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Objective This study aimed to establish prediction models for respiratory-related mortality in microscopic polyangiitis (MPA) complicated by interstitial lung disease (ILD) using clinical characteristics. Methods We enrolled patients with MPA with ILD between May 2005 and June 2021 in a multicentre cohort of Japanese patients with MPA (REVEAL cohort). We evaluated the demographic, clinical, laboratory, radiological findings, treatments and the presence of honeycombing 1 cm above the diaphragm using chest high-resolution CT (HRCT) on admission. We explored the risk factors predictive of respiratory-related mortality. Results Of 115 patients, 26 cases died of respiratory-related diseases during a median follow-up of 3.8 years. Eighteen patients (69%) died due to respiratory infection, three (12%) had diffuse alveolar haemorrhage, and five (19%) had exacerbation of ILD. In univariate analysis, older age, lower percent forced vital capacity (%FVC), lower percent diffusing capacity of carbon monoxide (%DLCO), and the presence of honeycombing in the right lower lobe were identified as risk factors. Additionally, in multivariate analysis adjusted for age and treatment, %FVC, %DLCO and the presence of honeycombing in the right lower lobe were independently associated with respiratory-related mortality. We created prediction models based on the values of %FVC, %DLCO and presence of honeycombing on chest HRCT (termed "MPF model"). The 5-year respiratory-related death-free rate was significantly different between patients with MPA with ILD stratified by the number of risk factors based on the MPF model. Conclusions Our study indicates that the MPF model may help predict respiratory-related death in patients with MPA with ILD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Measures to prevent exposure to anticancer drugs mitigate health hazards for caregivers, family members, and healthcare workers caring for patients with cancer. Previous studies have reported that anticancer drugs were detected on the linens of patients receiving chemotherapy. OBJECTIVES: This pilot study investigated the effectiveness of the washing methods recommended by Japanese guidelines for linens contaminated with cyclophosphamide (CTX). METHODS: This study used 15 shirts contaminated with 10 mg of CTX divided into three study groups washed with or without detergent, with or without an additional clean shirt. The CTX level on each shirt was measured after washing. Residual CTX levels on the shirts were compared to the measurable level of 1 ng/cm2 as a criterion for evaluating efficacy. FINDINGS: Washing a garment twice, as recommended in the Japanese guidelines, is effective in removing CTX contamination from clothing with or without detergent. However, contaminated garments should be washed separately from uncontaminated clothing. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the duration of cyclophosphamide (CPA) excretion in the sweat after administration when receiving high-dose CPA therapy as a conditioning regimen for hematopoietic stem-cell transplantation (HSCT). Methods: Shirts and pillowcases samples (changed once a day) from 12 patients, categorized as groups 1 (n = 6), 2 (n = 4), and 3 (n = 2), receiving high-dose CPA therapy were collected, sealed, stored at 4°C, and mailed to an analytical facility for CPA estimation using LC-MS/MS. CPA was administered intravenously at a dose of 60 mg/kg on days 1, 2 (closed-system delivery for group 3), and samples were collected during days 1–4 (groups 1,3) or days 1–9 (group 2). Results: CPA was detected in all 126 shirts and pillowcases. In 9 patients, excluding 1 patient who had fever during the study period and group 3 patients, the mean (range) rate of CPA excretion in sweat was 0.03% (0.01–0.12%). The mean CPA excretion in 9 patients adjusted for body weight was 19.9 μg/kg on day 1 and 0.3 μg/kg on day 4. Conclusions: This study showed that CPA was excreted for an extended duration in the patient's sweat, receiving a high-dose CPA therapy as a conditioning regimen against HSCT. [ABSTRACT FROM AUTHOR]

We conducted a phase II trial to prospectively evaluate the efficacy and safety of bortezomib-cyclophosphamide-dexamethasone (VCD) induction, autologous stem cell transplantation (ASCT), VCD consolidation, and bortezomib maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients in Japan (UMIN000010542). From 2013 to 2016, 42 patients with a median age of 58 (range 42–65) years with NDMM were enrolled in 15 centers. The primary endpoint was the complete response (CR) /stringent CR (sCR) rate after transplantation, and overall/progression-free survival rates were also evaluated. Following induction therapy, the overall response rate was obtained in 71% of patients, including a CR/sCR of 10% and a very good partial response (VGPR) of 26%. Twenty-six of the 42 patients completed ASCT following the protocol and CR/sCR and VGPR rate 100 days after ASCT was 26% and 17%, respectively. During consolidation therapy, 3 of the 24 patients achieved deeper responses. Eight of the 18 patients completed 2-year bortezomib maintenance without disease progression and grade 3/4 toxicities. Five patients were VGPR or partial response after ASCT but maintained response with 2-year bortezomib maintenance. Two-year overall and progression-free survival rates were 92.5% (95% confidence interval [CI]: 78.5%−97.5%) and 62.6% (95% CI: 45.8%−75.5%), respectively. Grade 3/4 toxicities (≥ 10%) included neutropenia (19%) and anemia (17%) in induction, and thrombocytopenia (29%) in consolidation. VCD induction/consolidation and bortezomib maintenance with ASCT for NDMM resulted in a high CR/sCR rate and provided good overall/progression-free survival in Japan. [ABSTRACT FROM AUTHOR]

In recent years, local governments in Japan have established a public financial support system for fertility preservation in pediatric, adolescent, and young adult cancer patients. Fertility preservation has become popular for patients with cancers included in the gonadal toxicity risk classification of the 2017 edition of the Guideline for Fertility Preservation in Children, Adolescents and Young Adult Cancer Patients from the Japan Society of Clinical Oncology. However, patients with cancer and non-cancer diseases that are not included in the Guideline's gonadal toxicity risk classification also often receive treatment that may affect fertility, but they are often denied the opportunity of fertility preservation because no public financial support is available for diseases not listed in the Guideline. The national research project proposes including these diseases in the indications and treatment for fertility preservation. Therefore, we cooperated with the Japan Society for Fertility Preservation and the Ministry of Health, Labour and Welfare research group to solicit opinions from experts in each therapeutic area and reviewed the literature and overseas guidelines. This paper summarizes the findings of the project. We believe that it will be an important source of information for clinicians treating patients who need fertility preservation but note that the appropriateness of fertility preservation for the disorders listed in this report needs to be continuously reviewed as medical care advances. [ABSTRACT FROM AUTHOR]

Purpose: Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) prodrug, is used to prevent graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). Although previous studies have reported that enterohepatic circulation (EHC) of MPA, which is usually observed in MMF-treated patients, does not occur in HSCT patients, it is unclear what happens in haploidentical–HSCT (haplo-HSCT) patients, who are using post-transplant cyclophosphamide. This study was conducted to investigate MPA pharmacokinetics in haplo-HSCT patients. Methods: Seventeen haplo-HSCT patients, who received MMF for GVHD prophylaxis, were enrolled in this study. We collected blood samples on days 14 and 28, and plasma MPA concentrations were measured by high-performance liquid chromatography; pharmacokinetic parameters such as area under the curve (AUC), mean residence time (MRT), and apparent oral clearance (CL/F) were measured with moment analysis. We also evaluated EHC as AUC6-12h/AUC0-12h. Results: There was no significant difference in MPA pharmacokinetic parameters between days 14 and 28. There was also no difference between the pharmacokinetic parameter changes and diarrhea. Additionally, varying plasma MPA concentrations suggested that MPA EHC did not occur. Conclusion: In this study, we revealed the pharmacokinetics of MMF in Japanese haplo-HSCT recipients. Additionally, our study demonstrated that MPA EHC might not occur in Japanese haplo-HSCT recipients. [ABSTRACT FROM AUTHOR]

Objectives: Gonadotoxic therapies, mainly cyclophosphamide, are used for the treatment of various systemic autoimmune diseases. In Japan, the number of patients who undergo gonadotoxic therapy for autoimmune diseases, fertility preservation procedures performed in these patients, and problems associated with performing such procedures have not been reported. This study was performed to address these issues. Methods: A questionnaire was sent to Certified Educational Facilities of the Japanese Society of Rheumatology, and a single rheumatologist at each center completed the questionnaire. Results: A total of 63 facilities completed the questionnaire. Between April 2014 and March 2019, a total of 1302 men and premenopausal women had received gonadotoxic therapies for systemic autoimmune disease. Nearly half of the respondents reported that gonadotropin releasing hormone analog therapy was available in their area. However, the availability of other fertility preservation procedures was limited, and the number of patients undergoing fertility preservation procedures was limited. 85.7% of the respondents responded that measures to preserve fertility in patients receiving gonadotoxic therapies for autoimmune diseases were inadequate. Conclusions: A substantial number of patients are receiving gonadotoxic therapies for the treatment of autoimmune diseases in Japan, and those patients may not be receiving adequate care regarding their fertility. [ABSTRACT FROM AUTHOR]

