Pioneering cord blood transplantation in relapsed/refractory HIV-related lymphoma: A case study with concurrent intramuscular antiretroviral therapy.

A 44-year-old HIV-positive man diagnosed with diffuse large B-cell lymphoma in 2021 achieved complete remission with six cycles of R-CHOP therapy but had a relapse in November 2022. ESHAP therapy failed to induce remission, leading to complete remission with four cycles of Pola-BR therapy. Post-failure of autologous stem cell harvest, cord blood transplantation (CBT) was performed in June 2023. Notably, this case used recently approved intramuscular antiretroviral therapy (ART) with cabotegravir and rilpivirine, addressing gastrointestinal complications during CBT. This innovative use of intramuscular ART in the treatment of malignancy represents a first in the field, offering a pioneering approach to HIV-related lymphoma.

A predictive model for HIV-related lymphoma: a case series and literature review in Japan.

OBJECTIVES: To address the paucity of human immunodeficiency virus (HIV)-related lymphoma (HRL)-specific prognostic scores for the Japanese population by analyzing domestic cases of HRL and constructing a predictive model. DESIGN: A single-center retrospective study coupled with a review of case reports of HRL. METHODS: We reviewed all patients with HRL treated at our hospital between 2007 and 2023 and conducted a comprehensive search for case reports of HRL from Japan using public databases. A multivariate analysis for overall survival (OS) was performed using clinical parameters, leading to the formulation of the HIV-Japanese Prognostic Index (HIV-JPI). RESULTS: A total of 19 patients with HRL were identified in our institution, while the literature review yielded 44 cases. In the HIV-JPI, a weighted score of 1 was assigned to the following factors: age ≥45 years, HIV-RNA ≥8.0×104 copies/mL, Epstein-Barr virus-encoded small RNA positivity, and Ann Arbor classification stage IV. The overall score ranged from 0 to 4. We defined the low-risk group as scores ranging from 0 to 2 and the high-risk group as scores ranging from 3 to 4. The 3-year OS probability of the high-risk group (30.8%; 95% confidence interval [CI]: 9.5-55.4%) was significantly poorer than that of the low-risk group (76.8%; 95% CI: 52.8-89.7%; P < 0.01). CONCLUSION: This retrospective analysis established pivotal prognostic factors for HRL in Japanese patients. The HIV-JPI, derived exclusively from Japanese patients, highlights the potential for stratified treatments and emphasizes the need for broader studies to further refine this clinical prediction model.

A Case of Fulminant Type 1 Diabetes with Transient Production of Anti-Glutamic Acid Decarboxylase Antibody.

BACKGROUND Fulminant type 1 diabetes is characterized by a low prevalence of autoantibodies, and was originally described as a nonautoimmune subtype of type 1 diabetes. Herein, we report a case in which we observed the process of extremely rapid onset of diabetes and early decline in anti-glutamic acid decarboxylase (GAD) antibody titers during the inpatient stay. CASE REPORT A 61-year-old man was brought to our hospital with marked hyperglycemia (1327 mg/dL), ketonemia (3-hydroxybutyrate: 14 012 µmol/L), and moderately elevated HbA1c (7.2%) and glycoalbumin (22.3%). C-peptide levels were undetectable. He had suffered from thirst, polyuria, and fatigue for 2 days. Abrupt onset was proven by the clinical data when he visited the hospital with respiratory symptoms 6 days before his admission; plasma glucose, glycoalbumin, C-peptide, and insulin levels were 117 mg/dL, 13.0%, 5.07 ng/mL, and 24.4 µIU/mL, respectively. The anti-GAD antibody titer measured by enzyme-linked immunosorbent assay was 111 U/mL at admission, 22.8 U/mL 2 weeks after admission, and negative 1 year later. He had a susceptible haplotype DRB1*09: 01-DQB1*03: 03, which is significantly more common in anti-GAD antibody-positive patients with fulminant type 1 diabetes. CONCLUSIONS The early decline of anti-GAD antibody titer likely reflected rapid and complete beta cell loss. The sequential metabolic and immunological observation in this case may provide insight into the pathogenesis of fulminant type 1 diabetes.

