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Objective: Recent randomized phase III trial has shown significant benefit in overall survival (OS) for patients with advanced cervical cancer by adding bevacizumab to conventional chemotherapy. The aim of this study was to evaluate the prognostic impact for Japanese recurrent, persistent, or metastatic cervical cancer patients where bevacizumab was added to paclitaxel plus carboplatin. Materials and methods: A retrospective analysis was performed on 90 patients with recurrent, persistent, or metastatic cervical cancer mainly treated by paclitaxel plus carboplatin between 2005 and 2019 at our hospital. Data for the following clinicopathological variables were analyzed: (1) bevacizumab use; (2) histology; (3) disease presentation; (4) performance status; (5) prior chemotherapy containing platinum agent; (6) pelvic disease; (7) prior pelvic radiotherapy; (8) location of target lesions. Survival analysis was performed using Kaplan–Meier curves, log-rank tests, Wilcoxon tests, and Cox proportional hazards models combined with propensity score matching. Results: Adding bevacizumab to paclitaxel plus carboplatin showed significantly increased complete response to compared with that of non-users. In a Cox regression hazard model, bevacizumab use tended to show better OS though without statistically significance. After propensity score matching, adding bevacizumab to paclitaxel plus carboplatin showed a significant better OS by univariate analysis using Wilcoxon test, not by log-rank test. Conclusion: Adding bevacizumab to paclitaxel plus carboplatin showed a limited prognostic impact for recurrent, persistent or advanced cervical cancer patients in the real world. Further effective second-line treatments are needed to prolong OS of patients with recurrent, persistent or advanced cervical cancer.

Abstract Background The major complication of renal biopsy is bleeding. Infection is an extremely rare complication of percutaneous renal biopsy, providing sterile techniques are used and bowel perforation does not occur. However, the questionnaire included in the Kidney Biopsy Guidebook 2020 in Japan reported that antibiotic prophylaxis was administered to patients undergoing percutaneous renal biopsy at 61% of 170 adult institutions and 57% of 54 pediatric institutions. The objective of this study is to show the non-inferiority of not administering antibiotic prophylaxis for percutaneous renal biopsy. Methods Patients aged ≥15 years who are scheduled to undergo percutaneous renal biopsy are eligible for inclusion in the study. Three hundred and sixty-four patients will be recruited at 6 hospitals. The patients will be randomly assigned at a 1:1 ratio to receive either a single dose of intravenous cefazolin (1 g) or no antibiotic prophylaxis. The primary outcome is the number of patients that exhibit positive urine cultures (>105 colony-forming units/ml) 3 or 4 days after the renal biopsy, or at which point the patients are diagnosed with pyelonephritis until 3 or 4 days after the renal biopsy. The secondary outcomes are the number of patients who are diagnosed with pyelonephritis within 30 days after the renal biopsy, the number of patients who are diagnosed with puncture site infections within 30 days after the renal biopsy, the number of patients who are diagnosed with an infection other than pyelonephritis or a puncture site infection within 30 days after the renal biopsy, and the number of patients who experience cefazolin-induced side effects. Discussion This randomized controlled trial aims to show the non-inferiority of not administering antibiotic prophylaxis for percutaneous renal biopsy. If this study shows that antibiotic prophylaxis is not needed, it would help to ensure patient safety and prevent the development of antibiotic-resistant bacteria. Trial registration UMIN Clinical Trials Registry (UMIN-CTR) UMIN000042378 . Registered on 7 Nov 2020.

Abstract Background Marfan syndrome (MFS) is a systemic disorder of connective tissues caused by insufficient elastic fiber formation that leads to structural weakness and results in various tissue disorders, including cardiovascular and periodontal disease. Notably however, the risk of periodontal disease in MFS patients affected by an aortic aneurysm or dissection has not yet been clarified. Methods We investigated the periodontal condition in the following three groups: MFS patients diagnosed with an aortic aneurysm or dissection with a planned aortic surgery (MFS surgery), MFS patients who had already undergone aortic surgery (MFS post-surgery) and healthy control patients (Healthy). The periodontal condition of all of these patients was evaluated at their first visit, reassessed again at two-month after the first visit, and evaluated again at a six-month follow-up after the reassessment. Results A total of 14 participants, 3 MFS surgery patients, 4 MFS post-surgery patients and 7 healthy control volunteers were examined. Saliva examinations revealed no significant differences between any of the groups at the first visit, reassessment, or follow-up. Interestingly, the MFS surgery cases showed a higher BOP and PISA at the first visit and follow-up compared with the other groups. In contrast, the MFS surgery patients showed an improvement in their LVDd and EF values, both markers of cardiac function, at the reassessment and follow-up compared with the first visit. Conclusions MFS associated with an aortic aneurysm or dissection leads to a higher risk of periodontal disease, indicating the need for more frequent oral hygiene maintenance in these patients. In addition, MFS patients who undergo frequent professional cleaning of their teeth show a lower onset of cardiovascular disease, suggesting that professional oral hygiene in these cases contributes to a healthier condition.

