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Background In the phase 2 KarMMa trial, patients with relapsed/refractory multiple myeloma (RRMM) achieved deep and durable responses with idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T cell therapy. Here we report a sub-analysis of the Japanese cohort of KarMMa. Methods Adult patients with RRMM who had received ≥ 3 prior treatment regimens, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, and had disease refractory to last treatment received ide-cel at a target dose of 450 × 106 CAR positive T cells. Results Nine patients were treated with ide-cel. The overall response rate was 89% (median follow-up, 12.9 months). The best overall response was stringent complete response in 5 patients (56%), very good partial response in 3 (33%), and stable disease in 1. Median duration of response was not reached. All patients experienced grade ≤ 2 cytokine release syndrome and one patient experienced grade 2 neurotoxicity, but all resolved. Two patients died, one each from plasma cell myeloma and general health deterioration. Conclusion Ide-cel yielded deep, durable responses with a tolerable and predictable safety profile in Japanese patients with RRMM. These results are similar to those of the non-Japanese population in KarMMa.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising treatment for adult acute lymphoblastic leukemia (ALL), an intractable hematological malignancy. The trends in allo-HCT outcomes over the past 30 years were examined to verify the efficacy of evolving treatment methods and to identify further challenges. We analyzed data from a registry database that included 8467 adult ALL patients who underwent their first allo-HCT between 1990 and 2019. The period was divided into three 10-year intervals for analysis. Five-year overall survival improved from 48.2% to 70.2% in the first complete remission (CR1), from 25.6% to 44.1% in subsequent CR, and from 10.0% to 22.7% in non-CR. Nonrelapse mortality improved over the 3 decades in each disease stage. However, the relapse rate only improved in CR1 every decade (26.3% to 15.9% in CR1, 33.4% to 32.8% in subsequent CR, and 53.6% to 54.8% in non-CR). Although there were continual improvements in adjusted survival for Philadelphia chromosome (Ph)-positive patients, the improvement was inadequate for Ph− patients with t(4;11), t(8;14), t(14;18), or hypodiploidy. Allo-HCT outcomes for adults with ALL have improved over the past 30 years. Improved outcomes in the future will require more effective prevention of relapse in patients with ALL not in CR1 and in those with high-risk chromosomal abnormalities.

Human leukocyte antigen (HLA)-matched sibling donors (MSDs) are the preferred choice for allogeneic hematopoietic cell transplantation (HCT). However, as myelodysplastic syndrome (MDS) is most frequently diagnosed in the elderly, MSDs are also likely to be of advanced age. It is unclear whether an MSD should be considered the primary choice for allogeneic HCT in elderly patients with MDS. We retrospectively compared survival and other outcomes in 1787 patients with MDS over 50 years of age and receiving allogeneic HCT between 2014 and 2020, using either MSD (n = 214), 8/8 allele-matched unrelated donor (MUD) (n = 562), 7/8 allele-MUD (n = 334), or unrelated cord blood (UCB) (n = 677) in Japan. In multivariate analysis, compared to MSD transplants, the risk of relapse was significantly lower following 8/8MUD transplants (hazard ratio [HR], 0.74; P = 0.047), whereas non-relapse mortality was significantly higher following UCB transplants (HR, 1.43; P = 0.041). However, donor type did not determine overall survival, disease-free survival, or graft-versus-host disease (GVHD)-free, relapse-free survival, but chronic GVHD-free, relapse-free survival was better after UCB (HR, 0.80; P = 0.025) and 8/8MUD (HR, 0.81; P = 0.032) compared to MSD transplants. Our study demonstrated that MSDs are not superior to alternative HCT methods, such as 8/8MUD, 7/8MUD, or UCB, in this population.

The introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment has dramatically improved the prognosis of CML patients and reduced the number of patients receiving allogeneic stem cell transplantation (allo-SCT). However, the impact of the newest-generation TKIs on the overall survival (OS) after allo-SCT has not been well described. To investigate the beneficial effects of TKIs on the prognosis after allo-SCT, we conducted a retrospective observational study using the Transplant Registry Unified Management Program database in Japan. We analyzed 1188 patients (male/female: 738/450; median age: 44 years; range: 16-75) who underwent their first allo-SCT between January 2001 and December 2018. We divided the patients into two groups according to the TKI treatment used before allo-SCT: group 1 was treated with the first generation TKI imatinib; group 2 was treated with the second generation TKIs nilotinib, dasatinib, or bosutinib and/or the third generation TKI ponatinib. We compared the post allo-SCT OS between the two groups. The 3-year OS rates (95%CI) of groups 1 and 2 were 59.3% (54.8%-63.5%) and 65.8% (61.6%-69.6%), respectively (p = 0.017). Multivariate analysis confirmed that group 2 had superior OS after allo-SCT compared to group 1 (p = 0.002). Other factors associated with superior prognosis were age ≤65, performance status (PS) 0/1, a 6/6 HLA-matched donor and chronic-phase (CP) disease status at allo-SCT. A subgroup analysis showed poor prognoses for patients who could not obtain a molecular response before allo-SCT and patients with positive T315I mutation in the BCR/ABL gene. In group 2, early allo-SCT was correlated with superior OS in patients with a blast-crisis disease status at allo-SCT (p = 0.001). The cumulative incidence of non-relapse mortality rate significantly decreased in group 2 (p = 0.0005). The post allo-SCT OS was improved both by pre- and post-management of allo-SCT and by the introduction of newer TKIs.

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, and some high-risk patients with ALL require hematopoietic stem cell transplantation (HSCT). Mainly due to small patient numbers, studies focusing specifically on children and adolescents with T-cell ALL (T-ALL) are limited. Using a nationwide registry, we retrospectively analyzed data from patients under 20 years old who underwent their first HSCT for T-ALL between 2000 and 2018. As a result, total 484 patients were included, and their median follow-up period was 6.9 years after HSCT for survivors. While patients receiving HSCT at first complete remission (CR) showed relatively good 5-year leukemia free survival (5yLFS, 73.5%), once relapse occurred, their prognosis was much worse (44.4%) even if they attained second remission again (p 0.001). Among patients receiving HSCT at CR1, grade II-IV acute graft versus host disease was associated with worse overall and LFS than grade 0-I (5yLFS 69.5% vs. 82.1%, p = 0.026) mainly due to high non-relapse mortality. Among those patients, patients receiving related bone marrow transplantation, unrelated bone marrow transplantation, or unrelated cord blood transplantation showed similar survival (5yLFS, 73.2%, 76.3%, and 77.0%, respectively). For patients undergoing cord blood transplantation at CR1, total-body irradiation-based myeloablative conditioning was associated with better 5yLFS than other conditioning regimens (85.4% vs. 62.2%, p = 0.044), as it reduced the risk of relapse. These results indicate that relapsed patients have much less chance of cure, and that identifying patients who require HSCT for cure and offering them HSCT with optimal settings during CR1 are crucial for children and adolescents with T-ALL.

Os estados de emergências na saúde pública têm um impacto sobre a saúde mental da população. O surto do novo coronavírus (COVID-19) afetou o mundo todo de forma psicológica, economica, educacional e política. O objetivo deste estudo foi relatar questões que envolvem os impactos psicológicos nos cirugiões dentistas em contextos pessoais, familiares, financeiros e profissionais, de modo a compreender a nova realidade durante a pandemia da COVID-19. A revisão abrangeu toda a literatura até agosto de 2021; sendo incluídos estudos mais relevantes. Com base na revisão da literatura, pode-se concluir que o profissional da odontologia teve grande impacto na vida pessoal e profissional, sendo abalados emocionalmente desde o início da pandemia até os dias atuais. A resiliência, o autocuidado e a interação com profissional da mesma área é fundamental neste momento para que o dentista estabeleça estratégias e permaneça atuante nos atendimentos odontológicos de seus pacientes. O aconselhamento psicológico profissional lhe dará a liberdade de expor suas angústias, medos e preocupações em meio à pandemia que o mundo está vivendo.

Table S1. Primer sequences Table S2. Patient characteristics in cell - surface SLAMF3 and CD138 expression analysis. Table S3. One hundred and sixty-eight gene sets that were significantly upregulated in SLAMF3-KMS34 cells compared with Î"SLAMF3 cells (NOM P-value