Changes in chronic myeloid leukemia treatment modalities and outcomes after introduction of second-generation tyrosine kinase inhibitors as first-line therapy: a multi-institutional retrospective study by the CML Cooperative Study Group.

This study investigated changes in treatment modalities and outcomes of chronic myeloid leukemia in the chronic phase (CP-CML) after the approval of second-generation tyrosine kinase inhibitors (2G-TKIs) for first-line therapy. Patients were grouped into those who underwent TKI therapy up to December 2010 (imatinib era group, n = 185) and after January 2011 (2G-TKI era group, n = 425). All patients in the imatinib era group were initially treated with imatinib, whereas patients in the 2G-TKI era group were mostly treated with dasatinib (55%) or nilotinib (36%). However, outcomes including progression-free survival, overall survival, and CML-related death (CRD) did not differ significantly between groups. When stratified by risk scores, the prognostic performance of the ELTS score was superior to that of the Sokal score. Even though both scoring systems predicted CRD in the imatinib era, only the ELTS score predicted CRD in the 2G-TKI era. Notably, the outcome of patients classified as high-risk by ELTS score was more favorable in the 2G-TKI era group than in the imatinib era group. Thus, expanding treatment options may have improved patient outcomes in CP-CML, particularly in patients classified as high-risk by ELTS score.

Evaluation of the cachexia index using a bioelectrical impedance analysis in elderly patients with non-Hodgkin's lymphoma: A single-center prospective study.

Cancer cachexia is a disorder that affects patient outcomes. The present study prospectively evaluated the prognostic value of the cachexia index (CXI) in elderly patients with non-Hodgkin's lymphoma (NHL). We prospectively analyzed 51 elderly patients who were diagnosed with NHL at our institution. CXI was calculated as follows: CXI = SMI × Alb/NLR (SMI: skeletal muscle index, Alb: serum albumin, NLR: neutrophil-to-lymphocyte ratio). SMI was measured by a bioelectrical impedance analysis (BIA) using the InBody 720. We determined the sex-specific cutoff values of the CXI by a receiver operating characteristic curve analysis and divided all patients into low- and high-CXI groups. The median age at the diagnosis was 78 years (60-93 years), and 28 (55%) were male. The histologic subtypes were B-cell lymphoma in 49 patients and T-cell lymphoma in 2. Twenty-eight (55%) patients were categorized into the high-CXI group, and 23 (45%) were categorized into the low-CXI group. The overall survival (OS) in the low-CXI group was significantly shorter than that in the high-CXI group (3-year OS, 70.4% vs. 95.7%, p = 0.007). Among 23 patients with DLBCL, patients with low-CXI had shorter OS than those with high-CXI (3-year OS, 55.6% vs. 92.9%, p = 0.008). On the other hand, sarcopenia had less impact on the clinical outcome of DLBCL patients. Low-CXI was associated with poor outcomes in elderly NHL and the CXI may be a clinical useful index for predicting prognosis. Further large prospective studies are needed to verify this conclusion.

Cost-Effectiveness of Nab-Paclitaxel and Gemcitabine Versus Gemcitabine Monotherapy for Patients with Unresectable Metastatic Pancreatic Cancer in Japan.

