Hiroshi Yamada’s research while affiliated with Wakayama Medical University and other places

Metaphyseal comminution in distal radius fracture (DRF) cases might indicate severe osteoporosis. The patients with DRFs and metaphyseal comminution showed 5.2-fold increased secondary fractures compared with those receiving combination osteoporosis therapy. High-risk DRF patients require aggressive osteoporosis management and fracture risk stratification. Distal radius fractures (DRFs) are common in patients with osteoporosis and associated with increased risks for subsequent fractures. Metaphyseal comminution in patients with DRFs may indicate severe osteoporosis and heightened bone fragility. However, its relationship with the risk of secondary fragility fractures remains unclear. This study aimed to evaluate the incidence of secondary fractures in patients with DRFs involving metaphyseal comminution and assess the effectiveness of osteoporosis treatment in reducing this risk. In this retrospective cohort study, 134 patients aged ≥ 50 years underwent DRF surgery at a single institution from July 2018 to December 2022. The patients were allocated into groups by the presence (n = 45) or absence (n = 89) of metaphyseal comminution. The primary outcome was secondary fracture incidence. A multivariate Cox model was used, adjusting for age, sex, body mass index, bone mineral density, osteoporosis treatment type, and dementia. Secondary fractures were significantly more frequent in the comminution group (17.8%) than in the non-comminution group (3.4%) (p = 0.004). Metaphyseal comminution was associated with 5.2-fold increased secondary fracture risk (hazards ratio: 5.2, 95% confidence interval: 1.4–10.7, p = 0.004). The patients administered combination therapy (active vitamin D plus bisphosphonates or anabolic agents) had notably lower secondary fracture rate than did those receiving vitamin D alone (5.6% vs. 15.4%, p = 0.046). Metaphyseal comminution in patient with DRFs significantly elevated secondary fracture risk; combination osteoporosis therapy might mitigate this risk. These findings underscore the need for robust osteoporosis management in high-risk patients, suggesting metaphyseal comminution should be crucial for fracture risk stratification.

Introduction: Chemonucleolysis with condoliase (chondroitin sulfate ABC endolyase) has been widely employed to treat patients with lumbar disc herniation (LDH) in Japan. Although it is an effective and relatively safe treatment for radicular neuropathy in patients with LDH, there have been no reports that investigate how severe low back pain (LBP) changes after condoliase injection. In this multicenter study, the effectiveness of condoliase injection for reducing severe LBP in patients with LDH was evaluated. Methods: This retrospective study involved patients treated with intradiscal condoliase injection for LDH at nine participating centers. Patients were diagnosed with subligamentous-type herniation based on pretreatment MRI. Patients with severe LBP (defined as a preinjection numeric rating scale [NRS] for LBP greater than or equal to that for leg pain) were categorized into the LBP group. Demographic data, adverse events, treatment costs, and the NRS for LBP and lower extremity pain were analyzed. A 50% response was defined as ≥50% improvement in the NRS at 1 year postinjection. On the basis of the Pfirman classification, the LBP group was divided into less-degenerative (Grades II and III) and degenerative (Grades IV and V) subgroups. Results: Seventy-nine patients were classified into the LBP group. Of these patients, 61 (77.2%) showed a >50% reduction in LBP, and another 61 (77.2%) demonstrated a >50% reduction in lower extremity pain. Improvement of lower limb pain was considerably better in the less-degenerative group than in the degenerative group, whereas that of low back pain was similar between the two subgroups. Medical costs, which include remuneration for injection, drug fees, inpatient costs, and other expenses, were similar between the LBP group and all cases. Conclusions: This retrospective multicenter study revealed that patients with LDH with severe LBP frequently experienced improvement in radicular pain and LBP, which is similar to LDH cases without severe LBP.

