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Background: Internet psychoeducational interventions improve employees' mental health. However, implementing them for employees in micro- and small-sized enterprises (MSEs) is challenging., Objectives: This randomized controlled trial examined the effectiveness of a fully automated text-based stress management program, "WellBe-LINE," in improving mental health and job-related outcomes for employees in workplaces with fewer than 50 employees., Methods: The program was developed based on stakeholder interviews and surveys of 1000 employees at MSEs. Adult full-time employees at an enterprise with fewer than 50 employees were recruited from registered members of a web survey company in Japan. Participants were randomly allocated to the intervention or control group (1:1). Participants in the intervention group were invited to register for the program using the LINE app. Psychological distress measured by Kessler 6 (K6) was a primary outcome, with self-administrated questionnaires at baseline, 2-month (post), and 6-month follow-ups. A mixed model for repeated measures conditional growth model analysis was conducted using a group ∗ time interaction as an intervention effect. Implementation outcomes were measured through implementation outcome scales for digital mental health (iOSDMH)., Results: 1021 employees were included in this study. No significant effects were shown in any outcome. The reported implementation outcomes were positively evaluated, with 80 % acceptability, 86 % appropriateness, and feasibility (ease of understanding the contents [88 %], frequency [86 %], and length of content [86 %])., Conclusions: A simple text-message program for employees at MESs was acceptable, appropriate, and feasible; however, it did not result in improved mental health or job-related outcomes., Trial Registration: UMIN clinical trial registration: UMIN000050624 (registration date: March 18, 2023)., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kotaro Imamura reports a relationship with Department of Digital Mental Health that includes: employment. Natsu Sasaki reports a relationship with Medilio Inc. that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Competing Interests: Dr. Hironori Kuga is an Editorial Board member of Psychiatry and Clinical Neurosciences Reports and a co‐author of this article. To minimize bias, he was excluded from all editorial decision‐making related to the acceptance of this article for publication.

Background: Although internet-based stress management programs are proven effective in improving mental health among workers, micro- and small-sized enterprises (MSEs), lacking in occupational healthcare services, face challenges implementing them. To address this gap, this study will develop the program with stakeholders at MSEs to aim for real-world implementation., Objectives: This paper describes a study protocol for a pre-post feasibility study of an effectiveness-implementation hybrid type 2 trial of text-based internet-based programs ("WellBe-LINE") in MSEs with less than 50 employees. This feasibility study primarily aims to evaluate trial methods for future effectiveness-implementation hybrid type 2 trials., Methods: For this study protocol, an internet- and text-based self-care intervention program using the LINE app (a popular message tool in Japan) will be prepared according to evidence-based psychoeducational topics. Based on our online survey findings, personalized algorithms will be implemented according to employees' gender, age, and psychological distress levels. A personalized program using a popular pre-existing text app is expected to reduce employees' burdens and be attractive to them, resulting in successful implementation outcomes and mental health benefits. A pre-post design feasibility study will be conducted on ten companies to evaluate trial methods (e.g., recruitment and procedures). The primary outcome will involve individual-level penetration, defined as the proportion of the number of employees who register for the program divided by the total number of invited employees at the company. The progression criterion to go next trial specifies that more than 50% of the recruited companies obtain 60% individual penetration, which is set based on the findings of the prior survey of employees at MSEs and of interviews of stakeholders involved in this study, and will be measured by LINE system. Finally, acceptability, appropriateness, and feasibility will be measured using internet-based questionnaires and interviews., Discussion: This pre-post feasibility study for future effectiveness-implementation hybrid type 2 trials will provide in-depth knowledge about the successful implementation of text-based, semi-personalized, self-care mental health interventions in real-world settings using both quantitative and qualitative data., Conclusions: This feasibility study will help validate the effectiveness of text-based interventions using a widely used social networking service (SNS) tool for employees in MSEs., Trial Registration: UMIN clinical trial registration, UMIN000046960. Registered on February 21, 2022. https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000053570., (© 2024. The Author(s).)