OBJECTIVES: The purpose of this study was to evaluate the cost-effectiveness of nab-paclitaxel and gemcitabine (GnP) compared with gemcitabine monotherapy (G) for patients with unresectable metastatic pancreatic cancer in Japan from the perspective of healthcare payer. METHODS: A partitioned survival analysis model was developed to predict costs and quality-adjusted life years (QALYs) for GnP and G. The time horizon of the model was set at 20 years. An annual discount rate of 2% for both costs and QALYs was applied. Data on overall survival and progression-free survival were derived from the Metastatic Pancreatic Adenocarcinoma Clinical Trial. Cost parameters were estimated from a Japanese medical claims database. The incremental cost-effectiveness ratio (ICER) of GnP compared with G was estimated. One-way sensitivity analysis was performed to assess the uncertainty in the parameter settings. In addition, scenario and probability sensitivity analyses were performed. RESULTS: The incremental cost and QALY of GnP compared with G were US$25 089 and 0.13 QALY, respectively. The ICER of GnP was estimated to be US$192 992 per QALY gained. Although the ICER was influenced by utility parameters and the survival curves, the ICERs remained higher than the willingness to pay (WTP) threshold of US$68 000 (JPY 7.5 million). The probability that GnP becomes cost-effective compared with G was estimated to be 29.2%. CONCLUSIONS: Applying the WTP threshold of US$68 000 per QALY, GnP was not cost-effective for patients with unresectable metastatic pancreatic cancer in Japan from the perspective of healthcare payer. Further research is needed to obtain utility data from Japanese patients with pancreatic cancer.

Proactive Engagement of the Expert Meeting in Managing the Early Phase of the COVID-19 Epidemic, Japan, February-June 2020.

To deal with the risk of emerging diseases with many unknowns, close and timely collaboration and communication between science experts and policymakers are crucial to developing and implementing an effective science-based intervention strategy. The Expert Meeting, an ad hoc medical advisory body, was established in February 2020 to advise Japan's COVID-19 Response Headquarters. The group played an important role in the policymaking process, promoting timely situation awareness and developing science-based proposals on interventions that were promptly reflected in government actions. However, this expert group may have been overly proactive in taking on the government's role in crisis management. For the next stage of managing the coronavirus disease pandemic and future pandemics, the respective roles of the government and its advisory bodies need to be clearly defined. Leadership and strategic risk communication by the government are key.

Impact of Specific Antibody Level on Human Herpesvirus 6 Reactivation after Allogeneic Stem Cell Transplantation.

The majority of adults are seropositive for human herpesvirus 6 (HHV-6). HHV-6 reactivation can occur after allogeneic hematopoietic stem cell transplantation (HSCT) and lead to life-threatening central nervous system disorders. In this prospective study, we evaluated the relationship between HHV-6 reactivation and anti-HHV-6 IgG antibody levels in recipients of allogeneic HSCT. The HHV-6 viral load in the plasma was quantitatively measured weekly after allogeneic HSCT by real-time polymerase chain reaction. The level of anti-HHV-6 IgG antibody was measured by enzyme-linked immunosorbent assay before and serially after transplantation. In 28 of the 56 evaluated patients (50%), HHV-6 reactivation was detected after transplantation. In a multivariate analysis, cord blood as the stem cell source was the only significant factor associated with HHV-6 reactivation (odds ratio, 8.6; 95% confidence interval, 2.3 to 32.6; P < .01). When evaluated in the recipients of cord blood transplantation (CBT), the anti-HHV-6 antibody level before transplantation was significantly lower in the patients with HHV-6 reactivation compared with those without (sample positivity index: median, 2.04 [range, 0.95 to 5.98] versus 4.15 [range, 3.93 to 5.65]; P < .05). The anti-HHV-6 antibody level was significantly decreased at 3 months post-transplantation compared with before transplantation (P < .01). Such differences were not observed in other stem cell sources. Our results demonstrate that the low anti-HHV-6 antibody level before transplantation was associated with the reactivation of HHV-6 after CBT, and that the anti-HHV-6 antibody level was significantly decreased specifically after CBT. These results suggest that HHV-6-specific humoral immunity plays a role in HHV-6 reactivation after CBT.

Distinct Relevance of Nightly Sleep Duration to Metabolic, Anthropometric, and Lifestyle Factors in Patients with Type 2 Diabetes.