This is a prognostic report by the Japanese Breast Cancer Society on breast cancer extracted from the National Clinical Database-Breast Cancer Registry of Japan. Here, we present a summary of 457,878 breast cancer cases registered between 2004 and 2016. The median follow-up duration was 5.6 years. The median age at the start of treatment was 59 years (5-95%: 38-82 years) and increased from 57 years between 2004 and 2008 to 60 years between 2013 and 2016. The proportion of patients with Stage 0-II disease increased from 74.5% to 78.3%. The number of cases with estrogen and progesterone receptor positivity increased from 74.8% to 77.9% and 60.5% to 68.1%, respectively. Regarding (neo-)adjuvant chemotherapy, the taxane (T) or taxane-cyclophosphamide (C) regimen increased by 2.4% to 8.2%, but the (fluorouracil (F)) adriamycin (A)-C-T/(F) epirubicin (E)C-T and (F)AC/(F)EC regimens decreased by 18.6% to 15.2% and 13.5% to 5.0%, respectively. Regarding (neo-)adjuvant anti-human epidermal growth factor-2 (HER2)-targeted therapy, the use of trastuzumab increased from 4.6% to 10.5%. The rate of sentinel lymph node biopsy increased from 37.1% to 60.7%, while that of axillary dissection decreased from 54.5% to 22.6%. Improvements in disease-free and overall survival were observed in patients with HER2-positive breast cancer, but there was no apparent trend in patients with hormone receptor-positive, HER2-negative, or triple-negative breast cancers., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Purpose: Sarcopenia has been reported to be associated with higher mortality and increased toxicity of chemotherapy in breast cancer patients. However, evidence from Asian countries is scarce. Here, we investigated the association between sarcopenia and the frequency of severe laboratory adverse events due to perioperative chemotherapy in Japanese breast cancer patients.Methods: Eighty-two patients with breast cancer receiving perioperative epirubicin plus cyclophosphamide therapy were evaluated. Skeletal muscle of the cross-sectional area at the third lumbar vertebra was measured by computed tomography, and sarcopenia was defined as skeletal muscle index < 40 cm2/m2. Laboratory toxicity during all cycles of perioperative chemotherapy was assessed. The study endpoint was the frequency of severe (grade 3 or more) laboratory adverse events.Results: Overall, 10 patients (12.2%) were classified as sarcopenic. The frequency of severe laboratory adverse events was 28.0%, and this was significantly higher in sarcopenic patients compared to non-sarcopenic patients (70% vs. 22.2%, odds ratio 7.9 (95% CI, 1.6-52.8), p = 0.004). Neither of body weight, body mass index, area of visceral adipose tissue, subcutaneous adipose tissue, nor skeletal muscle density was significantly associated with the frequency of severe laboratory adverse events.Conclusion: Sarcopenia was a significant risk factor of severe laboratory toxicity in breast cancer patients receiving perioperative epirubicin plus cyclophosphamide therapy. This finding raises the potential use of body composition assessment to predict the risk of chemotherapy toxicity and determine an individualized treatment strategy. [ABSTRACT FROM AUTHOR]

Purpose: Docetaxel is known to cause eye disorders. In this study, current status of eye disorders caused by docetaxel administration every 3 weeks in Japanese patients was examined. Methods: This case-control study targeted patients who were newly administered docetaxel at the Kyoto Okamoto Memorial Hospital between 1 July 2015 and 30 June 2018. Eye disorder occurrence was defined as an event in which the pharmacist confirmed the symptoms in a patient interview and the ophthalmologist diagnosed the disorder. Results: Of the 89 subjects, 7 (7.9%) had eye disorders. The symptoms were watering eyes (7.9%), a stye and eye discharge (2.2% each), corneal and conjunctival disorder, visual acuity reduction, and blepharedema (1.1% each). Four patients who presented with watering eyes, eye discharge, or corneal and conjunctival disorder showed improvement with the use of eye drops such as artificial tears. Two patients who presented with a stye showed improvement with the use of oral cefcapene. One patient with mild symptoms showed spontaneous improvement. However, one patient had irreversible visual acuity reduction. The multivariate logistic regression analysis revealed that a cumulative docetaxel dose of ≥300 mg/m2 (odds ratio: 15.50, 95% confidence interval: 1.37–175.00, p = 0.027) and concomitant cyclophosphamide use (odds ratio: 13.20, 95% confidence interval: 1.13–153.00, p = 0.039) were significant risk factors associated with eye disorders. Conclusion: In conclusion, it was determined that docetaxel-related eye disorders might be influenced by the cumulative dose of docetaxel and concomitant cyclophosphamide use. In addition, relatively mild symptoms improved with medication. [ABSTRACT FROM AUTHOR]

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL.Methods: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up.Findings: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment.Interpretation: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation.Funding: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center. [ABSTRACT FROM AUTHOR]

Background: Owing to the rarity of this tumor, there is limited information about second‐line chemotherapy for patients with previously treated advanced thymic carcinoma. Material and Methods: We performed a multi‐institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second‐line chemotherapy were obtained from medical records. Results: In total, 191 patients were enrolled in this study. Second‐line chemotherapy included platinum‐based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow‐up time was 50.5 months, and the median overall survival (OS) from the start of second‐line chemotherapy was 22.4 (95% confidence interval, 17.5‐26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum‐based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum‐based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively). Conclusion: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second‐line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study. Implications for Practice: Owing to the rarity of this tumor, there is limited information about second‐line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second‐line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients. Thymic carcinoma is rare and highly progressive. This study aimed to evaluate the efficacy of second‐line chemotherapy for patients previously treated for advanced thymic carcinoma and to identify promising chemotherapeutic regimens for clinical practice and further investigation. [ABSTRACT FROM AUTHOR]

Background: Myelosuppressive chemotherapy-induced febrile neutropenia (FN) is a life-threatening condition. Patients receiving granulocyte colony-stimulating factors (G-CSF) have shorter duration of neutropenia, faster recovery from fever, and shorter duration of antibiotics use. Most strategies for FN prevention using daily G-CSF and pegfilgrastim are based on overseas studies. Data on Japanese patients were lacking; thus, we previously determined the incidence of FN in non-Hodgkin B cell lymphoma (B-NHL) patients at our center. Here, we aimed to gain additional insights into pegfilgrastim use in this population.Methods: This single-center, retrospective, observational study (STOP FN in NHL 2) enrolled patients with B-NHL who underwent a regimen comprising rituximab and CHOP therapy over a 2-year period (January 2015-June 2017). The incidence of FN in cycle 1 of chemotherapy, risk factors for FN development, and use of daily G-CSF and pegfilgrastim were evaluated.Results: We evaluated 239 patients: 61 patients did not receive G-CSF and 178 received G-CSF. The incidence of FN was 10.5% (95% confidence interval [CI] 6.9-15.1%) in cycle 1 and 13.0% (95% CI 9.0-17.9%) in all cycles. The FN incidence was significantly lower (P = 0.0008) in patients receiving daily G-CSF and pegfilgrastim than patients not receiving G-CSF. Significant risk factors for FN were age ≥ 65 years, albumin < 3.5 g/dL, hemoglobin < 12 g/dL, and no prophylaxis with daily G-CSF/pegfilgrastim during cycle 1.Conclusions: The incidence of FN in cycle 1 and in all cycles and the identified risk factors were similar with those we previously reported; thus, our results validate previous findings.Trial Registration: UMIN000029534. [ABSTRACT FROM AUTHOR]

