Characterization of disease-specific alterations in metabolites and effects of mesenchymal stromal cells on dystrophic muscles.

Introduction: Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic inflammation during growth, resulting in progressive generalized weakness of the skeletal and cardiac muscles. We previously demonstrated the therapeutic effects of systemic administration of dental pulp mesenchymal stromal cells (DPSCs) in a DMD animal model. We showed preservation of long-term muscle function and slowing of disease progression. However, little is known regarding the effects of cell therapy on the metabolic abnormalities in DMD. Therefore, here, we aimed to investigate the mechanisms underlying the immunosuppressive effects of DPSCs and their influence on DMD metabolism. Methods: A comprehensive metabolomics-based approach was employed, and an ingenuity pathway analysis was performed to identify dystrophy-specific metabolomic impairments in the mdx mice to assess the therapeutic response to our established systemic DPSC-mediated cell therapy approach. Results and Discussion: We identified DMD-specific impairments in metabolites and their responses to systemic DPSC treatment. Our results demonstrate the feasibility of the metabolomics-based approach and provide insights into the therapeutic effects of DPSCs in DMD. Our findings could help to identify molecular marker targets for therapeutic intervention and predict long-term therapeutic efficacy.

Difference of oncological efficacy between two immune checkpoint inhibitors following first-line platinum-based chemotherapy in patients with unresectable, metastatic, advanced urothelial carcinoma: a multicenter real-world Japanese cohort.

BACKGROUND: Maintenance avelumab is currently recommended for patients with unresectable and/or metastatic (mUC) achieving at least stable disease (SD) on first-line platinum-based chemotherapy (1L-CT). Pembrolizumab is an alternative therapeutic avenue for this patient cohort in clinical practice. We investigated real-world data, focusing on the correlation between response to 1L-CT and oncological efficacy of subsequent immune checkpoint inhibitor (ICI) therapy with avelumab or pembrolizumab. METHODS: A multicenter database registered 626 patients with mUC diagnosed from 2008-2023; among these, 175 receiving 2-6 cycles of 1L-CT followed by ICI therapy. Patients were categorized based on response to 1L-CT using the Response Evaluation Criteria in Solid Tumors (v1.1). Objective response rate on ICI, progression to ICI-free survival (ICI-PFS), and overall survival from start of 1L-CT were compared between avelumab-treated and pembrolizumab-treated patients in each response subgroup. RESULTS: ICI-PFS was significantly longer in patients achieving partial response on 1L-CT and subsequently receiving pembrolizumab compared to those receiving avelumab. Notably, patients achieving SD on 1L-CT and subsequently receiving pembrolizumab manifested significantly higher objective response rate (14% and 41%, respectively) and prolonged ICI-PFS relative to those receiving avelumab. In contrast, overall survival did not delineate difference between patients treated with avelumab versus pembrolizumab. Similar findings were discerned in the subanalysis of patients having favorable SD (tumor shrinkage, from - 29 to 0%) and unfavorable SD (tumor enlargement, from + 1 to + 19%) on 1L-CT. CONCLUSIONS: Our study provides real-world evidence regarding difference of oncological efficacy between maintenance avelumab and subsequent pembrolizumab in patients with mUC who achieved partial response or SD on 1L-CT.

Cytomegalovirus infection during daratumumab therapy in patients with newly diagnosed multiple myeloma.

The introduction of daratumumab has improved treatment outcomes for multiple myeloma (MM). However, infectious complications are a concern in patients receiving daratumumab. Although some reports have explored the association between daratumumab and cytomegalovirus (CMV) infection, most of these have focused on relapsed or refractory cases, and few describe patients with newly diagnosed MM (NDMM). In this study, we retrospectively analyzed CMV infections in 53 patients with NDMM who received daratumumab as induction therapy. CMV infection was defined as CMV antigenemia positivity. The median age at treatment initiation was 71 years (range, 50-82 years), and 50.9% of the patients were female. The median duration of daratumumab administration was 10.0 months (range, 0.3-63.8 months). Nine patients developed CMV infection, and the cumulative incidence rate at six months was 18.1% (95% confidence interval: 8.9-30.1%). One patient experienced CMV retinitis and required antiviral therapy, while the remaining eight patients did not require treatment and could be managed through observation. Few cases of CMV infection during daratumumab treatment for NDMM required treatment. However, the incidence of CMV infection was not negligible, suggesting that regular monitoring for CMV is worth considering to ensure more appropriate management during daratumumab treatment.