Aim: The Mental Health Supporter Training Program is a national project conducted in Japan. This study aimed to determine the effects on mental health-related stigma, mental health literacy, and knowledge about mental health difficulties and support techniques among program participants., Methods: The target population was local residents of a wide range of generations in Japan. Outcomes were assessed at baseline (T1), immediately postintervention (T2), and at the 6-month follow-up (T3). A mixed model for repeated-measures conditional growth model analyses were employed to examine the effects of the intervention over time (T1, T2, T3). We also calculated effect sizes using Cohen's d ., Results: The program had a significantly favorable pooled effect on the Japanese version of the Reported and Intended Behaviour Scale score after adjusting for covariates (reported behavior [ t  = 3.20, p  = 0.001]; intended behavior [ t  = 8.04, p  < 0.001]). However, when compared at each time point, only intended behavior from T1 to T2 showed a significant difference ( t  = 8.37, p  < 0.001). Significant pooled effects were found for mental health literacy (knowledge: t  = 19.85, p  < 0.001; attitude: t  = 15.02, p  < 0.001), knowledge of mental health ( t  = 28.04, p  < 0.001), and psychological distress ( t  = -2.41, p  = 0.016)., Conclusion: The results suggest that the program might be effective for improving intended, but not reported, behavior in the short term and for improving mental health literacy, knowledge of mental health, and psychological distress., Competing Interests: Dr Hironori Kuga is an Editorial Board member of Psychiatry and Clinical Neurosciences Reports and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication., (© 2024 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: Team-level job crafting has been put forward as a method to promote nurses' mental health. However, a longitudinal association is unclear. Therefore, the objective of this study was to investigate the association between team job crafting at baseline and work engagement, work performance, psychological distress, and intention to leave at three-month and six-month follow-ups among Japanese hospital nurses. Also, whether an increase in the team job crafting during 3 or 6 months was associated with an increase in the work engagement during 3 or 6 months of individual nurses was examined., Methods: A multilevel prospective cohort study was conducted. Data were collected from nurses of five hospitals in Japan at baseline (T1) and follow-ups at 3-months (T2) and 6-months (T3). A total of 2,478 nurses were included. The team job crafting scale for nurses and its three subscales were measured for the independent variables. Ward-means were used as ward-level variables. The dependent variables were work engagement, work performance, psychological distress, and intention to leave. Hierarchical Linear Modeling (HLM) was used to examine the multilevel association. The study protocol was registered at the UMIN Clinical Trials Registry (ID = UMIN000047810) (May 22, 2022)., Results: A total of 460 nurses completed the T1 survey (response rate = 18.6%), and data from 391 nurses nested in 30 wards were included in the analyses. The intraclass correlation coefficients (ICCs) at T1 were 0.02 for work engagement and 0.07 for team job crafting. The HLM revealed that ward-level team job crafting at T1 was not significantly associated with work engagement, work performance, psychological distress, and intention to leave at T2 or T3. The ward-level change (T3-T1) of "crafting for the task considering the team's growth" (subscale for team job crafting) was significantly and positively associated with the change (T3-T1) in work engagement., Conclusions: Ward-level team job crafting at baseline did not predict nurses' work engagement, work performance, psychological distress, or intention to leave at a three-month or six-month follow-up. The impact of ward-level team job crafting may attenuate over several months., (© 2024. The Author(s).)

Unintended pregnancy (UP) can negatively impact the health of mothers, children, and families. While Adverse Childhood Experiences (ACEs) are increasingly known to affect sexual health, the influence on pregnancy intention is not fully understood. This study examines the relationship between ACEs and UP and explores other related factors, using 5049 pregnant and postpartum women data from the Japan COVID-19 and Society Internet Survey (JACSIS). We measured participants' pregnancy intentions, ACEs, family functioning, and social network size. Logistic regression analysis provided odds ratios and 95% confidence intervals (CI). The prevalence of UP was approximately 16.5% ( n  = 893). Cumulative ACEs were consistently associated with UP, even after adjusting for intermediate variables in adulthood. The odds ratio for UP with a single ACE was 1.00 (CI: 0.82-1.21) but rose significantly with multiple ACEs: 1.39 (CI: 1.10-1.76) with double, 1.38 (CI: 1.02-2.86) with triple, and 1.81 (CI: 1.37-2.39) with more. Additionally, bad family functioning and lack of social networks emerged as contributors to UP. In conclusion, this study showed that ACEs are potentially correlated with UP. A deeper understanding of the transition from childhood experiences to UP is important for health interventions, necessitating further investigation.

Competing Interests: None declared.

Competing Interests: None declared.

A 40-year-old man presented at our hospital with anaemia that had been undiagnosed for 2 years. Blood tests, endoscopy, and contrast-enhanced computed tomography were performed, but a definitive diagnosis could not be made. A subsequent bone marrow biopsy revealed basophilic stippling in transformed red blood cells, which led to a differential diagnosis of lead poisoning. Additional tests revealed elevated levels of lead in the blood. Basophilic stippling is generally found on a peripheral blood smear in lead poisoning patients; however, in this case, basophilic stippling was found only on the bone marrow smear and not in the blood smear. Even if basophilic stippling is not found in the peripheral blood, lead poisoning cannot be excluded.