Cytomegalovirus reactivation (CMVR) after allogeneic hematopoietic cell transplantation (HCT) is a frequent complication related to survival outcomes, but the impact of CMVR on relapse is still unclear, especially in acute lymphoblastic leukemia (ALL). In this nationwide retrospective study, we included patients with acute myeloid leukemia (AML) and ALL in first or second complete remission who underwent their first HCT using pre-emptive strategy for CMVR. Because ninety percent of cases with CMVR had occurred by day 64 and ninety percent of cases with grades II to IV acute GVHD had occurred by day 58, a landmark point was set at day 65. In the landmark analyses, 3793 patients with AML and 2213 patients with ALL who survived without relapse for at least 65 days were analyzed. In the multivariate analyses, CMVR was associated with a lower incidence of relapse in both AML (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.69-0.95; P = 0.009) and ALL (HR, 0.81; 95% CI, 0.66-0.99; P = 0.045). These findings were confirmed when we treated CMVR as a time-dependent covariate. Moreover, our study suggested that the protective effect of CMVR on relapse was independent of acute GVHD. A post-hoc subgroup analysis that combined AML and ALL showed that CMVR had a mild anti-leukemia effect without effect modification in contrast to the impact of CMVR on NRM. Our findings may provide important implications for the strategy used for CMV prophylaxis after HCT.

To evaluate the long-term efficacy of high-dose dexamethasone (HD-DXM) treatment for immune thrombocytopenia (ITP), we retrospectively analysed 36 newly diagnosed ITP patients treated with HD-DXM as a first-line treatment. An initial response was obtained in 23 (63.9%) patients, including 11 with a complete response (CR) and 12 with a partial response (PR). Six months after HD-DXM treatment, 26 of 33 (78.8%) evaluable patients achieved objective responses, including 18 CR and 8 PR. Among 13 patients without initial response, very early increased platelet count within a week (VEIP) was observed in 7 patients, 5 (71.4%) of whom achieved a response at 6 months. In 29 patients who had available platelet count within a week, patients showing VEIP revealed longer survival than those who did not (p = 0.026). HD-DXM was an effective treatment for newly diagnosed ITP patients. VEIP after HD-DXM treatment initiation was associated with a long-term objective response in newly diagnosed ITP patients.

We herein report two cases of thrombotic thrombocytopenic purpura (TTP) complicated by other autoimmune disorders, autoimmune hepatitis and immune thrombocytopenia, respectively. In both cases, corticosteroids were continuously administered for the treatment of preceding autoimmune disorders. However, a sufficient objective response for TTP was not obtained by plasma exchange and corticosteroid treatment. Once a week rituximab (375 mg/m2) treatment for 4 times was initiated within 2 weeks from the diagnosis. Both patients achieved a sufficient response, and have never had any recurrence as of the last follow-up dates. The early introduction of rituximab could be an effective treatment option in TTP patients complicated with other autoimmune disorders.

Cellular therapies for malignant lymphoma include autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and adaptive cellular therapy using EBV-specific T cells, cytokine-induced killer (CIK) cells, NKT cells, NK cells, chimeric antigen receptor T (CAR-T) cells and chimeric antigen receptor NK (CAR-NK) cells. In this review we discusses recent advances of these cellular therapies and consider ways to optimize these therapies. Not only a single strategy using one of these cellular therapies, but also multi-disciplinary treatment combines with antibodies, such as an anti-tumor antibody and an immune checkpoint antibody, may be more effective for relapsed and refractory lymphoma.

Transplant recipients (TRs) are at high risk for severe coronavirus disease 2019 (COVID-19). Neutralizing monoclonal antibodies (mAbs) are used for treating mild-to-moderate COVID-19. However, reports comparing the efficacy of COVID-19 treatment without/with mAbs in TRs are limited. We assessed the efficacy of casirivimab/imdevimab against mild-to-moderate COVID-19 in TRs.Forty-one patients were retrospectively evaluated. The duration until defervescence, oxygen (OCasirivimab/imdevimab was correlated with shorter duration until defervescence and non-requirement of OCasirivimab/imdevimab was effective and increased the neutralizing antibody in TRs with mild-to-moderate COVID-19, it may contribute toward preventing the progression.

Multiple myeloma (MM) is an incurable hematological malignancy. Despite the introduction of several novel drugs, most patients relapse. Biomarkers to identify the early signs of relapse will make it possible to adjust the therapeutic strategy before the disease worsens. Although understanding genetic changes is important for the treatment of MM, currently known biomarkers of relapse, including serum free-light chains and monoclonal paraproteins, are not associated with genetic changes. We therefore performed a multicenter study to examine the usefulness of circulating cell-free DNA (cfDNA) present in the peripheral blood (PB) plasma of patients as a biomarker for MM relapse. We identified several driver mutations by combined analysis of next-generation sequencing and existing databases of candidate oncogenes. Furthermore, relapse was detected more sensitively by monitoring the circulating cfDNA with these driver mutations than by conventional serum free-light chain examination. These results suggest the potential utility of cfDNA in the PB plasma of patients as a relevant early biomarker for MM relapse.