Purpose: Epirubicin and cyclophosphamide (EC) therapy, a major chemotherapy for patients with early-stage breast cancer, has a low risk (< 10%) of febrile neutropenia (FN). However, data used in reports on the incidence rate of FN were derived primarily from non-Asian populations. In this study, we investigated the FN incidence rate using EC therapy among Japanese patients with breast cancer and evaluated the significance of prophylactic administration of granulocyte colony-stimulating factor (G-CSF).Methods: We evaluated medical records of patients with early-stage breast cancer who had been treated with EC therapy as neoadjuvant or adjuvant therapy between November 2014 and July 2018.Results: The incidence rate of FN was 23.9%. In patients who received G-CSF as primary prophylaxis, FN expression was completely suppressed. The incidence rate of severe leucopenia/neutropenia, emergency hospitalization, and the use of antimicrobial agents were low in patients receiving primary prophylaxis with G-CSF compared with those not receiving G-CSF (27.3% vs. 64.8%, 9.1% vs. 27.3%, and 27.3% vs. 71.6%, respectively). Furthermore, in all patients who received primary prophylaxis with G-CSF, a relative dose intensity > 85% using EC therapy was maintained.Conclusion: The incidence of FN in EC therapy among Japanese patients was higher than expected, EC therapy appears to be a high-risk chemotherapy for FN, and prophylactic administration of G-CSF is recommended. Maintaining high therapeutic intensity is associated with a positive prognosis for patients with early breast cancer, and prophylactic administration of G-CSF is likely to be beneficial in treatment involving EC therapy. [ABSTRACT FROM AUTHOR]

Trematodes of the genus Mesocoelium Odhner, 1910 (Digenea: Plagiorchioidea: Mesocoeliidae) are globally distributed and parasitize amphibians, reptiles, or occasionally fishes. This genus is one of the most confusing taxa in trematodes because of its poor morphological features. In this study, we examined species of Mesocoelium collected from Japanese amphibians and found that they can be morphologically assigned to two species of Mesocoelium. Mesocoelium brevicaecum Ochi in Goto and Ozaki, 1929 parasitizes various both urodelan and anuran amphibians and occurred widely in Japan, while M. japonicum Goto and Ozaki, 1930 parasitizes a few hynobiid species in a limited part of Japan. We proposed ceca length as a valid key characteristic for species identification in this genus. M. elongatum Goto and Ozaki, 1929, M. lanceatum Goto and Ozaki, 1929, M. minutum Park, 1939, M. ovatum Goto and Ozaki, 1930, and M. pearsei Goto and Ozaki, 1930 are junior synonyms of M. brevicaecum, while M. japonicum can be distinguishable from them by morphologically and molecularly. Our molecular study supported the validity of both species and showed intraspecific divergence associated with geographic distance. Molecular identification suggests that the land snail Euhadra quaesita can serve as the first intermediate host for M. japonicum in Japan. This study also indicates the extremely low specificity of this genus for vertebrate hosts. Finally, we conclude that at least three species of Mesocoelium (M. brevicaecum, M. japonicum, and Mesocoelium sp. 1) are distributed in Japan. Further studies in other regions are undoubtedly required for a better understanding of the taxonomy and ecology of the genus Mesocoelium., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Interstitial lung disease (ILD) is recognized a prognostic factor and leading cause of death in patients with systemic sclerosis (SSc). The aim of the present study is to clarify factors at an initial visit that are associated with the deterioration of ILD in SSc patients with anti-topoisomerase I (anti-topo I) antibodies. This was a single-center, retrospective, observational study. Fifty-three consecutive SSc patients with anti-topo I antibodies were included in this study. Of the 53 patients, 43 had ILD at their initial visit, whereas 10 did not. We examined the clinical and immunological factors at an initial visit that were associated with the deterioration of ILD. The deterioration of ILD was defined as the administration of intravenous cyclophosphamide (IVCY) therapy. In this cohort, 45 (85%) patients had ILD at the time of the final observation, and only two who did not have ILD at their initial visit developed ILD during the follow-up period. Until the final observation, 26 (49%) patients received IVCY therapy for the progression of ILD. The age at onset, disease duration, SSc subtype, and skin score were similar between patients with and those without IVCY therapy. Approximately 60% (26 of 43) of patients with ILD at their initial visit received IVCY therapy. On the other hand, none of the 10 patients without ILD at their initial visit received IVCY therapy. Our multivariate analyses using Cox proportional hazards regression model revealed that the presence of ILD at an initial visit was an independent factor associated with the introduction of IVCY therapy (odds ratio, 2.8e+7 [95% confidence interval, 1.8e+17-uncalculated], p = 0.0048). Although anti-topo I antibodies are strongly associated with ILD, it was unlikely for SSc patients with anti-topo I antibodies to receive IVCY therapy when they did not have ILD at an initial visit., (© 2023 Japanese Dermatological Association.)

Real-world evidence for clinical outcomes and treatment patterns in patients with hormone receptor-positive(HR+)and human epidermal growth factor receptor 2-negative(HER2-)early breast cancer(EBC)in Japan is limited. We aimed to provide recent evidence in this population using the National Database of Health Insurance Claims and Specific Health Check-ups of Japan(NDB). Adults ≥20 years old who were diagnosed with HR+/HER2- breast cancer and underwent breast resection surgery were followed up. Patient characteristics and treatment patterns were evaluated. Durations of overall post-operative endocrine therapy(ET)and luteinizing hormone-releasing hormone(LH-RH)agonist therapy, and time to metastasis/recurrence after surgery were analyzed using Kaplan-Meier method. Overall, 294,904 patients were included. Cyclophosphamide and tamoxifen were the most common peri-operative chemotherapeutic and ET drugs. Median(95% confidence interval[CI])duration of post-operative ET and LH-RH agonist therapy was 5.01(5.01-5.01)years and 2.13 (2.12-2.14)years, respectively. Five-year cumulative rate(95% CI)of any recurrence was 8.6%(8.5-8.7), visceral metastasis being the most common. Nation-wide treatment patterns were described, which were consistent with guideline recommendations for patients with HR+, HER2- EBC. Further discussion is required to delay metastasis/recurrence and improve clinical outcomes(Fig. 1: Plain language summary of the study).

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The geriatric nutritional risk index (GNRI) is a simple and well-established nutritional assessment tool that is a significant prognostic factor for various cancers. However, the role of the GNRI in predicting clinical outcomes of diffuse large B cell lymphoma (DLBCL) patients has not been investigated. To address this issue, we retrospectively analyzed a total of 476 patients with newly diagnosed de novo DLBCL. We defined the best cutoff value of the GNRI as 96.8 using a receiver operating characteristic curve. Patients with a GNRI < 96.8 had significantly lower overall survival (OS) and progression-free survival (PFS) than those with a GNRI ≥ 96.8 (5-year OS, 61.2 vs. 84.4%, P < 0.001; 5-year PFS, 53.7 vs. 75.8%, P < 0.001). Multivariate analysis showed that performance status, Ann Arbor stage, serum lactate dehydrogenase, and GNRI were independent prognostic factors for OS. Among patients with high-intermediate and high-risk by National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI), the 5-year OS was significantly lower in patients with a GNRI < 96.8 than in those with a GNRI ≥ 96.8 (high-intermediate risk, 59.5 vs. 75.2%, P = 0.006; high risk, 37.4 vs. 64.9%, P = 0.033). In the present study, we demonstrated that the GNRI was an independent prognostic factor in DLBCL patients. The GNRI could identify a population of poor-risk patients among those with high-intermediate and high-risk by NCCN-IPI. [ABSTRACT FROM AUTHOR]

Purpose: The incidence of and risk factors for febrile neutropenia (FN) in Japanese non-Hodgkin B-cell lymphoma (B-NHL) patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and predonisolone (R-CHOP) chemotherapy are unknown. We conducted this study to address this issue.Methods: In this single-center, retrospective, observational study, 466 patients with B-NHL who completed an R-CHOP regimen within a 7-year period and who planned to undergo at least three cycles of this regimen were analyzed. The following FN-related factors were assessed: fever, infection, disease state, neutrophil count, and prophylactic interventions such as use of antibiotics and/or granulocyte colony-stimulating factor (G-CSF). We simulated the FN incidence and 95% confidence interval (CI) of patients without prophylaxis with G-CSF (cycle 1) using bootstrap sampling.Results: The incidence of FN was 9.1% (42 of 462) in cycle 1 and 12.3% (57 of 462 patients) throughout all cycles, with 73.7% (42/57) developing FN during cycle 1. Risk factors for FN among patients with B-NHL treated with R-CHOP were albumin <35 g/L (p = 0.0047), relative dose intensity <85% (p = 0.0007), and lack of prophylaxis with G-CSF (p = 0.0006) in cycle 1. In the simulation analysis, the estimated FN incidence in cycle 1 was 16.2% (95% CI [10.9-22.2]).Conclusions: At 9.1% in cycle 1 and 12.3% throughout all cycles, the incidence of FN was lower than previously reported, possibly reflecting the appropriate use of G-CSF in this clinical setting. For patients with risk factors, the prophylaxis with G-CSF may decrease the occurrence of FN. [ABSTRACT FROM AUTHOR]