Objective Although a number of studies have shown that both short and long sleep durations were associated with the risk of metabolic disorders related to obesity, the underlying mechanism is still not fully understood. In this study, we analyzed the association of sleep duration with metabolic, anthropometric, and lifestyle factors in patients with type 2 diabetes. Methods The subjects were 279 patients with type 2 diabetes 63 (52-70) years old (median and interquartile range) with a body mass index of 25.0 (22.2-28.3) kg/m2 and HbA1c levels of 8.7% (7.6-10.3%). Patients with advanced complications were excluded from the study. Diets were evaluated by registered dietitians using a software program. Body composition was assessed by the multifrequency bioelectrical impedance method. Results The mean self-reported nightly sleep duration was 6.4 hours with no marked gender difference. Sleep duration was inversely correlated with the HbA1c levels, total energy intake, and intakes of carbohydrate, protein, and fat. The body fat ratio and skeletal muscle mass were correlated positively and negatively, respectively, with sleep duration. When the subjects were divided into three groups based on sleep duration, the intakes of total energy, carbohydrates, and fat tended to be high in those with <5.5 hours of sleep, and the percentage of patients who had habitual physical activities was lower in those with >7 hours of sleep. Conclusion The observation that sleep duration is distinctly associated with excessive eating and a sedentary lifestyle may provide a basis for effective lifestyle management of patients with type 2 diabetes.

Pseudo-hyperglucagonemia was observed in pancreatectomized patients when measured by glucagon sandwich enzyme-linked immunosorbent assay.

Glucagon is detected in plasma even after total pancreatectomy, and it is debated whether this glucagon is derived from the gastrointestinal tract. Here, we applied sandwich enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-high-resolution mass spectrometry to measure plasma glucagon levels in one patient after partial pancreatectomy (one-seventh of the pancreas remaining) and three patients after total pancreatectomy. Sandwich ELISA detected higher glucagon levels in pancreatectomy patients than in healthy individuals. In contrast, liquid chromatography-high-resolution mass spectrometry showed that plasma glucagon levels in pancreatectomy patients were below the lower limit of quantification. Plasma glucagon measured by sandwich ELISA showed a striking correlation with plasma glicentin, suggesting cross-reaction with this gastrointestinal glucagon-related peptide. These results indicated that pancreatectomized patients falsely showed pseudo-hyperglucagonemia when measured by glucagon sandwich ELISA.

The work style and living condition survey of diabetologists and the expectations for the Japan Diabetes Society: results of questionnaires about the current state and the future prospect of their carrier in 2017.

The Japan Diabetes Society's Committee to Promote Female Diabetologists conducted a questionnaire survey from May to June 2017 to investigate the work style and living situation of diabetologists. The survey targeted 5298 Board Certified Diabetologists (diabetologists), with answers obtained from 1566 diabetologists (male, n = 1003: females, n = 563). Ninety-four percent of the males and 72% of the females worked full time. Twenty-one percent of the male subjects and 7% of the female subjects were heads of clinical departments, and 23% of the male subjects and 13% of the female subjects were diabetes training instructors, showing that there were fewer women than men in both roles. Regarding the allocation of time per day, men spent 10.7 h working, while women spent 8.5 h working. Both men and women slept 6.3 h. Men spent 1.0 h on housework, while women spent 3.3 h on housework. Men spent 0.7 h on childcare and nursing care, while women, spent 2.8 h. Among diabetologists in the childrearing generation, men spent 1.4 h providing childcare and nursing care, while women spent 4.9 h, showing that women spent significantly more time on these tasks than men. To encourage female diabetologists to work more actively, to reduce overworking on the part of male diabetologists, and to enhance the careers of both men and women as diabetologists, we conclude it necessary to improve the workplace environment and for the Japan Diabetes Society to offer support.

[Systemic varicella-zoster infection during ixazomib-containing multiagent chemotherapy for multiple myeloma].

