Severe lactic acidosis during tenofovir disoproxil fumarate and cobicistat combination for HIV patient.

Lactic acidosis is a rare but serious side effect in individuals receiving nucleoside reverse transcriptase inhibitors. An underweight woman with HIV was admitted to our hospital because of nausea and diffuse myalgia. Her antiretroviral regimen had been changed to tenofovir disoproxil fumarate (TDF)/emtricitabine and darunavir/cobicistat 3 months prior, after which her renal function had gradually declined. After admission, she was diagnosed with lactic acidosis, and a liver biopsy suggested mitochondrial damage. Her plasma tenofovir levels were elevated at the onset of lactic acidosis. We hypothesise that the patient's low body weight, combined with the addition of cobicistat, induced renal dysfunction and led to elevated plasma tenofovir concentrations, resulting in mitochondrial damage and lactic acidosis. Careful monitoring of renal function and lactic acidosis is required during use of TDF-containing regimens for underweight HIV patients, particularly when combined with cobicistat.

Isolated ACTH deficiency: an uncommon cause of hyperferritinaemia.

Isolated adrenocorticotropic hormone deficiency (IAD) is a rare disorder but not a known cause of hyperferritinaemia. We here report a man with IAD who presented with mild anaemia and unexpected hyperferritinaemia (serum ferritin, 1796 µg/L). He had high serum hepcidin and relatively low erythropoietin levels for his anaemia, with hepcidin and ferritin levels reducing with hydrocortisone supplementation. We speculate that low glucocorticoid levels might suppress erythropoiesis and anti-inflammatory activity, resulting in a higher hepcidin level and hyperferritinaemia. The possibility of adrenal insufficiency including IAD should be considered as a differential diagnosis in patients with unexplained hyperferritinaemia.

Prevalence and clinical outcomes of vitamin D deficiency among Japanese multiple myeloma patients: a single-center observational study.

PURPOSE: Vitamin D plays a crucial role in skeletal metabolism and holds significant importance in the pathophysiology of multiple myeloma (MM). This study aimed to determine the prevalence of vitamin D deficiency among Japanese MM patients and its correlation with clinical outcomes. METHODS: Serum 25-hydroxyvitamin D (25(OH)D) levels were assessed in 68 MM patients at a single institution in Japan, analyzing their association with clinical status, laboratory parameters including procollagen type 1 N-propeptide (P1NP) and tartrate-resistant acid phosphatase 5b (TRACP-5b), health-related quality of life (HR-QOL) scores, and overall survival. Additionally, patients with suboptimal 25(OH)D levels received cholecalciferol supplementation (1000 IU/day), and changes in laboratory parameters were monitored. RESULTS: The median 25(OH)D level was 22 ng/ml, with 32% and 51% of patients exhibiting vitamin D deficiency (< 20 ng/ml) and insufficiency (20-29 ng/ml), respectively. The 25(OH)D levels were unrelated to sex, age, MM stage, or bone lesions, but the vitamin D-deficient group showed a tendency towards lower HR-QOL scores. Among patients achieving complete remission, vitamin D supplementation increased P1NP, while TRACP-5b remained unchanged. Overall survivals from vitamin D measurement and from MM diagnosis were significantly worse in the vitamin D-deficient group compared to the vitamin D-insufficient/-sufficient group. CONCLUSION: The study identified a considerable number of Japanese MM patients with insufficient serum vitamin D levels, with one-third being deficient. Additionally, vitamin D deficiency predicted poor overall survival in Japanese MM patients. Further investigation is required to determine whether vitamin D supplementation can improve the frailty and survival of vitamin D-deficient MM patients.

Higher Serum Soluble TREM2 as a Potential Indicative Biomarker for Cognitive Impairment in Inadequately Controlled Type 2 Diabetes Without Obesity: The DOR-KyotoJ-1.

Objective: Type 2 diabetes is a risk factor for dementia. We investigated whether serum levels of soluble triggering receptor expressed on myeloid cell 2 (sTREM2), a soluble form of the cell surface receptor TREM2, were predictive of cognitive impairment in type 2 diabetes without obesity. Methods: A total of 166 Japanese patients with type 2 diabetes without obesity were followed-up for 2 years. We measured clinical parameters, assessed cognitive function using the mini-mental state examination (MMSE), quantified and divided serum sTREM2 levels into quartiles, and examined the longitudinal associations. Results: During the follow-up, HbA1c levels were elevated in 98 patients and decreased in 68 patients. In the HbA1c-elevated group, higher sTREM2 levels at baseline showed a significant association with a greater tendency for reduction in MMSE scores (P for trend = 0.015), whereas they were not significantly associated with other examined parameters. In the HbA1c-decreased group, there was no significant association between sTREM2 levels at baseline and changes in MMSE scores, but higher sTREM2 levels at baseline were significantly associated with a greater tendency for reduction in waist circumference (P for trend = 0.027), homeostasis model assessment of insulin resistance (P for trend = 0.039), and sTREM2 levels (P for trend = 0.023). Conclusions: Glycemic control is suggested to be important in preventing cognitive impairment in patients with type 2 diabetes without obesity. Higher serum sTREM2 levels would be a predictive marker for cognitive impairment in inadequately controlled type 2 diabetes without obesity.

