Forodesine Enhances Immune Responses through Guanosine-Mediated TLR7 Activation while Preventing Graft-versus-Host Disease.

Recent evidence indicates that specific types of nuclear acids, including guanosine and its derivatives, act as natural ligands for TLR7. This led us to hypothesize that purine nucleoside phosphorylase inhibitors not only can induce apoptosis of T cells but also can lead to TLR7 activation by accumulation of guanine nucleosides, in particular under systemic inflammation, where damaged tissues release a large amount of nucleotides. We demonstrate in the present study that a purine nucleoside phosphorylase inhibitor, forodesine, can reduce the disease severity and prolong the survival in a xenogeneic mouse model of graft-versus-host disease (GVHD). Guanine nucleosides were undetectable in mice during GVHD but increased significantly following forodesine treatment. Our in vitro experiments showed that forodesine enhanced guanosine-mediated cytokine production from APCs, including alveolar macrophages and plasmacytoid dendritic cells, through TLR7 signaling. Forodesine also enhanced Ag-presenting capacity, as demonstrated by increased CD8+ T cell proliferation and higher secretion of IFN-γ and IL-12p40 in an MLR with plasmacytoid dendritic cells. Furthermore, forodesine stimulated IFN-γ production from activated T cells in the presence of a low concentration of guanosine while inhibiting their proliferation and inducing apoptotic cell death. Although forodesine ameliorated GVHD severity, mice treated with forodesine showed significantly higher levels of multiple proinflammatory cytokines and chemokines in plasma, suggesting in vivo upregulation of TLR7 signaling. Our study suggests that forodesine may activate a wide range of immune cells, including T cells, through TLR7 stimulation while inhibiting GVHD by inducing apoptosis of T cells, after allogeneic hematopoietic stem cell transplant.

Antibody-mediated pathogenesis of chronic GVHD through DBY/HLA class II complexes and induction of a GVL effect.

Chronic graft-versus-host disease (cGVHD) is a multiorgan syndrome with clinical features resembling those of autoimmune diseases. Thus, understanding commonalities in the pathophysiology of cGVHD and autoimmune diseases, such as the presence of disease-risk HLA alleles, is imperative for developing novel therapies against cGVHD. Alloantibodies against H-Y antigens encoded on the Y-chromosome are well-described risk factors for cGVHD in female-to-male transplantation. However, because H-Y antigens generally localize intracellularly in the male reproductive organs, how they emerge at affected organ levels remains elusive. Here, by analyzing nationwide registry data stratified per donor-recipient sex, we identified specific HLA class II alleles that contributed to susceptibility to male cGVHD after transplantation from HLA-identical female siblings (HLA-DRB1∗15:02: hazard ratio, 1.28; 95% confidence interval, 1.03-1.58; P = .025). Coexpression of HLA-DRB1∗15:02 efficiently transported full-length H-Y antigens, especially DBY, to the surface. The presence of alloantibodies against DBY/HLA class II complexes significantly predicted the occurrence of cGVHD (68.8% vs 31.7% at 1 year; P = .002). Notably, the ability of HLA class II molecules to transport and present DBY to alloantibodies was closely associated with the susceptibility of HLA class II alleles to cGVHD. DBY specifically colocalized with HLA class II molecules on the dermal vascular endothelium in cGVHD and provoked complement-dependent cytotoxicity. Moreover, these complexes were observed in some male leukemic cells. Altogether, these findings suggest that vascular endothelial cells facilitate alloantibody-mediated cGVHD and highlight that alloantibodies against DBY/HLA class II complexes could be common targets for cGVHD and a graft-versus-leukemia effect.

The impact of daratumumab pretreatment on multiple myeloma patients undergoing autologous transplantation.

