Induction of SGK1 via glucocorticoid-influenced clinical outcome of triple-negative breast cancer patients.

PURPOSE: Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive breast malignancy. Glucocorticoid (GC)-glucocorticoid receptor (GR) pathway plays a pivotal role in the cellular responses to various stresses including chemotherapy. Serum- and glucocorticoid-induced kinase-1 (SGK1) is known as an important downstream effector molecule in the GR signaling pathway, we attempted to explore its clinicopathological and functional significance in TNBC in which GR is expressed. METHODS: We first immunolocalized GR and SGK1 and correlated the results with clinicopathological variables and clinical outcome in 131 TNBC patients. We also evaluated the effects of SGK1 on the cell proliferation and migration in TNBC cell lines with administration of dexamethasone (DEX) to further clarify the significance of SGK1. RESULTS: The status of SGK1 in carcinoma cells was significantly associated with adverse clinical outcome in TNBC patients examined and was significantly associated with lymph node metastasis, pathological stage, and lymphatic invasion of the patients. In particular, SGK1 immunoreactivity was significantly associated with an increased risk of recurrence in GR-positive TNBC patients. Subsequent in vitro studies also demonstrated that DEX promoted TNBC cell migration and the silencing of gene expression did inhibit the cell proliferation and migration of TNBC cells under DEX treatment. CONCLUSIONS: To the best of our knowledge, this is the first study to explore an association between SGK1 and clinicopathological variables and clinical outcome of TNBC patients. SGK1 status was significantly positively correlated with adverse clinical outcome of TNBC patients and promoted carcinoma cell proliferation and migration of carcinoma cells.

Exploring the ethics of physical restraints: Students' questioning.

BACKGROUND: Physical restraints are routinely employed to ensure patient safety in Japanese acute care. Little is known about nursing students' perspectives and how they begin to question their value and knowledge in the face of restraint experiences in clinical practice. OBJECTIVE: To investigate nursing students' questions about patient restraints and how they understand the ethics of the use of restraints in nursing. RESEARCH DESIGN: Qualitative descriptive research using narrative analysis. PARTICIPANTS AND RESEARCH CONTEXT: Experiential data were generated and thematically analyzed from semi-structured interviews with 16 nursing students who had completed their bachelor's degree program requirements. ETHICAL CONSIDERATIONS: The study was approved by academic and clinical ethics agencies. Participants provided written informed consent. RESULTS: Physical restraints were encountered in 16 incidents, 3 with children and 13 with older patients with dementia. Students struggled to comprehend the policies and protocols of restraint use and worried their use was primarily for security rather than therapeutic purposes. Five themes were identified: (1). Questioning the tension between person-centered care, patient autonomy, and restraints, (2). Questioning the nature of restraints in which participants analyzed the policies and protocols around restraint use, (3). Questioning the professional nursing self whereby students reflected on how restraint use challenged their nursing values, and (4). Questioning professional nursing practice, in which students explored how restraints fit within a nursing perspective and positioned themselves as patient advocates. Students encountering physical restraints should ask questions based on values of patient-centeredness, autonomy, and advocacy. There is a need for education that facilitates reflection and questioning so that it informs students' ethical thinking which may enhance nurse advocacy to reduce restraint use. CONCLUSIONS: Restraints provide contexts in which students must face tensions between nursing values and clinical reality. Further research on nursing education strategies within non-psychiatric settings is needed to reduce physical restraints.

Effects of n-3 polyunsaturated fatty acid supplementation on quadriceps weakness immediately after total knee arthroplasty: a pilot, randomized, open-label clinical trial.