Abstract Background Simultaneous bilateral hip fractures without major trauma in the elderly are rare and usually symmetrical. To the best of our knowledge, only two cases of bilateral simultaneous asymmetric hip fracture in the elderly without major trauma have been reported. Case presentation We present the case of a 90-year-old Japanese man with simultaneous bilateral asymmetric hip fractures with trochanteric fracture on the right side and greater trochanteric fracture on the left side. He complained of dyspnea at midnight and was referred to our emergency department. He was admitted to the internal medicine department for bacterial pneumonia treatment. On the 8th day of hospitalization, he was referred to our orthopedic surgery department for hip pain and was found to have fractures of both hips. Computed tomography findings showed that the left femoral neck fracture was an old fracture, while the left greater trochanteric fracture and the right trochanteric fracture were fresh fractures. He was surgically treated through open reduction and internal fixation with an intramedullary nail on the right and hemiarthroplasty on the left in supine position, performed during the same surgical sessions on the 12th day of hospitalization. Conclusions We report a new form of simultaneous bilateral asymmetric hip fracture in the elderly. The fracture types of the case were femoral trochanteric fracture and greater trochanteric fracture of the femur, which were different from the fracture types in the previously reported two cases. Clinicians should be aware of the possibility of simultaneous bilateral hip fractures, especially in the elderly.

Abstract Background The purpose of the current study was to investigate factors related to morphological changes in the masseter muscle after preoperative orthodontic treatment in patients with skeletal class III dentofacial deformities for analysis of muscle changes and malocclusions. Methods Twenty female patients with dentofacial deformities were included in the study. Computed tomography was performed before and after preoperative orthodontic treatment, and the lengths, widths, and cross-sectional areas of the masseter muscles were measured. Changes in these parameters were evaluated, and factors related to changes in masseter muscle area after preoperative orthodontic treatment were analyzed. Results The lengths, widths, and areas of masseter muscles were significantly smaller after preoperative orthodontic treatment. Smaller masseter muscle area was significantly associated with changes in overbite and pretreatment values of SNA angle. Conclusions Atrophy of the masseter muscle during preoperative orthodontic treatment was greater in patients with increased open bite due to improved dental compensation in patients with skeletal class III dentofacial deformities with maxillary retraction.

Abstract We investigated the biofilm removal effects of laser activated irrigation (LAI) using a pig model, focusing on the impact of the fiber tip position, and used a high-speed camera to observe the occurrence and positioning of the cavitation associated with laser irradiation. A total of 16 roots of deciduous mandibular second premolars from 4 pigs were used. After a pulpectomy, the canals were left open for 2 weeks and sealed for 4 weeks to induce intraradicular biofilm. Root canal irrigation was then performed with Er:YAG laser activation. The fiber tip was inserted at two different positions, i.e., into the root canal in the intracanal LAI group and into the pulp chamber in the coronal LAI group. Intracanal needle irrigation with saline or 5% NaOCl was utilized in the positive control and conventional needle irrigation (CNI) groups. SEM and qPCR were carried out to evaluate treatment efficacy. Statistical analysis was performed using ANOVA and a Tukey–Kramer post-hoc test for qPCR and with a Steel–Dwass test to compare the SEM scores, with α = 0.05. A high-speed camera was used to observe the generation of cavitation bubbles and the movement of the induced bubbles after laser irradiation. The intracanal and coronal LAI groups showed significantly lower amounts of bacteria than either the positive control or CNI groups. There was no significant difference found between the intracanal and coronal LAI groups. SEM images revealed opened dentinal tubules with the destruction of biofilm in both LAI groups. High-speed camera images demonstrated cavitation bubble production inside the root canal after a single pulse irradiation pulse. The generated bubbles moved throughout the entire internal multi-rooted tooth space. Coronal LAI can generate cavitation in the root canal with a simply placed fiber inside the pulp chamber, leading to effective biofilm removal. This method could thus contribute to the future development of endodontic treatments for refractory apical periodontitis caused by intraradicular biofilm.