The anti-CD38 antibody daratumumab (Dara) has been reported to improve the prognosis of multiple myeloma (MM) patients, but its use before autologous stem cell transplantation (ASCT) remains controversial. To clarify the prognostic impact of Dara before ASCT on MM, we performed a retrospective observational analysis. We analyzed 2626 patients who underwent ASCT between 2017 and 2020. In the comparison between patients not administered Dara (Dara- group) and those administered Dara (Dara+ group), the 1-year progression-free survival (PFS) rates were 87.4% and 77.3% and the 1-year overall survival (OS) rates were 96.7% and 90.0%, respectively. In multivariate analysis, age <65 years (p = 0.015), low international staging system (ISS) stage (p < 0.001), absence of unfavorable cytogenic abnormalities (p < 0.001), no Dara use before ASCT (p = 0.037), and good treatment response before ASCT (p < 0.001) were independently associated with superior PFS. In matched pair analysis, the PFS/OS of the Dara- group were also significantly superior. For MM patients who achieved complete or very good partial response (CR/VGPR) by Dara addition before ASCT, both PFS and OS significantly improved. However, in patients who did not achieve CR/VGPR before ASCT, the PFS/OS of the Dara+ group were significantly inferior to those of the Dara- group.

The arousal level of consciousness required for working memory performance: An anaesthesia study.

Regarding the stage of arousal level required for working memory to function properly, limited studies have been conducted on changes in working memory performance when the arousal level of consciousness decreases. This study aimed to experimentally clarify the stages of consciousness necessary for optimal working memory function. In this experiment, the sedation levels were changed step-by-step using anaesthesia, and the performance accuracy during the execution of working memory was assessed using a dual-task paradigm. Participants were required to categorize and remember words in a specific target category. Categorization performance was measured across four different sedative phases: before anaesthesia (baseline), and deep, moderate and light stages of sedation. Short-delay recognition tasks were performed under these four sedative stages, followed by long-delay recognition tasks after participants recovered from sedation. The results of the short-delay recognition task showed that the performance was lowest at the deep stage. The performance of the moderate stage was lower than the baseline. In the long-delay recognition task, the performance under moderate sedation was lower than that under baseline and light sedation. In addition, the performance under light sedation was lower than that under baseline. These results suggest that task performance becomes difficult under half sedation and that transferring information to long-term memory is difficult even under one-quarter sedation.

Daratumumab in first-line therapy is cost-effective in transplant-eligible patients with newly diagnosed myeloma.

Triplet regimens, such as lenalidomide, bortezomib, and dexamethasone (RVd) or thalidomide, bortezomib, and dexamethasone (VTd), are standard induction therapies for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to RVd and VTd has been investigated in the GRIFFIN and CASSIOPEIA trials, respectively, resulting in improvement in the rate of minimal residual disease (MRD) negativity. In this study, we conducted a cost-effectiveness analysis with a 10-year time horizon to compare first-line and second-line use of daratumumab for transplant-eligible patients with NDMM. Because long-term follow-up data for these clinical trials are not yet available, we developed a Markov model that uses MRD status to predict progression-free survival. Daratumumab was used either in the first-line setting in combination with RVd or VTd or in the second-line setting with carfilzomib plus dexamethasone (Kd). Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were calculated from a Japanese and US payer perspective. In the Japanese analysis, D-RVd showed higher QALYs (5.43 vs 5.18) and lower costs (¥64 479,793 vs ¥71 287 569) compared with RVd, and D-VTd showed higher QALYs (5.67 vs 5.42) and lower costs (¥43 600 310 vs ¥49 471,941) compared with VTd. Similarly, the US analysis demonstrated dominance of a strategy incorporating daratumumab in first-line treatment regimens. Given that overall costs are reduced and outcomes are improved when daratumumab is used as part of a first-line regimen, the economic analysis indicates that addition of daratumumab to first-line RVd and VTd regimens is a dominant strategy compared with reserving its use for the second-line setting.

Impact of stem cell selection between bone marrow and peripheral blood stem cells for unrelated hematopoietic stem cell transplantation for hematologic malignancies: on behalf of the Donor/Source Working Group of the Japanese Society for Transplantation and Cellular Therapy.