Background: Decision‐making models for elderly patients with diffuse large B‐cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) are in great demand. Patients and Methods: The Society of Lymphoma Treatment in Japan (SoLT‐J), in collaboration with the West‐Japan Hematology and Oncology Group (West‐JHOG), collected and retrospectively analyzed the clinical records of ≥65‐year‐old patients with DLBCL treated with R‐CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R‐CHOP. Results: A total of 836 patients with a median age of 74 years (range, 65–96 years) were analyzed. In the SoLT‐J cohort (n = 555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score ≥3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into “excellent” (0 points), “good” (1 point), “moderate” (2 points), and “poor” (3 points) groups. This grouping effectively discriminated the 3‐year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R‐CHOP discontinuance rates, febrile neutropenia rates, and treatment‐related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West‐JHOG cohort (n = 281). Conclusion: The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R‐CHOP. Implications for Practice: Currently, little is known regarding how to identify elderly patients with diffuse large B‐cell lymphoma who may tolerate a full dose of chemotherapy or to what extent cytotoxic drugs should be reduced in some specific conditions. The Society of Lymphoma Treatment in Japan developed a host‐dependent prognostic model consisting of higher age (>75 years), hypoalbuminemia (<3.7 g/dL), and higher Charlson Comorbidity Index score (≥3) for such elderly patients. This model can stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of these patients and thus help clinicians in formulating personalized treatment strategies for this growing patient population. R‐CHOP has improved the clinical outcome of diffuse large B‐cell lymphoma compared with CHOP alone; however, patients with unfavorable prognostic factors have less change of benefitting from such standard treatments. Advanced age is a crucial risk factor for unfavorable prognosis, as is hypoalbuminemia and medical comorbidities. This study measured the effects of these three biomarkers on clinical outcomes and developed a decision‐making treatment model that can serve as a guide for optimal personalized therapy for elderly patients treated with R‐CHOP. [ABSTRACT FROM AUTHOR]

Recent large-scale randomized clinical trials in Europe and the US demonstrated that maintenance therapy with rituximab significantly improved the progression-free survival (PFS) in indolent B-cell non-Hodgkin lymphoma (B-NHL) patients, especially those with follicular lymphoma (FL). However, rituximab maintenance has not been approved in Japan, because there are no clinical data supporting the benefit of rituximab maintenance in Japanese patients. Therefore, we conducted a single-arm, multicenter bridging study in previously untreated indolent B-NHL patients with high tumor burden. The primary endpoint was 4-year PFS and was expected to be 70 % based on previous studies. Sixty-two patients, including 55 FL patients, were enrolled and received induction therapy with CHOP combined with rituximab (R-CHOP). Fifty-eight patients responding to R-CHOP induction received rituximab at 375 mg/m2 every 8 weeks for 2 years as for the rituximab maintenance arm in the PRIMA study. A 4-year PFS of 69.8 % was obtained (95 % confidence interval 55.9-80.0 %). Rituximab maintenance was well tolerated and common adverse events were infections, neutropenia, and/or leukopenia that were manageable with conventional supportive care. No patients died. These data were compatible with the PRIMA data. R-CHOP induction followed by rituximab is useful in Japanese patients with untreated indolent B-NHL having high tumor burden. Clinical trial number UMIN000001191. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the impact of medication on antibody response to severe acute respiratory syndrome coronavirus-2 mRNA vaccines in Japanese patients with rheumatic diseases., Methods: This prospective multicentre cohort study evaluated the humoral response in 12 different medication groups. Antibody levels before the first vaccination and 3-6 weeks after the second vaccination were measured using the Elecsys Anti-SARS-CoV-2 S assay. Statistical analysis included comparing antibody titres among the different medication groups using the Kruskal-Wallis test followed by the Bonferroni-Dunn test and multiple linear regression analysis., Results: 295 patients were analysed. The seroconversion rate was 92.2% and the median antibody titre was 255 U/ml (interquartile range, 34.1-685) after the second mRNA vaccination. Antibody levels were significantly lower in the groups treated with Tumour necrosis factor inhibitor with methotrexate, abatacept, mycophenolate mofetil (MMF), MMF or mizoribine combined with calcineurin inhibitor, and rituximab or cyclophosphamide compared with those treated with sulfasalazine and/or bucillamine or calcineurin inhibitor (p < 0.01). The correlation between antibody titre and treatment was significant after adjusting for age, gender, and glucocorticoid dose (p < 0.01)., Conclusions: Additional early vaccination is required in patients treated with Tumour necrosis factor inhibitor and methotrexate, abatacept, MMF, MMF or mizoribine combined with calcineurin inhibitor and rituximab or cyclophosphamide., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The aim of this study was to determine the efficacy of cyclophosphamide (CY) on anti-neutrophil cytoplasmic antibody (ANCA)-positive microscopic polyangiitis (MPA) with renal involvement in Japanese patients. Methods: Eighty-two patients with newly diagnosed ANCA-positive MPA were enrolled in this retrospective study. Patients were divided into two groups based on whether they received combination therapy with a corticosteroid (CS) plus CY (CY group) or CS alone or with other therapies (non-CY group). The primary outcome was defined as the combination of death and end-stage renal disease (ESRD). Results: The CY and non-CY groups included 29 and 53 patients, respectively. In the non-CY group, 31 patients were treated with CS alone, and 22 with a combination of CS and other therapeutics. The percentage of males and mean Birmingham vasculitis activity scores were higher in the CY group than those in the non-CY group, but other factors such as age, serum creatinine, serum albumin, or CRP at baseline were equivalent in the two groups. No differences were observed in remission rates using induction therapy for the two groups. However, the survival rate 5 years after induction therapy was lower in the CY group than in the non-CY group (0.50 vs. 0.73; P = 0.041), although the hazard ratio of CY for the primary outcome adjusted for all confounding factors was 1.321 [95 % confidence interval (CI), 0.662-2.637; P = 0.171]. Conclusions: CY may not have an additive effect on induction therapy with CS for Japanese patients with renal vasculitis associated with ANCA-positive MPA. [ABSTRACT FROM AUTHOR]

Okinawa Prefecture, located in the subtropics, is an area of endemic adult T-cell leukemia-lymphoma (ATL) in Japan. We retrospectively analyzed 659 patients with aggressive ATL in seven institutions in Okinawa between 2002 and 2011. The median patient age was 68 years. More patients were aged ≥90 years (2.6 %), in this study, than in a nationwide survey (<1 %). The median survival time (MST) of the entire cohort was 6.5 months. Of the 217 patients who had a clinical status similar to that stated in the eligibility criteria of JCOG9801 (a randomized phase III study comparing VCAP-AMP-VECP with CHOP-14), 147 who received the CHOP regimen had a poorer MST than those in the CHOP-14 arm of JCOG9801 (8 vs 11 months). The prevalence of strongyloidiasis in the ATL patients was much higher (12.4 %) than in the historical cohort who visited the University of the Ryukyus Hospital (3.4 %). Furthermore, strongyloidiasis may be associated with ATL-related deaths. These findings suggest that, compared with other areas in Japan, in Okinawa, the proportion of patients aged ≥90 years with clinical features of aggressive ATL is higher, outcomes are poorer, and the disease is associated with a higher prevalence of strongyloidiasis. [ABSTRACT FROM AUTHOR]

Background: To clarify the clinical manifestations of pediatric complement component C3 glomerulonephritis (C3GN), we retrospectively evaluated differences in the clinicopathological findings and prognosis between C3GN and immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). Methods: Thirty-seven patients diagnosed with 'idiopathic MPGN' were enrolled in this retrospective study. The patients were divided into two groups, with Group 1 consisting of 19 patients diagnosed with IC-MPGN and Group 2 consisting of 18 patients diagnosed with C3GN. The clinical findings and the prognosis were investigated for both groups. Results: Thirteen patients in Group 2 were identified by mandatory annual school screening for urinary abnormalities. The incidence of macro-hematuria and the frequency of low serum C4 values were lower in Group 2 patients than in Group 1 patients. At the time of the second renal biopsy, urinary protein excretion, incidence of hematuria, frequency of low serum C3 values, and scores for mesangial proliferation, glomerular sclerosis, and interstitial fibrosis were higher in Group 2 patients than in Group 1 patients. At the most recent follow-up examination, the number of patients categorized as non-responding or with end-stage renal disease was higher in Group 2 patients than in Group 1 patients. Conclusions: Our results suggest that the treatment response and prognosis of patients with C3GN are worse than those of patients with IC-mediated MPGN. Therefore, in the clinical context regarding treatment options and prognosis, it may be useful to classify idiopathic MPGN as C3GN or IC-MPGN. In addition, long-term follow-up of C3GN is necessary. [ABSTRACT FROM AUTHOR]