Dysgeusia in patients with advanced urothelial carcinoma receiving enfortumab vedotin, platinum-based chemotherapy, or immune check point inhibitors: time-course assessment using chemotherapy-induced taste alteration scale.

A time-course questionnaire survey using the chemotherapy-induced taste alteration scale (CiTAS) was conducted in patients with advanced urothelial carcinoma (UC) treated with systemic chemotherapy and/or immunotherapy. A total of 37 patients receiving systemic therapy with enfortumab vedotin (EV), platinum-based chemotherapy and immune checkpoint inhibitors were included in this study. No significant changes were observed in any of the CiTAS subscales during platinum-based chemotherapy and immune checkpoint inhibitor treatment, while EV therapy induced significant dysgeusia. Among 10 patients treated with EV, dysgeusia was associated with a substantial negative effect on the health-related quality-of-life domains, particularly global health status/QOL (mean ± standard deviation: 52 ± 19 in dysgeusia group vs 89 ± 13 in non-dysgeusia group) and mental component summary (47 ± 5.1 vs 53 ± 2.0). The fatigue symptom score was higher in the dysgeusia group at the post-third cycle of EV (47 ± 16 vs 15 ± 17). Severe dysgeusia can be induced by EV therapy, which is usually not observed in other systemic therapies for advanced UC.

Cytomegalovirus Reactivation during Elotuzumab Therapy in Patients with Multiple Myeloma.

INTRODUCTION: Some treatments are associated with cytomegalovirus (CMV) reactivation (CMVRA) in patients with multiple myeloma (MM). However, no reports exist on the association between elotuzumab and CMVRA. Therefore, we assessed the incidence of CMVRA in patients with MM who received elotuzumab therapy. METHODS: The medical records of 85 patients who underwent elotuzumab therapy were included in the retrospective analysis for CMV positivity. RESULTS: Thirty patients were tested for CMV antigenemia during elotuzumab therapy, and 16 were positive for CMV antigenemia; the cumulative incidence rate of CMVRA 6 months after elotuzumab initiation was 18.4%. The history of allogeneic stem cell transplantation (allo-HSCT) was significantly more common in the CMVRA group (31.2%) than that of the group without CMVRA (8.7%). However, even among patients who did not undergo allo-HSCT, the cumulative incidence rate of CMVRA at 6 months was 15.1%. During CMVRA, the symptoms included fever in 8 cases, while retinitis was observed in 1 case. Five patients required antiviral therapy and CMV antigenemia resolved in all but 1 case. CONCLUSION: Although the patient population was heterogeneous, CMVRA cannot be underestimated during elotuzumab therapy, and evaluation of CMVRA, especially in symptomatic cases, is clinically important.

Impact of Complete Surgical Resection of Metastatic Lesions in Patients with Advanced Renal Cell Carcinoma in the Era of Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors.

Complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) has demonstrated efficacy in the cytokine era, but its effectiveness in the era of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains unclear. A multi-institutional database included clinicopathological data of 367 patients with mRCC. Patients were divided into two groups: the CM group and the non-CM group. These two groups were compared before and after propensity score matching (PSM). Cox proportional hazard models were used to detect factors associated with disease-free survival (DFS) and overall survival (OS) from mRCC diagnosis. The CM group showed a significant association with longer overall survival compared to the non-CM group in the PSM-unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35-0.69), but no superiority was noted in the adjusted cohorts. The median DFS after CM was 24 months, with no significant differences based on relapse timing. Notably, the international metastatic RCC database consortium risk categories and metastatic burden were associated with DFS. This study supports the potential of CM in mRCC management during the TKI/ICI era, although limitations including sample size and selection bias need to be considered.

Comparison of dental plaque flora between intellectually disabled patients and healthy individuals: a cross-sectional study.

Periodontal diseases, including gingivitis, are highly prevalent in individuals with intellectual disability (ID). In particular, gingivitis can be difficult to cure owing to the lack of patient cooperation. Here, we evaluated differences in the oral bacterial flora between individuals with ID (n = 16) and healthy controls (n = 14) to facilitate the development of strategies for the prevention of periodontal disease in people with ID. Our results showed no significant difference in the number of decayed, missing, and filled teeth between the two groups. However, there were significant differences in the median papillary-marginal-attached index, plaque index, and gingival index between groups (P < 0.0001). Additionally, the mean probing depth in the ID group was significantly higher than that in the control group (P < 0.0001). The diversity of oral flora in people with ID and concurrent gingivitis was significantly lower than that of healthy individuals without periodontal disease. The relative abundances of Tannerella spp. and Treponema spp. were significantly higher in the ID group than in the control group at the genus level (P = 0.0383 and 0.0432, respectively), whereas that of Porphyromonas spp. was significantly lower in the ID group (P < 0.0001). Overall, our findings provided important insights into differences in the oral microbiota between patients with ID and healthy controls.