BACKGROUND AIMS: This study aimed to comprehensively assess the impact of stem cell selection between bone marrow (BM) and peripheral blood (PB) in unrelated hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Our objective was to identify specific factors associated with better transplant outcomes. METHODS: A retrospective analysis was conducted using data from the Japanese HSCT registry. Inclusion criteria were patients aged 0-70 years who underwent their first unrelated HSCT with BM or PB, with an 8/8 or 7/8 allele HLA match for hematological malignancies between 2010 and 2020. RESULTS: Among 10 295 patients, no significant difference was observed in overall survival, relapse, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) or non-relapse mortality between the groups. Patients who received PB showed no clear difference in acute GVHD but had a greater rate of chronic GVHD, resulting in poor chronic GVHD-free, relapse-free survival (CRFS). Subgroup analyses highlighted the importance of patient-specific factors in source selection. Patients with non-Hodgkin lymphoma and a greater hematopoietic cell transplantation-comorbidity index showed better CRFS and GRFS when BM was the preferred source. Similar trends were observed among patients with standard-risk disease for CRFS. However, no such trends were evident among patients aged 0-24 years, indicating that both sources are viable choices for young patients. CONCLUSIONS: This real-world retrospective analysis showed similar basic outcomes for BM and PB in an unrelated setting. The results support that BM may still be preferred over PB, especially when the long-term quality of life is a major concern. A consideration of individual factors can further optimize transplant success. Further research is warranted to explore the long-term implications of stem cell source selection.

Language and sensory characteristics are reflected in voice-evoked responses in low birth weight children.

BACKGROUND: Children born with very low birth weight (VLBW) are at higher risk for cognitive impairment, including language deficits and sensorimotor difficulties. Voice-evoked response (P1m), which has been suggested as a language development biomarker in young children, remains unexplored for its efficacy in VLBW children. Furthermore, the relation between P1m and sensory difficulties in VLBW children remains unclear. METHODS: 40 children with VLBW were recruited at 5-to-6 years old (26 male, 14 female, mean age of months ± SD, 80.0 ± 4.9). We measured their voice-evoked brain response using child-customized magnetoencephalography (MEG) and examined the relation between P1m and language conceptual inference ability and sensory characteristics. RESULTS: The final sample comprised 36 children (23 boys, 13 girls; ages 61-86 months; gestational ages 24-36 weeks). As a result of multiple regression analysis, voice-evoked P1m in the left hemisphere was correlated significantly with language ability (ß = 0.414 P = 0.015) and sensory hypersensitivity (ß = 0.471 P = 0.005). CONCLUSION: Our findings indicate that the relation between P1m and language conceptual inference ability observed in term children in earlier studies is replicated in VLBW children, and suggests P1m intensity as a biomarker of sensory sensitivity characteristics. IMPACT: We investigated brain functions related to language development and sensory problems in very low birth-weight children. In very low birth weight children at early school age, brain responses to human voices are associated with language conceptual inference ability and sensory hypersensitivity. These findings promote a physiological understanding of both language development and sensory characteristics in very low birth weight children.

Effects of CD34+ cell dose on engraftment and long-term outcomes after allogeneic bone marrow transplantation.

BACKGROUND: The number of CD34+ cells in the graft is generally associated with time to engraftment and survival in transplantation using cord blood or allogeneic peripheral blood stem cells. However, the significance of abundant CD34+ in bone marrow transplantation (BMT) remained unclear. METHODS: We retrospectively reviewed 207 consecutive adult patients who underwent their first BMT at Jichi Medical University between January 2009 and June 2021. RESULTS: The median nucleated cell count (NCC) and CD34+ cell dose were 2.17 × 108/kg (range .56-8.52) and 1.75 × 106/kg (.21-5.84), respectively. Compared with 104 patients in the low CD34+ group (below the median), 103 patients in the high CD34+ group (above the median) showed faster engraftment at day +28 in terms of neutrophil (84.6% vs. 94.2%; p =  .001), reticulocyte (51.5% vs. 79.6%; p < .001), and platelet (39.4% vs. 72.8%; p < .001). There were no significant differences in overall survival, relapse, nonrelapse mortality, acute or chronic graft-versus-host disease, or infectious complications between the two groups in univariate and multivariate analyses. Low or high NCC had no significant effect on overall survival, nonrelapse mortality, cumulative incidence of relapse and graft-versus-host disease, either. While a positive correlation was observed between NCC and the CD34+ cell dose, a high CD34+ cell dose was associated with rapid hematopoietic recovery, even in patients with NCC below the median. CONCLUSION: Measurement of CD34+ cell dose in addition to NCC was useful for predicting hematopoietic recovery, but seemed to have little influence on the long-term outcome in BMT.