Background Anti-programmed cell death 1 antibodies (PD-1 Abs) are widely used for advanced melanoma, but information on the efficacy of anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Ab-treatment, particularly in patients with melanoma who are refractory to anti-PD-1 Abs. The aim of this study was to evaluate anti-PD-1 Ab-treatment in combination with TM5614 (a plasminogen activator inhibitor-1 inhibitor) in patients with unresectable melanoma. Methods The TM5614-MM study was a multicentre, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at seven Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0–4 weeks) and 180 mg once daily (5–8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614. Results Thirty-nine patients were enrolled, and 34 patients were included in the anti-PD-1 Ab-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% confidence interval 12.9–44.9%, P = 0.027) in 27 patients who were anti-PD-1 Ab-refractory based on investigator assessment in the protocol per set cohort. Seven patients discontinued treatment owing to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort. Conclusions TM5614 in combination with nivolumab is well tolerated and effective in anti-PD-1 Ab-refractory unresectable melanoma. [ABSTRACT FROM AUTHOR]

Abstract In this study, we examined the antileukemic effects of pterostilbene, a natural methylated polyphenol analog of resveratrol that is predominantly found in berries and nuts, using various human and murine leukemic cells, as well as bone marrow samples obtained from patients with leukemia. Pterostilbene administration significantly induced apoptosis of leukemic cells, but not of non-malignant hematopoietic stem/progenitor cells. Interestingly, pterostilbene was highly effective in inducing apoptosis of leukemic cells harboring the BCR/ABL fusion gene, including ABL tyrosine kinase inhibitor (TKI)-resistant cells with the T315I mutation. In BCR/ABL+ leukemic cells, pterostilbene decreased the BCR/ABL fusion protein levels and suppressed AKT and NF-κB activation. We further demonstrated that pterostilbene along with U0126, an inhibitor of the MEK/ERK signaling pathway, synergistically induced apoptosis of BCR/ABL+ cells. Our results further suggest that pterostilbene-promoted downregulation of BCR/ABL involves caspase activation triggered by proteasome inhibition-induced endoplasmic reticulum stress. Moreover, oral administration of pterostilbene significantly suppressed tumor growth in mice transplanted with BCR/ABL+ leukemic cells. Taken together, these results suggest that pterostilbene may hold potential for the treatment of BCR/ABL+ leukemia, in particular for those showing ABL-dependent TKI resistance.

The obturator nerve originates from the lumbar plexus and innervates sensation in the thigh and movement of the adductor muscle group of the hip. Reports on physical therapy for patients with obturator nerve injuries have been limited due to insufficient injuries, and there have been no reports on rehabilitation after neurotmesis. Furthermore, there are no reports on the status of activities of daily living (ADL) and details of physical therapy in patients with paralysis of the adductor muscle group. In this study, we reported on a patient with adductor paralysis due to obturator neurotmesis, including the clinical symptoms, characteristics of ADL impairment, and effective movement instruction. The patient is a woman in her 40's who underwent laparoscopic total hysterectomy, bilateral adnexectomy, and pelvic lymph node dissection for uterine cancer (grade-2 endometrial carcinoma). During pelvic lymph node dissection, she developed an obturator nerve injury. She underwent nerve grafting during the same surgery by the microsurgeon. Donor nerve was the ipsilateral sural nerve with a 3-cm graft length. Due to obturator nerve palsy, postoperative manual muscle test results were as follows: adductor magnus muscle, 1; pectineus muscle, 1; adductor longs muscle, 0; adductor brevis muscle, 0; and gracilis muscle, 0. On postoperative day 6, the patient could independently perform ADL; however, she was at risk of falling toward the affected side when putting on and taking off her shoes while standing on the affected leg. The patient was discharged on postoperative day 8. Through this case, we clarified the ADL impairment of a patient with adductor muscle palsy following obturator neurotmesis, and motion instruction was effective as physical therapy for this disability. This case suggests that movement instruction is important for acute rehabilitation therapy for patients with hip adductor muscle group with obturator neurotmesis.

