Effects of SGLT2 Inhibitors and DPP-4 Inhibitors on Advanced Glycation End Products.

Clinical trials have revealed that sodium glucose cotransporter 2 (SGLT2) inhibitors suppress the onset of heart failure and cardiovascular death in diabetic patients. On the other hand, few reports have been published concerning such effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. We undertook the present study to evaluate the effects of SGLT2 inhibitors and DPP-4 inhibitors on the advanced glycation end products (AGEs), well known as a risk factor for the development of cardiovascular disorders.Type 2 diabetes mellitus were divided into two groups and treated with either SGLT2 inhibitors or DPP-4 inhibitors for 3 months. Before and after the 3-month treatment period with each drug, the AGEs and diabetes-related parameters were measured. Methylglyoxal-derived hydroimidazolone-1 (MG-H1) was measured as one of the AGEs.In the SGLT2 inhibitor group, both the blood HbA1c and MG-H1 levels decreased significantly after the 3-month treatment period. In the DPP-4 inhibitor group, only the blood HbA1c level decreased significantly, with no significant change of the blood MG-H1 level.SGLT2 inhibitor reduced both the blood levels of HbA1c and AGEs (MG-H1). Considering that the blood levels of AGEs are associated with the risk of heart failure and cardiovascular disorders, the results of the present study suggest that the effect of SGLT2 inhibitors in suppressing cardiovascular death might be mediated by the reduction in the blood levels of AGEs induced by this class of drugs. DPP-4 inhibitors showed no significant effects on the blood levels of AGEs.

Effects of SGLT2 inhibitors on the intestinal bacterial flora in Japanese patients with type 2 diabetes mellitus.

Selective inhibitors of sodium glucose co-transporter-2 (SGLT2) suppress renal glucose reabsorption and promote urinary glucose excretion, thereby lowering blood glucose. SGLT2 inhibitors have been reported to reduce body weight. However, the mechanism underlying the reduction in the body weight induced by SGLT2 inhibitor treatment remains to be elucidated. In this study, we investigated the effects of SGLT2 inhibitors on the intestinal bacterial flora. A total of 36 Japanese patients with type 2 diabetes mellitus received a SGLT2 inhibitor (luseogliflozin or dapagliflozin) for 3 months, and the prevalences of balance-regulating bacteria and balance-disturbing bacteria in the feces of the patients before and after SGLT2 inhibitor treatment were determined. SGLT2 inhibitor treatment was associated with a significant increase of the overall prevalence of the 12 types of balance-regulating bacteria. In addition, significant increases in the prevalences of the short-chain fatty acid (SCFAs)-producing bacteria among the balance-regulating bacteria were also observed. Individual analyses of the balance-regulating bacteria revealed that the SGLT2 inhibitor treatment was associated with a significant increase in the prevalence of Ruminococci, which are balance-regulating bacteria classified as SCFAs-producing bacteria. However, SGLT2 inhibitor had no effect on the balance-disturbing bacteria. These results suggested that SGLT2 inhibitor treatment was associated with an overall increase in the prevalence of balance-regulating bacteria. Among the balance-regulating bacteria, the prevalences of SCFAs-producing bacteria increased. SCFAs have been reported to prevent obesity. The results of the present study suggest that SGLT2 inhibitors might induce body weight reduction via their actions on the intestinal bacterial flora.

Pure White Cell Aplasia Complicated by Systemic Sclerosis with Accompanying Scleroderma Renal Crisis.

Pure white cell aplasia (PWCA) is a rare neutropenic disorder caused by absence of neutrophil-lineage cells. A 49-year-old man was diagnosed with scleroderma renal crisis 2 months prior to admission to Ohta-Nishinouchi Hospital after experiencing a fever and abdominal pain. Blood tests revealed severe neutropenia, and bone marrow aspirate showed the absence of neutrophil-lineage cells. He was diagnosed with PWCA. Steroids alone were not effective, but adding cyclosporine A and high-dose immunoglobulin recovered his neutropenia and improved his condition. Cyclosporine A and high-dose immunoglobulin are thus considered effective for treating PWCA in autoimmune diseases.

[Acute HIV infection pathologically mimicking T-cell lymphoma].

A 49-year-old man was hospitalized with infectious mononucleosis-like symptoms, hepatosplenomegaly, and circulating abnormal lymphocytes. Hepatosplenic T-cell lymphoma was suspected, and bone marrow aspiration and liver biopsy were performed. The pathological diagnosis was T-cell lymphoma. When explaining malignant lymphoma to the patient, he disclosed his Men Who Have Sex with Men (MSM) status. HIV RNA test showed a markedly high viral load, and TCR gene rearrangement was negative. In view of these results, the patient was diagnosed with acute HIV infection. The previous lack of information concerning his MSM status led to a misdiagnosis, highlighting the relevance of this case to raise awareness of the importance of previously interviewing the patient.