Real-world outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma in Japanese patients: data with a minimum of 3 years of follow-up.

BACKGROUND: Long-term follow-up data regarding treatment outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma as a first-line therapy are limited in real-world Japanese populations. METHODS: We retrospectively evaluated data of 56 advanced renal cell carcinoma patients treated with nivolumab plus ipilimumab, with a follow-up of at least 3 years. Survival, tumour response and adverse event profiles were assessed. RESULTS: A total of 41 patients (73%) were histopathologically diagnosed with clear-cell renal cell carcinoma, and 34 (61%) were categorized into the International Metastatic renal cell carcinoma Database Consortium intermediate-risk group. The median follow-up period was 34.4 months. Regarding an effectiveness profile, median progression-free survival, time to treatment failure and overall survival were 9.01, 12.5 and 49.0 months, respectively. Objective response was observed in 27 patients (48%), including eight patients with complete response (14%), and the median duration of response was 30.8 months. Multivariate analyses showed that clear-cell histology was an independent factor of longer overall survival (hazard ratio: 0.23, P = 0.0013). Regarding safety profiles, adverse events of any grade and those with grade ≥3 developed in 40 (71%) and 25 patients (45%), respectively. Median time to adverse event development was 1.68 months. Treatment was interrupted in 28 patients (50%), and corticosteroid administration was needed in 25 (45%). CONCLUSION: The 3-year follow-up data showed that nivolumab plus ipilimumab combination therapy exhibited a feasible effectiveness in real-world Japanese patients with advanced renal cell carcinoma. Accordingly, the high risk of adverse event development, which often requires treatment withdrawal and corticosteroid administration, should be considered.

Dual-MEG interbrain synchronization during turn-taking verbal interactions between mothers and children.

Verbal interaction and imitation are essential for language learning and development in young children. However, it is unclear how mother-child dyads synchronize oscillatory neural activity at the cortical level in turn-based speech interactions. Our study investigated interbrain synchrony in mother-child pairs during a turn-taking paradigm of verbal imitation. A dual-MEG (magnetoencephalography) setup was used to measure brain activity from interactive mother-child pairs simultaneously. Interpersonal neural synchronization was compared between socially interactive and noninteractive tasks (passive listening to pure tones). Interbrain networks showed increased synchronization during the socially interactive compared to noninteractive conditions in the theta and alpha bands. Enhanced interpersonal brain synchrony was observed in the right angular gyrus, right triangular, and left opercular parts of the inferior frontal gyrus. Moreover, these parietal and frontal regions appear to be the cortical hubs exhibiting a high number of interbrain connections. These cortical areas could serve as a neural marker for the interactive component in verbal social communication. The present study is the first to investigate mother-child interbrain neural synchronization during verbal social interactions using a dual-MEG setup. Our results advance our understanding of turn-taking during verbal interaction between mother-child dyads and suggest a role for social "gating" in language learning.

Changes in outcome of patients with advanced non-clear cell renal cell carcinoma from the tyrosine kinase inhibitor era to the immuno-oncology era.