Background: As the morphological and immunohistochemical manifestations of immunoglobulin A (IgA) nephropathy and Henoch-Schonlein purpura nephritis (HSPN) are very similar, they are considered to share a common pathogenesis. Although HSPN usually develops after the appearance of anaphylactoid purpura, we have encountered patients whose renal symptoms preceded purpura. Methods: We reviewed the clinical courses of patients who were first diagnosed with IgA nephropathy, but developed purpura later, at the National Center for Child Health and Development in Tokyo, Japan. Results: Of the 53 patients who were diagnosed with primary IgA nephropathy at our institute during the study period (March 2002 to July 2015), six (11 %) developed anaphylactoid purpura after the diagnosis of primary IgA nephropathy and therefore met the inclusion criteria. Duration between the onset of nephritis and subsequent appearance of purpura ranged from 5 months to 14 years. One patient reached end-stage renal failure due to IgA nephropathy and developed purpura after renal transplantation. All renal biopsies performed before the appearance of purpura showed mesangial proliferation with predominant IgA deposits. Urinary findings deteriorated in three patients after the appearance of purpura, including one patient who developed rapidly progressive glomerulonephritis. Renal biopsy findings worsened in two patients. At the last observation, two patients showed mild renal insufficiency. Conclusions: Our clinical experience and previous reports support the argument that IgA nephropathy and HSPN are different manifestations of a single disease. Hence, it is acceptable to consider that they are variants of a single disease. [ABSTRACT FROM AUTHOR]

This article reviews the current status of treatment for children with rhabdomyosarcoma, according to the four risk groups. Low-risk subgroup A: the Children's Oncology Group in the USA recently performed a clinical trial consisting of a chemotherapy regimen with a shortened treatment period and a reduced drug dosage. Patients in this group received only four cycles of vincristine and actinomycin D (VA) after four cycles of vincristine, actinomycin D, and cyclophosphamide (VAC) with cyclophosphamide (CPM) 1.2 g/m2 and their outcome was no worse than that obtained with previous regimens. Low-risk subgroup B: although marked improvement in survival was seen with an intensive VAC regimen with CPM 2.2 g/m2/cycle (Intergroup Rhabdomyosarcoma Study [IRS]-V, 1997-2004), the total dose of CPM in this regimen caused serious and fatal hepatic veno-occlusive disease during treatment and probably cannot avoid infertility or possible secondary cancer as a late effect. Thereafter, a reduced-dose regimen consisting of four cycles of VAC with CPM 1.2 g/m2 followed by 12 cycles of VA was investigated in the next study, but the outcome appeared to be worse than in IRS-V. Intermediate-risk group: no significant difference was found between VAC/vincristine, topotecan and cyclophispahamide (VTC) and intensive VAC in IRS-V. The results of a subsequent regimen of VAC with CPM 1.2 g/m2 alternating with vincristine and irinotecan are awaited. High-risk group: overall survival is approximately 30% and has not improved over the last 25 years. Although 18 month failure-free survival (FFS) was improved with an intensive combination therapy regimen, 36 month FFS dropped to 32% and thus better novel approaches or additive treatments are needed. [ABSTRACT FROM AUTHOR]

Purpose/Objectives: To measure the total amount of cyclophosphamide (CPA) excreted in the urine of patients with cancer and their cohabitating family members seven days after CPA administration. Design: Biological monitoring. Setting: Home setting with outpatients receiving chemotherapy. Sample: 8 patients administered CPA, 10 cohabitating family members, and 10 control participants. Methods: During the first seven days after CPA administration, urine samples were collected from the participants. The samples were analyzed for the unchanged form of CPA using gas chromatography in tandem with mass spectroscopy. Main Research Variables: CPA levels. Findings: CPA was detected in 112 of 276 patient urine samples. The last sample containing detectable CPA levels was collected after more than 48 hours in 63% of the patients, with a maximum length of five days post-treatment. In addition, 243 urine samples were collected from family members, and CPA was detected in the samples of five family members (17-252 ng per member). CPA was not detected in any control participants. Conclusions: These findings indicate that family members in close contact with patients receiving CPA are at high risk for drug exposure as many as seven days post-treatment. Implications for Nursing: Nurses should educate patients and their family members about preventing exposure to antineoplastic drugs in the home setting. [ABSTRACT FROM AUTHOR]

Purposes: (a) To measure the urinary excretion of antineoplastic drugs of three patients during 48 h after the administration of cyclophosphamide (two patients) and 5-fluorouracil (one patient). (b) To evaluate environmental contamination with antineoplastic drugs via excreta of patients in the home setting. (c) To evaluate exposure of family members to antineoplastic drugs by measuring the drugs in their urine during the 48 h after completion of the chemotherapy by the patients. Methods: Two patients were administered cyclophosphamide by i.v. bolus injection. One patient was administered 5-fluorouracil by i.v. bolus injection and thereafter immediately administered the same drug by continuous infusion for 46 h. Urine samples from the patients administered cyclophosphamide and their family members, and wipe samples from their home environment, were analysed for the unchanged form of cyclophosphamide. For 5-fluorouracil, the urine samples from the patient and the family member were analysed for the 5-fluorouracil metabolite a-fluoro-b-alanine. Wipe samples were analysed for 5-fluorouracil. Drugs were detected and quantified with gas chromatography in tandem with mass spectroscopy-mass spectroscopy or by high-performance liquid chromatography with ultraviolet-light detection. Results: A total of 35 and 16 urine samples were collected from the three patients and their family members, respectively. The drugs were detected in all samples. Cyclophosphamide was detected at levels of 0.03–7.34 ng/cm2 in 8 of the 12 wipe samples obtained from the homes of the patients administered cyclophosphamide. For the patient administered 5-fluorouracil, drug levels in his home environment were below the limit of detection. Conclusion: We demonstrated contamination of the home setting and exposure of family members to cyclophosphamide via the excreta of outpatient receiving chemotherapy. Exposure of the family member of the patient administered 5-fluorouracil was also demonstrated. These findings indicate the importance of strict precautions by the members of treated cancer patients as well as healthcare workers, to reduce the risk of exposure to antineoplastic drugs. [ABSTRACT FROM AUTHOR]

Abstract: We analyzed the outcomes of 61 patients with hematologic malignancies who underwent double-unit cord blood transplantation (dCBT) after myeloablative conditioning performed as part of a prospective multicenter phase II study. The conditioning regimen for dCBT included total body irradiation, cyclophosphamide, and granulocyte colony-stimulating factor combined with cytosine arabinoside for myeloid malignancies and with total body irradiation and cyclophosphamide for lymphoid malignancies. The cumulative incidence of neutrophil engraftment after dCBT was 85% (95% confidence interval [CI], 73%-92%). All 51 of the patients who engrafted had complete chimerism derived from a single donor by day +60. Only the degree of HLA disparity in the host-versus-graft direction had an impact on unit dominance. The cumulative incidence of grade II-IV acute graft-versus-host disease was 25% (95% CI, 15%-37%), and that of chronic graft-versus-host disease was 32% (95% CI, 20%-44%). The 1-year cumulative incidence of relapse was 23% (95% CI, 13%-34%), and that of transplantation-related mortality was 28% (95% CI, 17%-39%). With a median follow-up of 41 months, event-free survival was 48% (90% CI, 37%-58%) at 1 year and 46% (90% CI, 35%-56%) at 3 years. Event-free survival at 3 years was 67% (95% CI, 46%-81%) for patients with standard risk and 29% (95% CI, 15%-45%) for those with advanced risk. This study suggests that dCBT after myeloablative conditioning is a promising alternative for adults and large children with hematologic malignancies who need stem cell transplantation but lack a suitable adult donor or an adequate single-unit cord blood graft. [Copyright &y& Elsevier]