The alkylating agent busulfan is commonly used as conditioning in allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). However, a consensus has not yet been reached regarding the optimal busulfan dose in cord blood transplantation (CBT). Therefore, we conducted this large nationwide cohort study to retrospectively analyze the outcomes of CBT in patients with AML receiving busulfan at intermediate (6.4 mg/kg i.v.; BU2) or higher (12.8 mg/kg i.v.; BU4) doses within a fludarabine/i.v. busulfan (FLU/BU) regimen. Among 475 patients who underwent their first CBT following FLU/BU conditioning between 2007 and 2018, 162 received BU2 and 313 received BU4. Multivariate analysis identified BU4 as a significant factor for longer disease-free survival (hazard ratio [HR], .85; 95% confidence interval [CI], .75 to .97; P = .014) and a lower relapse rate (HR, .84; 95% CI, .72 to .98; P = .030). No significant differences were observed in non-relapse mortality between BU4 and BU2 (HR, 1.05; 95% CI, .88-1.26; P = .57). Subgroup analyses showed that BU4 provided significant benefits for patients who underwent transplantation while not in complete remission (CR) and those age

Adult T cell leukemia-lymphoma (ATL) is clinically heterogeneous and is classified into four subtypes: acute, lymphoma, chronic, and smoldering. Recently, a new prognostic index based on the value of soluble interleukin-2 receptor, denoted the "iATL-PI," has been proposed for patients with smoldering and chronic ATL. To evaluate the effectiveness of the iATL-PI, we re-analyzed our previously published data on 176 patients with smoldering or chronic ATL (76 smoldering, 100 chronic) diagnosed between 2010 and 2011, as well data from the subsequent follow-up study on prognosis between 2016 and 2017. The proportions for the low-, intermediate-, and high-risk iATL-PI groups at the time of ATL diagnosis were 44.7%, 48.7%, and 5% for smoldering ATL; 6.3%, 71.9%, and 21.9% for favorable chronic ATL; and 5.9%, 27.9%, and 66.2% for unfavorable chronic ATL, respectively. The survival of patients with smoldering or chronic ATL as a whole was significantly stratified according to the three iATL-PI groups. Most patients with unfavorable chronic ATL in the low iATL-PI risk group had indolent clinical courses. Our results showed that iATL may become a useful tool to predict the prognosis of smoldering and chronic ATL, which have diverse clinical courses.

Adult T‐cell leukemia/lymphoma (ATL) is a mature T‐cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983‐1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010‐2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow‐up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016‐2017. Of 770 evaluable patients, 391 (50.8%) had acute‐type, 192 (24.9%) had lymphoma‐type, 106 (13.8%) had chronic‐type, and 81 (10.5%) had smoldering‐type ATL. The initial therapy regimens used for acute/lymphoma‐type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP‐AMP‐VECP)‐like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)‐like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma‐type ATL patients. The 4‐year survival rates (the median survival time, days) for acute‐, lymphoma‐, unfavorable chronic‐, favorable chronic‐, and smoldering‐type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4‐year survival rates for acute‐ and lymphoma‐type ATL improved compared with those reported in 1991, but those for chronic‐ and smoldering‐type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan., The survival curve shows that the prognoses of patients with acute and lymphoma‐type ATL in Japan have improved modestly, but those of patients with chronic and smoldering‐type ATL have not improved.

Although treatment outcomes for diffuse large B cell lymphoma (DLBCL) have improved with the introduction of rituximab, approximately half of patients experience relapsed/refractory (r/r) disease. Furthermore, no standard salvage therapy has yet been established to date, while limitations in treatment options exist due to toxicity and restricted tolerability among elderly patients and/or those with comorbidities. The ICE (ifosfamide, cyclophosphamide, and etoposide) regimen is often used as salvage therapy for r/r DLBCL. Several modified ICE regimens not requiring continuous ifosfamide infusion are available, which can be used in outpatient clinics. This study analyzed the efficacy and toxicity of fractionated ICE with rituximab (f-R-ICE) as a salvage regimen among 47 patients with relapsed/refractory DLBCL (median age upon f-R-ICE initiation, 71 years). The whole cohort had an overall (ORR) and complete response rate of 53.1% (n = 25) and 25.5% (n = 12), respectively, and an estimated 1-year overall survival after f-R-ICE initiation of 57%. Comorbidities were evaluated using the Charlson Comorbidity Index (CCI) upon f-R-ICE initiation. Patients with low CCI scores (68%) had a higher ORR than those with high CCI scores (36.4%) upon f-R-ICE initiation (P = 0.042). In contrast, no significant differences in overall survival (OS) were observed between the low and high CCI groups (1-year OS 56.6% vs. 52.2%; median OS 24 vs. 22.8 months) after initiating f-R-ICE. Our results suggest that f-R-ICE is a safe and effective salvage therapy for r/r DLBCL and can be used for older patients and/or those with high CCI scores in outpatient clinics.