BACKGROUND: The therapeutic benefit of immuno-oncology (IO) therapy for patients with advanced non-clear-cell renal cell carcinoma (nccRCC) remains unclear. PATIENTS AND METHODS: We reviewed clinical data from 93 patients with advanced nccRCC who received first-line systemic therapy including IO combination therapy and tyrosine kinase inhibitor (TKI) monotherapy at our affiliated institutions. Patients were divided based on the period when the treatment was implemented as the standard of care into the IO and TKI eras. Survival and tumor response outcomes were compared between the IO and TKI eras. RESULTS: Of the 93 patients, 50 (54%) and 43 (46%) were categorized as IO era and TKI era groups, respectively. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the IO era than in the TKI era (median PFS: 8.97 vs. 4.96 months, p = 0.0152; median OS: 38.4 vs. 13.5 months, p = 0.0001). After the adjustment using other covariates, the treatment era was an independent factor for PFS (hazard ratio: 0.59, p = 0.0235) and OS (hazard ratio: 0.27, p < 0.0001). Objective response and disease control rates was not significantly different between the treatment eras (26% vs. 16.3%, p = 0.268; 62% vs. 62.8%, p = 0.594). CONCLUSION: The implementation of IO therapy was significantly associated with longer survival in the nccRCC population. Further studies are needed to establish a more effective treatment strategy in this population using multiple regimens of IO combination therapy.

First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data.

BACKGROUND: There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. METHODS: We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. RESULTS: Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). CONCLUSION: IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.

Renal cell carcinoma outcomes in end-stage renal disease: A 40-year study from two Japanese institutions.

OBJECTIVES: The objective of the study was to analyze the outcomes of patients with renal cell carcinoma (RCC) arising in end-stage renal disease (ESRD) over a 40-year span. METHODS: We retrospectively evaluated data of patients with ESRD-RCC diagnosed between 1979 and 2020 at two institutions. We assessed changes in stage, surgical approaches, and cancer-specific survival (CSS) following nephrectomy according to era between ESRD-RCC and sporadic RCC. Furthermore, perioperative outcomes in patients with ESRD-RCC were compared between laparoscopic and open surgery. RESULTS: Patients with ESRD-RCC (n = 549) were diagnosed at an earlier stage (p = 0.0276), and the ratio of laparoscopic nephrectomy was increased (p < 0.0001) according to eras. Since 2000 (i.e., after implementation of laparoscopic nephrectomy), patients with ESRD-RCC (n = 305) had significantly shorter CSS (p = 0.0063) after nephrectomy than sporadic RCC (n = 2732). After adjustment by multivariate analysis and propensity score matching, ESRD status was independently associated with shorter CSS (p = 0.0055 and p = 0.0473, respectively). Improved CSS in sporadic RCC (p < 0.0001), but not ESRD-RCC (p = 0.904), according to era contributed to this difference. Laparoscopic nephrectomy showed favorable outcomes, including shorter surgery time, lower estimated bleeding volumes, transfusion rates, and readmission rates, and shorter postoperative hospitalization than open nephrectomy (p < 0.05). CONCLUSIONS: Advances in diagnostic and treatment modalities potentially enable early diagnosis and minimally invasive surgery for patients with ESRD-RCC. As ESRD-RCC may not present indolently, careful post-operative monitoring is needed.

Visual working memory resolution defined by figural complexity in kindergarten children.

Visual working memory (VWM) allows us to store and manipulate incoming visual information briefly. Information acquisition (i.e., encoding) accuracy is critical for VWM to function properly. The accuracy of very young children's VWM encoding has not been explained adequately in previous studies. Therefore, this study clarified it by manipulating the complexity of the visual stimuli and examining kindergarten children's performance in a recognition task. Furthermore, we examined the relationship between encoding accuracy and the 4- to 6-year-old children's individual traits in a subanalysis, as individual traits (such as IQ and attention to detail-a trait of autism spectrum disorder) reportedly affect VWM capacity. The results revealed that distinguishing between target and probe stimuli becomes more difficult as stimulus and discrimination complexity increase. In addition, this study results in narrow attention (attention to detail) that could contribute to VWM capacity saving if VWM capacity is sufficient. However, if the VWM's capacity is exceeded, the relationship with IQ, such as the simultaneous processing score, is strengthened. This study clarified the degree of accuracy of information retained by preschool children aged 4 to 6 years. In addition to providing basic knowledge about VWM, we believe the findings can be useful in education and other fields.

Impact of GVHD on lymphoma progression: Nationwide study from Japanese Society for Transplantation and Cellular Therapy.