A 58-year-old man received high-dose melphalan with autologous peripheral blood stem cell transplantation for multiple myeloma in stringent complete response (sCR). Relapse occurred 4 years after the transplantation, and he was placed on ixazomib, lenalidomide, and dexamethasone (IRd) and achieved sCR. On the 10th day of the 10th course of IRd, he developed fever followed by generalized skin eruption with vesicles, headache, and dizziness. Varicella-zoster virus (VZV) antigen from the vesicle and VZV-DNA from the cerebrospinal fluid were detected, and he was diagnosed with systemic VZV infection. He was placed on intravenous acyclovir (ACV), and the infection resolved completely. VZV infection has been recognized as an important complication associated with the use of proteasome inhibitors; however, to our knowledge, there have been no reported cases of serious systemic VZV infection associated with ixazomib. The clinical course of this case strongly suggests the importance of prophylaxis for VZV infection during treatment with ixazomib.

Clinical characteristics of human herpesvirus-6 myelitis after allogeneic hematopoietic stem cell transplantation and its favorable outcome by early intervention.

After allogeneic hematopoietic stem cell transplantation (HSCT), human herpesvirus-6 (HHV-6) can cause serious central nervous system (CNS) disorder and typically presents as encephalitis. Another manifestation of HHV-6 is myelitis, which has not been fully evaluated. In this study, we retrospectively analyzed 19 patients who developed HHV-6 myelitis after allogeneic HSCT. Median onset was 20 days after transplantation (range, 13-31), with a cumulative incidence of 4.1% at day 40 after transplantation. Median age at transplant was 50 years (range, 17-61). Median copy number of HHV-6 DNA was 3000 copies/ml in cerebrospinal fluid (CSF; range, 200-100,000). The most common symptoms were pruritus, pain of the extremities/back, and numbness. Three patients subsequently developed encephalitis in the clinical course of myelitis; their HHV-6 copy numbers in CSF had been higher than 10,000 copies/ml at the onset of myelitis. Antiviral agents were initiated shortly after onset in all patients, resulting in recovery. These results suggest that myelitis would be an important subtype of HHV-6-associated CNS disorders after allogeneic HSCT, whose prognosis could be favorable by an early intervention. Transplant physicians should recognize early posttransplant neurological symptoms such as pruritus, pain, or numbness as possible signs of HHV-6 myelitis, which could also progress to encephalitis.

Seasonal changes in indoor airborne fungal concentration in a hematology ward.

Invasive fungal disease (IFD) is an important infectious complication of hematological disorders, especially in hematopoietic stem cell transplantation recipients. Evidences suggest seasonal and/or geographical variations in the airborne fungal counts and a relationship between those counts and the incidence of IFD. We evaluated the concentrations of indoor airborne fungi quantitated over the course of one year in a hematology ward in Japan. In January, April, July, and October, fixed volumes of air samples were obtained by an air sampler in a hematology ward not equipped with a high-efficiency particulate air filter and incubated in fugal cultures. Samples were also obtained from a protective environment in the same ward and were evaluated. The number of fungal colonies per 50 L of sampled air was highest in October (median 2.25 (range, 0.2-7.0)), which was significantly higher than those in the other three months (0.1 (range, 0-1.0) in January; 0 (0-0) in April; 0.55 (0-2.5) in July; P < 0.01)). Commonly identified pathogens included Penicillium and Cladosrporium species, but Aspergillus species was detected only in July and October samples. These results suggest a seasonal variation in indoor airborne fungal concentrations in Japan, which could affect the epidemiology of IFD.

Metreleptin Supplementation for Improving Lipid and Glycemic Profiles in Acquired Diabetes Lipodystrophy: A Case Report.