Background: The Japanese version of the individualized Supported Employment Fidelity scale (JiSEF) was developed by modifying the 25-item Individual Placement and Support Fidelity Scale (IPS-25). While a preliminary study partly confirmed the concurrent validity with vocational outcomes, this replication study aimed to examine the stability of the concurrent validity and the inter-rater reliability of the JiSEF and to test its convergent validity with IPS-25., Methods: Fidelity assessments were conducted in 2016 (n = 17), 2017 (n = 13), and 2018 (n = 18) to examine the employment rate and the fidelity scores at the agency level. We also evaluated the fidelity scores for the IPS-25 in 2018. We examined the associations between the fidelity scale scores and vocational outcomes for the concurrent validity and between the fidelity scales for convergent validity. The inter-rater reliability was examined in the 2016 and 2017 assessments., Results: High intraclass correlation coefficients (0.93 in 2016 and 0.92 in 2017) were obtained for the inter-rater reliability. The JiSEF score in each year was associated with the agency employment rate (r = 0.710, P = 0.001 in 2016; r = 0.722, P = 0.005 in 2017; and r = 0.665, P = 0.003 in 2018). A supplementary longitudinal data analysis also confirmed the association between the JiSEF score and the employment outcomes. Additionally, the JiSEF was significantly correlated with the IPS-25 (r = 0.760, P < 0.001)., Conclusions: This study stably replicated good inter-rater reliability and concurrent validity of the JiSEF. Additionally, the convergent validity was confirmed. Further studies with large samples are needed to confirm these findings., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of Neuropsychopharmacology.)

Background: Good social climate and high work engagement are important factors affecting outcomes in healthcare settings. This study observed the effects of a program called Civility, Respect, and Engagement in the Workplace (CREW) on social climate and staff work engagement in a psychiatric ward of a Japanese hospital., Methods: The program comprised 18 sessions installed over six months, with each session lasting 30-min. Participation in the program was recommended to all staff members at the ward, including nurses, medical doctors, and others, but it was not mandatory. A serial cross-sectional study collected data at four time-points. Nurses (n = 17 to 22), medical doctors (n = 9 to 13), and others (n = 6 to 10) participated in each survey. The analysis of variance was used to evaluate the changes in the following dependent variables, the Essen climate evaluation schema (EssenCES), the CREW civility scale, and the Utrecht work engagement scale (UWES) over time., Result: We found no significant effects. The effect size (Cohen's d) for EssenCES was 0.35 from baseline to post-installation for all staff members. Effect sizes for EssenCES for medical doctors and UWES for nurses were 0.79 and 0.56, respectively, from baseline to post-program., Conclusions: Differences in social climate and work engagement among Japanese healthcare workers between the baseline and post-installation of the CREW program were non-significant.

Aims: Personal agency is a variable which potentially facilitates personal recovery in people with serious mental illness. This study aimed to develop a new brief measure for subjective personal agency that can be completed by people with serious mental illness., Methods: Two focus group interviews were first conducted with 11 people with schizophrenia to understand the fundamental components of subjective personal agency for people with serious mental illness living in the community. One group comprised six people with schizophrenia living in the community, while the other consisted of five people with schizophrenia working as peer-support workers. We then developed scale items through collaboration with people with schizophrenia and qualitative analysis (stage 1). A cross-sectional survey was then conducted to test the psychometric properties of the new scale among service users with schizophrenia in 18 assertive community treatment teams (stage 2). Factor validity was tested via exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). We evaluated convergent validity with the Boston University Empowerment Scale (BUES), divergent validity with the global assessment of functioning (GAF), internal consistency, and test-retest reliability., Results: Seven items were included in the scale at stage 1. In stage 2, 195 participants completed this scale. EFA revealed a one-factor model with five items. CFA indicated good model fit (χ2 statistics [CMIN] = 8.445, df = 5 (CMIN/df = 1.689), p = 0.133, comparative fit index = 0.974, Tucker-Lewis fit index = 0.949, root mean square error of approximation = 0.077 and standardised root mean squared residual = 0.042). The new scale was significantly correlated with total BUES score (r = 0.526, p < 0.001), but not with GAF score. Cronbach's α for internal consistency was 0.79, and intra-class correlation coefficient for test-retest reliability was 0.70., Conclusion: We developed a new, five-item Subjective Personal Agency scale (SPA-5) that can be completed by people with serious mental illness. Further studies are needed to confirm the results outside Japan.