[Purpose] Severe quadriceps weakness immediately after total knee arthroplasty can be problematic. The n-3 long-chain polyunsaturated fatty acids have antioxidant and anti-inflammatory effects against ischemia-reperfusion injury, whereas n-6 long-chain polyunsaturated fatty acids exert pro-inflammatory effects, thereby promoting ischemia-reperfusion injury. [Participants and Methods] We explored the efficacy of preoperative n-3 long-chain polyunsaturated fatty acid supplementation against early quadriceps weakness among 20 patients scheduled for total knee arthroplasty (intervention group, n=10; control group, n=10). The intervention group received 645 mg of eicosapentaenoic acid) and 215 mg of docosahexaenoic acid daily for 30 days preoperatively. Serum eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels were measured preoperatively. We compared serum derivatives of reactive oxygen metabolites as oxidative stress biomarkers, knee circumference, thigh volume, knee pain during the quadriceps strength test, and quadriceps strength preoperatively and 4 days postoperatively to quantify the change. [Results] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation significantly increased the (eicosapentaenoic acid+docosahexaenoic acid)/arachidonic acid ratio in the intervention group. A significantly lower increase in quadriceps weakness was exhibited in the intervention group than in the control group. However, changes in oxidative stress, knee/thigh swelling, and knee pain during strength testing did not significantly differ between the two groups. [Conclusion] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation exhibited beneficial effects on quadriceps weakness immediately after total knee arthroplasty.

Oncolytic herpes simplex virus HF10 (canerpaturev) promotes accumulation of CD8+ PD-1- tumor-infiltrating T cells in PD-L1-enriched tumor microenvironment.

Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a "cold" tumor into a "hot" tumor with high CD8+ T-cell infiltration. CD8+ T-cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction. To date, it remains unclear why OVs alone have a significant antitumor activity even when PD-L1 expression persists on tumor or immune cells. In this study, we found that canerpaturev (C-REV) treatment significantly suppressed tumor growth, even though it induced a significant increase in PD-L1 expression in tumors in vivo as well as persistence of high PD-L1 expression on antigen-presenting cells (macrophage and dendritic cells [DCs]). Surprisingly, we observed that C-REV treatment increased the abundance of activated CD8+ PD-1- tumor-infiltrating lymphocytes (TILs) in the tumor on both the injected and contralateral sides, although infiltration of CD8+ PD-1high TILs into the tumor was observed in the control group. Moreover, the difference in PD-1 expression was observed only in tumors after treatment with C-REV, whereas most CD8+ T cells in the spleen, tumor-draining lymph nodes and blood were PD-1-negative, and this did not change after C-REV treatment. In addition, changes in expression of T-cell immunoglobulin and mucin-domain containing-3 and T-cell immune-receptor with Ig and ITIM domains were not observed on CD8+ TILs after C-REV treatment. Taken together, our findings may reveal mechanisms that allow OVs to trigger an antitumor immune response, irrespective of a PD-L1-enriched tumor microenvironment, by recruitment of CD8+ PD-1- TILs.

Association between discontinuation of benzodiazepine receptor agonists and post-operative delirium among inpatients with liaison intervention: A retrospective cohort study.

BACKGROUND: Several studies have investigated the association between benzodiazepine receptor agonist (BZDRA) use during the perioperative period and an elevated incidence of delirium. However, no study has focused on the time course of BZDRA use, including continuation, discontinuation, initiation, and no use. This study aimed to examine the influence of the time course of BZDRA use on post-operative delirium. METHODS: This retrospective cohort study was conducted by reviewing medical records. We included patients who were scheduled for surgery under general anesthesia and had been referred to a liaison psychiatrist for pre-operative psychiatric assessment. The patients were classified into four groups based on the pre- and post-operative time course of oral BZDRA use, as follows: continuation, discontinuation, initiation, and no use (never used). The primary outcome was the prevalence of post-operative delirium in non-intensive care unit settings. We also performed stratified analyses according to age, the presence of cognitive impairment, the presence of delirium history, and antipsychotic drug use on admission. RESULTS: Among 250 patients, 78 (31%) developed post-operative delirium. The Discontinuation group had a higher rate of delirium (49%, 24/49) than the other groups (Continuation [14%, 4/29]; Initiation [38%, 3/8], Never used [29%, 47/164], p = 0.008). CONCLUSIONS: Abrupt discontinuation of BZDRAs during the perioperative period may be a risk factor for post-operative delirium and should therefore be avoided.

Androgen receptor expression is useful to predict the therapeutic effect in HER2-positive breast carcinoma.

