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Abstract Objective To investigate the efficacy and safety of robot-assisted radical hysterectomy (RARH) as a minimally invasive procedure in patients with cervical cancer that is curable by surgery. Materials and methods This study was a multicenter, open-label, single-arm clinical trial. The short-term outcome of open radical hysterectomy was used as the historical control. The primary endpoint was successful surgery with minimal blood loss (300 mL or less) and negative surgical margins. Secondary endpoints included surgical outcomes, recurrence-free survival (RFS), and overall survival (OS) rates. Results Overall, 101 cases were enrolled in this study at 10 participating medical institutions and 100 underwent RARH. Among these cases, 89 met the primary endpoint, exceeding the threshold of 0.75 set by the lower limit. At 2 years postoperatively, 17 cases had recurrences, 4 were classified as International federation of Obstetrics and Gynecology Stage IB1 or lower, while 13 as IB2 or higher. There were three deaths, including one in Stage IB1 and two in Stage IIB in the second postoperative year, all of which had lymph node metastasis. The oncological outcomes for all cases showed RFS and OS rates of 82.7% and 96.9%, respectively, over a median observation period of 37 months. For cases with Stage IB1, RFS and OS were 94.1% and 98.5%, respectively. Conclusion RARH demonstrated a significant reduction in blood loss while ensuring radicality, indicating the safety and efficacy of this procedure compared to conventional RH. Although it is conceivable that the results of this oncological analysis could change, as the data collection has not been fully completed, we plan to further evaluate the oncologic outcomes of RARH in future studies. Trial registration UMIN-CTR: UMIN000022278, registered on 11th May 2016.

Background: Basal cell hyperplasia is commonly observed in nasal polyp epithelium of eosinophilic chronic rhinosinusitis (eCRS). We examined the function and mechanisms of basal cell hyperplasia in the pathophysiology of eCRS. Methods: We found that normal human bronchial epithelial (NHBE) cells obtained basal cell characteristics when cultured with PneumaCult™-Ex Plus Medium. Most of the cells passaged three times expressed basal cell surface markers CD49f and CD271 by flow cytometry, and basal cell nuclear marker p63 by immunohistochemical staining. We named these NHBE cells with basal cell characteristics cultured Basal-like cells (cBC), and NHBE cells cultured with BEGM™ cultured Epithelial cells (cEC). The characteristics of cBC and cEC were examined and compared by RNA sequencing, RT-PCR, ELISA, and cell proliferation studies. Results: RNA sequencing revealed that cBC showed higher gene expression of thymic stromal lymphopoietin (TSLP), IL-8, TLR3, and TLR4, and lower expression of PAR-2 compared with cEC. The mRNA expression of TSLP, IL-8, TLR3, and TLR4 was significantly increased in cBC, and that of PAR-2 was significantly increased in cEC by RT-PCR. Poly(I:C)-induced TSLP production and LPS-induced IL-8 production were significantly increased in cBC. IL-4 and IL-13 stimulated the proliferation of cBC. Finally, the frequency of p63-positive basal cells was increased in nasal polyp epithelium of eCRS, and Ki67-positive proliferating cells were increased in p63-positive basal cells. Conclusions: Type 2 cytokines IL-4 and IL-13 induce basal cell hyperplasia, and basal cells exacerbate type 2 inflammation by producing TSLP in nasal polyp of eCRS.

Abstract In the phase 3 KEYNOTE-355 study (NCT02819518), pembrolizumab plus chemotherapy demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy among patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 10 tumors. We analyzed outcomes for the subgroup of patients enrolled in Asia in KEYNOTE-355. Patients received pembrolizumab 200 mg or placebo (2:1 randomization) every 3 weeks for 35 cycles plus investigator’s choice chemotherapy. Primary endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 and OS. Among patients enrolled in Hong Kong, Japan, Korea, Malaysia and Taiwan (pembrolizumab plus chemotherapy, n = 113; placebo plus chemotherapy, n = 47), 117 (73.1%) had PD-L1 CPS ≥ 1 and 56 (35.0%) had PD-L1 CPS ≥ 10. Median time from randomization to data cutoff (June 15, 2021) was 43.8 (range, 36.8‒53.2) months (intent-to-treat [ITT] population). Hazard ratios (HRs [95% CI]) for PFS in the CPS ≥ 10, CPS ≥ 1, and ITT populations were 0.48 (0.24‒0.98), 0.58 (0.37‒0.91), and 0.66 (0.44‒0.99), respectively. Corresponding HRs (95% CI) for OS were 0.54 (0.28‒1.04), 0.62 (0.40‒0.97), and 0.57 (0.39‒0.84). Grade 3/4 treatment-related adverse events (AEs) occurred in 77.9% versus 78.7% of patients with pembrolizumab plus chemotherapy versus placebo plus chemotherapy. No grade 5 AEs occurred. Clinically meaningful improvement in PFS and OS with manageable toxicity were observed with pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients enrolled in Asia with previously untreated, inoperable or metastatic TNBC. Trial registration: ClinicalTrials.gov, NCT02819518.

Abstract Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib–tamoxifen in patients with HR+/HER2− advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib–tamoxifen or placebo–tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1–32.4) with palbociclib–tamoxifen and 11.1 months (95% CI, 7.4–14.6) with placebo–tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43–0.85; P = 0.002). Palbociclib–tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44–1.21) with palbociclib–tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib–tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo–tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2− advanced breast cancer, palbociclib–tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib–tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.

Abstract We study the dynamic orbit about Phobos of the Martian Moon eXploration (MMX) spacecraft and simulate gravity field estimation using Doppler, image landmarks, and LIght Detection And Ranging (LIDAR) data based on a mission plan of MMX and investigate whether the differences in the internal density structure of Phobos can be detected through this mission. Degree 2 Stokes coefficients of the Phobos gravity field, $${\overline{C} }_{20}$$ C ¯ 20 and $${\overline{C} }_{22}$$ C ¯ 22 , which are necessary to obtain the moment of inertia by combining with the libration amplitude, could be determined with an accuracy within the order of 0.1% using datasets from two-dimensional (2D) quasi-satellite orbits (QSOs). If observations from 3D-QSO could be realized at low altitude, coefficients up to degree and order 5 could be estimated, which could be used to detect regional density anomalies. Moreover, the observation data from the ascending trajectory after landing on the Phobos surface can be used to detect local density anomalies around the landing site, which could help interpret the origin of the samples and understand the internal structure of Phobos. Graphical Abstract

This paper aims to clarify the behavior and damage conditions of batteries when multi-rotor unmanned aerial vehicles (drones) in horizontal flight collide with a structure to obtain the engineering knowledge that serves to consider the method of the safety performance evaluation of drone batteries in the collision. Drones with maximum takeoff weight of 15.5 kg, 24.5 kg, and 50 kg for aerial photographing, agricultural chemical spraying, and material transporting were used in the experiment analysis. The drones were ejected from an ejection system and collided with a barrier. The behavior of the drones and the batteries were captured on high-speed cameras. In addition, collision loads on the barrier and accelerations of the drones and their batteries were measured. The behavior of the drones and the batteries were considered based on the analysis results of the high-speed cameras. When the drones collided with the barrier, the batteries attached to the drones with snap-fit, rubber bands, and hook-and-loop fasteners separated from the drones. The separated batteries subsequently collided with the barrier. In the collision of the batteries and the barrier, the acceleration of the battery attached to the front of the drone by snap-fit was maximum. The acceleration was approximately 2.2 times larger than the acceleration given to the battery by the impact testing machine in the JIS standard (JIS C62133-2) that defines the test method for the safe operation of lithium secondary batteries used for portable devices. The damage conditions of batteries were presented and discussed from the viewpoint of the collision safety of batteries.