Aims: In the past two decades, there has been growing interest in patient-doctor communication in psychiatry, and several treatment options have been established. This study aimed to develop the Interpersonal Processes of Care Survey-Japanese version (IPC-J), which measures multidimensional communication and the relationship between doctors and patients in Japanese psychiatry., Method: We conducted a cross-sectional questionnaire survey at one psychiatric hospital and two psychiatric clinics in Japan and investigated the factor validity, convergent validity, internal consistency, and test-retest reliability of the IPC-J., Result: Overall, 148 eligible patients participated in the study and were included in the analyses. Data from 16 participants were used to examine test-retest reliability. An exploratory factor analysis using 23 items from the IPC scale was performed to clarify the factor structure in a Japanese psychiatric setting. The final IPC-J contained 22 items and a two-factor structural model. High internal consistency (α > .8) and moderate test-retest reliability (interclass correlation > .65) were observed. Regarding convergent validity, the factor 1 "Doctor's communication-related attitudes and skills" was significantly correlated with service satisfaction, empowerment, and medication adherence, whereas the factor 2 "Consideration for the patient's to promote own treatment decisions" was correlated with service satisfaction and medication adherence., Conclusion: The IPC-J appears to be a useful tool for assessing patient views on interpersonal communication with doctors in a Japanese psychiatric setting. While the analysis suggested utilizing an IPC-J with 22 items, the full IPC-J can be used in cross-cultural studies., (© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology.)

Background: Supporting personal recovery in people with mental health difficulties is central to mental health services. This study aimed to develop the Japanese version of INSPIRE and Brief INSPIRE measure of staff support for personal recovery and to evaluate its reliability and validity., Methods: A questionnaire survey was conducted from October to December 2015. The authors asked users to participate in the survey of 14 community mental health services in the Kanto region of Japan. The service users completed self-administered questionnaires that include the Japanese version of INSPIRE, the Recovery Assessment Scale, the Client Satisfaction Questionnaire, the patient version of the Scale to Assess Therapeutic Relationship in Community Mental Health care and the Short Form Health Survey. Internal consistency was assessed using Cronbach's alpha coefficient, and test-retest reliability was assessed using the intraclass correlation coefficient (ICC) and weighted kappa. Convergent validity was examined by assessing correlation with other scales. Factor validity was evaluated by exploratory factor analysis (EFA) with generalized least-squares mean and oblimin rotation. In addition, confirmatory factor analysis was used to check the fitness of the factor structure models derived from the EFA., Results: A total of 195 out of 212 users gave written informed consent and participated in the study. Data from 190 respondents were analyzed (response rate 89.6%). INSPIRE, Brief INSPIRE, and the subscales all showed Cronbach's alpha coefficient over 0.78. ICC and weighted kappa derived more than 0.92 for subscales and Brief INSPIRE. These numerical values indicated good reliability. The convergent validity of Brief INSPIRE and the subscales was significantly positively correlated with the other scales. Different from the previous study, the factor structure was extracted using EFA. Both factor structures were checked by CFA, but the degree of fitness index was not good in either. Therefore, the factor analysis did not show goodness of fit., Conclusions: This study found the Japanese version of INSPIRE and Brief INSPIRE to be reliable and valid for use among community mental health service users in Japan.

Background: A good therapeutic relationship between patient and psychiatrist is vital for effective mental health care. However, no instruments to assess this relationship are available in Japan. This study aimed to develop a Japanese version of a Scale To Assess Therapeutic Relationship (STAR-J), which measures such relationships from the viewpoints of both the patient (STAR-J-P) and clinician (STAR-J-C). We examined the tool's psychometric properties, including factor structure, internal consistency, convergent validity, and test-retest reliability among psychiatric outpatients and psychiatrists. Methods: Study participants comprised 139 outpatients and 10 psychiatrists. Exploratory factor analysis was conducted to investigate factor structure; to confirm cross-validity, confirmatory factor analysis was conducted using a different sample constituting 195 participants in an assertive community treatment program and their 91 case managers. Cronbach's alpha was used to assess internal consistency. For STAR-J-P only, the intra-class correlation coefficient (ICC) was computed for 17 patients to determine test-retest reliability. Spearman's correlation coefficients were calculated to examine convergent validity with service satisfaction, empowerment, and medication adherence. Results: We identified a two-factor structure for STAR-J-P and a one-factor structure for STAR-J-C. Cronbach's alphas for the two STAR-J-P factors were 0.897 and 0.645, and that for the STAR-J-C factor was 0.949. The ICCs for STAR-J-P factors 1 and 2 were 0.765 and 0.630, respectively. STAR-J-P and STAR-J-C were not significantly correlated. STAR-J-P factors 1 and 2 showed significant correlations with service satisfaction (factor 1: ρ = 0.648, p < 0.001; factor 2: ρ = 0.238, p = 0.005) and medication adherence (factor 1: ρ = 0.508, p < 0.001; factor 2: ρ = 0.347, p < 0.001), but only factor 1 showed a significant relationship with empowerment (ρ = 0.283, p = 0.001). STAR-J-C was significantly correlated only with empowerment (ρ = 0.207, p = 0.017). Conclusions: STAR-J appears to be a useful instrument for assessing therapeutic relationships in the Japanese psychiatric outpatient setting. Further studies should test its validity and applicability in different mental health service settings., (Copyright © 2019 Matsunaga, Yamaguchi, Sawada, Shiozawa and Fujii.)