Study Design Retrospective cohort study. Purpose Balloon kyphoplasty (BKP) is a minimally invasive surgical treatment for osteoporotic vertebral compression fractures (OVCFs), with good clinical outcomes reported in short-term investigations. However, the impact of BKP on health-related QOL in the long term remains unclear. This study aimed to evaluate the effects of BKP on global sagittal balance and alignment and to determine the association between predictive factors before BKP and health-related QOL in the long term. Methods A longitudinal cohort study was conducted on 62 patients (13 men and 49 women) diagnosed with OVCF who underwent BKP and were followed up for more than 12 months. Spinopelvic parameters, including sagittal vertical axis (SVA), thoracic kyphosis (TK), pelvic incidence (PI) minus lumbar lordosis (LL), and low back pain (LBP) severity, were measured preoperatively, at 3 months post-BKP, and at final follow-up. Multivariate logistic regression analysis was performed to identify predictive factors for unhealthy condition after BKP, with adjustment for age, sex, and duration from onset of back pain to BKP. Results The mean follow-up duration was 20.7 months. The mean SVA values were 7.42 cm preoperatively, 7.62 cm at 3 months post-BKP, and 8.01 cm at final follow-up. The mean self-reported numerical rating scale scores for LBP were 8.4 preoperatively, 0.4 post-BKP, 0.6 at 3 months post-BKP, and 1.0 at final follow-up. Imbalanced spine (SVA ≥5.0 cm) and PI-LL mismatch (PI-LL ≥20°) before BKP were significantly associated with unhealthy condition (EuroQol 5 dimensions 5-level <0.65) (odds ratio and 95% confidence intervals: imbalanced spine, 4.76 and 1.32–17.2; PI-LL mismatch, 3.78 and 1.18–12.1, respectively). Conclusion BKP did not improve global spinopelvic parameters or health-related QOL in imbalanced patients. Higher SVA measurements and PI-LL mismatch before BKP were associated with lower health-related QOL after BKP.

Introduction: Condoliase-based chemonucleolysis and microendoscopic discectomy (MED) are considered to be minimally invasive treatments for lumbar disc herniation (LDH). The aim of this study was to compare the clinical outcomes of both treatments, specifically focusing on whether the outcomes vary by age group. Methods: Patients with LDH who received intradiscal condoliase injections (condoliase group) or underwent MED (MED group) with 1-year follow-up were enrolled in this study. A numerical rating scale (NRS) was developed for leg and back pains. Using magnetic resonance imaging, changes in disc height and degeneration were evaluated. The data were assessed at baseline and at 3-month and 1-year follow-ups. The therapy was considered effective in patients whose NRS for leg pain improved by ≥50% at 1 year from baseline and for whom surgery was not required. Comparative analyses were conducted between the condoliase and MED groups and among the <20-, 20–39-, 40–59-, and ≥60-year age groups. Results: In this study, a total of 345 patients (condoliase group, n = 233; MED group, n = 112) were enrolled. Subsequent surgery was required in 23 patients (9.9%) in the condoliase group because of the ineffectiveness of the condoliase therapy. Because of herniation recurrence, reoperation was required in five patients (4.5%) in the MED group. The efficacy rates were respectively 74.4% and 74.6% in the condoliase and MED groups, and no intergroup or age-group differences were found. The condoliase group had a significantly higher decrease in disc height when compared with the MED group (9.0% vs. 4.4%, p < 0.05). Compared with the older age group, the younger age group had a greater decrease in disc height and disc degeneration; however, their recovery was better than that of the older age group. Among the age groups, the herniation reduction rate did not significantly vary. Conclusions: Condoliase and MED had equivalent 1-year outcomes, with no differences observed in efficacy across age groups. For informed decision-making, the advantages and disadvantages of each treatment must be understood.

Intervertebral disc disease (IDD) is a debilitating spine condition that can be caused by intervertebral disc (IVD) damage which progresses towards IVD degeneration and dysfunction. Recently, human pluripotent stem cells (hPSCs) were recognized as a valuable resource for cell-based regenerative medicine in skeletal diseases. Therefore, adult somatic cells reprogrammed into human induced pluripotent stem cells (hiPSCs) represent an attractive cell source for the derivation of notochordal-like cells (NCs) as a first step towards the development of a regenerative therapy for IDD. Utilizing a differentiation method involving treatment with a four-factor cocktail targeting the BMP, FGF, retinoic acid, and Wnt signaling pathways, we differentiate CRISPR/Cas9-generated mCherry-reporter knock-in hiPSCs into notochordal-like cells. Comprehensive analysis of transcriptomic changes throughout the differentiation process identified regulation of histone methylation as a pivotal driver facilitating the differentiation of hiPSCs into notochordal-like cells. We further provide evidence that specific inhibition of histone demethylases KDM2A and KDM7A/B enhanced the lineage commitment of hiPSCs towards notochordal-like cells. Our results suggest that inhibition of KDMs could be leveraged to alter the epigenetic landscape of hiPSCs to control notochord-specific gene expression. Thus, our study highlights the importance of epigenetic regulators in stem cell-based regenerative approaches for the treatment of disc degeneration.