The graft-versus-lymphoma (GVL) effect and its association with acute and chronic GVHD (aGVHD, cGVHD) has not been comprehensively elucidated. We retrospectively analysed 2204 Japanese patients with non-Hodgkin lymphomas (NHLs; indolent B-NHLs, n = 689; aggressive B-NHLs, n = 720; mature T/NK-NHLs, n = 795) receiving a first allo-HSCT in 2003-2017. Pre-transplant lymphoma control showed complete response (CR) in 759 and non-CR in 1445. We assessed the impact of aGVHD/cGVHD on lymphoma progression and other outcomes. Although aGVHD/cGVHD showed no statistical impact on lymphoma progression in the overall cohort, their impact was clear in certain groups: Grade I-II aGVHD in CR patients (HR, 0.63; 95% CI, 0.43-0.91), especially in mature T/NK-NHL (HR, 0.46; 95% CI, 0.26-0.83) and extensive cGVHD in patients with mature aggressive B-NHLs (HR, 0.55; 95% CI, 0.31-0.97). In total, limited cGVHD was associated with superior survivals (progression-free survival: HR, 0.71; 95% CI, 0.56-0.90), whereas severe GVHDs showed negative impacts on them. Our results support the presence of GVL effects differentially associated with GVHD in different lymphoma subtypes/controls. Meanwhile, it was also suggested that we should manage GVHDs within a limited activity, considering the negative impact of severe GVHDs. As pre-transplant lymphoma control remains a strong factor influencing transplant outcomes, improving its management is an important issue to be addressed.

Relapsed and refractory multiple myeloma: A systematic review and network meta-analysis of the efficacy of novel therapies.

The prognosis of multiple myeloma (MM) has dramatically improved with the development of new drugs, and it has become important to determine the appropriate combinations of these novel agents. This study was a systematic review and network meta-analysis (NMA) of randomized trials in patients with relapsed and/or refractory (RR) MM. The PubMed, Cochrane, and Embase databases were searched for randomized trials from 1 January 2002 to 28 February 2022 of patients treated for MM. The primary end-point was progression-free survival (PFS), evaluated as a hazard ratio (HR) with a 95% confidence interval (95% CI) compared to dexamethasone (DEX). The p-score was used to rank treatments. Of a total of 1136 abstracts screened, 37 studies were selected, including 34 treatment options for RRMM. Daratumumab, lenalidomide and DEX was found to be the best treatment for RRMM, with the best HR compared to DEX (HR, 0.13; 95% CI, 0.08-0.20; p-score 0.9796). There was no evidence of significant heterogeneity (I2 , 41.3%; p = 0.146). The current NMA confirmed the excellent efficacy of three-drug regimens including anti-CD38 antibodies to treat RRMM and provides background data to evaluate the efficacy of chimeric antigen receptor T-cell treatments and bispecific T-cell engager therapies.

Anti-CD38 antibody isatuximab monotherapy for Japanese individuals with relapsed/refractory multiple myeloma: An update of the phase 1/2 ISLANDs study.

The primary analysis of the phase 1/2 ISLANDs study in Japanese individuals with relapsed/refractory multiple myeloma (RRMM) showed that isatuximab monotherapy was well tolerated and effective, even in participants with high-risk cytogenetic abnormalities. Here, we report a prespecified second analysis conducted 20 months after the first dosing of the last participant (ClinicalTrials.gov identifier: NCT02812706). The primary objectives were to evaluate the safety and tolerability of isatuximab in phase 1 and to evaluate the efficacy of isatuximab, including assessment of overall response rate (ORR) at the recommended dose (RD), in phase 2. In phase 1, three participants received isatuximab 10 mg/kg every week (QW) for 4 weeks/cycle followed by every 2 weeks (Q2W) and five participants received 20 mg/kg QW/Q2W. Since no dose-limiting toxicities occurred in phase 1, 20 mg/kg QW/Q2W was identified as the RD for the phase 2 study (n = 28). At the time of data cut-off, three participants (one in phase 1 and two in phase 2) continued to receive isatuximab; disease progression and treatment-related adverse events were the most common reasons for treatment discontinuation. The overall safety profile was consistent with the primary analysis. One death, not related to isatuximab treatment, was reported since the first analysis. The ORR and clinical benefit rate remained unchanged from the primary analysis at 36.4% (95% confidence interval [CI]: 20.4%-54.9%) and 54.5% (95% CI: 36.4%-71.9%), respectively. The median progression-free survival (PFS) was 5.6 months, longer than the median PFS reported in the primary analysis (4.7 months), whereas median overall survival was not reached. Overall, isatuximab 20 mg/kg QW/Q2W had an acceptable safety and tolerability profile and showed promising antitumor activity in Japanese individuals with RRMM.

Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan.

Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1 mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1 year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).

Early reversal of the lymphocyte-to-monocyte ratio after allogeneic-hematopoietic stem cell transplantation is associated with reduced relapse and improved prognosis.

BACKGROUND: The early recovery of lymphocyte and monocyte cells is associated with a favorable prognosis after allogeneic stem cell transplantation (allo-HSCT); however, it is not clear whether the balance of lymphocyte and monocyte recovery affects the post-transplant prognosis. METHODS: We examined whether the time-point at which the number of lymphocytes exceeded the number of monocytes, which we termed lymphocyte-to-monocyte ratio reversal (LMRR), affected the prognosis after allo-HSCT. We retrospectively evaluated 235 patients who underwent their first allo-HSCT at our institution. RESULTS: The median number of days from HSCT to LMRR was 46 (range, 0-214), and the patients were divided into two groups according to the occurrence of LMRR by day 45 (LMRR45). In a multivariate analysis, early LMRR contributed favorably to overall survival (hazard ratio [HR] .519; 95% confidence interval [CI] .332-.812; p = .004) with fewer post-transplant relapses (HR .462; 95% CI, .274-.777; p = .004). Differences in the timing of LMRR did not affect non-relapse mortality (HR 1.477; 95% CI .779-2.80; p = .23) or the incidence of grade II-IV acute GVHD (LMRR45(+): 25.0% vs. LMRR45(-) 35.2%. p = .111). In subgroup analyses, LMRR45(+) was found to be a favorable factor for survival with less relapse, regardless of the disease risk, stem cell source, or the recovery of either lymphocyte or monocyte counts. CONCLUSIONS: An early LMRR may be a novel factor that is associated with reduced relapse and improved survival after allo-HSCT.

Headache education by leaflet distribution during COVID-19 vaccination and school-based on-demand e-learning: Itoigawa Geopark Headache Awareness Campaign.

OBJECTIVE: We prospectively performed the Itoigawa Headache Awareness Campaign from August 2021 to June 2022, with two main interventions, and evaluated its effectiveness. BACKGROUND: Headache is a common public health problem, but its burden could be reduced by raising awareness about headache and the appropriate use of acute and prophylactic medication. However, few studies on raising headache awareness in the general public have been reported. METHODS: The target group was the general public aged 15-64. We performed two main interventions synergistically supported by other small interventions. Intervention 1 included leaflet distribution and a paper-based questionnaire about headache during COVID-19 vaccination, and intervention 2 included on-demand e-learning and online survey through schools. In these interventions, we emphasize the six important topics for the general public that were described in the Clinical Practice Guideline for Headache Disorders 2021. Each response among the two interventions' cohorts was collected on pre and post occasions. The awareness of the six topics before and after the campaign was evaluated. RESULTS: We obtained 4016 valid responses from 6382 individuals who underwent vaccination in intervention 1 and 2577 from 594 students and 1983 parents in intervention 2; thus, 6593 of 20,458 (32.2%) of the overall working-age population in Itoigawa city experienced these interventions. The percentage of individuals' aware of the six topics significantly increased after the two main interventions ranging from 6.6% (39/594)-40.0% (1606/4016) to 64.1% (381/594)-92.6% (1836/1983) (p < 0.001, all). CONCLUSIONS: We conducted this campaign through two main interventions with an improved percentage of individuals who know about headache. The two methods of community-based interventions could raise headache awareness effectively. Furthermore, we can achieve outstanding results by doing something to raise disease awareness during mass vaccination, when almost all residents gather in a certain place, and school-based e-learning without face-to-face instruction due to the COVID-19 pandemic.