Background: Depression is a major problem among nurses; hence, it is important to develop a primary prevention strategy to manage depression among nurses. This randomized controlled trial (RCT) study aims to investigate the effects of a newly developed internet-based cognitive behavioral therapy (iCBT) program on depressive symptoms, measured at baseline and three- and six-month follow-ups, among nurses in Japan., Methods: Nurses working at three university hospitals, one public hospital, and twelve private hospitals who meet inclusion criteria will be recruited and randomized either to the intervention group or the control group (planned N = 525 for each group). The newly developed iCBT program for nurses consists of six modules, which cover different components of cognitive behavioral therapy (CBT); transactional stress model (in module 1), self-monitoring skills (in module 2), behavioral activation skills (in module 3), cognitive restructuring skills (in modules 4 and 5), relaxation skills (in module 5), and problem-solving skills (in module 6). Participants in the intervention group will be asked to read these modules within 9 weeks. The primary outcome will be depressive symptoms as assessed by the Beck Depression Inventory-II (BDI-II) at baseline, three-, and six-month follow-ups., Discussion: The greatest strength of this study is that it is the first RCT to test the effectiveness of the iCBT program in improving depressive symptoms among nurses. A major limitation is that all measurements, including major depressive episodes, are self-reported and may be affected by situational factors at work and participants' perceptions., Trial Registration: This trial was registered at the University Hospital Medical Information Network clinical trials registry (UMIN-CTR; ID =  UMIN000033521 ) (Date of registration: August 1, 2018).

Renaming schizophrenia is a potential strategy to reduce the stigma attached to people with schizophrenia. However, the overall associations between renaming schizophrenia and stigma-related outcomes have not been fully elucidated. We conducted a systematic review of studies that empirically examined the outcomes between new or alternative terms and old or existing terms for schizophrenia. We searched for relevant articles in eight bibliographic databases, conducted a Google search, examined reference lists, and contacted relevant experts. We found a total of 2601 reference records, and 23 articles were included in this review. Overall, in countries where schizophrenia has been renamed, the name changes may be associated with improvements in adults' attitudes toward people with schizophrenia, and with increased diagnosis announcement. However, studies conducted in countries where schizophrenia has not been renamed report inconsistent findings. In addition, renaming may not influence portrayals of schizophrenia in the media. Most studies included in our review had a risk of bias in their methodology, and we employed a vote-counting method to synthesize study results; therefore, the impacts of renaming are still inconclusive. Future studies are needed to address the following issues: use of univariate descriptive statistics, adjustment for confounding variables, use of reliable measures, and employing a question that addresses the image of split or multiple personalities. Evidence is limited regarding the associations between renaming and stigma experienced by both people with schizophrenia and their families (e.g., perceived stigma, self-stigma, discrimination experience, and burden). Further research in these populations is needed to confirm the effects of renaming schizophrenia., (© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.)

The Philadelphia chromosome (Ph) is the most frequent chromosomal abnormality detected in adult acute lymphoblastic leukemia (ALL). This chromosome forms the BCR/ABL1 fusion gene; thus, ABL1 exon a2 is generally used as a primer-binding region for the detection of the fusion transcript via reverse transcription polymerase chain reaction (RT-PCR). We observed a rare case of adult Ph-positive (Ph(+)) ALL, in which the BCR/ABL1 fusion transcript was not detected using the ABL1 exon a2 region primer. However, we were able to isolate a PCR product by RT-PCR with the BCR exon 13 (b2) and ABL1 exon a3 primers. Analysis of the sequence of the RT-PCR product revealed that the fusion point was between BCR exon 14 (b3) and ABL1 exon a3, and that the transcript lacked ABL1 exon a2. The patient achieved cytogenetic remission through combination chemotherapies, but relapse occurred before hematopoietic stem cell transplantation and the patient died 11 months after the initialization of chemotherapies. If the BCR/ABL1 fusion transcript is undetected with the ABL1 exon a2 region primer in Ph(+) ALL cases, an RT-PCR analysis that can detect the b3a3 type BCR/ABL1 fusion transcript should be considered to improve diagnosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We retrospectively evaluated the safety and efficacy of high-dose chemotherapy consisting of cyclophosphamide, etoposide and ranimustine (CEM) with autologous peripheral blood stem cell transplant (PBSCT) in 55 adult patients with relapsed or high-risk de novo diffuse large B-cell lymphoma (DLBCL) or DLBCL associated with follicular lymphoma. This included 36 patients in the upfront setting in their first complete remission. The median follow-up of 42 patients surviving at the time of the analysis was 52 months (range 1-159). Relapse or disease progression after PBSCT was a frequent cause of death, but no therapy-related mortality associated with PBSCT was observed. The 5-year overall survival and progression-free survival were 70.6% (95% confidence interval [CI], 54.0-82.1) and 57.0% (95% CI, 39.5-71.2), respectively. Chronic renal impairment, therapy-related myelodysplastic syndrome and prostate cancer were the major late complications. The CEM regimen is a tolerable, effective conditioning regimen for autologous PBSCT for DLBCL, with no therapy-related mortality observed.