Abstract Background Feeding and eating disorders are severe mental disorders that gravely affect patients’ lives. In particular, patients with anorexia nervosa (AN) or bulimia nervosa (BN) appear to have poor social cognition. Many studies have shown the relationship between poor social cognition and brain responses in AN. However, few studies have examined the relationship between social cognition and BN. Therefore, we examined which brain regions impact the ability for social cognition in patients with BN. Methods We used task-based functional magnetic resonance imaging (fMRI) to examine brain responses during a social cognition task and the Reading Mind in the Eyes Test (RMET). During the fMRI, 22 women with BN and 22 healthy women (HW) took the RMET. Participants also completed the eating disorder clinical measures Bulimic Investigatory Test, Edinburgh (BITE) and Eating Disorders Examination Questionnaire (EDE-Q), the Patient Health Questionnaire (PHQ-9) measure of depression; and the Generalized Anxiety Disorder (GAD-7) measure of anxiety. Results No difference was observed in the RMET scores between women with BN and HW. Both groups showed activation in brain regions specific to social cognition. During the task, no differences were shown between the groups in the BOLD signal (p

Abstract Introduction Hypersensitivity reactions (HSRs) to chemotherapy are serious adverse events associated with cancer drug therapy and can occur with any antitumor drug. This study investigated the safety and efficacy of carboplatin desensitization therapy in Japan and established a method for treating carboplatin HSRs. Methods Patients diagnosed with gynecological (ovarian, endometrial, or cervical) cancers who underwent carboplatin desensitization therapy between 2016 and 2020 at the Gynecologic Cancer Study Group of Japan Clinical Oncology Group were included. The carboplatin desensitization therapy at each institution and the implementation cases were registered in an online case report form. Results This retrospective study enrolled 136 patients (ovarian, 108; endometrial, 17; and cervical cancer, 11). Pre‐existing allergies were present in 37 (27.2%) patients, and 32 (23.5%) patients exhibited prodromal symptoms during treatment before HSR onset. Erythema was the most common symptom at HSR onset, affecting 93 (68.4%) patients, followed by itching in 72 (52.9%) patients and decreased oxygen saturation in 43 (31.6%) patients. Loss of consciousness occurred in three (2.2%) patients. The most common timing of HSR onset was during the first recurrence treatment (47%). The mean total carboplatin dose until HSR onset was 7331 (2620–18,282) mg, and the mean number of doses was 14 (4–63). Desensitization treatment was completed in 75% of cases, and breakthrough HSRs occurred in 25% (34/136). No deaths occurred in the study cohort. The risk factors for HSRs were not identified. Conclusion Although carboplatin desensitization therapy has high success rates in Japan, erythema and pruritus are important HSRs to consider.

Abstract Background Femoral neurovascular injury is a serious complication in a direct anterior approach (DAA) total hip arthroplasty. However, dynamic neurovascular bundle location changes during the approach were not examined. Thus, this study aimed to analyze the effects of leg position on the femoral neurovascular bundle location using magnetic resonance imaging (MRI). Methods This study scanned 30 healthy volunteers (15 males and 15 females) with 3.0T MRI in a supine and 30-degree hip extension position with the left leg in a neutral rotation position and the right leg in a 45-degree external extension position. The minimum distance from the edge of the anterior acetabulum to the femoral nerve (dFN), artery, and vein were measured on axial T1-weighted images at the hip center level, as well as the angle to the horizontal line of the femoral nerve (aFN), artery (aFA), and vein from the anterior acetabulum. Results The dFN in the supine position with external rotation was significantly larger than supine with neutral and extension with external rotation position (20.7, 19.5, and 19.0; p = 0.031 and 0.012, respectively). The aFA in supine with external rotation was significantly larger than in other postures (52.4°, 34.2°, and 36.2°, p

Background: Abemaciclib-induced diarrhea (AID) impairs quality of life (QOL) and treatment adherence in patients with breast cancer. Supportive treatment with loperamide is associated with constipation. We hypothesized that probiotics and trimebutine maleate (TM) would decrease the frequency of AID without causing constipation. Methods: Hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer patients were randomized into the probiotic Bifidobacterium (A) or probiotic Bifidobacterium and TM (B) groups. Endocrine therapy, Abemaciclib and probiotic Bifidobacterium three times a day for 28 days, was administered to both arms. Arm B was treated with TM upon the onset of diarrhea. The primary endpoint was the percentage of patients who experienced grade ≥2 diarrhea. The secondary endpoints were safety, frequency, and duration of all-grade diarrhea; frequency of emesis and constipation; usage of loperamide; and health-related QOL/patient-reported outcome during the study. We evaluated whether the primary endpoint of each arm exceeded the predetermined threshold. Results: Fifty-one patients completed treatment. Grade 2 diarrhea occurred in 52% and 50% of patients in Arm A and Arm B, respectively. One patient experienced grade 3 diarrhea in each arm. The median duration of grade2 diarrhea was 2 and 2.5day, and only one patient required dose reduction. Grade ≥2 constipation was observed in 4% of Arm A and 3.6% of Arm B. Conclusions: Probiotic Bifidobacterium or the combination of probiotic Bifidobacterium with TM did not decrease the incidence of grade 2 or greater diarrhea compared with historical control, although the grade 3 or greater diarrhea was reduced. Clinical trial registration: jRCT (Japan registry of clinical trials).jRCTs031190154.

Abstract Background Although cervical cancer is often characterized as preventable, its incidence continues to increase in low‐ and middle‐income countries, underscoring the need to develop novel therapeutics for this disease.This study assessed the distribution of fusion genes across cancer types and used an RNA‐based classification to divide cervical cancer patients with a poor prognosis into subgroups. Material and Methods RNA sequencing of 116 patients with cervical cancer was conducted. Fusion genes were extracted using StarFusion program. To identify a high‐risk group for recurrence, 65 patients who received postoperative adjuvant therapy were subjected to non‐negative matrix factorization to identify differentially expressed genes between recurrent and nonrecurrent groups. Results We identified three cases with FGFR3‐TACC3 and one with GOPC‐ROS1 fusion genes as potential targets. A search of publicly available data from cBioPortal (21,789 cases) and the Center for Cancer Genomics and Advanced Therapeutics (32,608 cases) showed that the FGFR3 fusion is present in 1.5% and 0.6% of patients with cervical cancer, respectively. The frequency of the FGFR3 fusion gene was higher in cervical cancer than in other cancers, regardless of ethnicity. Non‐negative matrix factorization identified that the patients were classified into four Basis groups. Pathway enrichment analysis identified more extracellular matrix kinetics dysregulation in Basis 3 and more immune system dysregulation in Basis 4 than in the good prognosis group. CIBERSORT analysis showed that the fraction of M1 macrophages was lower in the poor prognosis group than in the good prognosis group. Conclusions The distribution of FGFR fusion genes in patients with cervical cancer was determined by RNA‐based analysis and used to classify patients into clinically relevant subgroups.