[A child case of surfer's myelopathy].

We report a case of so-called "surfer's myelopathy" involving a 15-year-old girl. Preceding episodes of vaccination and infection were absent. She experienced back pain during a surfing class for beginners, followed by weakness in both legs, which progressed to paraperesis. Then, 2 days later, sensory disturbance and bladder/rectal disturbance also developed. Spinal MRI revealed a ischemic lesion compatible with anterior spinal cord syndrome. A combination of methylprednisolone pulse therapy and high-dose intravenous immunoglobulin therapy was effective leaving no residual dysfunction. The acute onset during the surfing class and characteristic MRI findings led to the diagnosis of surfer's myelopathy. Although rarely reported, warnings are warranted to prevent surfer's myelopathy and avoid the progressive deterioration of neurological dysfunction.

Factors associated with enrollment and adherence in outpatient cardiac rehabilitation in Japan.

PURPOSE: Despite the effectiveness of cardiac rehabilitation (CR), the participation percentage is low in Japan. Therefore, we investigated factors associated with enrollment and adherence in outpatient cardiac rehabilitation (OCR) in Japan. METHODS: This was a single-hospital, case-controlled study. During a 2-year study period, 544 patients were hospitalized for ischemic heart disease, heart failure, or open heart surgery, and recommended for in-hospital CR. Among them, 78 OCR participants and 179 randomly selected nonparticipants were included in the study. These 2 groups were compared to examine factors associated with OCR enrollment. In addition, OCR participants were divided into those who continued OCR for 3 months (adherence group) and those who did not (nonadherence group), and these 2 groups were compared to examine factors associated with OCR adherence. Univariate and multivariate logistic regression analyses were conducted for both objectives and included sociodemographic, clinical, and OCR-related variables. RESULTS: OCR enrollment was significantly associated with younger age (OR, 0.96; 95% CI, 0.93-0.98) and shorter distance to the hospital (OR, 0.97; 95% CI, 0.95-0.99). OCR adherence was significantly associated with a history of ischemic heart disease (OR, 6.03; 95% CI, 1.62-22.5) and prescription of antidepressants and/or sleeping pills (OR, 4.14; 95% CI, 1.07-16.0). CONCLUSIONS: The main factors associated with OCR enrollment and adherence were sociodemographic factors related to easier hospital access and clinical conditions that reflected high disease awareness, respectively.

The useful preliminary diagnosis of Niemann-Pick disease type C by filipin test in blood smear.

Niemann-Pick disease type C (NP-C) is an autosomal recessive lysosomal lipid storage disorder characterized with accumulation of cholesterol in endosomes and lysosomes. The diagnosis of NP-C is difficult due to its heterogeneous group of diseases. Biochemical diagnosis of NP-C is conducted by cholesterol staining with cultured skin fibroblasts and confirmed by the analysis of genetic mutations of NPC1 or NPC2 gene. Here, we report an easier biochemical diagnostic method with blood smear by filipin staining.

Cladribine combined with rituximab (R-2-CdA) therapy is an effective salvage therapy in relapsed or refractory indolent B-cell non-Hodgkin lymphoma.

Although cladribine has been reported to be an active purine analog against indolent B-cell non-Hodgkin lymphoma (B-NHL), there are few reports of combination use of cladribine and rituximab. This multicenter phase II study evaluated the efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy in relapsed or refractory indolent B-NHL. Twenty patients with the median age of 58.5 yrs (range, 42-72) were enrolled and received R-2-CdA therapy from April 2005 to July 2007. The median number of prior regimens was 2 (range, 1-3), and fifteen patients (75%) were previously treated with rituximab-containing regimens. Disease histology included follicular lymphoma in 16 patients, MALT lymphoma in two patients, nodal marginal B-cell lymphoma in one patient, and lymphoplasmacytic lymphoma in one patient. The overall response rate (ORR) was 90%, with a complete response rate (CRR) of 70%. Estimated median progression-free survival (PFS) time was 22.4 months (95%CI, 10.9-32.6 months) at a median follow-up time of 27 months (range, 12-43). Two-year PFS and 2-yr overall survival (OS) were 52.6% (95%CI, 31.0-73.2%) and 89.5% (95%CI, 66.1-97.3%), respectively. Grade 3 or grade 4 toxicities were neutropenia in 74% and thrombocytopenia in 11%. R-2-CdA therapy was demonstrated to have a high activity with durable PFS and acceptable toxicity in relapsed or refractory indolent B-NHL mostly pretreated with rituximab-containing therapy. Although a large-scale trial is needed for confirmation, R-2-CdA therapy could be a good salvage therapy option in relapsed or refractory indolent B-NHL.