We report the first case of primary central nervous system lymphoma (PCNSL) developing in a patient with rheumatoid arthritis (RA) undergoing low-dose methotrexate therapy (LD-MTX). The characteristic clinical management and course in our experience of the present case illustrate the important points about PCNSL in methotrexate-associated lymphoproliferative disorders (MTX-LPD). The number of cases of MTX-LPD in RA patients may increase in the future, since current treatment strategies for RA recommend starting MTX use in early stage RA, and recent insights have tended to show an increase with higher doses.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of non-Hodgkin lymphomas, often resulting in poor prognoses. The CHOP chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine and prednisone, has been used previously to treat other types of lymphomas. Here, we examined the efficacy and safety of a dose-intensified CHOP regimen (Double-CHOP), which was followed by autologous stem-cell transplantation (ASCT) or high-dose methotrexate (HDMTX), in PTCL patients. Twenty-eight PTCL patients, who received 3 courses of Double-CHOP at our institution, were retrospectively studied from 1996 to 2012. Patients with anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK+-ALCL) were excluded from this study. The median age of patients was 58 years (range: 17-69). They had low-intermediate (n=11), high-intermediate (n=10) or high (n=7) risk according to the International Prognostic Index (IPI). The overall complete remission (CR) rate following Double-CHOP treatment was 68%. Of the CR patients, 10 successfully tolerated a consolidated high-dose chemotherapy followed by ASCT and 7 received HDMTX. A single case of treatment-related mortality was recorded during the study. On a median 31-month follow-up, the estimated 3- or 5-year overall survival (OS) rates were 68 or 63%, respectively, while 3- or 5-year relapse-free survival (RFS) rates after CR were 60 or 43%, respectively. Although this study included elderly and excluded low-risk IPI and ALK+-ALCL patients, OS results were superiorly favourable, indicating the efficacy of this Double-CHOP regimen. However, an effective treatment strategy for refractory or relapsing patients needs to be validated and established.

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP (i.e., R-CHOP)] is considered to be the standard regimen for treating localized, primary gastric diffuse large B-cell lymphoma (PG-DLBCL). However, few studies have reported the long-term efficacy of R-CHOP therapy in the management of localized PG-DLBCL. In the present study, we performed a retrospective analysis of 11 patients with localized PG-DLBCL, who were treated with R-CHOP at Nihon University Itabashi Hospital and Kasukabe Municipal Hospital (Japan) from 2001 to 2008. Limited stage cancer was defined as stage I/II according to the Lugano staging system for gastrointestinal (GI) lymphomas. The relative dose intensity (RDI) of CHOP therapy was calculated for each patient. The median age of the patients was 68 years (range, 48-82). Gastralgia and anemia were common symptoms at initial presentation. All patients except 1 received 6 cycles of R-CHOP treatment without consolidative radiation therapy or prior surgery. RDI was maintained at over 80% in 9 out of 11 patients. All patients achieved complete remission and the estimated overall survival with a median follow-up of 54 months (range, 39-103) was 100%, without relapse or significant GI adverse effects, such as perforation or bleeding during R-CHOP treatment. No long-term adverse effects of rituximab were recorded during the observation period. Helicobacter pylori infection was diagnosed in 72.7% (8 cases) of the patients, but was eradicated in a limited number of patients. Our data suggest the feasibility and effectiveness of the addition of rituximab to conventional CHOP therapy in the management of localized PG-DLBCL.