PURPOSE: Although HER2-positive (HER2+) invasive breast carcinomas (BC) have a different clinical therapeutic responsiveness according to estrogen and progesterone receptor expression, the relationship with androgen receptors (AR), which are the same family of steroid hormones, is poorly understood. We investigated the relationship between AR expression in HER2 BCs and therapeutic responsiveness and prognosis in this study. METHODS: We evaluated patients with HER2 (H) + invasive BC undergoing surgery after neoadjuvant chemotherapy (± HER2-targeted therapies) from 2007-2017, classified as hormone receptor-positive (Allred score: 2-8) (luminal B: LH) and receptor-negative groups (Allred: score 0) (non-luminal: NLH). AR expression was assessed by immunostaining pre-neoadjuvant chemotherapy biopsy specimens, positive with Allred score ≥ 4. The pathological complete response, disease-free survival, and overall survival rates were compared between AR-positive and AR-negative groups. RESULTS: We classified 82 patients with HER2 + invasive BC into LH (n = 45, 54.9%) and NLH groups (n = 37, 45.1%), and AR + was observed in 43 patients (52.4%) (LH: 23, 51.1%; NLH: 20, 54.1%; p = 0.79). Quasi-pathological complete response was observed in 40 patients (48.8%) (LH: 18, 40%; NLH: 22, 59.5%; p = 0.08) overall, and in 31 AR + patients (72.1%) (LH: 15, 34.9%; NLH: 16, 37.2%), significantly higher than in the AR - group for both subgroups (p < 0.001). Regarding prognosis, disease-free survival was relatively better in the AR + group in all HER2 + BCs (p = 0.085), and overall survival was significantly better in the AR + group for NLH (p = 0.029). CONCLUSIONS: High AR expression may be a useful predictor of therapeutic effects and prognosis in both subgroups of HER2 + BCs.

Significance of glucocorticoid signaling in triple-negative breast cancer patients: a newly revealed interaction with androgen signaling.

PURPOSE: Chemotherapy is the only current effective systemic treatment for triple-negative breast cancer (TNBC) patients. Therefore, the identification of active biological pathways that could become therapeutic targets is crucial. In this study, considering the well-reported biological roles of glucocorticoid and androgen receptors (GR, AR) in TNBC, we attempted to explore the effects of glucocorticoids (GCs) on cell kinetics as well as the potential interaction between GR and AR in TNBC. METHODS: We first explored the association between the status of GR, AR, and/or GCs-metabolizing enzymes such as 11ß-hydroxysteroid dehydrogenase (11ßHSD) 1 and 2 and the clinicopathological variables of the TNBC patients. Thereafter, we also studied the effects of dexamethasone (DEX) with/without dihydrotestosterone (DHT) on TNBC cell lines by assessing the cell proliferation, migration and GC response genes at the transcriptional level. RESULTS: GR positivity in carcinoma cells was significantly associated with adverse clinical outcome of the patients and AR positivity was significantly associated with lower histological grade and Ki-67 labeling index of the cases examined. In particular, AR positivity was significantly associated with decreased risks of developing recurrence in GR-positive TNBC patients. The subsequent in vitro studies revealed that DEX-promoted cell migration was inhibited by the co-treatment with DHT in GR/AR double-positive HCC38 cells. In addition, DHT inhibited the DEX-increased serum and glucocorticoid-regulated kinase-1 (SGK1) mRNA expression. CONCLUSION: This is the first study to reveal that the interaction of GR and AR did influence the clinical outcome of TNBC patients and GCs induced cell migration in TNBC cells.

Diverse histomorphology of HER2-positive breast carcinomas based on differential ER expression.