Introduction Spinal cord injury (SCI) is a devastating injury and remains one of the largest medical and social burdens because of its intractable nature. According to the recent advances in stem cell biology, the possibility of spinal cord regeneration and functional restoration has been suggested by introducing appropriate stem cells. Multilineage-differentiating stress enduring (Muse) cells are a type of nontumorigenic endogenous reparative stem cell. The positive results of Muse cell transplantation for SCI was shown previously. As a first step for clinical application in human SCI, we conducted a clinical trial aiming to confirm the safety and feasibility of intravenously injected donor-Muse cells. Methods The study design of the current trial was a prospective, multicenter, nonrandomized, nonblinded, single-arm study. The clinical trial registration number was JRCT1080224764. Patients with a cervical SCI with a neurological level of injury C4 to C7 with the severity of modified Frankel classification B1 and B2 were included. A primary endpoint was set for safety and feasibility. Our protocol was approved by the PMDA, and the trial was funded by the Life Science Institute, Tokyo, Japan. The present clinical trial recruited 10 participants (8 males and 2 females) with an average age of 49.3 ± 21.2 years old. All 10 participants received a single dose of allogenic CL2020 (a total of 15 × 10⁶ cells, 2.1–2.7 × 10⁵ cells/kg of body weight), which is a Muse cell-based product produced from human mesenchymal stem cells, by an intravenous drip. Results There were two reported severe adverse events, both of which were determined to have no causal relationship with Muse cell treatment. The change in the ISNCSCI motor score, the activity of daily living and quality of life scores showed statistically significant improvements compared to those data at the time of CL2020 administration. Conclusion In the present trial, no safety concerns were identified, and Muse cell product transplantation demonstrated good tolerability. Future clinical trials with appropriate study designs incorporating a control arm will clarify the definitive efficacy of single-dose allogenic Muse cell treatment with intravenous administration to treat SCI. Trial registration: jRCT, JRCT1080224764. Registered 03 July 2019, https://jrct.niph.go.jp/latest-detail/jRCT1080224764.

Introduction Spinal cord injury (SCI) is a devastating injury and remains one of the largest medical and social burdens because of its intractable nature. According to the recent advances in stem cell biology, the possibility of spinal cord regeneration and functional restoration has been suggested by introducing appropriate stem cells. Multilineage-differentiating stress enduring (Muse) cells are a type of nontumorigenic endogenous reparative stem cell. The positive results of Muse cell transplantation for SCI was shown previously. As a first step for clinical application in human SCI, we conducted a clinical trial aiming to confirm the safety and feasibility of intravenously injected donor-Muse cells. Methods The study design of the current trial was a prospective, multicenter, nonrandomized, nonblinded, single-arm study. The clinical trial registration number was JRCT1080224764. Patients with a cervical SCI with a neurological level of injury C4 to C7 with the severity of modified Frankel classification B1 and B2 were included. A primary endpoint was set for safety and feasibility. Our protocol was approved by the PMDA, and the trial was funded by the Life Science Institute, Tokyo, Japan. The present clinical trial recruited 10 participants (8 males and 2 females) with an average age of 49.3 ± 21.2 years old. All 10 participants received a single dose of allogenic CL2020 (a total of 15 × 10⁶ cells, 2.1–2.7 × 10⁵ cells/kg of body weight), which is a Muse cell-based product produced from human mesenchymal stem cells, by an intravenous drip. Results There were two reported severe adverse events, both of which were determined to have no causal relationship with Muse cell treatment. The change in the ISNCSCI motor score, the activity of daily living and quality of life scores showed statistically significant improvements compared to those data at the time of CL2020 administration. Conclusion In the present trial, no safety concerns were identified, and Muse cell product transplantation demonstrated good tolerability. Future clinical trials with appropriate study designs incorporating a control arm will clarify the definitive efficacy of single-dose allogenic Muse cell treatment with intravenous administration to treat SCI. Trial registration: jRCT, JRCT1080224764. Registered 03 July 2019, https://jrct.niph.go.jp/latest-detail/jRCT1080224764