after 3 weeks (95%). The subjects in the game group showed high levels of satisfaction with the app. The time spent playing the mobile game in the game group was longer than that spent for self-education in the control group (mean 22.2, SD 6.1 vs mean 5.5, SD 4.0 minutes a day; P<.001). The mobile game group showed better drug adherence (Korean version of the Medication Adherence Rating Scale; mean 7.6, SD 0.7 vs mean 6.5, SD 0.5; P<.001). The use of the mobile game was associated with lower rates of chemotherapy-related side effects, such as nausea, fatigue, numbness of hand or foot, and hair loss, than the control group. The game group exhibited better QoL during chemotherapy (mean 74.9, SD 3.5 vs mean 72.2, SD 5.3; P=.01). However, there were no significant differences in terms of depression and anxiety scales. CONCLUSIONS: This study suggests the feasibility and potentiality of the use of smartphone mobile games for patients with breast cancer receiving chemotherapy. Education using a mobile game led to better patient education, improved drug compliance, decreased side effects, and better QoL compared with conventional education. Mobile games can be used as easy, fun, and effective measures for patient education and have the potential to improve treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03205969; http://clinicaltrials.gov/ct2/show/NCT03205969 (Archived by WebCite at http://www.webcitation.org/71jfSBOq9).

Calsenilin, a Presenilin Interactor, Regulates RhoA Signaling and Neurite Outgrowth.

Calsenilin modulates A-type potassium channels, regulates presenilin-mediated γ-secretase activity, and represses prodynorphin and c-fos genes expression. RhoA is involved in various cellular functions including proliferation, differentiation, migration, transcription, and regulation of the actin cytoskeleton. Although recent studies demonstrate that calsenilin can directly interact with RhoA and that RhoA inactivation is essential for neuritogenesis, it is uncertain whether there is a link between calsenilin and RhoA-regulated neuritogenesis. Here, we investigated the role of calsenilin in RhoA-regulated neuritogenesis using in vitro and in vivo systems. We found that calsenilin induced RhoA inactivation, which accompanied RhoA phosphorylation and the reduced phosphorylation levels of LIM kinase (LIMK) and cofilin. Interestingly, PC12 cells overexpressing either full-length (FL) or the caspase 3-derived C-terminal fragment (CTF) of calsenilin significantly inactivated RhoA through its interaction with RhoA and p190 Rho GTPase-activating protein (p190RhoGAP). In addition, cells expressing FL and the CTF of calsenilin had increased neurite outgrowth compared to cells expressing the N-terminal fragment (NTF) of calsenilin or vector alone. Moreover, Tat-C3 and Y27632 treatment significantly increased the percentage of neurite-bearing cells, neurite length, and the number of neurites in cells. Finally, calsenilin deficiency in the brains of calsenilin-knockout mice significantly interfered with RhoA inactivation. These findings suggest that calsenilin contributes to neuritogenesis through RhoA inactivation.