AIMS: HER2-positive (HER2+) breast carcinoma (BC) cases are often treated similarly; however, they can be classified as either luminal B (LH) or non-luminal type (NLH) BC, which have different prognoses. In this study, we investigated the clinicohistomorphological features of each HER2+ BC subgroup. METHODS AND RESULTS: We classified 166 patients with HER2+ invasive BC into LH (n = 110, 66.3%) and NLH groups (n = 56, 33.7%). We further subclassified LH into patients with carcinomas expressing high levels of hormone receptors [LH-high; Allred score, oestrogen receptor (ER) and/or progesterone receptor (PgR) 4-8, n = 89, 53.6%] or low levels (LH-low; Allred score, ER and/or PgR 2 or 3, n = 21, 12.7%) for clinicohistomorphological characterisation. Morphological review showed that NLH included a percentage of patients with comedo necrosis, while LH patients had significantly more central scarring. In terms of immune responsiveness, NLH showed significantly higher rates of tumour-infiltrating lymphocytes and healing. The LH-high and NLH groups showed distinct characteristics (by both models, P < 0.05) and the LH-low group appeared to demonstrate intermediate characteristics according to multinomial analyses using covariates reflecting tumour morphology and immune response outcomes. CONCLUSIONS: These results support the classification of HER2+ BC into two major subgroups, LH-high and NLH, based on tumour morphology and immune response; LH-high proliferates via scirrhous and/or spiculated growth with a central scar, while the primary proliferation pattern of NLH is based on in-situ carcinomas containing comedo necrosis with noticeable TILs and healing.

Biological responses following one-stage full-mouth scaling and root planing with and without azithromycin: Multicenter randomized trial.

BACKGROUND AND OBJECTIVE: Full-mouth scaling and root planing (FM-SRP) increases the systemic levels of inflammatory mediators via early inflammation but may be inhibited using an antimicrobial agent. This prospective intervention study evaluates the biological response and clinical effects of FM-SRP with and without systemically administered azithromycin (AZM). MATERIALS AND METHODS: A multicenter parallel randomized controlled and open-label trial. A central randomization center used computer-generated tables to allocate treatments. Sixty-three patients with moderate to severe generalized periodontitis (New American Academy of Periodontology Classification: Stage3 or 4, Grade B) were randomly assigned to receive FM-SRP with AZM (test group, n = 32) or FM-SRP without AZM (control group, n = 31). Clinical parameters and body temperature were measured, and subgingival plaque, peripheral blood, and gingival crevicular fluid were collected before and after treatment. Periodontopathic bacteria and IgG titers were measured by gingival crevicular fluid and peripheral blood. High-sensitivity assays were used to analyze systemic and local inflammatory markers, such as endotoxin, high-sensitive CRP (hs-CRP), and six inflammatory cytokines. Follow-up 6 weeks. RESULTS: The total number of bacteria and the number of Porphyromonas gingivalis and Prevotella intermedia were significantly lower in the test group after FM-SRP. IgG titers for P gingivalis significantly decreased after FM-SRP with AZM, and the body temperature increased significantly after FM-SRP without AZM. In the control group, serum hs-CRP, IFN-γ, IL-12p70, and IL-6 were significantly increased one day after treatment, but subsequently decreased below the original numerical value. In the test group, only hs-CRP showed a significant increase. CONCLUSIONS: FM-SRP resulted in similar improvements in clinical parameters with and without the use of AZM. Inflammatory mediators showed no difference between the two groups after FM-SRP treatment. The use of AZM was effective in preventing the elevation of body temperature after FM-SRP.

Gender differences in physical activity and sedentary behavior of Japanese primary school children during school cleaning time, morning recess and lunch recess.

BACKGROUND: The school environment provides crucial opportunities for children to engage in health-promoting physical activity (PA). Japanese children clean their schools and have recess time every school day. The primary aim of the study is to describe the levels of physical activity during school cleaning and recess time while comparing it between genders. METHODS: PA and sedentary behavior (SB) of 230 boys and 252 girls aged 6-12 years-old from 14 public primary schools were assessed for 7 consecutive days with a triaxial accelerometer. Minutes of SB, and moderate-to-vigorous PA (MVPA) as a percentage in each of school cleaning time (15 min/day: 58% of the 14 schools or 20 min/day), morning recess time (15 min/day: 6% or 20 min/day) or lunch recess time (15 min/day: 29%, 20 min/day: 47% or 25 min/day) were evaluated. A one-way analysis of variance or Student's t test was used to examine differences in %PAs and %SB between school cleaning time and morning and lunch recess time, and between genders. RESULTS: In a school day, the percentage of total daily MVPA during school cleaning time, morning recess and lunch recess time was 19.4 ± 6.8% (15.2 ± 5.3 min/day) for boys and 16.9 ± 5.8% (10.5 ± 4.3 min/day) for girls. For boys, the proportions of MVPA in morning and lunch recesses and SB during the morning recess were significantly higher than during school cleaning time (p < 0.001). For girls, similar results were obtained and the SB during lunch recess was also higher than during school cleaning time (p < 0.001). CONCLUSIONS: These findings suggest that the total amount of school cleaning time, recess and lunch time likely contribute to daily MVPA but the beneficial effects should be further explored in future intervention studies.