Abstract Pembrolizumab plus chemotherapy improved progression‐free survival (PFS) and overall survival (OS) compared with placebo plus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic triple‐negative breast cancer with tumor programmed cell death ligand 1 (PD‐L1) combined positive score (CPS) ≥10 in the global, phase 3, randomized controlled trial KEYNOTE‐355. We report results for patients enrolled in Japan. Patients were randomized 2:1 to pembrolizumab 200 mg or placebo Q3W for 35 cycles plus chemotherapy (nab‐paclitaxel, paclitaxel, or gemcitabine–carboplatin). Primary endpoints were PFS per RECIST version 1.1 by blinded independent central review and OS in patients with PD‐L1 CPS ≥10, PD‐L1 CPS ≥1, and the intention‐to‐treat (ITT) population. No alpha was assigned to this exploratory analysis. Eighty‐seven patients were randomized in Japan (pembrolizumab plus chemotherapy, n = 61; placebo plus chemotherapy, n = 26), 66 (76%) had PD‐L1 CPS ≥1, and 28 (32%) had PD‐L1 CPS ≥10. Median time from randomization to data cutoff (June 15, 2021) was 44.7 (range, 37.2–52.9) months in the ITT population. Hazard ratios (HRs; 95% CI) for OS were 0.36 (0.14–0.89), 0.52 (0.30–0.91), and 0.46 (0.28–0.77) in the PD‐L1 CPS ≥10, PD‐L1 CPS ≥1, and ITT populations, respectively. HRs (95% CI) for PFS were 0.52 (0.20–1.34), 0.61 (0.35–1.06), and 0.64 (0.39–1.05). Grade 3 or 4 treatment‐related adverse events occurred in 85% of patients in each group (no grade 5 events). Consistent with the global population, pembrolizumab plus chemotherapy tended to show improvements in OS and PFS with manageable toxicity versus placebo plus chemotherapy in Japanese patients and supports this combination in this setting.

Background Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies.Methods This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers.Results From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy.Conclusions Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs.Trial registration number JapicCTI-194782, jRCT2080224706, UMIN000036970.

Abstract Lymph node metastasis (LNM) is a well-established prognostic factor in endometrial cancer (EC). We aimed to construct a model that predicts LNM and prognosis using preoperative factors such as myometrial invasion (MI), enlarged lymph nodes (LNs), histological grade determined by endometrial biopsy, and serum cancer antigen 125 (CA125) level using two independent cohorts consisting of 254 EC patients. The area under the receiver operating characteristic curve (AUC) of the constructed model was 0.80 regardless of the machine learning techniques. Enlarged LNs and higher serum CA125 levels were more significant in patients with low-grade EC (LGEC) and LNM than in patients without LNM, whereas deep MI and higher CA125 levels were more significant in patients with high-grade EC (HGEC) and LNM than in patients without LNM. The predictive performance of LNM in the HGEC group was higher than that in the LGEC group (AUC = 0.84 and 0.75, respectively). Patients in the group without postoperative pathological LNM and positive LNM prediction had significantly worse relapse-free and overall survival than patients with negative LNM prediction (log-rank test, P

Abstract Japanese asteroid explorer Hayabusa2 arrived at C-type asteroid 162,173 Ryugu in June 2018. The laser altimeter (LIDAR) onboard Hayabusa2 measured its own transmitted laser and returned pulse intensities from a Ryugu surface until November 2019. Because the Ryugu surface is extremely rough, topography dominates over the material properties in the conventional derivation of normal albedo. Thus, we developed a method to retrieve the normal albedo from the rough surface of a C-type asteroid at a LIDAR laser wavelength of 1.064 μm. The albedo map covering an equatorial band between – 40° and + 20° in latitude was created with 3˚-by-3˚ resolution using the intensity data obtained before the conjunction of the spacecraft with the Sun. The average of the normal albedo is 0.0405 $$\pm$$ ± 0.0027, whereas approximately half of the 3°-by-3° grids are between 0.04 and 0.045. The low and uniform normal albedo feature is common to other remote-sensing observations of Ryugu by visible and near-infrared cameras onboard Hayabusa2. Graphical Abstract

Abstract Background Human papillomavirus (HPV) type 67 is phylogenetically classified into Alphapapillomavirus species 9 (alpha-9) together with other carcinogenic types (HPV16, 31, 33, 35, 52 and 58), but is the only alpha-9 type defined as possibly carcinogenic. This study aimed to determine whole-genome sequences of HPV67 isolated from Japanese women with cervical cancer or cervical intraepithelial neoplasia (CIN) to better understand the genetic basis of the oncogenic potential of HPV67. Methods Total cellular DNA isolated from cervical exfoliated cells that were single positive for HPV67 (invasive cervical cancer, n = 2; CIN3, n = 6; CIN 2, n = 1; CIN1, n = 2; the normal cervix, n = 1) was subjected to PCR to amplify HPV67 DNA, followed by next generation sequencing to determine the complete viral genome sequences. Variant lineages/sublineages were assigned through viral whole-genome phylogenetic analysis. The transcriptional activity of the virus early promoter was assessed by luciferase reporter assays in cervical cancer cell lines. Results Phylogenetic analyses of HPV67 genomes from Japan (n = 12) revealed that 11 belonged to lineage A (sublineage A1, n = 9; sublineage A2, n = 2) and one belonged to lineage B. All cancer cases contained sublineage A1 variants, and one of these contained an in-frame deletion in the E2 gene. The long control region of the HPV67 genome did not induce transcription from the virus early promoter in HeLa cells, but showed weak transcriptional activity in CaSki cells. Conclusions The single detection of HPV67 in cervical cancer and precancer specimens strongly suggests the carcinogenic potential of this rare genotype. The phylogenetic analysis indicates a predominance of lineage A variants among HPV67 infections in Japan. Since only 23 complete genome sequences of HPV67 had been obtained until now, the newly determined genome sequences in this study are expected to contribute to further functional and evolutionary studies on the genetic diversity of HPV67.

Introduction Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have demonstrated differences in extensive brain structure, activity and network. However, there remains heterogeneity and inconsistency across these findings, presumably because of the diversity of the disorders themselves, small sample sizes, and site and parameter differences in MRI scanners, and their overall pathogenesis remains unclear. To address these gaps in the literature, we will apply the travelling-subject approach to correct site differences in MRI scanners and clarify brain structure and network characteristics of children with ADHD and ASD using large samples collected in a multi-centre collaboration. In addition, we will investigate the relationship between these characteristics and genetic, epigenetic, biochemical markers, and behavioural and psychological measures.Methods and analysis We will collect resting-state functional MRI (fMRI) and T1-weighted and diffusion-weighted MRI data from 15 healthy adults as travelling subjects and 300 children (ADHD, n=100; ASD, n=100; and typical development, n=100) with multi-dimensional assessments. We will also apply data from more than 1000 samples acquired in our previous neuroimaging studies on ADHD and ASD.Ethics and dissemination The study protocol has been approved by the Research Ethics Committee of the University of Fukui Hospital (approval no: 20220601). Our study findings will be submitted to scientific peer-reviewed journals and conferences.

Introduction The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has led to a change in the clinical management of breast cancer. Nausea and vomiting are the most common adverse events of T-DXd, which cannot be completely alleviated by standard prophylactic regimens. Olanzapine is particularly effective in preventing delayed nausea caused by chemotherapy. In this study, we will evaluate the efficacy of olanzapine in managing persistent nausea and vomiting during T-DXd treatment.Methods and analysis The ERICA study is a multicentre, placebo-controlled, double-blind, randomised phase II study with the aim to evaluate the antiemetic effects of the prophylactic olanzapine (5 mg orally, on days 1–6) or placebo combined with a 1,5-hydroxytryptamine-3 (5-HT3)–receptor antagonist and dexamethasone in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer undergoing T-DXd treatment. For a period of 22 days from the day of T-DXd treatment, patients will document their experience in an electronic symptom diary daily during observational periods. The primary endpoint is the complete response rate, defined as no vomiting and no rescue medications during the ‘delayed phase’ of 24–120 hours post-T-DXd administration. In addition, we define 120–504 hour as the ‘persistent phase’ and 0–504 hours as the ‘overall phase’ for secondary endpoint analysis. We have estimated that a total sample size of at least 156 patients is needed to allow a power of 80% at a one-sided significance level of 20% in this study. The target sample size is set to 166 to account for possible case exclusions.Ethics and dissemination The study protocol is approved by the West Japan Oncology Group protocol review committee and the SHOWA University Clinical Research Review Board. The study results will be presented at international conferences and published in a peer-reviewed journal.Trial registration number jRCTs031210410.