The primary aim of this randomized in vitro study was to compare the effectiveness of carbide, fibreglass and polymer burs on resinous remnant removal after bracket debonding, by the evaluation of enamel surface roughness and morphology. The secondary objective was to compare the time dispended on the procedures.The buccal surfaces of 28 bovine incisors were analysed by a profilometer to initial roughness measurement (Ra-T1). Brackets were bonded with a light-cured resin and debonded with a debonding plier. The samples were randomly divided into four groups, according to the bur used (n=7): A-Tungsten carbide; B-Fibreglass; C-Polymer; D-Polymer with 75% ethanol pre-treatment. The second roughness measurements were made after resin removal (Ra-T2). Time for removal procedures was also recorded. The third measurements were made after polishing (Ra-T3). Scanning Electronic Microscopy was performed in two samples of each group: after resin removal and after polishing. Results of roughness and time measurements were statically analysed by analysis of variance with post-hoc Bonferroni.After polishing, tungsten carbide (P=0.1555) and fibreglass burs provided final surface roughness statistically similar to the baseline condition (P=1.0000). Yet, polymer burs, associated (P0.0001) or not to alcohol (P0.0001), provided surface roughness significantly higher when compared to baseline values. Polymer burs were more time-consuming on resinous remnant removal than tungsten carbide and fibreglass burs (P0.05).Polymer burs were less effective and more time-consuming to remove the remaining resin than tungsten carbide and fibreglass burs. The polishing step created smoother surfaces regardless of the burs used for resin removal.

It remains unclear whether the HLA haplotype of unrelated cord blood (UCB) should be matched to that of the patient in single UCB transplantation. Thus, using data from a Japanese registry, we analyzed the effect of haplotype matching on outcomes. Patients with hematologic diseases aged 16 years or older who had undergone their first transplant were included (N = 1347). The effects of haplotype matching and high-frequency HLA haplotype on outcomes were analyzed. Median patient age was 55 years. The cumulative incidences of neutrophil engraftment among groups with 0, 1, and 2 HLA haplotype matches were 79%, 82%, and 88%, respectively (P = .008). In a multivariate analysis, the group with 0 haplotype matches was marginally associated with worse neutrophil engraftment (P = .087) and significantly associated with platelet engraftment (P = .044) compared with the group with 1 haplotype match. Two-haplotype matches were associated with a higher risk of relapse. In the group with 1 haplotype match, the top 3 shared haplotypes were "A*24:02-B*52:01-C*12:02-DRB1*15:02" (HP-P1), "A*33:03-B*44:03-C*14:03-DRB1*13:02" (HP-P2), and "A*24:02-B*07:02-C*07:02-DRB1*01:01" (HP-P3). The presence of HP-P2 but not HP-P1 or HP-P3 was associated with a decreased risk of grades II to IV acute graft-versus-host disease (hazard ratio, .56; P = .001) but an increased risk of relapse (hazard ratio, 1.35; P = .045). HLA haplotype matching might be considered to improve engraftment. Two-haplotype matches should be avoided if the relapse risk is high. The haplotype itself may have an effect on the risk of acute graft-versus-host disease and relapse.

There are few reports on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia (B-ALL) harboring t(1;19)(q23;p13.3). We used nationwide registry data of Japan for 2003–2016 to evaluate transplant outcomes and clarified prognostic factors among adult allo-HSCT recipients with B-ALL harboring t(1;19)(q23;p13.3) (n = 125). Compared with cytogenetically normal (CN) B-ALL patients (n = 1057), their 3-year overall survival (OS) rates were comparable (55.4% for t(1;19) and 54.4% for CN; P = 0.76). Considering only patients in first complete hematological remission (CR1), the 3-year OS rates remained comparable (70.5% for t(1;19) and 67.8% for CN; P = 0.86). For t(1;19) patients in CR1, minimal residual disease (MRD) at transplantation was associated with relatively worse outcomes. The 3-year OS rates were 43.6% for patients with MRD and 77.4% for those without it (P = 0.016). The 3-year relapse rates were 54.5% for patients with MRD and 12.8% for those without it (P

Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered to be indicated for children and adolescents with high-risk or relapsed T-cell acute lymphoblastic leukemia (T-ALL); however, the outcomes are unsatisfactory. Killer cell immunoglobulin-like receptors (KIRs) are the main receptors on natural killer (NK) cells that play an important role in the graft-versus-leukemia effect after allo-HSCT. In allo-HSCT, when the recipient lacks a donor KIR-ligand (KIR-ligand mismatch in the graft-versus-host [GVH] direction), donor NK cells will be activated against recipient cells. KIR-ligand mismatch in the GVH direction improves outcomes after unrelated cord blood transplantation (UCBT) with acute myeloid leukemia, but the effect in T-ALL is unclear. We evaluated the impact of KIR-ligand mismatch in the GVH direction on the transplantation outcomes of children and adolescents with T-ALL who received UCBT. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients diagnosed with T-ALL, aged 0 to 19 years, and who underwent first UCBT between 1999 and 2017 were included. A total of 91 patients were included in this study. In all, 23 (25.3%) percent of patients had KIR-ligand mismatch in the GVH direction. The 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 65.8% and 69.6%, respectively. In a multivariate analysis, KIR-ligand mismatch in the GVH direction was associated with a significant reduction in the relapse rate (hazard ratio [HR], 0.19; P = .002), resulting in better LFS (HR, 0.18; P =.010) and OS (HR, 0.26; P = .048) without increasing non-relapse mortality (NRM; HR, 1.90; P = .264). The cumulative incidence of GVH disease (GVHD) did not differ between patients with and without KIR-ligand mismatch (grade II-IV acute GVHD, 39.1% versus 36.8%, P = .648, grade III-IV acute GVHD, 13.0% versus 11.8%, P =.857, and chronic GVHD, 26.1% versus 22.9%, P =.736, respectively). Furthermore, acute and chronic GVHD were not associated with good patient outcomes. Notably, no relapse was observed in patients who received KIR-ligand mismatched UCBT in complete remission. KIR-ligand mismatch in the GVH direction improved LFS and decreased relapse rates without increasing NRM in children and adolescents with T-ALL who received UCBT, which was not mediated by GVHD.

Background: Solid organ transplant recipients (SOTRs) are at high risk for severe coronavirus disease 2019 (COVID-19) due to comorbidities and immunosuppression. Moreover, the treatment for COVID-19 is limited. Neutralizing monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 are used for treating mild-to-moderate COVID-19. However, reports comparing the efficacy of COVID-19 treatment with and without neutralizing mAbs in SOTRs are limited. Here, we assessed the efficacy of casirivimab/imdevimab as neutralizing mAbs against mild-to-moderate COVID-19 in SOTRs. Methods: Forty-one patients hospitalized from September 2020 to September 2021 at Tokyo Women’s Medical University Hospital were included. The duration until antifebrile and of hospitalization, requirement of oxygen (O2) ≥ 5 L, and neutralizing antibody levels were compared in SOTRs with COVID-19 who received and those who did not receive casirivimab/imdevimab therapy.Results: Casirivimab/imdevimab therapy correlated with less duration until antifebrile and of hospitalization and non-requirement of O2 ≥ 5 L in SOTRs with COVID-19 [mean days without vs. with casirivimab/imdevimab: 6 vs. 2; P = 0.0002, hazard ratio (HR) = 0.3333, 95% confidence interval (CI) = 0.1763–0.6301; mean days: 15 vs. 8; P < 0.0001, HR = 0.5333, 95% CI = 0.2878–0.9883; P = 0.0377, HR = 0.1502, 95% CI = 0.02511–0.8980, respectively]. Further, casirivimab/imdevimab therapy was associated with early antifebrile after adjusting for sex and age (P = 0.013, HR = 0.412, 95% CI = 0.205–0.826). Although no significant difference was observed in neutralizing antibody levels between patients without and with casirivimab/imdevimab therapy on the day of hospitalization (P = 0.1055), including 13 SOTRs who had received vaccination. Neutralizing antibody levels were higher in patients with casirivimab/imdevimab therapy at 3–5 days after hospitalization including such patients in whom the levels tended to stay lower despite vaccination than in those without casirivimab/imdevimab at 7–9 days after hospitalization (P < 0.0001, mean antibody without vs. with, 414.9 vs. 40000). Conclusion: Casirivimab/imdevimab therapy was effective and increased the neutralizing antibody levels in SOTRs with mild-to-moderate COVID-19. Therefore, casirivimab/imdevimab therapy could contribute to preventing the progression of mild-to-moderate COVID-19 in SOTRs.

