The purpose of this paper is to consider the reconstruction of the guarantee system for general education opportunities by distinguishing between "matriculation " and "attendance." The children of ...Japanese citizens are guaranteed the right to general education based on the duty of their parents to have them attend school (so-called Article 1 schools) as stipulated by the School Education Law. In this situation, it is assumed that children will attend school. Therefore, there is an institutional "pitfall" in which the right to education is not guaranteed if the child does not attend school. Special schools for chronic absenteeism are efforts to deal with school absenteeism within the framework of "Japanese-style public education" through special provisions in the curriculum. However, only students who are chronically absent can enroll in these schools, while other children are not eligible for this special curriculum. During the COVID-19 pandemic from 2020 on, online learning and lessons have become widespread. For example, in Kumamoto City, online lessons have been distributed to students who are chronically absent. In this situation, the 2021 report of the Central Council for Education states that ICT should be positioned as the future foundation of school education in the future, and that it is necessary to promote a hybrid of face-to-face instruction and remote/online education. Based on the above situation, if a chronically absent student attends a school class online, handling this as attendance in their cumulative guidance record means that they have attended a class at school (online "attendance"). Therefore, a priority should be placed on establishing the conditions under which attending online classes is considered attendance. In addition, online (ICT) education in children's native language and culture can be a powerful way to ensure general educational opportunities. Even given the declining birth rate and population, rather than having smaller schools cling to standard (suitable) class and school sizes based on attendance at a specific school, a more active discussion will be called for based on organizing the ICT (online) educational environment and realizing various forms of learning groups which make use of this environment to guarantee diverse educational opportunities. This paper argues that a new system guaranteeing general educational opportunities is called for, separating matriculation and attendance and relativizing attendance at specific schools, in place of the existing system based on compulsory matriculation at Article 1 schools. Under this system, municipal boards of education would be required to relativize attendance at specific public schools, allow online attendance, and create and guarantee diverse educational opportunities through networking of public schools. The paper concludes with a proposal that prefectures establish "General Education Opportunity Guarantee Councils and Comprehensive Support Centers (tentative)," responsible for wide-area networking of public school networks in each municipality and for support for solving various problems and collecting and providing information based on these networks.
Myeloid sarcoma (MS) is an extramedullary tumor of immature myeloid cells. We analyzed 131 patients with MS, including: (1) de novo MS; (2) MS with concomitant acute myeloid leukemia (AML); (3) MS ...following myelodysplastic syndrome, myeloproliferative neoplasm, or chronic myelogenous leukemia; and (4) MS as a recurrence of AML. The most common development site was the lymph node. Testicular lesions were statistically more frequent in MS as a recurrence of AML than in other types of MS (P=0.0183). MS tended to lack myeloid markers (myeloperoxidase was present in 63.2%, CD68 in 51.3%, CD13 in 48.7%, and CD33 in 48.7% of patients) and express T-cell markers such as CD3 (20.7%) and CD5 (34.2%). All T-cell marker-positive MS cases were negative for the αβ and γδ T-cell receptors on immunohistochemistry. Underlying myelodysplastic syndrome or myeloproliferative neoplasm was a poor prognostic factor (vs. de novo MS: P=0.0383; vs. MS with concomitant AML: P=0.0143). However, there was no statistical difference in prognosis between de novo MS and MS with concomitant AML (P=0.288). There were no significant differences in prognosis between the prognoses of T-cell marker-positive and T-cell marker-negative MS cases. In addition, CXCR4 expression was a poor prognostic factor in MS (P=0.0229). This study involves the largest MS cohort to date and expands the clinical and pathologic knowledge of the disease.
Polatuzumab vedotin (pola) is a CD79b‐targeted antibody‐drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open‐label, single‐arm study of pola ...1.8 mg/kg, bendamustine 90 mg/m2, rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography–computed tomography (PET‐CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty‐five patients (median age 71 range 46‐86 years) were enrolled. Twenty‐three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow‐up of 5.4 (0.7‐11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval CI 19.1‐52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression‐free survival was 5.2 months (95% CI 3.6‐not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3‐4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1‐2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI‐184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.
We report the results of an open‐label, single‐arm study of polatuzumab vedotin 1.8 mg/kg, bendamustine 90 mg/m2, rituximab 375 mg/m2 in patients with transplant‐ineligible relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL). A complete response rate of 34.3% at the end of the treatment and consistent safety profile with previous studies with polatuzumab vedotin were observed.