Abstract Magnetic resonance vessel wall imaging is desirable for evaluating Kawasaki disease (KD)-associated coronary arterial lesions. To evaluate the reproducibility of three-dimensional turbo spin-echo (3D-TSE) and two-dimensional dual inversion-recovery turbo spin-echo (2D-DIR-TSE) for coronary vessel wall imaging in KD. Ten patients were prospectively enrolled. Coronary vessel wall imaging with axial-slice orientation 3D-TSE and 2D-DIR-TSE were acquired for cross-sectional images in aneurysmal and normal regions. Lumen area (LA), wall area (WA), and normalized wall index (NWI) of cross-sectional images were measured in both regions. Reproducibility between 3D-TSE and 2D-DIR-TSE was evaluated via intraclass correlation coefficients (ICCs) and Bland–Altman plots. 48 points (aneurysmal, 27; normal, 21) were evaluated. There were high ICCs between 3D-TSE and 2D-DIR-TSE in LA (0.95) and WA (0.95). In aneurysmal regions, 95% limits of agreement were LA, WA, and NWI of − 29.9 to 30.4 mm2, − 18.8 to 15.0 mm2, and − 0.22 to 0.20, respectively. In normal regions, the 95% limits of agreement were LA, WA, and NWI of − 4.44 to 4.38 mm2, − 3.51 to 4.30 mm2, and − 0.14 to 0.16, respectively. No fixed and proportional biases between 3D-TSE and 2D-DIR-TSE images in aneurysmal and normal regions were noted. 3D-TSE was reproducible with conventional 2D-DIR-TSE for coronary vessel wall assessment on KD.

Human papillomavirus type 31 (HPV31) is detected less frequently in cervical cancer than two major causative types, HPV16 and HPV18. Here, we report a comprehensive analysis of HPV31 genome sequences in cervical lesions collected from Japanese women. Of 52 HPV31-positive cervical specimens analyzed by deep sequencing, 43 samples yielded complete genome sequences of around 7900 base pairs and 9 samples yielded partially deleted genome sequences. Phylogenetic analysis showed that HPV31 variant distribution was lineage A in 19 samples (36.5%), lineage B in 28 samples (53.8%), and lineage C in 5 samples (9.6%), indicating that lineage B variants are dominant among HPV31 infections in Japan. Deletions in the viral genome were found in the region from the E1 to L1 genes, but all the deleted genomes retained the E6/E7 genes. Among intra-patient nucleotide variations relative to a consensus genome sequence in each sample, C-to-T substitutions were most frequently detected, followed by T-to-C and C-to-A substitutions. High-frequency, intra-patient mutations (>10%) in cervical cancer samples were found in the E1, E2, and E7 genes, and all of them were nonsynonymous substitutions. The enrichment of high-frequency nonsynonymous substitutions strongly suggests that these intra-patient mutations are positively selected during the development of cervical cancer/precancer.

Abstract Martian moons exploration, MMX, is the new sample return mission planned by the Japan Aerospace Exploration Agency (JAXA) targeting the two Martian moons with the scheduled launch in 2024 and return to the Earth in 2029. The major scientific objectives of this mission are to determine the origin of Phobos and Deimos, to elucidate the early Solar System evolution in terms of volatile delivery across the snow line to the terrestrial planets having habitable surface environments, and to explore the evolutionary processes of both moons and Mars surface environment. To achieve these objectives, during a stay in circum-Martian space over about 3 years MMX will collect samples from Phobos along with close-up observations of this inner moon and carry out multiple flybys of Deimos to make comparative observations of this outer moon. Simultaneously, successive observations of the Martian atmosphere will also be made by utilizing the advantage of quasi-equatorial spacecraft orbits along the moons’ orbits. Graphical Abstract

ObjectivesWe investigated prospectively whether, in cervical cancer (CC) treated with concurrent chemoradiotherapy (CCRT), the Apparent diffusion coefficient (ADC) histogram and texture parameters and their change rates during treatment could predict prognosis.MethodsFifty-seven CC patients treated with CCRT at our institution were included. They underwent MRI scans up to four times during the treatment course (1st, before treatment [n = 41], 2nd, at the start of image-guided brachytherapy (IGBT) [n = 41], 3rd, in the middle of IGBT [n = 27], 4th, after treatment [n = 53]). The entire tumor was manually set as the volume of interest (VOI) manually in the axial images of the ADC map by two radiologists. A total of 107 image features (morphology features 14, histogram features 18, texture features 75) were extracted from the VOI. The recurrence prediction values of the features and their change rates were evaluated by Receiver operating characteristics (ROC) analysis. The presence or absence of local and distant recurrence within two years was set as an outcome. The intraclass correlation coefficient (ICC) was also calculated.ResultsThe change rates in kurtosis between the 1st and 3rd, and 1st and 2nd MRIs, and the change rate in grey level co-occurrence matrix_cluster shade between the 2nd and 3rd MRIs showed particularly high predictive powers (area under the ROC curve = 0.785, 0.759, and 0.750, respectively), which exceeded the predictive abilities of the parameters obtained from pre- or post-treatment MRI only. The change rate in kurtosis between the 1st and 2nd MRIs had good reliability (ICC = 0.765).ConclusionsThe change rate in ADC kurtosis between the 1st and 2nd MRIs was the most reliable parameter, enabling us to predict prognosis early in the treatment course.

Abstract The science operations of the spacecraft and remote sensing instruments for the Martian Moon eXploration (MMX) mission are discussed by the mission operation working team. In this paper, we describe the Phobos observations during the first 1.5 years of the spacecraft’s stay around Mars, and the Deimos observations before leaving the Martian system. In the Phobos observation, the spacecraft will be placed in low-altitude quasi-satellite orbits on the equatorial plane of Phobos and will make high-resolution topographic and spectroscopic observations of the Phobos surface from five different altitudes orbits. The spacecraft will also attempt to observe polar regions of Phobos from a three-dimensional quasi-satellite orbit moving out of the equatorial plane of Phobos. From these observations, we will constrain the origin of Phobos and Deimos and select places for landing site candidates for sample collection. For the Deimos observations, the spacecraft will be injected into two resonant orbits and will perform many flybys to observe the surface of Deimos over as large an area as possible. Graphical Abstract

Abstract In order to investigate the origin of Phobos and Deimos, the Japanese Martian Moons eXploration (MMX) mission is scheduled for launch in 2024. MMX will make comprehensive remote-sensing measurements of both moons and return regolith samples from Phobos to Earth. Geodetic measurements of gravity, shape, and rotation parameter of a body provides constraints on its internal structure reflecting its origin and evolution. Moments of inertia are important parameters to constrain the internal mass distribution, but they have not been well determined for the Martian moons yet. We discuss the mission requirements related to the moments of inertia to detect a potential heterogeneity of the mass distribution inside Phobos. We introduce mission instruments and operational strategies to meet the mission requirements. We present a preliminary imaging strategy from a quasi-satellite orbit for a base shape model that is expected to be created at the early stage of the mission. Geodetic products including ephemeris, gravity field, rotation parameter of Phobos, and spacecraft orbit are of importance not only for the geodetic study, but also for interpreting data from various mission instruments and selecting possible landing sites. Graphical Abstract