Alternating bortezomib-dexamethasone and lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma aged over 75 years.

More than 40% of Japanese patients with multiple myeloma (MM) are over 75 years of age at diagnosis. Regardless of the treatment benefits, complications and relapses obstruct long-term survival. We conducted a phase II, open-label, single-arm, multicenter clinical trial to assess the efficacy and safety of alternating bortezomib-dexamethasone (Bd) and lenalidomide-dexamethasone (Ld) (Bd/Ld) treatment in MM patients aged over 75 years (MARBLE trial). Patients received Bd therapy from days 1 to 35 and Ld therapy from days 36 to 63. For Bd therapy, patients were administered bortezomib 1.3 mg/m2 and oral dexamethasone 20 mg on days 1, 8, 15, and 22. For Ld therapy, they were administered lenalidomide 15 mg from days 36 to 56 and dexamethasone 10 mg on days 36, 43, 50, and 57. They underwent six treatment cycles in total, each consisting of a 63-day regimen. In total, 10 patients were enrolled, with a median age of 81 years. Efficacy was not evaluated because the patients were fewer than planned. The overall response rate was 80.0% and complete response rate 40.0%. Seventy percent of patients completed the study treatment. Progression-free survival and overall survival at 2 years were 40.0% and 80.0%, respectively. Adverse events of grade 3 or higher, including anemia, decreased lymphocyte count, neutropenia, and hypokalemia, were observed in eight patients. Alternating chemotherapy with Bd/Ld might be feasible, but its efficacy should be verified further.

Efficacy of Intravenous Itraconazole Versus Liposomal Amphotericin B as Empirical Antifungal Therapy in Hematological Malignancy with Persistent Fever and Neutropenia: Study Protocol for a Multicenter, Prospective, Randomized Non-inferiority Trial.

Febrile neutropenia, a serious complication that can occur during the treatment of hematological malignancies, can sometimes be fatal owing to fungal infection. Prospective randomized trials indicated the utility of liposomal amphotericin B or caspofungin as an empirical antifungal therapy. Itraconazole, a broad-spectrum tri azole antifungal agent, is poorly absorbed in the intestines after oral absorption and makes it difficult to achieve a stable serum drug concentration. Therefore, an intravenous formulation might offer a potentially safer and more effective alternative. To compare the efficacy and safety of empirical antifungal therapy, patients will be randomly assigned to either the liposomal amphotericin B 3.0 mg/kg once daily group or the intravenous itraconazole 200 mg dose group with five stratification factors (disease risk, previous antifungal prophylaxis, age, sex, and institute). The primary endpoint will be overall favorable response, comprising five secondary endpoints: successful treatment of baseline infection by the end of the treatment; absence of breakthrough infection; no discontinuation of the antifungal treatment due to drug-related toxicity; fever resolution during neutropenia; and 7-day survival after termination of the antifungal treatment. The target sample size of 850 subjects is sufficient to prove the non inferiority of itraconazole compared with liposomal amphotericin B, with a non-inferiority margin of 10%, one sided significance level of 5%, and power of 90%.

Comparison of prognostic scores in transplant-ineligible patients with peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma: a retrospective study from the national hospital organization in Japan.

We retrospectively analyzed the risk factors for outcomes among patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, n = 100) and angioimmunoblastic T-cell lymphoma (AITL, n = 128) who did not receive hematopoietic stem cell transplantation between 2008 and 2018. We designed a comparison of prognostic scores specifically for PTCL-NOS and AITL. The international prognostic index (IPI) was useful for investigating the risk factors associated with outcomes among transplant-ineligible patients with PTCL-NOS (Harrell's c-statistic 0.715) and AITL (c-statistic 0.615). The prognostic index for T-cell lymphoma (PIT), modified PIT, and the International Peripheral T Cell Lymphoma Project for overall survival (OS) seemed to identify separate prognostic groups, based on visual assessment of Kaplan-Meier curves. However, better c-statistics (>0.7) were only found for the IPI score for OS in PTCL-NOS. Strategies that carefully select PTCL patients with higher IPI scores may help to identify individuals suitable for novel therapies.