The Vps13a gene encodes a lipid transfer protein called VPS13A, or chorein, associated with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondria–endosomes, and lipid ...droplets. This protein plays a crucial role in inter-organelle communication and lipid transport. Mutations in the VPS13A gene are implicated in the pathogenesis of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder characterized by chorea, orofacial dyskinesias, hyperkinetic movements, seizures, cognitive impairment, and acanthocytosis. Previous mouse models of ChAc have shown variable disease phenotypes depending on the genetic background. In this study, we report the generation of a Vps13a flox allele in a pure C57BL/6N mouse background and the subsequent creation of Vps13a knockout (KO) mice via Cre-recombination. Our Vps13a KO mice exhibited increased reticulocytes but not acanthocytes in peripheral blood smears. Additionally, there were no significant differences in the GFAP- and Iba1-positive cells in the striatum, the basal ganglia of the central nervous system. Interestingly, we observed abnormal spermatogenesis leading to male infertility. These findings indicate that Vps13a KO mice are valuable models for studying male infertility and some hematological aspects of ChAc.
Genomic alterations and protein expression levels have been established as prognostic factors for survival in patients with diffuse large B‐cell lymphoma (DLBCL). In particular, double‐hit DLBCL ...(DHL), which exhibits translocations in MYC and BCL2 and/or BCL6, is known to be associated with a poor prognosis. However, the clinical significance of gene alterations and protein expression levels for MYC, B‐cell lymphoma (BCL)2, and BCL6 are unclear. In this study, we analyzed 61 adult patients diagnosed with DLBCL without DHL, who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, or similar regimens. There were no differences in the distribution of MYC expression rates among the different MYC gene statuses. In log–rank tests, MYC translocation was a prognostic factor for overall survival (OS; P = 0.011), whereas BCL2 and BCL6 translocation were not prognostic indicators (P = 0.999 and P = 0.925, respectively). Although the expression levels of MYC and BCL6 were not significantly associated with OS, the expression of BCL2 was a prognostic factor for OS (P = 0.027). Furthermore, copy number gains in the MYC, BCL2, and BCL6 genes did not affect OS. MYC translocation (hazard ratio, 4.769; range, 1.518–14.98; P = 0.007) and BCL2 protein expression (hazard ratio, 3.072; range, 1.002–9.413; P = 0.049) were independent prognostic factors for survival in multivariate analyses. In conclusion, MYC translocation and BCL2 expression may need to be investigated at the initial diagnosis to predict prognosis in patients with DLBCL.
In this study, we examined the relationships between genomic alterations and protein expression of MYC, BCL2, and BCL6 in diffuse large B‐cell lymphoma. Although the clinical utility of protein expression and translocation of MYC and BCL2 is controversial in diffuse large B‐cell lymphoma, we confirmed that MYC translocation, as detected by fluorescence in situ hybridization, and BCL2 expression, as analyzed by immunohistochemistry, were important for predicting survival.
The interaction between CD47 and signal‐regulatory protein‐α (SIRPα) inhibits phagocytosis, thus affecting the clinical outcomes of neoplastic diseases. Although CD47 upregulation is associated with ...poor prognosis in several malignancies, the effect of SIRPα expression and its coexpression with CD47 remains unclear. This study aimed to investigate the clinicopathologic effect of CD47 and SIRPα expression in diffuse large B‐cell lymphoma (DLBCL). Immunostaining of 120 biopsy samples showed that CD47 is primarily expressed in tumor cells, whereas SIRPα is expressed in nonneoplastic stromal cells, mostly macrophages. CD47high cases showed higher MYC protein expression and lower MYC translocation. The SIRPαhigh cases presented significantly shorter overall survival (OS) and progression‐free survival (PFS) than SIRPαlow cases in the activated B‐cell (ABC) subtype of DLBCL (P = .04 and P = .02, respectively). Both CD47high and SIRPαhigh presented significantly shorter OS and PFS than other cases among all DLBCL patients (P = .01 and P = .004, respectively), and the ABC type (P = .04 and P = .008, respectively) but not the germinal center B‐cell type. Both CD47high and SIRPαhigh yielded a constant independent prognostic value for OS and PFS in multivariate analysis (hazard ratio HR, 2.93; 95% confidence interval CI, 1.20‐7.43; P = .02; and HR, 2.87; 95% CI, 1.42‐5.85; P = .003, respectively). To the best of our knowledge, this is the first study to report that combinatorial CD47 and SIRPα expression is a potential independent prognostic factor for DLBCL. Evaluation of CD47 and SIRPα expression could be useful before CD47 blockade therapy.
This study investigated the clinicopathologic effect of CD47 and signal‐regulatory protein‐α (SIRPα) in diffuse large B‐cell lymphoma by immunohistochemical staining. CD47 and SIRPα coexpression is associated with a poor prognosis in the activated B‐cell type, but not in the germinal center B‐cell type.