Clinical impact of the intensity of follow-up cystoscopy in patients with high-risk non-muscle-invasive bladder cancer.

PURPOSE: There is significant lack on evidence regarding the effect of non-adherence to a recommended protocol in follow-up of high-risk non-muscle-invasive bladder cancer (NMIBC), or the impact of delaying detection of recurrent lesion. Here, we aimed to investigate the optimal frequency of follow-up cystoscopy of high-risk NMIBC with respect to oncological safety in the Japanese real-world clinical practice. METHODS: This retrospective single-center study included 206 patients with primary high-risk NMIBC. The intensity (%) of follow-up cystoscopy was calculated based on actual visits for cystoscopy and guideline-recommended frequency in the first 24-month follow-up period. Inverse probability of treatment weighting analyses was used to reduce the risk of bias between groups. We performed a restricted cubic spline analysis with knots at intensity of follow-up cystoscopy ≤ 100% group to examine the possible association of progression risk with the intensity of follow-up as a continuous exposure. RESULTS: The median intensity was 87.5% (interquartile range, 75-100). Adjusted multivariate analysis for MIBC-free and progression-free survival demonstrated no significant difference between adjusted ≤ 75% and > 75% intensity groups. A restricted cubic spline analysis suggested no significant effect of the intensity of follow-up on progression risk, and hazard ratios of patients of < 100% intensity were equivalent to those of patients of 100% intensity. CONCLUSION: Our finding suggested decreased intensity of follow-up cystoscopy did not affect oncological outcomes in patients with high-risk NMIBC. Further prospective trials directly aimed at investigating optimized follow-up schedules for NMIBC are mandatory before substantial changes to existing clinical guidelines.

Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort.

OBJECTIVE: Real-world evidence regarding enfortumab vedotin for unresectable or metastatic urothelial carcinoma is scarce, particularly in Japan. We investigated real-world data focusing on patient background, previous treatments, response, survival and adverse events in patients receiving enfortumab vedotin. METHODS: A multicentre database was used to register 556 patients diagnosed with metastatic urothelial carcinoma from 2008 to 2023; 34 patients (6.1%) treated with enfortumab vedotin were included. Best radiographic objective responses were evaluated using the Response Evaluation Criteria in Solid Tumors (v1.1) during treatments. Overall survival and progression-free survival were estimated (Kaplan-Meier method). Toxicities were reported according to the Common Terminology Criteria for Adverse Events, version 5.0. The relative dose intensity, which could impact oncological outcomes, was calculated. RESULTS: The median number of enfortumab vedotin therapy cycles was 5. The best objective response to enfortumab vedotin was partial response, stable disease and progressive disease in 19 (56%), 5 (15%) and 10 (29%) patients, respectively. The median overall survival and progression-free survival after the first enfortumab vedotin dose were 16 and 9 months, respectively. No significant relationship was observed between survival outcomes after enfortumab vedotin initiation and the enfortumab vedotin relative dose intensity. The median overall survival from first-line platinum-based chemotherapy initiation was 42 months. Twenty-six (76%) patients experienced any grade of enfortumab vedotin-related toxicities; eight (24%) experienced Grades 3-4 toxicities, the most common being skin toxicity (any grade, 47%; Grades 3-4, 12%). CONCLUSIONS: Here, we report real-world evidence for enfortumab vedotin therapy in Japan. Tumour responses and safety profiles were comparable with those of clinical trials on this novel treatment.

[A retrospective analysis of 124 patients with multiple myeloma who received up-front autologous hematopoietic cell transplantation following triplet induction therapy].

The IFM/DFCI group reported that VRD induction followed by up-front autologous peripheral blood stem cell transplantation (ASCT) and maintenance therapy led to median PFS of 50 months, which established up-front ASCT as the standard of care even in the era of novel agents. We conducted a retrospective analysis on outcomes of patients who received triplet induction therapy followed by up-front ASCT at our institution. A total of 124 patients received ASCT between November 2016 and December 2021 at Japanese Red Cross Medical Center. Patient characteristics, treatment response before and after ASCT, and PFS and OS were retrospectively analyzed. VRD-based induction therapy was used for 94%. Among 118 evaluable patients, 116 (98%) received either consolidation and/or maintenance therapy. Best responses were ≥CR 77% and ≥VGPR 94%, respectively. Sixty-eight out of 104 patients achieved MRD-negativity by multiparameter FCM (<10-5). Five-year estimated PFS and OS were 54.7% and 80.2%, respectively. Age ≥65, high-risk cytogenetic abnormalities, and

Real-World Clinical Outcomes in Patients With Multiple Myeloma Administered With Elotuzumab-Based Treatment.