[A Vesected Case of Pancreatic Metastasis from Breast Cancer Which Recurred Six Years after Breast Surgery].

A 43-year-old woman who underwent surgical resection of invasive ductal carcinoma in the left breast at the age of 37 years old presented at our hospital for evaluation of pancreatic tumor. The original tumor was estrogen receptor(ER)progesterone receptor(PgR)and HER2 positive. At that time, she underwent radical mastectomy with no evident nodal disease. Postoperatively, the patient was placed on adjuvant tamoxifen therapy for several years. Six years following the original diagnosis of breast cancer, she was referred to the hospital for routine check-up while asymptomatic. Follow-up examination showed a solitary hypodense mass approximately 0.9 cm in size in the pancreas body on dynamic CT scan. The patient underwent a standard distal pancreatectomy with standard regional lymphadenectomy. Histopathological examination and immunohistochemical features revealed that the tumor was compatible with metastatic pancreatic adenocarcinoma from breast cancer.

A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer.

BACKGROUND: Prognosis of pancreatic cancer is poor with a 5-year survival rate of only 7%. Although several new chemotherapy treatments have shown promising results, all patients will eventually progress, and we need to develop newer chemotherapy treatments to improve response rates and overall survival (OS). HF10 is a spontaneously mutated oncolytic virus derived from a herpes simplex virus-1, and it has potential to show strong antitumor effect against malignancies without damaging normal tissue. We aimed to evaluate the safety and anti-tumor effectiveness in phase I dose-escalation trial of direct injection of HF10 into unresectable locally advanced pancreatic cancer under endoscopic ultrasound (EUS)-guidance in combination with erlotinib and gemcitabine administration. The mid-term results have been previously reported and here we report the final results of our study. METHODS: This was a single arm, open-label Phase I trial. HF10 was injected once every 2 weeks and continued up to four times in total unless dose-limiting toxicity (DLT) appears. A total of nine subjects in three Cohorts with dose-escalation were planned to be enrolled in this trial. The primary endpoint was the safety assessment and the secondary endpoint was the efficacy assessment. RESULTS: Twelve patients enrolled in this clinical trial, and ten subjects received this therapy. Five patients showed Grade III myelosuppression and two patients developed serious adverse events (AEs) (perforation of duodenum, hepatic dysfunction). However, all of these events were judged as AEs unrelated to HF10. Tumor responses were three partial responses (PR), four stable diseases (SD), and two progressive diseases (PD) out of nine subjects who completed the treatment. Target lesion responses were three PRs and six SDs. The median progression free survival (PFS) was 6.3 months, whereas the median OS was 15.5 months. Two subjects from Cohort 1 and 2 showed downstaging and finally achieved surgical complete response (CR). CONCLUSIONS: HF10 direct injection under EUS-guidance in combination with erlotinib and gemcitabine was a safe treatment for locally advanced pancreatic cancer. Combination therapy of HF10 and chemotherapy should be explored further in large prospective studies. TRIAL REGISTRATION: This study was prospectively registered in UMIN-CTR (UMIN000010150) on March 4th, 2013.

Objectively evaluated physical activity and sedentary time in primary school children by gender, grade and types of physical education lessons.