Adult T-cell leukemia/lymphoma (ATL) is one of the peripheral T-cell malignant neoplasms strongly associated with human T-cell leukemia virus type-I (HTLV-I). Although the viral transactivator protein Tax has been proposed to play a critical role in leukemogeneis, additional cellular events are required for the development of ATL. One of the genetic events of the disease is inactivation of tumor suppressor genes. The CDKN2A locus on chromosome 9p encodes 2 cell cycle regulatory proteins, p14ARF and p16INK4a, which share exon 2 using different reading frames. The p14ARF and p16INK4a genes have been implicated as tumor suppressor genes by their frequent mutation, deletion or promoter hypermethylation in a variety of human tumors. In this report, we describe the expression status of p14ARF and p16INK4a in 9 ATL cell lines (MT1, MT2, OKM3T, F6T, K3T, Oh13T, S1T, Su9T01 and HUT102). By reverse transcription polymerase chain reaction (RT-PCR), expression of p14ARF was not detected in one cell line (OKM3T), while expression of p16INK4a was not detected in 6 cell lines (OKM3T, MT1, MT2, Oh13T, S1T and Su9T01). In the OKM3T cell line, the shared exon 2 of the p14ARF/p16INK4a gene was deleted; however, the p16INK4a gene, was epigenetically inactivated in 5 other cells lines. In primary tumor cells obtained from ATL patients, p14ARF expression was absent in 6 of the 11 samples. We confirmed the methylation of the p16INK4a gene in MT1 and MT2 cells using the methylation-specific PCR (MSP) method. Treatment with 2.0 µM of Azacitidine (AZA), a demethylating agent, for 72 h restored p16INK4a transcript expression and induced growth inhibition in MT2 cells. Our results demonstrate that p16INK4a is epigenetically silenced in ATL. AZA offers a potential new therapeutic approach to improve the poor outcomes associated with ATL.

We evaluated the efficacy and toxicity of a new salvage regimen, consisting of rituximab (375 mg/m(2), day 1), ifosfamide (1500 mg/m(2) on days 3-7), etoposide (150 mg/m(2), days 3-5), cytarabine (100 mg/m(2), days 3-5) and dexamethasone (40 mg/body, days 3-5) (R-IVAD) for relapsed or refractory aggressive B-cell lymphoma. In this study, a total of 32 patients with a median age of 64 years (range 38-79) who received an average of 2.6 cycles of R-IVAD from 2001 to 2009 in our institution were retrospectively analyzed. R-IVAD was given every 3 weeks up to a total of three courses with support by granulocyte colony stimulating factor. The overall response rate was 72%, with 56% complete response. On a median follow-up of 16 months (range 2-99), estimated 2-year overall survival (OS) and event-free survival were 55% and 36%, respectively. Of these patients, 10 successfully proceeded to consolidating high-dose chemotherapy followed by autologous stem cell transplantation, accounting for 90% of the 2-year OS. No treatment-related mortality was observed during the investigation. We, therefore, conclude that R-IVAD regimen is a safe and efficacious alternative for patients with relapsed or refractory aggressive B-cell lymphoma.

A 45-year-old woman was referred to our hospital with acute renal failure and pyrexia. In August 2005, the patient was diagnosed with IgA-λ type multiple myeloma with chromosome 13 deletion, and received three cycles of vinclistine, adriamycin and dexamethasone followed by high-dose melphalan-based autologous peripheral stem cell transplantation: this resulted in remission 2 months before admission to our hospital. Serum IgA concentration was within the normal limit, but an excess of myeloma cells in bone marrow was confirmed. Immunoelectrophoresis revealed BJP-λ production with no IgA-λ. The patient received several courses of chemotherapy with mechanical ventilation and regular hemodialysis. The progression of the illness was rapid: multiple organ failure promptly developed and the patient died 2 months after admission. Autopsy revealed deposition of light chain λ protein in multiple organs. We report this unusual case of aggressive myeloma recognized shortly after successful autologous transplantation.

Although great advancements have been witnessed in treatment results for hematopoietic tumors in recent years, development of secondary malignant tumors induced by anti-cancer drugs still remains a serious issue. We experienced a case of secondary myelodysplastic syndrome (MDS), possibly induced by cyclophosphamide (CY), which was spontaneously resolved by discontinuance of CY. A 24-year-old woman was diagnosed with follicular lymphoma in January 1998: she had developed bulky intra-abdominal lymphadenopathy, with repeated relapse and remission by several chemotherapy treatments. Remission was induced by rituximab, administered at the time of relapse in 2001, followed by administration of 50 mg/day of CY since December 2001 for the prevention of relapse. Anemia and thrombocytopenia developed around January 2003. Bone marrow aspiration revealed abnormality in two lineages and a complicated chromosomal anomaly, and the patient was diagnosed with MDS. Discontinuance of CY and administration of an anabolic steroid improved anemia and thrombocytopenia within 2 years. Bone marrow aspiration in 2006 showed improvement in morphological abnormality and disappearance of chromosomal abnormality.