Objectives: To determine cyclophosphamide exposure to preparers during tablet crushing and subsequent handling by analyzing indoor air collected using a high-performance volatile organic compounds-solvent desorption (VOC-SD) passive air sampler.Methods: The passive sampler was taped to the mask over the mouth of the preparer and indoor air was collected during crushing and preparation of cyclophosphamide tablets (Endoxan®). After collection, the carbon molecular sieve adsorbent of the passive sampler was placed in a centrifuge tube, and 1 mL of carbon disulfide was used to elute cyclophosphamide from the adsorbent. Liquid–liquid extraction with 1 mL of water was performed, and the aqueous phase was used as the test solution. Cyclophosphamide concentration was determined by liquid chromatography with ultraviolet and tandem mass spectrometry detection.Results: Cyclophosphamide concentration was detected in the range of 7.6–157.7 ng/sampler. Our results showed that low-level exposure occurred near the mouth of the preparer, which could present risks for long-term exposure, especially if combined with multiple toxic drug exposures.Conclusion: The anticancer drug monitoring methodology described here is a simple exposure assessment that can be used to ensure the safety of hospital pharmacy tablet preparers. Furthermore, since the anticancer drug exposure risk is very high for preparers, preparation should be in hood or with face mask. [ABSTRACT FROM PUBLISHER]

Background: This study aimed to describe the epidemiologic characteristics of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan. Methods: We used the database of the Ministry of Health, Labour and Welfare (MHLW) from 2006 to 2008, and analyzed data from 938 patients (MPA = 697, GPA = 241) who fulfilled the MHLW diagnostic criteria and had registered within a year after onset. Results: The mean ages of the MPA and GPA patients were 69.4 ± 0.4 and 58.4 ± 1.1 years, respectively. Renal (86.9 %), chest (73.7 %), and nervous system (45.2 %) symptoms were common in MPA patients. Ear, nose, and throat (86.7 %), chest (78.0 %), and renal (60.6 %) symptoms were frequently observed in GPA patients. The concomitant use of cyclophosphamide (CY) with corticosteroids was observed in 22.2 % of the MPA patients and 58.5 % of the GPA patients. In multivariate analysis, the concomitant use of CY was associated with a younger age and pulmonary hemorrhage in MPA patients, and the avoidance of CY was associated with nervous system symptoms and rapidly progressive glomerulonephritis in GPA patients. Plasma exchanges were inducted in 5.2 % of the MPA patients and 4.1 % of the GPA patients. The addition of plasma exchange was associated with elevation of the serum creatinine level in patients with both MPA and GPA. Conclusion: A dominance of MPA and a reduced frequency of renal involvement in GPA patients may be significant features of the Japanese population. Clinical practice relating to MPA and GPA in Japan can be characterized as follows: CY is used less commonly, and plasma exchange is employed for patients with deteriorated renal function. [ABSTRACT FROM AUTHOR]

Objectives: Recent studies have shown that mycophenolate mofetil (MMF) is similar to intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis (LN), but that treatment response may vary according to location and race/ethnicity. Moreover, no studies have been conducted to compare the efficacy of MMF with that of IVC for a Japanese population. We therefore conducted a retrospective study to clarify the efficacy and safety of MMF compared with that of IVC for induction therapy for active LN, classes III and IV, in a Japanese population of 21 patients, 11 of whom received MMF and 10 IVC. Methods: The primary endpoint was expressed as the percentage of responders, who in turn were defined as the patients who met complete or partial response criteria according to the European consensus statement. The secondary endpoints comprised the renal activity component and serological activity. Results: The primary endpoint was achieved in nine (81.8 %) patients receiving MMF and in four (40.0 %) receiving IVC, with no significant difference between the two groups ( p = 0.081), while there was also no significant difference between them in terms of secondary endpoints. However, the MMF group suffered significantly fewer hematologic toxic effects than the IVC group. Conclusions: MMF may be used as an alternative to IVC for inducing renal remission of LN in Japanese patients. [ABSTRACT FROM AUTHOR]

Objectives. To compare the effectiveness of an alkylating agent with that of a biologic agent in the treatment of patients with amyloid A (AA) amyloidosis secondary to RA and to assess the association of the serum AA (SAA) 1.3 allele with treatment.Methods. CYC and etanercept (ETN) were administered to 62 and 24 RA patients, respectively, who were confirmed with biopsy as having AA amyloidosis. We evaluated whether the SAA1.3 allele, a factor indicating genetic risk and poor prognosis of Japanese RA patients with AA amyloidosis, influenced treatments and retrospectively analysed the effectiveness of both agents via statistical methods.Results. Two treatment groups were similar, except for the SAA1.3 genotype (P = 0.015) and duration of AA amyloidosis since diagnosis (P < 0.001). Also, patients given ETN had somewhat worse renal function, i.e. 24-h proteinuria (P = 0.02), at the initiation of treatment. ETN demonstrated greater effectiveness than CYC, as shown by significantly improved levels of serum CRP and serum albumin (both P < 0.01) and estimated glomerular filtration rate (eGFR; P = 0.032). ETN improved survival (P = 0.025), and the hazard ratios for the risk of death endpoint with eGFR and 24-h proteinuria were significant by P = 0.024 and P = 0.025, respectively. The SAA1.3 allele did not affect the response to medications in AA amyloidosis secondary to RA.Conclusion. ETN treatment was more effective than CYC treatment, and CRP, albumin and eGFR may be valuable biomarkers for analysis. The SAA1.3 allele was not a factor affecting treatment in Japanese patients with AA amyloidosis secondary to RA. [ABSTRACT FROM AUTHOR]

The current therapeutic regimen recommended by the European League against Rheumatism (EULAR) for anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is continuation of initially administered doses of glucocorticoids (GCs) in combination with cyclophosphamide (CYC) for 1 month followed by gradual tapering. Considering the adverse effects of GCs, another tapering regimen of GCs with CYC, which was characterized by tapering GCs weekly, was reported by the British Society of Rheumatology (weekly-reduction regimen). The aim of the present study is to evaluate the safety and efficacy of this weekly-reduction regimen for Japanese AAV patients in comparison with the monthly-reduction regimen recommended by the EULAR. We retrospectively reviewed medical records of adult patients newly diagnosed with AAV during the period from April 2000 to December 2010. The outcome measures were rates of remission, relapse, infection, and GC-induced diabetes mellitus during the first 12 months. Clinical data in the two groups and categorial variables with a possible relation to the outcomes were compared by using the t test and chi-square test, respectively. Twenty-four patients were enrolled in our study. All of the patients achieved remission, and the rates of relapse during the first 12 months were not statistically different between the two groups ( P = 0.16). Patients treated with the weekly-reduction regimen were less liable to have infection ( P = 0.03) and impaired glucose tolerance ( P = 0.017), compared with those treated with the monthly-reduction regimen. A therapeutic strategy using the weekly-reduction regimen of GCs would be effective and would have fewer side effects than the monthly-reduction regimen. [ABSTRACT FROM AUTHOR]

Background: This study was conducted to standardize treatment and determine patient and renal outcome in Japanese anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis/rapidly progressive glomerulonephritis (AAV/RPGN) patients, because the prognosis of AAV/RPGN patients in Japan had been poor compared with that of other countries. Methods: The participants in this retrospective cohort study were 824 ANCA-positive RPGN patients, 705 of whom were only myeloperoxidase (MPO)-ANCA positive. Results: Among the early-years cohort (group A; cases diagnosed between 1988 and 1998), patients frequently died due to opportunistic infection. Therefore, we recommended a reduced dose of prednisolone (oral prednisolone dose <0.8 mg/kg/day) with or without cyclophosphamide for initial treatment of Japanese RPGN patients. After this recommendation, 1-year survival of the patients improved: 75% in group A, 79% in group B (between 1999 and 2002), and 81% in group C (after 2003). During the entire observation period, average serum creatinine level at the start of treatment decreased, and improvement of 1-year renal survival was also found (72% in group A, 83% in group B, and 83% in group C), while the recurrence rate was significantly increased in group C (0.05/patient-year in group A, 0.07/patient-year in group B, and 0.13/patient-year in group C). Conclusions: Oral prednisolone dose <0.8 mg/kg/day with or without cyclophosphamide as an initial treatment could improve patient survival in older Japanese AAV/RPGN patients. However, maintenance treatment avoiding relapse should be established to improve renal outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Cyclophosphamide (CP) contamination has been detected in Japanese hospitals. In other countries, the surface contamination of CP vials has been reported; however, the manufacturing process of Japanese CP vials is unknown, so the conditions are not necessarily the same as in other countries. This study aimed to establish whether vial surface contamination also occurs in Japan.Method: Contamination of vial surfaces was examined with a wipe test. Urine samples were taken from a pharmacist, engaged solely in dispensing work, for 29 h. It was also investigated whether CP vials were dispensed during the urine sampling period. In addition, vial surfaces, purposely coated with CP and then washed, were examined using wipe tests.Result: CP was detected at 30–60% in vials, which was 11–62 ng (0.10–0.54 ng/cm2). One of the urine samples was contaminated (CP 13.5 ng); this was taken on Day 2 (11:35 AM). CP was not detected among the washed vials.Discussion: This study shows that the surface of Japanese CP vials was contaminated and that it was probable that healthcare workers were exposed to CP. CP absorption by the pharmacist was probably due to dermal uptake while dispensing. Washing the vial is considered effective to avoid CP exposure. Manufacturers should be more proactive to prevent contamination and healthcare workers should comply with exposure prevention rules. Cytotoxic drugs should be included in institution monitoring lists. [ABSTRACT FROM PUBLISHER]