Abstract An altimeter is a critical instrument in planetary missions, for both safe operations and science activities. We present required specifications and link budget calculations for light detection and ranging (LIDAR) onboard the Martian Moons Exploration (MMX) spacecraft. During the mission phase, this LIDAR will continuously measure the distance between the spacecraft and its target. The time-series distance provides important diagnostic information for safe spacecraft operations and important information for geomorphological studies. Because MMX is a sample return mission, its LIDAR must accommodate physical disturbances on the Martian satellite surface. This resulted in changes to the optical system design. Graphical abstract

The purpose was to explore potential biomarkers of the efficacy and toxicity of triple therapy of nivolumab, bevacizumab and paclitaxel in patients with HER2-negative metastatic breast cancer (MBC). Tumor tissues before treatment and blood samples at pretreatment, during and after treatment were collected. The serum samples were used to measure the concentrations of cytokines. Progression-free survival (PFS), overall survival (OS), and response were analyzed in association with the biomarker data using the Kaplan–Meier method and log-rank tests. Fifty patients were included in the biomarker analysis. Programmed death-ligand 1 (PD-L1) expression on tumor cells and immune cells were evaluated in tumor tissue samples using a Dako 28-8 immunohistochemistry assay and using a VENTANA SP142 immunohistochemistry assay. PD-L1 positive rates using anti-PD-L1 antibodies 28-8 (Combined positive score [CPS] ≥1) and SP142 (Immune cells [IC] ≥1) were 15% and 17%, respectively. The PFS and OS were not significantly different in the subgroups by PD-L1 expression. The median pretreatment vascular endothelial growth factor (VEGF)-A concentration was 116.1 pg/ml (range 0–740.23 pg/ml) on day 1 and decreased to

Regional anatomical structures of the brain are intimately connected to functions corresponding to specific regions and the temporospatial pattern of genetic expression and their functions from the fetal period to old age. Therefore, quantitative brain morphometry has often been employed in neuroscience investigations, while controlling for the scanner effect of the scanner is a critical issue for ensuring accuracy in brain morphometric studies of rare orphan diseases due to the lack of normal reference values available for multicenter studies. This study aimed to provide across-site normal reference values of global and regional brain volumes for each sex and age group in children and adolescents. We collected magnetic resonance imaging (MRI) examinations of 846 neurotypical participants aged 6.0–17.9 years (339 male and 507 female participants) from 5 institutions comprising healthy volunteers or neurotypical patients without neurological disorders, neuropsychological disorders, or epilepsy. Regional-based analysis using the CIVET 2.1.0. pipeline provided regional brain volumes, and the measurements were across-site combined using ComBat-GAM harmonization. The normal reference values of global and regional brain volumes and lateral indices in our study could be helpful for evaluating the characteristics of the brain morphology of each individual in a clinical setting and investigating the brain morphology of ultra-rare diseases.

The construction year of road bridges plays an important role in bridge management systems. Based on the age of road bridges and other factors, deterministic and probabilistic deterioration models can be used to calculate deterioration rates and predict the future physical condition of road bridges. Two new techniques are proposed in this manuscript for estimating the construction year of road bridges by analyzing the normalized difference water index 2 (NDWI_2). Technique 1 uses both the target bridge point (TBP) and a selected optimal reference control point, while Technique 2 uses only the TBP. Landsat 5 Thematic Mapper NDWI_2 data were analyzed at all 44 road bridges in Nago City, Japan of the bridges’ overall length ≤ 100 m and construction year between 1990 and 2006. The sequential t-test analysis of the regime shift method, at a significance level α = 0.05 and cutoff length l = 2 to l = 27, was used to interpret the estimated construction year from the NDWI_2 for both techniques. Both techniques successfully determined the estimated construction year, which was statistically significant with p-values < 0.05, except for seven road bridges in Technique 1 and one road bridge in Technique 2. The correlation and comparative analysis of the actual and estimated construction years yielded R2 = 0.24 and R2 = 0.33, as well as an average deviation of S = 5.81 years and S = 4.08 years for Technique 1 and Technique 2, respectively. The findings suggest that Technique 2 is more accurate and provides a better estimate than Technique 1. It was observed that, as the cutoff length l increased, the absolute error between the actual and estimated construction year increased. Therefore, as a measure of accuracy, the upper limit of cutoff length l was set to l≤ 12. It was also observed that the increase in the bridge’s overall length and forested area contributed to the accuracy of the results. By using the construction year as one of the inputs into bridge management systems, bridge managers can make more informed decisions about how best to maintain and improve road bridges to ensure user safety and road bridge preservation for the future.

Abstract Background The appropriate position of retractors to minimize the risk of femoral nerve palsy remains uncertain. The purpose of this imaging study was to evaluate the distance between the femoral nerve (FN) and anterior acetabulum (AA) in hip osteoarthritis (OA). Methods Forty-one patients with unilateral hip OA underwent magnetic resonance imaging. Three measurement levels were defined and the minimum distance between the femoral nerve (FN) margin and anterior acetabulum (AA) rim was measured on axial T1-weighted images on the OA and normal sides at each level, with reference to an advanced neurography view. The cross-sectional area (CSA) of the iliopsoas muscle was also measured at each level bilaterally by three observers. Distances and CSAs were compared between the OA and normal side. Multiple regression analysis was performed to identify variables associated with the distance in OA. Results The mean minimum FN to AA distances in OA were 19.4 mm at the top of the anterior inferior iliac spine (AIIS), 24.3 mm at the bottom of the AIIS, and 21.0 mm at the tip of the greater trochanter. These distances were significantly shorter than in normal hips at the top and bottom of the AIIS, with mean differences of 1.6 and 5.8 mm, respectively (p = 0.012, p

Study Design Retrospective observational study. Purpose Lumbar spinal stenosis (LSS) has traditionally been evaluated morphologically, there is a paucity of literature on quantitative assessment of LSS. The purpose of this study was to investigate whether intraspinal diffusion tensor imaging (DTI) parameters such as apparent diffusion coefficient (ADC) and fractional anisotropy (FA) are useful for assessing LSS. Overview of Literature Quantitative assessment of LSS is challenging. Methods Study participants comprised five healthy volunteers (mean age, 27.2 years) and 27 patients with LSS (mean age, 58.4 years) who were individually assessed using 3.0 Tesla magnetic resonance imaging. Intraspinal ADC and FA values of 10 intervertebral discs from healthy volunteers and 52 intervertebral discs from LSS patients were measured. Also, intraspinal canal area, Schizas classification (A: normal, B: mild stenosis, C: severe stenosis) and correlations with symptoms were investigated. Clinical symptoms were checked for the presence of low back pain (LBP), intermittent claudication (IMC), and bladder and bowel dysfunction (BBD). Results Compared to healthy individuals, LSS patients had significantly lower ADC (p

The long-term performance of the concrete–polymer cement mortar (PCM) interface under environmental exposure is crucial to the safety of the PCM overlaying method as the environmental exposure of the repaired structures caused further degradation of the interface, leading to a significant reduction in intended service life. This study investigates the durability enhancement effect of silica fume of the concrete–PCM interface, considering an individual action of elevated temperature (e.g., 60 °C) [constant (short and moderate duration) and cyclic conditions] and moisture content [continuous immersion and wetting/drying (W/D) cycle]. Our previous research confirmed that the use of silica fume forms more C-S-H with strong binding force and enhances the interfacial bonding strength due to the denser microstructure at the interface, and it is expected to be utilized for durability purposes under the aforementioned exposure conditions. Under all elevated temperature exposure conditions, the reduction percentage of the interfacial performance corresponding to the respective reference specimens reduced significantly with the inclusion of silica fume with overlay material. The occurrence of interface fracture at lower load and a greater number of pure interface fracture modes observed in normal PCM specimens compared to modified PCM specimens indicates a positive influence of higher adhesion with better durability of modified PCM overlay with substrate concrete. Under both conditions of moisture content, significant reduction in interfacial strength was observed in normal PCM specimens. In all cases, the reducing ratio of interfacial strength was higher in normal PCM compared to modified PCM, indicating a positive influence of silica fume under moisture content. Furthermore, silica fume inclusion shifts the fracture mode from pure interfacial fracture to composite fracture mode, indicating a positive response of silica fume to improve the resistance of interface fracture under moisture content. Conclusively, the use of silica fume improves concrete–overlay layer adhesion and enhances the bonding durability under environmental exposure.