BACKGROUND: During the typical school day, physical education (PE) gives children an opportunity for physical activity (PA) and reduces their sedentary time, but little is known about objectively evaluated PA and sedentary time during PE lessons and the differences across genders and grades. There is also a lack of research comparing PA and sedentary time among the different types of PE lessons. The primary aim of this study was to examine primary school students' moderate-to-vigorous PA (MVPA) levels and sedentary time during PE and whether there are gender or grade differences in a cross-sectional study. The secondary aim was to determine which types of PE lessons are best for increasing PA and reducing sedentary time. METHODS: Objectively evaluated MVPA and sedentary time during PE lessons in Japan with a triaxial accelerometer (Active style Pro HJA-350IT, Omron Healthcare) in girls (n = 221) and boys (n = 181). Minutes of sedentary time were categorized into metabolic equivalents (METs): categories ranged from sedentary time (METs ≤1.5) to MVPA (METs ≥3.0). Time tables and PE lesson types were evaluated using logs maintained by the class teachers. RESULTS: Time spent in MVPA and sedentary time were 27.3 and 24.3%, respectively. After adjustments for grade, relative body weight and school, boys spent significantly more time in MVPA compared with girls, but with an estimated mean difference of approximately 1 min. After adjustment for gender, relative body weight and school, the younger grades (1st and 2nd) spent significantly more time in MVPA and significantly less time in sedentary time compared with other grades. Moreover, after adjustments for gender, grade, relative body weight and school, the time spent in MVPA during gymnastic and track and field lessons was significantly lower than that during ball game lessons. Sedentary time during gymnastic lessons was significantly longer than in track and field and ball game lessons. CONCLUSIONS: Children did not engage in much MVPA and also spent time in sedentary time during PE, but there are no gender differences. The children were most active during ball game lessons. Therefore, it is important to increase MVPA and reduce sedentary time during PE in both genders.

Variability in school children's activity occurs in the recess and before-school periods.

BACKGROUND: An accurate description of physical activity (PA) at school is required for appropriate health interventions. We examined PA patterns in children, and identified the time periods that influenced them. METHODS: Forty students in five Japanese primary schools were asked to wear triaxial accelerometers for ≥7 days. We obtained coefficients of variance (CV) at 15 min intervals, and conducted factor analysis of the school periods. A questionnaire was used to investigate where students spent time before school, and during recess. RESULTS: The amount of PA, and its CV were higher around 8 a.m. (before-school period), 10 a.m. (morning recess), 1 p.m. (lunch recess), and 4 p.m. (commuting home from school). Moderate-vigorous PA (MVPA; ≥3.0 metabolic equivalent units [MET]) was highest during lunch recess and the after-school period (12.9 ± 7.4 min and 12.6 ± 6.2 min, respectively). The percentage of MVPA time was high (>15%) in the before-school period and morning and lunch recesses, but low (10%) in the after-school period. On factor analysis there were differences in PA patterns between the school period and the after-school period. The students who spent their time in the playground logged more MVPA time and less sedentary time (≤1.5 MET) than those who did not spend their time in the playground. CONCLUSION: Activities before school, and in the morning and lunch recesses influenced daily PA, and were different from after-school PA. Close attention to these periods may help in defining PA parameters during free time at school for PA interventions in children.

Role of HER2-Related Biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the Efficacy of Lapatinib plus Capecitabine in HER2-Positive Advanced Breast Cancer Refractory to Trastuzumab.

OBJECTIVE: The aim of this study was to investigate the correlation between human epidermal growth factor receptor 2 (HER2)-related biomarkers and the treatment outcomes using lapatinib plus capecitabine (LC) and to evaluate the influence of the estrogen receptor (ER) status in trastuzumab-refractory HER2-positive advanced breast cancer. METHOD: Eighty patients were enrolled in this study. Total HER2, p95HER2, and total HER3 expression were quantified using the VeraTag assays. PTEN (phosphatase and tensin homolog) and p95 expression was evaluated using immunohistochemistry and PIK3CA mutation using direct sequencing. RESULTS: The response rate to LC was 30%, clinical benefit rate was 51.3%, and the median progression-free survival (PFS) was 174.5 days. ER negativity significantly correlated with higher HER2 and p95HER2. The lower HER2 and PIK3CA mutations were often observed in the nonresponders. A high p95HER2 expression correlated with longer PFS especially in the high HER2- and ER-positive cases. Patients without the PIK3CA mutation showed longer PFS in the same subset. Overall survival after LC significantly correlated with the number of recurrence organs. CONCLUSION: LC therapy is effective in trastuzumab-refractory HER2-positive breast cancer. Moreover, the biomarker expression differed depending on ER status, and a high p95HER2 expression and wild-type PIK3CA gene correlated with longer PFS especially in the ER-positive cases.