Objective. The aim of this study is to evaluate the mechanism of long-term effect of autologous haematopoietic stem cell transplantation (ASCT) in treatment of SSc.Methods. Eleven patients (three males and eight females) with SSc were enrolled. Blood mononuclear cells were harvested after mobilization treatment with CYC and G-CSF. CD34+ haematopoietic stem/progenitor cell fractions were purified and cryopreserved. Patients were transplanted with >2 × 106/kg autologous CD34+ cells after high-dose CYC (50 mg/kg for 4 days) conditioning. Immune reconstitution was evaluated serially by analysing lymphocyte subpopulations for 36 months.Results. Progressive improvement of skin sclerosis has been observed for 3 years in most of the patients. The serum level of anti-Scl-70, an auto-antibody specific to SSc, was progressively decreased after ASCT. Improvement of skin sclerosis was significantly associated with the change in the serum anti-Scl-70 level after ASCT at 36 months. Serum levels of KL-6 and surfactant protein D, indicators for interstitial pneumonia activity, were also significantly decreased. The number of CD8+ T cells immediately recovered within a month after ASCT, while the number of CD4+ T cells remained low for >36 months post-transplant. The majority of CD4+ cells were memory but not naïve T cells, and regulatory CD4+ T cells were not recovered. Th1/Th2 ratio was significantly increased after ASCT.Conclusions. ASCT with purified CD34+ cells was effective in controlling the disease activity of SSc. Th1/Th2 ratio was significantly increased for at least 3 years after ASCT. [ABSTRACT FROM PUBLISHER]

Purpose. A multicenter field survey of environmental contamination and exposure of healthcare professionals to anticancer drugs were performed.Setting. Three university hospitals, one cancer specialty hospital and two corporate hospitals from across Japan.Method. The environmental contamination with cyclophosphamide (CP) was investigated. A wipe examination was performed at six sites apiece in two divisions. The urinary excretion of the CP over 24 h was determined. The subjects of the survey included physicians, pharmacists, and nurses, for a total of seven at each facility irrespective of job title. The wipe samples were collected at 12 sites within two divisions at each facility. For the exposure survey, the total urine volume was determined, and a portion of the urine sample was then collected from each participants at each facility. Urine was collected for 24 h. The samples were determined by using the GC-MS method.Results. Wipe examination: contamination with CP was identified at 50% of the sites. The concentration was high (CP > 1.00 ng/cm2) in the general environment in two hospitals and in the safety cabinet in one hospital. In the survey for the exposure of staff to anticancer drugs, 276 samples were obtained from 41 healthcare professionals. CP was detected in 90 samples obtained from 23 subjects. The amount of exposure was greatly different among the facilities. The urinary excretion of CP per subject was between 2.7 and 462.8 ng/24 h. The range of urinary excretion for each hospital was between 4.6 and 211.2 ng/24 h. [ABSTRACT FROM PUBLISHER]

Purpose. The aim of the present study was to evaluate the measurement of contamination by antineoplastic drugs for safer handling of such drugs by medical workers. We investigated the relationship between the contamination level of antineoplastic drugs and the conditions of their handling.Methods. Air samples and wipe samples were collected from equipment in the preparation rooms of five hospitals (hospitals A—E). These samples were subjected to measurement of the amounts of cyclophosphamide (CPA), fluorouracil (5FU), gemcitabine (GEM), and platinum-containing drugs (Pt). Twenty-four-hour urine samples were collected from the pharmacists who handled or audited, the antineoplastic drugs were analyzed for CPA and Pt.Results. Pt was detected from air samples inside BSC in hospital B. Antineoplastic drugs were detected from wipe samples of the BSC in hospitals A, B, D, and E and of other equipment in the preparation rooms in hospitals A, B, C, and D. Cyclophosphamide and 5FU were detected from wipe samples of the air-conditioner filter in hospital A, and CPA was detected from that in hospital D. Cyclophosphamide was detected from urine samples of workers in hospitals B, D, and E.Conclusion. The contamination level of antineoplastic drugs was suggested to be related with the amount of drugs handled, cleaning methods of the equipment, and the skill level of the technique of maintaining negative pressure inside a vial. In order to reduce the contamination and exposure to antineoplastic drugs in the hospital work environment very close to zero, comprehensive safety precautions, including adequate mixing and cleaning methods was required in addition to BSC and closed system device. [ABSTRACT FROM PUBLISHER]

Purpose. In Japan, concerns exist regarding the dangers inherent when handling cytotoxic drugs, particularly drugs such as 5-FU, Thiotepa, Cytarabine, Tegaful, and Sizofiran which are contained in ampoules or vials, since nurses and medical doctors have been preparing these cytotoxic drugs in the open spaces of wards in the absence of appropriate garments and personal protective equipment. In addition, the administration tubes for these dangerous drugs have been exchanged at the patients’ bedside, typically in rooms shared by several patients. To gain insight into the severity of the occupational hazards posed by these practices, we conducted a pilot study of environmental and biological monitoring of occupational exposure to cyclophosphamide (CP).Setting. At Nagoya University Hospital, Nagoya, Japan, in February 2006, two departments, A and B, were monitored with surface-wipe, and urine samples were analyzed using the Sessink method (exposure control, The Netherlands). Department A had a preparation room with biological safety cabinet (BSC) where the pharmacists prepare cytotoxic drugs. Department B did not have a BSC.Results. Many areas of the treatment rooms were contaminated with CP. CP was detected on tables and telephone stands where cytotoxic drugs were not used as well as tables used to prepare cytotoxic drugs. Significant differences in CP concentrations were detected from the urine of two of the three nurses who cared for the same patients without gloves. The nurses rotated and inherited the patient who had the highest risk of contamination. CP was detected only once from the urine of the medical doctor who prepared CP. He was not wearing any PPE other than gloves. All of the pharmacists wearing PPE were free from contamination of CP.Discussion. Regardless of the use of BSC, wards were contaminated with CP. The contamination may not occur due to the sealing used in CP containers and administration tubes when discarding them. CP was detected only once in the urine of a medical doctor who prepared CP by warming it. The cause may be inhalation of CP gas from the injector. The contamination of the nurses may be from dermal absorption because absorption continued even after the shift ended and the nurses left the facility. CP was not detected in pharmacists who followed the guidelines for preparation of CP. All of the medical staff should follow the guidelines when they handle CP. [ABSTRACT FROM PUBLISHER]