Abstract In this study, we determined the alignment of the laser altimeter aboard Hayabusa2 with respect to the spacecraft using in-flight data. Since the laser altimeter data were used to estimate the trajectory of the Hayabusa2 spacecraft, the pointing direction of the altimeter needed to be accurately determined. The boresight direction of the receiving telescope was estimated by comparing elevations of the laser altimeter data and camera images, and was confirmed by identifying prominent terrains of other datasets. The estimated boresight direction obtained by the laser link experiment in the winter of 2015, during the Earth’s gravity assist operation period, differed from the direction estimated in this study, which fell on another part of the candidate direction; this was not selected in a previous study. Assuming that the uncertainty of alignment determination of the laser altimeter boresight was 4.6 pixels in the camera image, the trajectory error of the spacecraft in the cross- and/or along-track directions was determined to be 0.4, 2.1, or 8.6 m for altitudes of 1, 5, or 20 km, respectively.

A lot of exploration missions have been planned for the moon, and lunar activity is likely to increase. The moon’s surface is covered by a great deal of dust, called regolith, and these particles can seriously damage mechanical components. The design of any mechanism that will operate on the moon must take regolith into account. This includes the wheels and crawlers of lunar rovers, and many other mechanical components. This study considers measures for protecting small bearings in a lunar rover that operate close to the surface, in particular simple collar seals. These seals will require exceptional sealing ability, low torque, light weight, and easy installation. Collar seals made of three polymer composite materials (such as PTFE and PEEK) were evaluated. The seals have a convex portion that slides on the end face of the inner ring of a bearing or that of the outer ring; the sliding between the convex portion and the rings prevents regolith from entering the bearing. The seal performance and torque of each type of collar seal were tested using a regolith simulant in vacuum. The test conditions were decided based on the lunar environment and specification of a lunar rover under development. In order to maintain seal performance and to obtain lower torque, the thicknesses of the collar seals and their axial deflection were varied. Sliding on the end face of the inner ring of the bearing showed good seal performance and lower torque with optimum collar thickness and axial deflection for all composite materials. There was some variation in sealing and torque between the composites. The tribological performance and results of surface analysis by XPS are discussed.

Abstract The precise orbit of the Hayabusa2 spacecraft with respect to asteroid Ryugu is dynamically determined using the data sets collected by the spacecraft’s onboard laser altimeter (LIght Detection And Ranging, LIDAR) and automated image tracking (AIT). The LIDAR range data and the AIT angular data play complementary roles because LIDAR is sensitive to the line-of-sight direction from Hayabusa2 to Ryugu, while the AIT is sensitive to the directions perpendicular to it. Using LIDAR and AIT, all six components of the initial state vector can be derived stably, which is difficult to achieve using only LIDAR or AIT. The coefficient of solar radiation pressure (SRP) of the Hayabusa2 spacecraft and standard gravitational parameter (GM) of Ryugu can also be estimated in the orbit determination process, by combining multiple orbit arcs at various altitudes. In the process of orbit determination, the Ryugu-fixed coordinate of the center of the LIDAR spot is determined by fitting the range data geometrically to the topography of Ryugu using the Markov Chain Monte Carlo method. Such an approach is effective for realizing the rapid convergence of the solution. The root mean squares of the residuals of the observed minus computed values of the range and brightness-centroid direction of the image are 1.36 m and 0.0270°, respectively. The estimated values of the GM of Ryugu and a correction factor to our initial SRP model are 29.8 ± 0.3 m3/s2 and 1.13 ± 0.16, respectively.

Study Design Observational study. Purpose To evaluate healthy volunteers and patients with spinal canal lesions using apparent diffusion coefficient (ADC) maps with diffusion-weighted imaging. Overview of Literature Decompression surgery for lumbar spinal stenosis (LSS) is selected on the basis of subjective assessment and cross-sectional magnetic resonance imaging (MRI). However, there is no objective standard for this procedure. Methods We performed 3T MRI in 10 healthy volunteers and 13 patients with LSS. The ADC values in the spinal canal were evaluated at 46 vertebrae (L4/5 and L5/S1 for each participant), and the reduced and conventional fields of view were compared. Results The ADC values were 2.72±0.12 at L4/5 in healthy volunteers, 2.76±0.19 at L5/S1 in healthy volunteers, 1.77±0.58 at L4/5 in patients with LSS, and 2.35±0.29 at L5/S1 in patients with LSS. The ADC value at L4/5 in patients with LSS was significantly lower than that at L5/S1 in patients with LSS and that at L4/5 and L5/S1 in healthy volunteers (p

Abstract Background Thrombocytosis is related to tumor stage and survival in ovarian cancer in addition to the common complications of malignant diseases, such as anemia and inflammation. The aim of our study was to clarify the precise prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer. Methods We retrospectively analyzed 280 consecutive patients who were treated for epithelial ovarian cancer at our institution between 2001 and 2011. Results Pretreatment thrombocytosis was observed in 18.9% of all patients and was associated with advanced FIGO stage, primary treatment, operation achievement, histologic subtype, microcytic hypochromic anemia (MHA), and nonmalignant inflammatory condition (P = 0.0018, 0.0028, 0.00050, 0.034, 0.00090 and 0.0022). In the patients who relapsed after primary adjuvant chemotherapy (n = 126), thrombocytosis was associated with a shorter treatment-free interval (TFI) (P = 0.0091). The univariate and multivariate analyses revealed that thrombocytosis was independently associated with TFI and MHA (P = 0.021 and 0.0091). Patients with thrombocytosis had worse progression-free survival (PFS) and overall survival (OS) than those without thrombocytosis (P

Abstract Purpose To investigate whether palonosetron is better than granisetron in preventing chemotherapy‐induced nausea and vomiting (CINV) in a three‐drug combination with dexamethasone and fosaprepitant (Fos) in patients with breast cancer who are placed on anthracycline and cyclophosphamide (AC‐based regimen). Patients and Methods Chemo‐naive women with primary breast cancer were randomly administered either palonosetron 0.75 mg (day 1) or granisetron 1 mg (day 1) combined with dexamethasone (12 mg at day 1, 8 mg at day 2 and day 3) and Fos 150 mg (day 1) before receiving AC‐based regimen in a double‐blind study. The primary endpoint was the complete response (CR) rate of emesis in cycle 1 in the delayed phase. This was defined as neither vomiting nor rescue drug usage for emesis at >24‐120 hours after chemotherapy. Secondary endpoints were the CR in the acute/overall phase (0‐24/0‐120 hours, respectively, after chemotherapy), no nausea and vomiting, Patient‐Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO‐CTCAE), and safety. Results From December 2012 to October 2014, 326 patients were treated and evaluated (164/162 evaluable patients in granisetron/palonosetron arm, respectively). The CR during the delayed phase was 60.4% in the granisetron regimen and 62.3% in the palonosetron regimen. The CR during acute phase (73.2% vs 75.9%, respectively) and the CR during overall phase (54.9% in both regimens) were very identical. A significantly higher number of patients in the palonosetron arm were free from nausea during the delayed phase (28% vs 40.1%; P = .029). Adverse events were also identical, although infusion site reactions (ISR) were higher (20.3%‐23.3%) than preceding studies in both regimens. Conclusion In combination with dexamethasone and Fos, this study suggests that palonosetron is not better than granisetron in chemo‐naive patients with primary breast cancer receiving AC‐based regimen. Administration of Fos in peripheral veins after AC‐based regimen increased ISR.