Objective Elotuzumab is used to treat relapsed and/or refractory multiple myeloma (MM). However, the optimal patient selection and sequencing in MM therapy are less clear. Therefore, this retrospective cohort study assessed the clinical outcomes of patients with MM who underwent elotuzumab-based therapy. Methods We reviewed the medical records of 85 patients with relapsed/refractory MM who received elotuzumab for the first time. Participants were divided into progressive disease (PD group) and those without PD (non-PD group) at elotuzumab treatment initiation, and each group was analyzed separately. Survival rates were calculated using Kaplan-Meier curves and compared using log-rank tests. Results The median follow-up period was 33.6 (range: 0.5-72.0) months. The median progression-free survival (PFS) and overall survival (OS) of PD and non-PD groups at elotuzumab therapy initiation were 5.3 months and not reached (NR), respectively (P < 0.0001), and 26.8 months and NR, respectively. Patients with triple-class refractory disease in both groups had worse PFS and OS. Twenty-one patients in the non-PD group received elotuzumab as post-hematopoietic stem cell transplantation, whose PFS and OS were NR (95% CI, 21.4 months-NR) and NR (95% CI, NR-NR), respectively. Conclusions Elotuzumab exhibited limited therapeutic efficacy in patients with triple-class refractory MM but better treatment outcomes in situations with adequate disease control and post-transplant treatment.

Calibration experiments for radon in drinking water measurements using portable-type electrostatic-collection radon monitors.

Portable-type electrostatic-collection radon monitors (RAD7) are often used for in-situ measurements of radon in water. In this study, we evaluated the calibration factors and their uncertainties for two RAD7 monitors based on comparative measurements with the liquid scintillation counting method. In the first experiment, we found that both RAD7 monitors had relatively large uncertainties due to leakage of radon gas that bubbled from the gaps between the lids of the desiccant container and the glass vial. Therefore, for the second experiment, these gaps were closed as much as possible using parafilm and clay, respectively. As a result, the relative uncertainties for both RAD7 monitors were significantly decreased. Furthermore, we collected spring water samples to confirm the reliability of radon concentrations. After closing the leakage point, the uncertainty of radon concentrations in spring water we measured using the typical protocol of the RAD7 were significantly lower, which improves the measurement.

Real-world clinical outcomes in patients with relapsed and refractory multiple myeloma receiving VTD-PACE treatment in the era of monoclonal antibodies.

Bortezomib (Velcade), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD-PACE) are commonly used as salvage treatment for patients with relapsed/refractory multiple myeloma (RRMM). However, its outcomes in the era of monoclonal antibodies remain unclear. Therefore, this retrospective cohort study assessed the clinical outcomes of 60 patients with RRMM (median four prior treatment lines) administered VTD-PACE. The median follow-up period was 11.1 months, during which they received a median of two cycles of VTD-PACE. The overall response rate (ORR) was 66.7%; ORRs of 53.1 and 82.1% were noted in patients with ≥ 4 and ≤ 3 prior lines (P = 0.027), respectively. The median overall survival (OS) was 17 months, with a median progression-free survival (PFS) of 9.8 months. Using the 3-month time point after VTD-PACE treatment as a landmark, 54 patients were still alive. Landmark analysis was conducted for PFS and OS of patients who received or did not receive HSCT or CART after VTD-PACE treatment. Patients who underwent subsequent hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell therapy (CART) following VTD-PACE showed a trend of longer PFS and OS than those who did not undergo subsequent HSCT or CART. The median OS in patients with and without renal dysfunction was 10.7 months and 21.5 months, respectively (P = 0.0091). Therefore, VTD-PACE is useful as a bridging therapy for HSCT or CART, as a response can be expected regardless of organ damage, disease risk, or history of anti-CD38 antibody use.

[Acute myeloid leukemia with t (8;21) translocation diagnosed at 21 weeks of gestation resulting in full-term delivery without chemotherapy].