Evaluation of prognosis following early disease progression in peripheral T-cell lymphoma.

Recently, progression of disease within 24 months (POD24) has been demonstrated as a strong prognostic indicator in various types of malignant lymphoma. Peripheral T-cell lymphoma (PTCL) has an aggressive course and poor clinical outcomes. In this multicenter retrospective study, 111 consecutively registered patients with newly diagnosed PTCL were analyzed. Of these patients, 72 (64.9%) experienced POD24 (POD24 group), and the other 39 patients (35.1%) were analyzed as the no POD24 group. In the POD24 group, overall survival (OS) was significantly inferior to all patients, and in the no POD24 group, subsequent OS was significantly superior to the POD24 group, although the clinical characteristics between the POD24 group and no POD24 group were not significantly different. Twenty-three patients (20.7%) showed primary refractory disease to first-line therapy, and the prognosis was poor. The International Prognostic Index score and POD24 were identified as independent predictors in multivariate analysis for OS in all patients, and only performance status was an independent prognostic factor for OS in the POD24 group in multivariate analysis. In conclusion, the clinical significance of assessing POD24 in PTCL and the poor prognosis in patients with early disease progression were demonstrated.

Pembrolizumab-induced Pure Red Cell Aplasia Successfully Treated with Intravenous Immunoglobulin.

We herein report a 64-year-old man who was treated with pembrolizumab for relapsed Hodgkin lymphoma. After the third administration of pembrolizumab, he showed acute anemia with a positive direct anti-globulin test. Because of the markedly erythroid hypoplasia, he was diagnosed with pure red cell aplasia (PRCA) caused by pembrolizumab. He was initially treated with prednisolone, but the reticulocytes decreased after tapering prednisolone. He then received high-dose intravenous immunoglobulin (IVIG) with prednisolone, and PRCA was successfully treated. Although the pathogenesis of PRCA caused by immune checkpoint inhibitors (CPIs) remains unclear, IVIG treatment may be effective for some steroid-refractory CPI-induced PRCA cases.

High-dose dexamethasone therapy as the initial treatment for idiopathic thrombocytopenic purpura.

There is a controversy which short term high dose dexamethasone therapy (HDD) or standard dose prednisolone therapy as the initial treatment leads to long term efficacy in idiopathic thrombocytopenic purpura (ITP) patients. We conducted a multicenter, prospective trial to determine the efficacy and safety of short-term HDD in ITP patients aged 18-80 years with platelet counts of < 20 × 109/l, or < 50 × 109/l and bleeding symptoms. The primary endpoints are the proportion of complete response (CR) plus partial response (R) on day 180 after the completion of the 46-day HDD. Twenty-three patients were enrolled. Test for Helicobacter pylori (H. pylori) was positive for 6 patients and negative for 17 patients. In positive patients, 5 were received successful H. pylori eradication therapy. The proportion of CR + R was 60.9% (14/23) with 90% confidence interval of 41.7-77.8%. For patients with positive H. pylori and successful eradication, the proportion of CR + R was 80.0% (4/5). There was one grade 4 adverse event. Although we have enrolled relatively old, severe ITP patients with a median age of 63 years in this study, the efficacy was comparable to the reported clinical trials with HDD therapy.

Phase II study of dose-adjusted gemcitabine, dexamethasone, cisplatin, and rituximab in elderly relapsed diffuse large B-cell lymphoma patients.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) are too toxic for elderly patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Therefore, effective and tolerable regimens for elderly patients are urgently needed. The present phase II study assessed the efficacy and safety of dose-adjusted therapy with gemcitabine, dexamethasone, cisplatin, and rituximab (GDP-R) in this population. ASCT-ineligible elderly patients with relapsed or refractory DLBCL received dose-adjusted GDP-R in each 28-day cycle for up to six cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete response (CR) rate, progression-free survival (PFS), and safety. Thirty-three patients were enrolled and received dose-adjusted GDP-R. The median age was 75 years (range: 68-87 years). The ORR was 82.8% (90% confidence interval [CI], 67.1-93.0%), with a CR rate of 58.6% (90% CI, 41.7-74.1%). At a median follow-up of 20.9 months, the 2-year PFS rate was 46.8% (90% CI, 30.7-61.5%) and the 2-year overall survival rate was 63.2% (90% CI, 45.8-76.3%). The most frequently observed grade 4 adverse events were neutropenia (63.6%), thrombocytopenia (57.6%), and lymphocytopenia (39.4%). Dose-adjusted GDP-R is a promising salvage regimen for ASCT-ineligible elderly patients with relapsed DLBCL after rituximab-containing chemotherapy and warrants further investigation.