Objective: To review the available scientific literature on the restorative treatment of non-carious cervical lesions; in particular, the restorative materials that present optimal performance in this type of clinical situation. Methods: A literature review was performed using Pubmed search engine with the aim of determining the ideal restorative material for restorations of non-carious cervical lesions. Results: Beautifil II (Shofu INC.) restorative material showed satisfactory results in terms of fracture resistance, flexural strength and excellent aesthetics, in addition to components that act as anti-cariogenic, anti-plaque and oral pH balance. The Clearfil SE Bond adhesive (Kuraray NORITAKE) showed in clinical research the highest bond strength rate compared to other adhesive systems available in the dental market. Conclusion: Non-carious cervical lesions are multifactorial lesions that require the professional knowledge to conduct the treatment effectively. The Shofu Beautifil II showed the best results in fracture resistance, flexural strength and excellent aesthetics, it has anticariogenic potential, anti-plaque bacteria and contributes to the oral pH balance. The Clearfil SE Bond adhesive showed the highest retention rate among its competitors. Keywords: Restorative materials; non-carious cervical lesions; class V

Tooth loss leads to several oral problems and although a large number of treatments have been proposed to rehabilitate partially or totally edentulous patients, none of them is based on replacement of a missing tooth by a new natural whole tooth. In the field of tissue engineering, some animal models have been developed to regenerate a natural tooth in the oral cavity. This review shows the state of the art in whole tooth regeneration based on data from

To elucidate the relevance of genetic alterations, we analysed 17 genes known to be involved in haematological neoplasms in patients with chronic leucocytosis and patients with persistent thrombocytosis. Mutations of the

Even in the era of high-intensity chemotherapy, disease recurrence remains a major cause of treatment failure in adult patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-negative B-ALL). For patients who achieved second complete remission (CR2) with salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be the best curative treatment. However, limited data are available on the outcomes of allo-HSCT for adult Ph-negative B-ALL in CR2 in the high-intensity chemotherapy era. We evaluated the transplantation outcomes of adult patients with Ph-negative B-ALL in CR2 compared with those in CR1. We also clarified the prognostic factors among adult allo-HSCT recipients with Ph-negative B-ALL in CR2. We conducted a nationwide retrospective study using the data form Japanese transplant registry database. Patients aged ≥16 years and underwent their first allo-HSCT between 2003 and 2017 were included. The 3-year overall survival (OS) rate of the patients in CR2 (n = 382) was significantly lower than that in first complete remission (n = 1375) (51.8% versus 68.1%; P.001), accompanied by a higher relapse rate (34.2% versus 17.6% at 3 years; P.001). In a multivariate analysis among CR2 patients, time from diagnosis to allo-HSCT (≤2 years) was a significant factor for OS (hazard ratio [HR] 1.87; P.001) and relapse (HR = 1.88; P.001), whereas age at allo-HSCT (≥30 years) was a significant factor for OS (HR = 2.10, P.001) and nonrelapse mortality (HR = 2.68; P.001). By assigning a score of 1 to each factor, the 3-year OS rate of CR2 patients significantly stratified: 70.7% in patients with score 0, 56.4% with score 1, and 28.4% with score 2 (P.001). The survival outcomes of allo-HSCT in adult Ph-negative B-ALL patients in CR2 were inferior to those in CR1 in the high-intensity chemotherapy era, mainly because of the higher relapse rate. Among the CR2 patients, the short time between diagnosis and allo-HSCT was a significant risk factor for disease recurrence and overall mortality. Better disease control with novel treatment strategies may be needed for early relapse. In addition, the nonrelapse mortality rate in patients over 30 years of age was particularly high among CR2 patients, suggesting the need for improved supportive care for these patients. Further studies are warranted on the outcomes of allo-HSCT after achieving CR2 with novel drugs, such as inotuzumab ozogamicin and blinatumomab.