Abstract Background The selection of radiation therapy dose fractionation schedules for bone metastases is often based on the estimation of life expectancy. Therefore, accurate prognosis prediction is an important issue. It is reported that the Katagiri scoring system can be used to predict the survival of patients with bone metastases. We aimed to assess prognostic factors and validate the Katagiri scoring system in patients who were treated with radiation therapy for bone metastases. Materials/Methods We retrospectively reviewed data of all patients who were treated with radiation therapy for bone metastases between 2004 and 2013. Age, sex, Karnofsky performance status (KPS), Eastern Cooperative Oncology Group performance status (ECOG PS), primary site (lesions and characteristics), visceral metastases, laboratory data, previous chemotherapy, and multiple bone metastases were analyzed for associations with overall survival (OS). Katagiri scores were calculated for each patient and were used to compare OS. Results Out of the 616 patients included in this analysis, 574 had died and 42 remained alive. The median follow-up time for survivors was 42 months. Univariate analysis revealed that age (P = 0.604) and multiple bone metastases (P = 0.691) were not significantly associated with OS. Multivariate analysis revealed that sex, ECOG PS, KPS, primary characteristics, visceral metastases, laboratory data, and previous chemotherapy were significantly associated with OS. The survival rates at 3, 6, 12, and 24 months, categorized by Katagiri score, were as follows: score 0–3, 94.4, 77.8, and 61.1%, respectively; score 4–6, 67.7, 48.7, and 31.2%, respectively; and score 7–10, 39.1, 22.1, and 9.0%, respectively (P

The prognostic impact of human papillomavirus (HPV) type on invasive cervical cancer (ICC) was analyzed for 137 women treated for ICC at a single institution between 1999 and 2007. The study subjects were divided into three groups according to HPV genotype: HPV16-positive (n = 59), HPV18-positive (n = 33), and HPV16/18-negative ICC (non-HPV16/18, n = 45). The median follow-up time was 102.5 months (range, 5–179). The 10-year overall survival (10y-OS) rates in women with FIGO stage I/II disease were similar among HPV genotypes: 94.7% for HPV16 (n = 39), 95.2% for HPV18 (n = 26), and 96.4% for non-HPV16/18 (n = 29). However, the 10y-OS rates in women with FIGO stage III/IV tumors were 73.7% for HPV16 (n = 20), 45.7% for HPV18 (n = 7), and 35.7% for other types (n = 16), with significantly higher survival in HPV16-positive compared with HPV16-negative ICC (10y-OS; 73.7% vs. 39.5%, P = 0.04). This difference in FIGO stage III/IV tumors remained significant after adjusting for age and histology (hazard ratio 0.30, 95% confidence interval 0.09–0.86, P = 0.02). These results suggest that detection of HPV16 DNA may be associated with a favorable prognosis in patients with FIGO stage III/IV ICC. Given that most women with FIGO stage III/IV tumors received concurrent chemoradiotherapy, this finding may imply that HPV16-positive tumors are more chemoradiosensitive. Keywords: Cervical cancer, Human papillomavirus (HPV), Prognosis, Radiosensitivity, Survival

Background: Transforaminal full endoscopic lateral recess decompression (TE-LRD) can decompress lateral recess stenosis transforaminally under the endoscopy procedure. However, the biomechanical effects of the TE-LRD compared to the conventional decompression techniques are not reported. The purpose of this study is to compare the biomechanical effects of TE-LRD with conventional decompression techniques using finite element method. Methods: Three finite element models of lumbar functional spinal unit (FSU) of the L4-L5 levels were created: 1) normal disc 2) moderate grade disc degeneration 3) severe grade disc degeneration. For each of these three models, the following decompression techniques were simulated, 1) 50% TE-LRD, 2) 100% TE-LRD, 3) Unilateral laminectomy, 4) Bilateral laminectomy. The lower endplate of the fifth lumbar vertebra was fixed and 10Nm of moment in flexion/extension, left/right bending and axial rotation was applied to the upper endplate of the fourth lumbar vertebra, under a follower load of 400N. The range of motion, intervertebral disc stress, and facet joint stress were compared. Results: 50% TE-LRD was found to be the most stable decompression technique in all intervertebral disc models. Though the increase in the range of motion of 100% TE-LRD was higher than other decompression techniques in the normal disc model, it was not significantly different from 50% TE-LRD or unilateral laminectomy techniques in the degenerated disc models. The increase in the intervertebral disc stress was lowest for the 50% TE-LRD surgery in all intervertebral disc models. The increase in the facet stresses for 50% TE-LRD was lower than in the conventional decompression techniques for all intervertebral disc models. Conclusions: 50% TE-LRD was the decompression surgical technique with the least effect on spinal instability. 100% TE-LRD showed to be effective for cases with degenerative discs. 50% TE-LRD may decrease the risk of postoperative intervertebral disc and facet joint degeneration.

Early life respiratory insults, such as viral infections or hyperoxia, often increase asthma susceptibility later in life. The mechanisms underlying this increased susceptibility are not fully understood. IL-33 has been shown to be critically involved in allergic airway diseases. IL-33 expression in the neonatal lung can be increased by various respiratory insults associated with asthma development. Therefore, we investigated whether and how early life increases in IL-33 impact allergic airway responses later in life. Using a novel IL-33 transgenic mouse model, in which full-length IL-33 was inducible overexpressed in lung epithelial cells, we transiently upregulated lung IL-33 expression in neonatal mice for one week. After resting for 4-6 weeks, mice were intranasally exposed to a single-dose of recombinant IL-33 or the airborne allergen Alternaria. Alternatively, mice were exposed to Alternaria and ovalbumin multiple times for one month. We found that a transient increase in IL-33 expression during the neonatal period promoted IL-5 and IL-13 production when mice were later exposed to a single-dose of IL-33 or Alternaria in adulthood. However, increased IL-33 expression during the neonatal period did not affect airway inflammation, type 2 cytokine production, lung mucus production, or antigen-specific antibody responses when adult mice were exposed to Alternaria and ovalbumin multiple times. These results suggest that transient increased IL-33 expression early in life may have differential effects on allergic airway responses in later life, preferentially affecting allergen-induced acute type 2 cytokine production.

Human papillomavirus type 16 (HPV16) is the most common HPV genotype found in invasive cervical cancer (ICC). Recent comprehensive genomics studies of HPV16 have revealed that a large number of minor nucleotide variations in the viral genome are present in each infected woman; however, it remains unclear whether such within-host variations of HPV16 are linked to cervical carcinogenesis. Here, by employing next-generation sequencing approaches, we explored the mutational profiles of the HPV16 genome within individual clinical specimens from ICC (n = 31) and normal cervix (n = 21) in greater detail. A total of 367 minor nucleotide variations (167 from ICC and 200 from the normal cervix) were detected throughout the viral genome in both groups, while nucleotide variations at high frequencies (>10% abundance in relative read counts in a single sample) were more prevalent in ICC (10 in ICC versus 1 in normal). Among the high-level variations found in ICC, six were located in the E1/E2 genes, and all of them were non-synonymous substitutions (Q142K, M207I, and L262V for E1; D153Y, R302T, and T357A for E2). In vitro functional analyses of these E1/E2 variants revealed that E1/M207I, E2/D153Y, and E2/R302T had reduced abilities to support viral replication, and that E2/D153Y and E2/R302T failed to suppress the viral early promoter. These results imply that some within-host variations of E1/E2 present at high levels in ICC may be positively selected for and contribute to cervical cancer development through dysfunction or de-stabilization of viral replication/transcription proteins.