PDCD1 and PDCD1LG1 polymorphisms affect the susceptibility to multiple myeloma.

Single-nucleotide polymorphisms (SNPs) of the programmed cell death protein-1 (PDCD1), programmed cell death protein-1 ligand-1 (PDCD1LG1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA4) genes are implicated in the pathogenesis of some cancers. We investigated the role of PDCD1, PDCD1LG1, and CTLA4 SNPs in MM pathogenesis and the susceptibility to and clinical features of multiple myeloma (MM). We obtained genomic DNA from 124 patients with MM and 211 healthy controls and detected PDCD1 (rs36084323, rs41386349, and rs2227982), PDCD1LG1 (rs2297136 and rs4143815), and CTLA4 (rs733618, rs11571316, rs231775, and rs3087243) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method or the TaqMan allelic discrimination real-time PCR method. The patients with MM had a significantly higher frequency of the PDCD1 GCC/GCC haplotype (rs36084323/rs41386349/rs2227982) compared with the healthy controls. PDCD1 rs2227982 CC genotype was associated significantly with a higher frequency of bone lesions. Patients with PDCD1LG1 rs2297136 TT and TC types (high-expression types) showed lower albumin level than those with CC genotype. In addition, the PDCD1LG1 rs4143815 CC and CG types (high-expression types) were associated significantly with higher frequency of patients who were treated with thalidomide and/or bortezomib. However, there was no statistical significance between CTLA4 polymorphisms and clinical variables of patients with MM. There were no significant differences between all the polymorphisms and OS. Our study indicates that the PDCD1 haplotype is associated with a susceptibility to MM. The PDCD1 rs2227982 and PDCD1LG1 rs2297136 affect the clinical features of multiple myeloma patients.

Phase II Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Over 75 Years Old with Alternating Bortezomib/dexamethasone and Lenalidomide/dexamethasone: the MARBLE Trial.

Elderly multiple myeloma (MM) patients, who are generally ineligible for transplantation, have high risks of death and treatment discontinuation, and require a regimen incorporating novel agents that balance safety, tolerability, and efficacy. We evaluated alternating bortezomib-dexamethasone and lenalidomide-dexamethasone treatments administered over a 63-day cycle in transplant-ineligible elderly patients with newly diagnosed MM. Subcutaneous bortezomib 1.3 mg/m2 was administered weekly on Days 1, 8, 15, and 22; oral lenalidomide 15 mg daily on Days 36-56; and oral dexamethasone 20 mg on Days 1, 8, 15, 22, 36, 43, 50, and 57 for 6 cycles. The primary endpoint was the overall response rate.

Evaluation of the Revised International Staging System (R-ISS) in Japanese patients with multiple myeloma.

In spite of recent development in the treatment armamentarium for multiple myeloma, overall survival (OS) still depends on risk status and sensitivity to treatment of each patient. We have evaluated the clinical relevance of the Revised International Staging System (R-ISS) by comparing it with the original ISS in 718 Japanese patients. The distribution of patients according to response was similar between the ISS and R-ISS stages. Treatment response was greatly influenced by initial treatment modalities and deeper response was observed more frequently in transplanted patients. The R-ISS discriminated the difference in OS between the stages more distinctly than the ISS (p = 9.0 × 10-15 and p = 4.0 × 10-10, respectively). Differences in OS were clarified by both R-ISS and ISS in non-transplanted patients (p = 2.4 × 10-12 and p = 1.4 × 10-8, respectively), but the ISS failed to distinguish the difference between the stages in transplanted patients (p = 0.13). In contrast, the R-ISS could at least discriminate the excellent prognosis of stage I patients whereas the distinction between stage II and III was not that clear (p = 0.033). The R-ISS stage II encompassed a large number of patients, and the prognosis was heterogeneous depending on the fulfillment of prognostic factors such as LDH and adverse cytogenetics. These results suggest that treatment factors and prognostic factors greatly affect the therapeutic response and outcome, and the R-ISS is superior to ISS in prognostication of both transplant-eligible and -ineligible patients in our current clinical practice.

Clinical characteristics of HIV-1-infected patients with high levels of plasma interferon-γ: a multicenter observational study.