Most childhood cancer survivors who undergo hematopoietic stem cell transplantation subsequently develop impaired glucose tolerance and hypertriglyceridemia. These conditions are presumably associated with total-body irradiation-related acquired lipodystrophy and may lead to cardiovascular disease. Metreleptin (recombinant leptin) may help improve the lipoprotein profile, insulin sensitivity, and quality of life of patients with total-body irradiation-related lipodystrophy. This report describes the safe and effective use of metreleptin supplementation for insulin resistance and dyslipidemia in acquired incomplete lipodystrophy. A 24-year-old Japanese woman with diabetes mellitus and hypertriglyceridemia was admitted to our hospital. She was diagnosed with acute lymphocytic leukemia at 3 years of age and had undergone systemic chemotherapy and total-body irradiation before allogeneic stem cell transplantation. She was also diagnosed with hypertriglyceridemia and diabetes mellitus at 11 years of age. She had a low adiponectin level, low-normal leptin level, and diabetes mellitus with marked insulin resistance. Thus, acquired incomplete lipodystrophy was diagnosed. Her serum triglyceride and lipoprotein profiles improved within 1 month of treatment initiation. Glycemic metabolism and insulin sensitivity in the skeletal muscles improved after 6 months. As previously reported, metreleptin therapy is effective in improving lipid and glycemic profiles in generalized lipodystrophy. In the present case, we considered that metreleptin supplementation could reduce the remnant VLDL cholesterol fraction and improve diabetes mellitus. We conclude that it may be an effective alternative therapy for improving the expected prognosis of patients with acquired incomplete lipodystrophy, including childhood cancer survivors.

Human Leukocyte Antigen (HLA) Subtype-Dependent Development of Myasthenia Gravis, Type-1 Diabetes Mellitus, and Hashimoto Disease: A Case Report of Autoimmune Polyendocrine Syndrome Type 3.

BACKGROUND Patients with type 1 diabetes mellitus, myasthenia gravis (MG), and Hashimoto disease are diagnosed as having autoimmune polyendocrine syndrome type 3 (APS3). APS3 is rare, and its pathogenesis is unclear. We describe a female patient with APS3 whose human leukocyte antigen (HLA) type could provide a clue to the pathogenesis of APS3. CASE REPORT A 40-year-old Japanese female patient who had been diagnosed with MG at 5 years of age, and which had been treated with cholinesterase inhibitors, was referred to our hospital with thirst, polydipsia, polyuria, weight loss, and hyperglycemia. She was found to have type 1 diabetes mellitus based on laboratory tests. She was also positive for anti-thyroid peroxidase antibody and was thus diagnosed with Hashimoto disease. This combination of type 1 diabetes mellitus, myasthenia gravis, and Hashimoto disease led to a diagnosis of APS3. Her HLA serotype was A24; B46/54; DR4/9; DQ8/9, and genotype was A*24: 02; B*46: 01: 01/54: 01: 01; C*01: 02; DRB1*04: 06/09: 01: 02; DQB1*03: 02: 01/03: 03: 02; and DQA1*03: 01/03: 02: 01. We subsequently reviewed 10 cases of APS3 combined with MG, including the present case and cases reported in Japanese. This review revealed that HLA-DR9/DQ9 might be a specific HLA subtype associated with APS3 with MG. Four of the 10 cases had MG diagnosed before diabetes mellitus and autoimmune thyroid disease. CONCLUSIONS The present case showed that, in people with HLA-B46 and -DR9, antibody-negative MG can precede the development of APS3 by many years. Physicians should consider the possibility of APS3 when evaluating patients with ocular-type myasthenia gravis, and screen them for type 1 diabetes.

Bromocriptine as a Potential Glucose-lowering Agent for the Treatment of Prolactinoma with Type 2 Diabetes.

A 22-year-old Japanese woman consulted an endocrinologist due to persistent galactorrhea for the past 10 months. She had hyperprolacinemia and had previously been diagnosed with type 2 diabetes mellitus based on her glycohemoglobin level of 11.6%. After two months, she was admitted to our hospital and finally diagnosed with prolactinoma. For the treatment of prolactinoma, bromocriptine 2.5 mg/day was started. After seven days, her post-prandial blood glucose levels, homeostasis model assessment of insulin resistance and plasma C-peptide levels were significantly improved. These results indicate that traditional bromocriptine can be an effective therapeutic alternative in patients with prolactinoma complicated with type 2 diabetes.