Allogeneic stem cell transplantation versus chemotherapy as post-remission therapy for intermediate or poor risk adult acute myeloid leukemia: results of the JALSG AML97 study.

We prospectively compared allogeneic hematopoietic stem cell transplantation (allo-HSCT) with chemotherapy as a post-remission therapy in a multicenter trial (JALSG AML97) of adult patients with intermediate or poor risk acute myeloid leukemia (AML). Of 503 patients aged 15-50 years old registered between December 1997 and July 2001, 392 achieved complete remission (CR). CR patients classified in the intermediate or poor risk group using a new scoring system were tissue typed. Seventy-three with and 92 without an HLA-identical sibling were assigned to the donor and no-donor groups. Of 73 patients in the donor group, 38 (52%) received allo-HSCT during CR1 and 17 (23%) after relapse. Intention-to-treat analysis revealed that the relapse incidence was reduced in the donor group (52 vs. 77%; p = 0.008), and the disease-free survival (DFS) improved (39 vs. 19%; p = 0.016), but overall survival (OS) was not significantly different (46 vs. 29%; p = 0.088). The OS benefit was seen in the patients aged 36-50 years old (49 vs. 24%; p = 0.031), suggesting an advantage of allo-HSCT among older patients with leukemia that is more resistant to chemotherapy than that among younger patients.

Randomized trial of response-oriented individualized versus fixed-schedule induction chemotherapy with idarubicin and cytarabine in adult acute myeloid leukemia: the JALSG AML95 study.

A multicenter, prospective, randomized study was conducted to compare a response-oriented individualized remission induction therapy with a standard fixed-schedule induction therapy, using idarubicin (IDR) and cytarabine (Ara-C), in adult patients with acute myeloid leukemia (AML). Newly diagnosed patients with AML of age less than 65 were randomly assigned to receive either of the two schedules. Both groups received IDR (12 mg/m2) for 3 days and Ara-C (100 mg/m2) for 7 days. In the individualized group, if the bone marrow on day 8 did not become hypocellular with less than 15% blasts, patients received additional IDR for one more day and Ara-C for 2 or 3 more days. Patients achieving complete remission (CR) received the same post-remission therapy. The CR rate was 79.4% for the individualized group (n = 209) and 81.9% for the fixed group (n = 221) (p = 0.598). At a median follow-up of 81 months, 7-year predicted overall survival was 37% for the individualized group and 39% for the fixed group (p = 0.496), and 7-year predicted event-free survival was 22% for the individualized group and 23% for the fixed group (p = 0.546). Thus, the present study could not demonstrate any advantage of a response-oriented individualized induction therapy over a fixed-schedule induction therapy in this protocol setting.

Phase I/II study of humanized anti-CD33 antibody conjugated with calicheamicin, gemtuzumab ozogamicin, in relapsed or refractory acute myeloid leukemia: final results of Japanese multicenter cooperative study.

The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of gemtuzumab ozogamicin (GO) in patients with relapsed and/or refractory CD33-positive acute myeloid leukemia (AML). Patients received 2-h infusions of GO twice with an interval of approximately 14 days. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria Version 2.0. Samples for pharmacokinetics were taken on day 1 and day 8 of the first treatment cycle. The dose was increased stepwise and, in each cohort, patients were treated at the same dose. Forty patients, median age 58 years (range 28-68) were treated; 20 and 20 patients were enrolled to the phase I and II parts, respectively. In the phase I part, dose-limiting toxicities (DLTs) were hepatotoxicities, and the recommended dose was established as 9 mg/m2 given as two intravenous infusions separated by approximately 14 days. The pharmacokinetic study revealed that Cmax and AUC were equivalent to those of non-Japanese patients. In the phase II part, complete remission was observed in 5 patients, and one patient had complete remission without platelet recovery. Four of these 6 in remission and one in the phase I are long-term survivors (alive for at least 44 months). GO is safe and effective as a single agent among Japanese CD33-positive AML patients. Remission lasted longer in a subset of patients than in non-Japanese patients in earlier studies. Further studies of this agent are warranted to establish standard therapy.

[Recurrent idiopathic cerebral infarction in a 5-year-old boy, with emphasis on the importance of platelet aggregation analysis for appropriate selection of anti-platelet drugs].