BACKGROUND: Circulating interferon-γ (IFN-γ) concentration may be sustained at a high level regardless of the initiation of antiretroviral therapy (ART) in some patients with HIV-1 infection. In the present study, we examined the clinical characteristics of HIV-1-infected patients with high levels of plasma IFN-γ. METHODS: The study subjects were patients infected with HIV-1 who were either naïve to ART with CD4+ cell count > 200 cells/µL (n = 12), or had achieved viral suppression after ART for over a year (n = 188). The levels of plasma IFN-γ and interleukin-6 (IL-6) were measured by the enzyme-linked immunosorbent assay. Patients were divided into high IFN-γ and low IFN-γ groups based on a cutoff level of 5 pg/mL. RESULTS: The high IFN-γ group included 41 patients (21%). Compared to the patients on ART with low IFN-γ levels, those on ART in the high IFN-γ group were more likely to be younger than 50 years of age (P = 0.0051) and less likely to have dyslipidemia (P = 0.0476) or to be on a protease inhibitor (P = 0.0449). There was no significant difference between groups in the median increase of CD4+ cell counts from the initiation of ART for up to 3 years. However, after 4 years, the increase in CD4+ cell counts was significantly lower in the high IFN-γ group compared with that in the low IFN-γ group. There were no such significant differences between patients with low and high (> 2 pg/mL) levels of plasma IL-6. CONCLUSION: We concluded that HIV-1-infected patients with high levels of circulating IFN-γ did not have a higher rate of comorbidities related to immune activation. However, they exhibited lower CD4+ cell count recovery after 4 years of being on ART. This deficit could be a consequence of persistent immune activation.

High-dose Dexamethasone Therapy as the Initial Treatment for Idiopathic Thrombocytopenic Purpura: Protocol for a Multicenter, Open-label, Single Arm Trial.

Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of <20, 000 /µL, or with <50, 000/ µL and bleeding symptoms. The primary endpoints of this trial are the proportion of responses (complete plus partial response) on day 180 (day 46+180) after the completion of the 46-day high-dose dexamethasone therapy. The results of this investigation of the effectiveness and safety of this regimen will be essential for the establishment of standard therapy for ITP.

Clinical characteristics and outcomes of diffuse large B-cell lymphoma in adolescents and young adults.

Clinical information regarding non-Hodgkin lymphoma (NHL) in adolescents and young adults (AYA) is lacking. We retrospectively analyzed 1426 consecutively registered patients with newly diagnosed NHL. Of 798 DLBCL patients, 42 (5.3%) were identified as AYA (16-39 years). The characteristics of AYA DLBCL patients showed no significant differences compared to older adult DLBCL patients (age ≥ 40 years). Progression-free survival (PFS) and overall survival (OS) in AYA were similar to those in patients aged 40-60 years. However, in older adult groups, PFS and OS were significantly different according to the age group (40-60, 61-79, and ≥ 80 years). In univariate analysis in AYA, performance status, clinical stage, International Prognostic Index (IPI), and age-adjusted IPI significantly affected both PFS and OS. In multivariate analysis, only clinical stage was identified as an independent predictor among AYA. In conclusion, disease characteristics and outcomes of DLBCL in AYA were nearly the same as those in older adults.

Clinical management and outcomes of completely resected stage I follicular lymphoma.

Recent studies have revealed the clinical and biological features of stage I follicular lymphoma (FL), but information about patients with stage I FL who underwent total resection after tissue biopsy is limited. Among 305 FL patients diagnosed between 2001 and 2013, clinical stage I disease was observed in 36 patients. Of these, 18 patients underwent total resection after diagnostic tissue biopsy. We used 18F-fluorodeoxyglucose positron emission CT for staging assessment in 13 of 18 patients (72.2%). The median age was 56.5 years. Six patients (33.3%) were male. The soluble interleukin-2 receptor alpha concentration was significantly lower than in patients with residual disease. Among these 18 patients, 7 patients (38.9%) were treated with a "watch-and-wait" (WW) policy, 7 (38.9%) were treated with involved-field irradiation, and 4 (22.2%) received systemic chemotherapy. Patients with resected disease were treated with significantly different strategies from those with residual disease (p = 0.0026). Five patients experienced relapse during follow-up (median follow-up: 48.2 months). All relapses were distant from the primary site, irrespective of treatment strategy. Among all stage I patients, disease resection was not a significant factor for survival (p = 0.9294). Collectively, the choice of treatment strategy was significantly influenced by patient status. Resection status was not significantly associated with survival after several treatment strategies.