Objective: We conducted a phase II trial in Japan to evaluate the efficacy and tolerability of weekly paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) as neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC). Methods: Patients with clinical stage IIIA-IIIB breast cancer received NAC consisting of 12 once-a-week cycles of paclitaxel followed by 4 once-every-third-week cycles of FEC. Results: Fifty patients with LABC were enrolled, 47 of whom were administered paclitaxel followed by FEC as NAC. The clinical response rate for all chemotherapies was 85.1%, and the pathological complete response rate was 27.7%. Regarding toxicity, grade 3-4 neutropenia was observed in 10% of patients. No serious toxicities requiring the discontinuation of treatment were encountered. The rate of breast conservation surgery was 31.9%, median survival had not been reached at the time of conclusion of this study, and the 3-year survival rate was 85.1%. Median disease-free survival was 40.2 months, and the 3-year disease-free survival rate was 62.1%. Conclusions: Weekly paclitaxel followed by FEC demonstrated efficacy and tolerable toxicity in a neoadjuvant setting for LABC. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We performed a retrospective analysis of patients with diffuse large B cell lymphoma treated with rituximab plus CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) as a first-line therapy at 22 hospitals of the Kyushu Lymphoma Study Group. During the period 1996-2005, 1,057 patients (aged 22-90 years) were analyzed. Of these, 678 were treated with CHOP, and 379 were treated with rituximab plus CHOP (R-CHOP). The complete response rate was 59.9% in the CHOP group and 67.0% in the R-CHOP group (P < 0.001). Three-year progression-free survival (PFS) and overall survival (OS) rates were significantly higher in the R-CHOP group than in the CHOP group (61.3 vs. 45.6% for PFS, P < 0.001; 68.3 vs. 54.5% for OS, P < 0.001). The International Prognostic Index was a good prognostic marker for both groups; a survival benefit of rituximab addition was found for each risk subgroup and also for both age groups (60 years). Among 345 patients who received localized radiation therapy, the adding rituximab to CHOP attenuated the survival difference between CHOP and R-CHOP groups (P = 0.104), compared with no radiation group (P < 0.001). Results of this large-scale, multicenter study confirm that rituximab plus CHOP provided a greater survival benefit than CHOP alone. [ABSTRACT FROM AUTHOR]

We conducted a retrospective analysis to evaluate the impact on clinical outcomes of adding rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment for diffuse large B-cell lymphoma (DLBCL) patients in Japan. A propensity score method was used to compensate for the non-randomized study design. From January 2000 to December 2004, 378 patients who were newly diagnosed with DLBCL at 13 institutes were enrolled: 123 in the rituximab plus CHOP-based chemotherapy (R+) group, and 255 in the CHOP-based chemotherapy only (R-) group. The complete response rate was significantly higher in the R+ group than in the R- group (77.7 vs. 69.4%, P < 0.001). The progression-free survival (PFS) at 2 years was 62.4% in the R+ group and 57.0% in the R- group. The 2-year overall survival (OS) was 76.9% for the R+ group and 70.5% for the R- group. A multivariate analysis revealed that the addition of rituximab was a strong independent prognostic factor for PFS (hazard ratio 0.64, 95% CI 0.43-0.96, P = 0.031). A subgroup analysis revealed that R+ particularly benefited younger patients (hazard ratio 0.25, 95% CI 0.08-0.75, P = 0.013). IPI also showed significant impact for PFS (hazard ratio 1.82, 95% CI 1.55-2.14 for one score increase, P < 0.001) as well as OS (hazard ratio 2.10, 95% CI 1.71-2.57, P < 0.001). In summary, the addition of rituximab to CHOP-based chemotherapy results in better outcomes for Japanese DLBCL patients, particularly younger patients. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus. We describe a rare case of PML in a 48-year-old female patient with diffuse large B-cell lymphoma who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy. While she was undergoing five cycles of R-CHOP, she noticed gradually progressive neurological symptoms, such as slurred speech and gait disturbance, and she eventually developed high-grade fever. She also developed Pneumocystis jiroveci pneumonia. The neurological symptoms deteriorated thereafter, and she developed spastic quadriparesis and bulbar palsy. Magnetic resonance imaging showed hyperintensity within the right cerebellar hemisphere on T2-weighted images. Polymerase chain reaction-based tests of the cerebrospinal fluid revealed the presence of the JC virus. Despite intravenous and intrathecal cytarabine treatment, the patient died of PML 5 months after it was diagnosed. Retrospective analysis of her laboratory data showed that her CD4(+) T-cell count before R-CHOP therapy had decreased to 68 microL(-1). Thus, when administering rituximab-containing chemotherapy, even to patients with no prior history of opportunistic infections, attention should be paid to the potential occurrence of PML, particularly in patients with low CD4(+) T-cell counts. [ABSTRACT FROM AUTHOR]

Among small-vessel vasculitides, microscopic polyangiitis (MPA), Wegener's granulomatosis (WG), and allergic granulomatous angiitis (AGA) are known collectively as ANCA-associated vasculitis (AAV) because of the involvement of anti-neutrophil cytoplasmic antibodies (ANCA) as the common pathogenesis. Major target antigens of ANCA associated with vasculitis are myeloperoxidase (MPO) and proteinase 3 (PR3). MPO-ANCA is related to MPA and AGA, and PR3-ANCA is the marker antibody in WG. MPO-ANCA-associated vasculitis is more frequent in Japan, whereas PR3-ANCA-associated vasculitis is more common in Europe and USA. ANCA appears to induce vasculitis by directly activating neutrophils. Therefore, no immunoglobulins or complement components are detected in the vasculitis lesions; hence, AAV is called pauci-immune vasculitis (pauci = few/little). Untreated patients with severe AAV with multi-organ involvement have a poor prognosis, which is improved by combination therapy with cyclophosphamide and high-dose corticosteroid. Randomized controlled trials (RCT) regarding induction and maintenance of remission of AAV indicated that the rate of remission induction by the standard regimen is approximately 90% in 6 months, that maintenance of remission can be achieved with oral azathioprine as well as cyclophosphamide, and that methotrexate can be used only for nonrenal mild AAV. As these data were obtained mostly in patients positive for PR3-ANCA, caution must be taken in applying these findings to Japanese patients, most of whom are positive for MPO-ANCA. A prospective study is now underway to clarify the effectiveness of the standard regimen in Japanese patients with MPO-ANCA-associated vasculitis. This article describes the diagnostic criteria and the recent evidence-based therapeutic strategy of AAV. [ABSTRACT FROM AUTHOR]

Several clinicopathologic studies of primary mediastinal large B-cell lymphoma (Med-DLBCL) have been reported from Western countries; however, only a few series of at most 10 cases are available in Japan. To further clarify the Med-DLBCL occurring in Japan, we analyzed the clinical features of 28 patients with Med-DLBCL diagnoses who were treated at the National Cancer Center Hospital between 1982 and 2002. The median age was 37 years (range, 18-80 years). The ages of 16 male patients ranged widely from 18 to 80 years, whereas the 12 female patients appeared to show a single age peak at 20 to 40 years. Only 13 patients (46%) achieved a complete response with initial treatments, mostly by CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisolone) followed by radiotherapy. The estimated 3-year overall and failure-free survival rates were 32% and 33%, respectively, indicating the relatively unfavorable prognosis of the patients in our series. The following factors were found to be significantly associated with shortened survival prospects: age >60 years, serum lactate dehydrogenase level greater than normal, performance status >1, and presence of bulky mediastinal mass. In conclusion, the clinical features of Japanese patients with Med-DLBCL may be different from those with the disease in Western countries. Because this investigation was a single-institution study with a limited number of patients, however, multicenter confirmatory studies are needed. [ABSTRACT FROM AUTHOR]

To investigate whether combination chemotherapy with vincristine, cyclophosphamide, prednisolone, and melphalan (COP/ MP) with the addition of ranimustine (MCNU) (MCNU-COP/MP) is superior to the slightly modified COP/MP (mCOP/MP) regimen in multiple myeloma (MM), a multicenter randomized study was performed. Two hundred ten patients with newly diagnosed, overt MM not treated with chemotherapy were enrolled from 32 institutions of the Lymphoma Study Group of the Japan Clinical Oncology Group and were randomized to receive either MCNU-COP/MP or mCOP/MP. The response rate (RR) to mCOP/MP was 43.7% (95% confidence interval [CI], 33.9%-53.8%] and to MCNU-COP/MP was 56.1% (95% CI, 46.1%-65.7%) (P = .097). The progression-free survival (PFS) was significantly longer for patients treated with MCNU-COP/MP than for patients treated with mCOP/MP (median, 23.0 months [95% CI, 18.9-25.8] versus 15.8 months [95% CI, 14.1-19.4]) (P = .014). However, no significant difference in overall survival rate (OS) was observed between the groups (median, 49.9 months [95% CI, 40.4-59.1] versus 44.0 months [95%, CI, 32.8-59.8]) (P = .75). Grades 3 and 4 hematological toxicities were more frequently observed with MCNU-COP/MP than with mCOP/MP, but the incidence of grades 3 and 4 nonhematological toxicities was low in both groups. In conclusion, MCNU-COP/MP in comparison with mCOP/MP improved RR and PFS in overt MM; however, this outcome did not contribute to prolonging OS, indicating that addition of MCNU to mCOP/MP has no benefit on survival. [ABSTRACT FROM AUTHOR]