Radiation therapy is one of the major treatment modalities for patients with cancers. However, ionizing radiation (IR) damages not only cancer cells but also the surrounding vascular endothelial ...cells (ECs). Hippo pathway effector genes Yap1 and Taz are the two transcriptional coactivators that have crucial roles in tissue homeostasis and vascular integrity in various organs. However, their function in adult ECs at the steady state and after IR is poorly understood. Here, we report sex- and context-dependent roles of endothelial YAP1/TAZ in maintaining vascular integrity and organismal survival. EC-specific Yap1/Taz deletion compromised systemic vascular integrity, resulting in lethal circulation failure preferentially in male mice. Furthermore, EC-specific Yap1/Taz deletion induced acute lethality upon sublethal IR that was closely associated with exacerbated systemic vascular dysfunction and circulation failure. Consistent with these findings, RNA-seq analysis revealed downregulation of tight junction genes in Yap1/Taz-deleted ECs. Collectively, our findings highlight the importance of endothelial YAP1/TAZ for maintaining adult vascular function, which may provide clinical implications for preventing organ injury after radiation therapy.
•Yap1/Taz deletion in ECs causes vascular dysfunction and lethality in male mice.•IR activates Yap1/Taz in EC to maintain vascular integrity and mouse survival.•Yap1/Taz deletion disrupts gene expression of tight junction components.
Abstract
Objective
Fludarabine, cyclophosphamide and rituximab (FCR) is the standard regimen for fit patients with untreated CD20-positive chronic lymphocytic leukemia (CLL). However, this ...combination is unavailable in Japan because rituximab is not approved for CLL. We investigated the efficacy and safety of FCR in this single-arm, multicenter study designed as a bridging study to the CLL8 study by the German CLL Study Group.
Methods
The study enrolled previously untreated patients with CLL of Binet stage B or C with active disease. Patients with a Cumulative Illness Rating Scale score of ≤6 and creatinine clearance of ≥70 ml/min were eligible. Patients received 6 cycles of FCR every 28 days and were followed for up to 1 year.
Results
Seven patients were enrolled. The best overall response rate according to the 1996 NCI-WG Guidelines, the primary endpoint of the study, was 71.4% (95% confidence interval, 29.0–96.3%), with one patient achieving complete response. No deaths or progression occurred during follow-up. The main adverse event was hematotoxicity. CD4-positive T-cell count decreased in all patients; most patients showed no reduction in serum immunoglobulin G.
Conclusion
Although the number of patients was limited, FCR appears to be effective with manageable toxicity for treatment-naïve fit Japanese patients with CD20-positive CLL.
Clinical trial number
JapicCTI-132285.
FCR regimen was feasible with manageable toxicity for treatment-naïve fit Japanese patients with CD20-positive CLL, and the efficacy was in line with that seen in the CLL8 study.
Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) of the elderly (EBV+DLBCL‐E) is classified as a subtype of DLBCL. Until now, its molecular pathogenesis has remained unknown. ...To identify pathways characteristic of EBV(+)DLBCL‐E, gene expression profiling of five EBV(+)DLBCL‐E and seven EBV‐negative DLBCL (EBV−DLBCL) cases was undertaken using human oligonucleotide microarray analysis. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the Janus kinase‐signal transducer and activator of transcription (JAK‐STAT) and nuclear factor kappa B (NF‐κB) pathways were enriched in EBV(+)DLBCL‐E cases. To confirm the results of the expression profiles, in vitro analysis was performed. Expression profiling analysis showed that high activation of the JAK‐STAT and NF‐κB pathways was induced by EBV infection into DLBCL cell lines. Activation of the NF‐κB pathway was confirmed in EBV‐infected cell lines using an electrophoretic mobility shift assay. Western blot analysis revealed an increased protein expression level of phosphorylated signal transducer and activator of transcription 3 (STAT3) in an EBV‐infected cell line. Protein expression of phosphorylated STAT3 was frequently observed in lymphoma cells of EBV(+)DLBCL‐E clinical samples using immunohistochemistry (EBV+DLBCL‐E: 80.0% n = 20/25 versus EBV−DLBCL: 38.9% n = 14/36; P = 0.001). The results of the present study suggest that activation of the JAK‐STAT and NF‐κB pathways was characteristic of EBV(+)DLBCL‐E, which may reflect the nature of EBV‐positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of EBV(+)DLBCL‐E.
EBV‐positive diffuse large B‐cell lymphoma (DLBCL) of the elderly is newly classified as a subtype of DLBCL in the 4th WHO classification. Comprehensive genetic analysis has not been investigaed. We identified the activation of JAK‐STAT and NF‐κB pathways was characteristic of the disease.
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