Seasonal changes in objectively measured sedentary behavior and physical activity in Japanese primary school children.

BACKGROUND: The recent prevalence of obesity in Japanese children is much higher compared to 1980. The present study compared daily sedentary behavior (SB) and physical activity (PA) between the school year and summer vacation in Japanese primary school children. METHODS: Participants were 98 Japanese boys (8.9 ± 1.8 years at baseline) and 111 girls (9.1 ± 1.8 years). SB and PA were measured in May (school term) and July/August (summer vacation), 2011. SB and PA were assessed using a triaxial accelerometer (Active style Pro HJA-350IT, Omron Healthcare) for 7 consecutive days. The average number of minutes spent in SB (no more than 1.5 metabolic equivalents (METs)), light intensity activity (LPA; more than 1.5 to less than 3.0 METs) and moderate-to-vigorous physical activity (MVPA; 3.0 METs or more), and step counts were calculated for each individual. Moreover, the determinants/moderators of changes in SB and PA were examined. RESULTS: Daily SB was significantly higher in the summer vacation than in the school year for both boys and girls (p < 0.05). Ambulatory and total LPA and MVPA, non-ambulatory LPA and step counts were lower in summer vacation in both genders (p < 0.001). Moreover, non-ambulatory MVPA was significantly lower in the summer vacation than in the school year for girls (p < 0.001). The decrease in non-ambulatory MVPA in boys and increase in SB in girls were significantly lower in those who participated in sports compared to those who did not (p < 0.040 or p < 0.033). The change in SB for boys was significantly associated with having a TV in the bedroom (p < 0.022). CONCLUSIONS: These findings show that primary school children in Japan are less active in the summer vacation, as indicated by both higher SB and lower LPA and ambulatory MVPA in both genders. Moreover, the seasonal change in non-ambulatory MVPA for Japanese children was affected by gender. This study also suggests that sports participation and bedroom TV ownership may moderate seasonal changes in PA and SB. The results emphasize the need to take summer vacation into account when planning interventions aimed at decreasing SB or increasing PA in Japanese children.

Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft.

Breast cancer is one of the most common and feared cancers faced by women. The prognosis of patients with advanced or recurrent breast cancer remains poor despite refinements in multimodality therapies involving chemotherapeutic and hormonal agents. Multimodal therapy with more specific and effective strategy is urgently needed. The oncolytic herpes simplex virus (HSV) has potential to become a new effective treatment option because of its broad host range and tumor selective viral distribution. Bevacizumab is a monoclonal antibody against VEGFA, which inhibits angiogenesis and therefore tumor growth. Our approach to enhance the antitumor effect of the oncolytic HSV is to combine oncolytic HSV HF10 and bevacizumab in the treatment of breast cancer. Our results showed that bevacizumab enhanced viral distribution as well as tumor hypoxia and expanded the population of apoptotic cells and therefore induced a synergistic antitumor effect. HF10 is expected to be a promising agent in combination with bevacizumab in the anticancer treatment.

Management of breast papillary lesions diagnosed in ultrasound-guided vacuum-assisted and core needle biopsies.