A 28-year-old female was diagnosed with acute myeloid leukemia (AML) due to t (8;21) (q22;q22.1); RUNX1-RUNX1T1 at 21 weeks of gestation. Because no adverse prognostic genetic mutations were discovered, we decided to continue the pregnancy without chemotherapy for as long as possible. After careful monitoring with blood tests every two weeks, the disease did not progress until full-term, and a cesarean section was performed at 39 weeks of gestation. About two months after delivery, blasts in the peripheral blood increased to 46.5%, and myeloblasts in the bone marrow increased to 21.2%. The patient received idarubicin and cytarabine induction therapy, followed by three cycles of high-dose cytarabine consolidation therapy, and complete remission was maintained. Here we report a rare case who could avoid chemotherapy until full-term labor without progression of AML.

Diagnostic and Prognostic Roles of Urine Nectin-2 and Nectin-4 in Human Bladder Cancer.

The clinical utility of urine nectins in bladder cancer (BCa) is unclear. We investigated the potential diagnostic and prognostic values of urine Nectin-2 and Nectin-4. Levels of urine Nectin-2, Nectin-4, and NMP-22 were quantified using an enzyme-linked immunosorbent assay in 122 patients with BCa, consisting of 78 with non-muscle-invasive BCa (NMIBC) and 44 with muscle-invasive BCa (MIBC), and ten healthy controls. Tumor nectin expression in MIBC was evaluated with immunohistochemical staining of transurethral resection specimens. The level of urine Nectin-4 (mean: 18.3 ng/mL) was much higher than that of urine Nectin-2 (mean: 0.40 ng/mL). The sensitivities of Nectin-2, Nectin-4, NMP-22, and cytology assays were 84%, 98%, 52%, and 47%, respectively; their specificities were 40%, 80%, 100%, and 100%, respectively. Both urine Nectin-2 and Nectin-4, though not NMP-22, were found to be significantly more sensitive than cytology. A four-titer grouping based on levels of urine Nectin-2/Nectin-4 (low/high, high/high, low/low, and high/low) showed a high capability for discriminating between NMIBC and MIBC. Neither urine Nectin-2 nor Nectin-4 levels had a significant prognostic value in NMIBC or MIBC. Urine levels correlated with tumor expression and serum levels in the Nectin-4 analysis, but not in the Nectin-2 analysis. Urine nectins are potential diagnostic biomarkers for BCa.

Clinical practice of UroVysion® urine test in patients with bladder carcinoma in situ treated with intravesical Bacillus Calmette-Guerin.

In January 2019, the use of the UroVysion® urine test for surveillance of non-muscle invasive bladder cancer with carcinoma in situ (CIS) was approved in Japan. Clinical evidence of its use remains limited. Herein, we report the real-world clinical practice of the UroVysion test. Of 29 patients underwent at least one UroVysion test at our hospital from 2019 to 2022, only two (6.9%) tested positive without any visible tumor on the cystoscopy after the initial transurethral resection: a 77-year-old man with T1 high-grade tumor and concomitant CIS and a 76-year-old woman with CIS. The remaining 27 patients (93.1%) tested negative post-transurethral resection. This study was the first to report the Japanese real-world practice of the UroVysion test, demonstrating relatively low positive rate as compared to the previous reports from other countries. Further clinical evidence from other Japanese institutes needs to be accumulated to update the true value of this test.

Real-world clinical outcomes in patients with multiple myeloma treated with isatuximab after daratumumab treatment.

Isatuximab and daratumumab are anti-CD38 monoclonal antibodies used to treat refractory multiple myeloma. Isatuximab is often used after unsuccessful daratumumab treatment; however, the clinical benefits of receiving isatuximab after daratumumab treatment have not been fully evaluated. Therefore, this retrospective cohort study assessed the clinical outcomes of 39 patients with multiple myeloma who were administered isatuximab after daratumumab. The median follow-up period was 8.7 months (range 0.1-25.0 months). The overall response rate was 46.2% (18 patients). The 1-year overall survival was 53.9%, with a median progression-free survival of 5.6 months. The median progression-free survival in patients with high and normal lactate dehydrogenase levels was 4.5 and 9.6 months, respectively (P = 0.004). The median progression-free survival in patients with and without triple-class refractory disease was 5.1 months and not reached, respectively (P = 0.001). The median overall survival in patients with high and normal lactate dehydrogenase levels was not reached and 9.3 months, respectively (P = 0.001). The median overall survival in patients with and without triple-class refractory disease was 9.9 months and not reached, respectively (P = 0.038). Our findings provide insight into the optimal use and timing of anti-CD38 antibody therapy.