Peroxisome proliferator-activated receptors (PPARs) compose a subfamily of nuclear hormone receptors functioning as transcriptional regulators. Originally, the PPARgamma ligand known as thiazolidinedione (TZD) was used for the treatment of diabetic patients. However, recent studies have shown that TZD also has an antitumor effect that inhibits cell growth in several types of human malignant neoplasms, including leukemia cell lines. Since pioglitazone is the only TZD currently available in clinics in Japan and the role of TZD in normal human hematopoietic cells or primary leukemia cells has not been previously reported, we investigated the effect of pioglitazone on human normal hematopoietic progenitor cells, primary leukemia cells, and leukemia cell lines (HL60, K562, U937, HEL, CEM, Jurkat, and NALM1). Pioglitazone inhibited the proliferation of leukemia cells in a dose-dependent manner. The viable cell numbers of HL60, K562, and Jurkat leukemia cell lines were profoundly reduced when the cells were cocultured with pioglitazone. Colony formation in the leukemia cell lines as well as the primary leukemia cells was significantly inhibited to 20-71% and 1-25% of that in control cultures by the addition of 100 and 300 microM of pioglitazone, respectively. However, the CFU-E and CFU-GM colonies of cells obtained from healthy volunteers were not altered in the presence of 100 microM of pioglitazone. Pioglitazone (300 microM) induced slight decrease of CFU-E and CFU-GM. BFU-E was more sensitive to pioglitazone than CFU-E and CFU-GM. Pioglitazone-induced growth inhibition in HL60 cells was associated with cell cycle arrest at the G1 phase, as has been reported for another TZD, troglitazone. Similar levels of PPARgamma protein were observed in both leukemia and normal bone marrow cells by Western blotting, suggesting that the expression of PPARgamma protein was not associated with the inhibitory potency of pioglitazone. In conclusion, our results suggest that pioglitazone may offer a new therapeutic approach to aid in the treatment of leukemia.

Background: The extent of clinical exposure needed to ensure quality care has not been well determined during internal medicine training. We aimed to determine the association between clinical exposure (number of cases seen), self- reports of clinical competence, and type of institution (predictor variables) and quality of care (outcome variable) as measured by clinical vignettes., Methods: Cross-sectional study using univariate and multivariate linear analyses in 11 teaching hospitals in Japan. Participants were physicians-in-training in internal medicine departments. Main outcome measure was standardized t-scores (quality of care) derived from responses to five clinical vignettes., Results: Of the 375 eligible participants, 263 (70.1%) completed the vignettes. Most were in their first (57.8%) and second year (28.5%) of training; on average, the participants were 1.8 years (range = 1-8) after graduation. Two thirds of the participants (68.8%) worked in university-affiliated teaching hospitals. The median number of cases seen was 210 (range = 10-11400). Greater exposure to cases (p = 0.0005), higher self-reports of clinical competence (p = 0.0095), and type of institution (p < 0.0001) were significantly associated with higher quality of care, using a multivariate linear model and adjusting for the remaining factors. Quality of care rapidly increased for the first 100 to 200 cases seen and tapered thereafter., Conclusion: The amount of clinical exposure and levels of self-reports of clinical competence, not years after graduation, were positively associated with quality of care, adjusting for the remaining factors. The learning curve tapered after about 200 cases.

Rituximab has markedly improved treatment results for B-cell lymphoma, but there are resistance problems similar to those of other chemotherapy drugs. With regard to the acquisition of rituximab resistance, there have been several reports describing the relation between rituximab and complement regulatory factors or CD20, but many points remain unclear. To further investigate acquisition of resistance to rituximab-related complement-dependent cytotoxicity (CDC), we established rituximab-resistant B-lymphoma cell lines (RAMOS) in vitro and then analyzed expression of CD20, CD55, and CD59 on these resistant cells by flow cytometry. With repeated exposure to a low concentration of rituximab and complement, RAMOS cells gradually acquired rituximab resistance, and selection and increase of CD55(bright) and CD59(bright) cell populations due to rituximab-related CDC were observed. With repeated exposure to a high concentration of rituximab and complement, RAMOS cells promptly acquired rituximab resistance, and CD20 expression of RAMOS cells was decreased. Not only selection of CD20(dim) cells but also down-modulation of CD20 caused by rituximab-related CDC appeared to cause the decrease in CD20 expression. We believe our findings will prove to be useful for prevention of or release from rituximab resistance in cases of B-cell lymphoma.