AIMS: To assess the outcome of breast papillary lesions diagnosed by ultrasound-guided core needle biopsy (CB) or vacuum-assisted 'mammotome' biopsy (MT), the accuracy of these diagnoses, and whether it is justified not to undertake surgical excision of non-malignant papillary lesions so diagnosed. METHODS AND RESULTS: Among 3219 (MT, 2195; CB, 1024) breast biopsies spanning 5 years, 185 (5.7%) papillary lesions [MT, 162 (88%); CB, 23 (12%)] were identified. Of these, 142 cases (77%; MT/CB, 125/17) were benign, 24 (13%, 23/1) were atypical, and 19 (10%; 14/5) were malignant. Of the 142 benign cases, 114 had imaging follow-up (FU) (FU period 2-81 months); 17 of 114 cases were excised, and four were malignant (3.5%) (FU period 4-57 months). Of the 24 atypical cases (23 had FU), 19 were excised: six were benign (32%) and 13 malignant (68%). The remaining four cases were considered to be non-malignant (FU period 7-54 months). CONCLUSIONS: Benign papillary lesions diagnosed by MT or CB might not require immediate excision, but should receive imaging FU for at least 5 years. Excision should be performed in cases showing changes in imaging features, as the possibilities of carcinoma coexisting with papilloma or carcinoma developing from papilloma cannot be excluded, as illustrated by the 4% upgrade rate at excision in this study.

[Effect of weekly paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide as neoadjuvant treatment for patients with triple-negative and luminal-type breast cancer - a multicenter study].

This study examined the pathological complete response (pCR )rate and safety of induction chemotherapy with 12 cycles of weekly paclitaxel (80 mg/m²) followed by 4 cycles of 5-fluorouracil (500 mg/m²), epirubicin (100 mg/m²), and cyclo- phosphamide (500 mg/m²). The study medication was administered to female patients (n=31)with a mean age of 51 years, diagnosed with stage II A (n=18), II B (n=11) and III A (n=2) disease and with an estrogen receptor positive rate of 65% (20/31). No patient was HER2-IHC [human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC)](3+) or HER2-FISH (fluorescence in situ hybridization) positive. Twenty-eight patients completed the treatment regimen. Treatment was halted in 2/31 patients due to progression of disease in one patient and a Grade 3 non-hematological adverse effect of skin eruption and itching in the other patient. A third patient died of causes unrelated to the study medication. Central review ascertained a pCR in 6 patients. In patients with triple-negative disease we observed a pCR rate of 67% (6/9). In patients with the Luminal (A+B) subtype, 0% (0/19) had a pCR. Grade 3/4 toxicity included leucopenia (58%), neutropenia (58%), febrile neutropenia (26%), fatigue (10%), and ALT elevation (7%). In terms of pCR, patients presenting with triple-negative disease and manageable safety profiles appear to respond well to this treatment regimen, while only a modest response was observed in patients with Luminal subtype disease.

Combination treatment of human pancreatic cancer xenograft models with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib and oncolytic herpes simplex virus HF10.

BACKGROUND: There is the potential to use replication-competent oncolytic viruses to treat cancer. We evaluated the efficacy of HF10, a herpes simplex virus type 1 (HSV-1) mutant, in combination with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in human pancreatic cancer xenograft models. METHODS: The viability of human pancreatic cancer cell lines (BxPC-3 and PANC-1) treated with HF10 and erlotinib, on their own or in combination, was determined. Effects of erlotinib on HF10 entry into tumor cells were also investigated. BxPC-3 subcutaneous tumor-bearing mice were treated with HF10 and erlotinib, on their own or in combination, with effects on tumor volume determined. Immunohistochemical examination of HSV-1 and CD31 was conducted to assess virus distribution and angiogenesis within tumors. A peritoneally disseminated BxPC-3 xenograft model was evaluated for survival. RESULTS: HF10 combined with erlotinib demonstrated the highest cytotoxicity against BxPC-3. A combination effect was not observed in PANC-1 cells, and erlotinib did not affect virus entry into tumor cells. In the peritoneally disseminated model, HF10 combined with erlotinib had no beneficial effect on survival. In the subcutaneous tumor model, combination therapy resulted in the inhibition of tumor growth to a greater extent than using each agent on its own. Immunohistochemistry revealed that virus distribution within the tumor persisted in the combination therapy group. CONCLUSIONS: Combination therapy with HF10 and erlotinib warrants further investigation to establish a new treatment strategy against human pancreatic cancers.