The polymer cement mortar (PCM) overlay method is a promising solution for strengthening deteriorated concrete structures in which the occurrence of premature debonding at the interfaces prevents the strengthened structures from achieving full serviceability. The purpose of this study is to improve the concrete–PCM interfacial bond to prevent premature debonding. There are two main focuses of this study: (i) investigation of the effectiveness of adding 5% silica fume to PCM in forming a chemical connection between concrete and PCM, based on a direct single-surface shear test using two roughness levels of concrete (smooth and rough) and microstructure analysis and (ii) performance evaluation of the bond between substrate concrete and a PCM overlay with/without silica fume at early ages and with different moisture conditions at the interface, based on a bi-surface shear test using rough substrate concrete surface. The inclusion of 5% silica fume with PCM caused an improvement in the interfacial strength (approximately 113% relative to the normal PCM in cases of without primer), with a smooth concrete substrate surface where mechanical bonding had less influence. In addition, lower Ca/Si values in the interface of modified 5% silica PCM specimens compared to the normal PCM specimens quantified by energy-dispersive X-ray spectroscopy (EDS) indicate the formation of a chemical connection at the concrete–PCM interface by transforming harmful Ca(OH)2 into more C-S-H which strongly improves the bonding strength. As a repair layer mortar, the positive influence of silica fume in modified 5% silica PCM specimens was also found at early ages and with different moisture conditions at the interface compared to the normal PCM. In conclusion, the addition of silica fume to the PCM caused chemical connection at the concrete–PCM interface and improved the interfacial performance.

Human papillomavirus (HPV) is a sexually transmitted virus with an approximately 8-kilo base DNA genome, which establishes long-term persistent infection in anogenital tissues. High levels of genetic variations, including viral genotypes and intra-type variants, have been described for HPV genomes, together with geographical differences in the distribution of genotypes and variants. Here, by employing a maximum likelihood method, we performed phylogenetic analyses of the complete genome sequences of HPV16, HPV18 and HPV58 available from GenBank (n = 627, 146 and 157, respectively). We found several characteristic clusters that exclusively contain HPV genomes from Japan: two for HPV16 (sublineages A4 and A5), one for HPV18 (sublineage A1) and two for HPV58 (sublineages A1 and A2). Bayesian phylogenetic analyses of concatenated viral gene sequences showed that divergence of the most recent common ancestor of these Japan-specific clades was estimated to have occurred ~98,000 years before present (YBP) for HPV16 A4, ~39,000 YBP for HPV16 A5, ~38,000 YBP for HPV18 A1, ~26,000 for HPV58 A1 and ~25,000 YBP for HPV58 A2. This estimated timeframe for the divergence of the Japan-specific clades suggests that the introduction of these HPV variants into the Japanese archipelago dates back to at least ~25,000 YBP and provides a scenario of virus co-migration with ancestral Japanese populations from continental Asia during the Upper Paleolithic period.

Since the human papillomavirus (HPV) vaccination program for Japanese girls aged 12–16 years began in 2010, vaccination uptake has been low in women born before 1993 but high (approximately 70%) in those born during 1994–1999. We previously compared the prevalence of vaccine types HPV16 and HPV18 in cervical intraepithelial neoplasia grade 1–3 (CIN1–3) or adenocarcinoma in situ (AIS) between vaccinated and unvaccinated cohorts and found direct protection effects among vaccinated women in Japan. In this study, we focused on changes in HPV16/18 prevalence among “unvaccinated” cohorts with CIN/AIS. We analyzed HPV16/18 prevalence among 5051 unvaccinated women aged trend = 0.03) and CIN2–3/AIS (62.5–36.4%, Ptrend = 0.07) among women aged p = 0.04). Significant reduction in HPV16/18 prevalence among young unvaccinated women with CIN1 and CIN2–3/AIS suggests herd effects of HPV vaccination in Japan.

Abstract Background Proximal junctional kyphosis (PJK) following adult spinal deformity (ASD) surgery in elderly patients is markedly influenced by osteoporosis causing additional vertebral fracture and loosening of pedicle screws (PS). This study aimed to investigate the association between mean bone density represented in Hounsfield units (HU) on spinal computed tomography (CT) and revision surgery for PJK or postoperative additional vertebral fracture following ASD surgery in elderly patients. Methods The subjects were 54 ASD patients aged 65 years or older who were treated with correction and fusion surgery of four or more levels and could be followed for 2 years or longer. Bone density was measured before surgery using lumbar dual-energy X-ray absorptiometry (DXA) and spinal CT in all patients. The patients were divided into group A (n = 14) in which revision surgery was required for PJK or additional vertebral fracture and group B (n = 40) in which revision surgery was not required. We retrospectively investigated incidences of PJK, additional vertebral fracture, and PS loosening, perioperative parameters, radiographic parameters before and after surgery, and osteoporosis treatment administration rate. Results No significant difference was noted in young adult mean (YAM) on DXA between groups A and B, respectively (P = 0.62), but the mean bone densities represented in HU of the T8 (P = 0.002) and T9 (P = 0.01) vertebral bodies on spinal CT were significantly lower in group A, whereas those of the L4 (P = 0.002) and L5 (P = 0.01) vertebral bodies were significantly higher in group A. The incidence of PJK was not significantly different (P = 0.07), but the incidence of additional vertebral fracture was significantly higher in group A (P

Abstract Background A persistent low-level elevation of serum human chorionic gonadotropin (hCG) without clinical or radiological evidence of pregnancy or tumors was recently defined as quiescent gestational trophoblastic disease (Q-GTD). Whether patients with Q-GTD should be treated or allowed to become pregnant remains unclear. We herein report a rare case of Q-GTD in which the hCG level spontaneously returned to normal after a successful pregnancy. Case presentation The patient was a 37-year-old primigravida who presented with a persistent low-level elevation of hCG after uterine evacuation of a hydatidiform mole. There was no evidence of neoplasia in the uterus or distant metastasis. The low-level elevation of hCG persisted for at least 2 years but never exceeded 200 mIU/mL. The patient had a successful pregnancy at the age of 40 years. Conclusions Interestingly, her hCG level subsequently normalized without chemotherapy. The present case may imply the safety and therapeutic effect of pregnancy in women with Q-GTD.

Patients with severe hemiplegia along with knee instability require knee–ankle–foot orthoses (KAFOs) for gait training. However, in these patients, it is unclear which type of walking training is more effective to improve gait function. Providing alternate gait training (AGT) improves walking function in patients with spinal cord injury, but it is still unclear whether this is effective in hemiplegic stroke patients. In this study, we defined “unified AGT” as AGT performed with the same therapeutic concept by physiotherapists. We then investigated whether AGT improved gait function quicker than our traditional gait training in hemiplegic stroke patients. We enrolled 15 subjects with severe hemiplegia and knee instability who had undergone unified AGT using KAFOs with hinged oil dampers at the ankles, and 30 historical control (HC) subjects who had undergone traditional gait training. We used multiple comparison and survival analyses to analyze the differences in the functional independence measure (FIM) gait score changes between the two groups. The multiple comparison revealed a significant increase (p < 0.05) in the FIM gait score compared with its initial score in the subjects with unified AGT. However, this improvement was not seen in the HC subjects. Additionally, the survival analysis of time taken to recover revealed a significant difference between the subjects with unified AGT and HC subjects (p < 0.05). These findings suggest that unified AGT using a KAFO facilitates gait improvement in patients with severe hemiplegia and knee instability.