Although autologous hematopoietic cell transplantation (HCT) is an established therapy for patients with relapsed acute promyelocytic leukemia (APL) after returning to complete remission (CR), the role of allogeneic HCT remains unclear for treating relapsed APL. This study aimed to investigate allogeneic HCT outcomes in patients with relapsed APL, focusing particularly on those who underwent transplantation in non-CR and those who had relapsed after prior autologous HCT. We retrospectively analyzed Japanese nationwide transplantation registry data of patients with relapsed APL age ≥16 years who underwent allogeneic HCT between 2006 and 2020. A total of 195 patients were eligible for this analysis, including 69 who underwent transplantation in non-CR and 55 who relapsed after prior autologous HCT. The median duration of follow-up for survivors was 5.4 years. Multivariate analysis revealed that both non-CR at transplantation (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.12 to 2.71; P = .014) and prior autologous HCT (HR, 2.10; 95% CI, 1.28 to 3.44; P = .013) were associated with higher risks of overall mortality. The 5-year overall survival (OS) rates for patients who underwent transplantation in CR and non-CR were 58% and 39%, respectively (P = .085), if they did not have a history of prior autologous HCT. In the patients who had relapsed after prior autologous HCT, the 5-year OS rate was 47% for those who underwent allogeneic HCT in CR and 6% for those who did so in non-CR (P = .001). Allogeneic HCT still provides an opportunity for long-term survival for certain patients with relapsed APL for whom autologous HCT is unlikely to be effective. The dismal outcome of those with prior autologous HCT who underwent allogeneic HCT in non-CR poses a significant therapeutic challenge.

An HLA-matched relative is the first-choice donor for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The most promising alternative donor is thought to be an HLA-matched unrelated donor (MUD) in patients who do not have an HLA-matched related donor. Cord blood transplantation (CBT) is an alternative option. Higher rates of engraftment failure and nonrelapse mortality (NRM) are significant problems, but the ready availability of cord blood can be an advantage, because patients can immediately undergo transplantation before progression. This study was conducted to identify an appropriate alternative donor in patients with Ph-negative ALL in CR1 who do not have an HLA-matched related donor (MRD). Decision analyses using a Markov model were performed to compare immediate CBT, in which CBT was performed at 1 month after the achievement of CR1, with elective unrelated bone marrow transplantation (uBMT) from an 8/8 MUD (8/8 uBMT) or uBMT from a 7/8 MUD (7/8 uBMT), in which uBMT was performed at 4 months, in patients age 16 to 55 years with Ph-negative ALL in CR1 who did not have an MRD. We constructed a decision tree. The cycle length was set at 3 months, and analyses were performed for 19 cycles for uBMT and 20 cycles for CBT, resulting in evaluation of the 5-year life expectancy after both decisions. Transition probabilities (TPs) and utilities were estimated from prospective and retrospective Japanese studies and the registry database of Japan. Subgroup analyses were performed according to risk stratification based on WBC count and cytogenetics at diagnosis and according to age stratification, with a cutoff of 25 years. One-way sensitivity analyses for TPs and utilities were performed as well. The baseline analyses showed that 8/8 uBMT or 7/8 uBMT had superior results to CBT, with quality-adjusted life years (QALYs) of 2.86 in 8/8 uBMT, 2.84 in 7/8 uBMT, and 2.75 in CBT. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probability of NRM in CBT improved. Subgroup analyses showed similar results in younger, older, and high-risk patients. However, QALY was worse in 8/8 uBMT compared with CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in younger and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the one-way sensitivity analyses. For patients with Ph-negative ALL in CR1 who decide to undergo transplantation from an alternative donor, elective uBMT from either an 8/8 MUD or a 7/8 MUD is expected to yield a better outcome than immediate CBT. Nonetheless, CBT is a viable option, and improvements to reduce the risk of NRM in CBT may change these results.

The nucleotide oligomerization domain (NOD)-like receptor 2 (NOD2) is an intracellular pattern recognition receptor that detects components of peptidoglycans from bacterial cell walls. NOD2 regulates bowel microorganisms, provides resistance against infections such as diarrhea, and reduces the risk of inflammatory bowel diseases in humans and mice. We previously demonstrated that a specific porcine NOD2 polymorphism (NOD2-2197A &gt, C) augments the recognition of peptidoglycan components. In this study, the relationships between porcine NOD2-2197A/C genotypes affecting molecular functions and symptoms in a porcine circovirus 2b (PCV2b)-spreading Duroc pig population were investigated. The NOD2 allele (NOD2-2197A) with reduced recognition of the peptidoglycan components augmented the mortality of pigs at the growing stage in the PCV2b-spreading population. Comparison of NOD2 allele frequencies in the piglets before and after invasion of PCV2b indicated that the ratio of NOD2-2197A decreased in the population after the PCV2b epidemic. This data indicated that functional differences caused by NOD2-2197 polymorphisms have a marked impact on pig health and livestock productivity. We suggest that NOD2-2197CC is a PCV2 disease resistant polymorphism, which is useful for selective breeding by reducing mortality and increasing productivity.