Information on the biodistribution (BD) of cell therapy products (CTPs) is essential for prediction and assessment of their efficacy and toxicity profiles in non-clinical and clinical studies. To conduct BD studies, it is necessary to understand regulatory requirements, implementation status, and analytical methods. This review aimed at surveying international and Japanese trends concerning the BD study for CTPs and the following subjects were investigated, which were considered particularly important: 1) comparison of guidelines to understand the regulatory status of BD studies in a global setting; 2) case studies of the BD study using databases to understand its current status in cell therapy; 3) case studies on quantitative polymerase chain reaction (qPCR) used primarily in non-clinical BD studies for CTPs; and 4) survey of imaging methods used for non-clinical and clinical BD studies. The results in this review will be a useful resource for implementing BD studies.

Abstract Birth order is a crucial environmental factor for child development. For example, later-born children are relatively unlikely to feel secure due to sibling competition or diluted parental resources. The positive effect of being earlier-born on cognitive intelligence is well-established. However, whether birth order is linked to social behavior remains controversial, and the neural correlates of birth order effects in adolescence when social cognition develops remain unknown. Here, we explored the birth order effect on prosociality using a large-scale population-based adolescent cohort. Next, since the amygdala is a key region for sociality and environmental stress, we examined amygdala substrates of the association between birth order and prosociality using a subset neuroimaging cohort. We found enhanced prosociality in later-born adolescents (N = 3160), and observed the mediating role of larger amygdala volume (N = 208) and amygdala-prefrontal functional connectivity with sex-selective effects (N = 183). We found that birth order, a non-genetic environmental factor, affects adolescent social development via different neural substrates. Our findings may indicate the later-born people’s adaptive survival strategy in stressful environments.

Abstract Background Patients with tethered cord syndrome often suffer severe spasticity. To the best of our knowledge, intrathecal baclofen (ITB) therapy in a patient with tethered cord syndrome has not been reported previously. We describe a case in which ITB therapy was useful for treating severe spasticity in an adult with tethered cord syndrome. Case presentation We present the case of a 50-year-old Japanese woman with tethered cord syndrome and related conditions suffering from severe spasticity and pain in the lower limbs. She was born with a lumbosacral myelomeningocele, which was closed in the neonatal period. For 4–5 years before this presentation, spasticity in the lower limbs had been exacerbated without any obvious cause. She received rehabilitation and pharmacotherapy from a local doctor, but symptoms were unimproved, and her previous doctor referred her to this department. A test with 50 μg of intrathecally delivered baclofen showed total relief of spasticity and pain, so a pump was implanted for continuous baclofen delivery. During 24 months of follow-up, spasticity has remained under excellent control with baclofen at 38.5–41.0 μg/day. Conclusions ITB therapy proved extremely effective in this adult with severe spasticity from tethered code syndrome.

Abstract Background Unilateral resistance training increases the strength of the contralateral non-trained homologous muscles known as the cross-education effect. We tested the hypothesis that unilateral eccentric resistance training (ET) would induce greater and longer-lasting cross-education effect when compared with concentric resistance training (CT). Methods Young (20–23 y) participants were allocated to ET (5 males, 4 females) or CT (5 males, 4 females) group that performed unilateral progressive ET or CT of the elbow flexors, twice a week for 5 weeks (10 sessions) followed by a 5-week detraining, and control group (7 males, 6 females) that did not perform any training. Maximum voluntary isometric contraction torque of the elbow flexors (MVIC), one-repetition maximum of concentric dumbbell curl (1-RM), and biceps brachii and brachialis muscle thickness (MT) were measured from the trained and non-trained arms before, several days after the last training session, and 5 weeks later. A ratio between the trained and non-trained arms for the change in MVIC or 1-RM from pre- to post-training (cross-body transfer ratio) was compared between ET and CT groups. Results The control group did not show significant changes in any variables. Both ET and CT increased (P 0.05) after ET and CT, and MVIC returned to the baseline after detraining, but 1-RM was maintained for both groups. An increase (P