We present a 5-year-old boy with recurrent idiopathic cerebral infarction in which analysis of platelet hyperaggregability was useful in choosing appropriate anti-platelet drugs. The patient presented with gait disturbance at the age of 5 years and 1 month. Brain MRI demonstrated multiple infarctions in the right thalamus and left cerebellum. There were no apparent underlying diseases including hematological, cardiac and vascular abnormalities. He was diagnosed as idiopathic cerebral infarction. First, we administered ticlopidine and he remained stable with persistent mild intention tremor in the left upper extremity for 4 months. Then he developed the second stroke at the age of 5 years and 5 months, and multiple infarctions in the right celebellum and cerebellar vermis were demonstrated. On platelet aggregation analysis, adenosine diphosphate (ADP)-induced aggregation was inhibited, probably due to ticlopidine administration. Collagen- and epinephrine-induced platelet aggregation showed hyperaggregation, so we started to administer cilostazol, which inhibits only epinephrine-induced hyperaggregation. We also added aspirin, which inhibits collagen-induced hyperaggregation. The combination of anti-platelet drugs inhibited epinephrine-, collagen- and ADP-induced hyperaggregation in this patient. He has been stable on the triple combination of anti-platelet drugs without further episodes of cerebral infarction or transient ischemic attack for 4 years to date. Appropriate selection of anti-platelet therapy was achieved by the simple and repeatable platelet aggregation analyses, which must be considered even in pediatric patients with cerebral infarction.

A case of accidental ingestion of a salbutamol sulfate inhalant, Venetlin®.

Pediatricians examine increasing numbers of children with bronchial asthma every year. In Japan, medical institutions can provide standardized therapies according to the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2005. Inhalation therapy is highly beneficial, and a substantial proportion of patients choose to purchase inhalators and practice inhalation therapy at home. Recently, we experienced a case of accidental ingestion of a salbutamol sulfate inhalant by a non-asthmatic child, which reminded us anew of the importance of managing the medicines for asthma. We also recognized the need to educate patients and their families on the knowledge of these medicines. In this report, we analyze the case and discuss measures that pediatricians can implement to avoid accidental inhalant ingestion by children.

Spontaneous expectoration of bronchial foreign body: a case report.

A nine-year-old girl with mental retardation accidentally swallowed an axle of a toy car and was urgently hospitalized with the diagnosis of left bronchial foreign body. While various monitors were installed and removal of the foreign body by a ventilating rigid bronchoscope was in preparation, the patient suddenly coughed and vomited, with the foreign body found in the vomit. When examining infant cases of air way foreign body, attention tends to be focused on the diagnosis and treatment. However, patients are at risk of aggravating difficulty in breathing or suffocation as long as foreign bodies are present in the air way. It is important to monitor carefully for changes in the breathing and to prepare for unexpected events.

Utility of virtual bronchoscopy in congenital tracheomalacia.

Utility of virtual bronchoscopy was evaluated in a case of congenital tracheomalacia by comparing virtual bronchoscopic images with those of fiberoptic bronchoscopy. Results indicate that virtual bronchoscopy is useful in diagnosing stationary lesions. However, its diagnostic value is inferior to that of fiberoptic bronchoscopy for mobile lesions, in that virtual bronchoscopy does not permit dynamic images. We recommend that the institutions, where fiberoptic bronchoscopy is available, should perform virtual bronchoscopy in parallel to explore its utility.

A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus three courses of standard-dose consolidation with maintenance therapy in adults with acute myeloid leukemia: the Japan Adult Leukemia Study Group AML 97 Study.

BACKGROUND: A major concern in the treatment of patients with acute myeloid leukemia (AML) is how to prevent disease recurrences. Although intensive consolidation therapy has proven useful, the effectiveness of maintenance therapy remains controversial. METHODS: Seven hundred eighty-nine patients ages 15-64 (median: 45 yrs) with de novo AML received induction therapy, which consisted of cytosine arabinoside (at a dose of 100 mg/m(2) on Days 1-7) and idarubicin (at a dose of 12 mg/m(2) on Days 1-3). The patients who achieved complete remission (CR) were then randomized into groups that received either four courses of standard-dose consolidation therapy without maintenance (Arm A) or three courses of standard-dose consolidation and six courses of maintenance therapy (Arm B). RESULTS: In total, 78.7% of patients achieved CR. The 5-year overall survival (OS) rate for the 789 eligible patients was 46.9%, and the disease-free survival (DFS) rate for the 621 patients who achieved CR was 32.9%. The 5-year OS rate for Arm A was 52.4%, and 58.4% for Arm B (P = 0.599). The 5-year DFS rate for the patients who achieved CR was 35.8% in Arm A and 30.4% in Arm B (P = 0.543). In analyzing the data according to the risk groups, no statistical difference was observed either in the 5-year OS rate or in the 5-year DFS rate between the 2 arms. CONCLUSIONS: In the current study, the Japan Adult Leukemia Study Group's conventional postremission therapy (three courses of standard-dose consolidation and six courses of maintenance therapy) was replaced successfully by a shorter duration of four courses of standard-dose consolidation therapy without the need for additional maintenance therapy.

Phase III study of ranimustine, cyclophosphamide, vincristine, melphalan, and prednisolone (MCNU-COP/MP) versus modified COP/MP in multiple myeloma: a Japan clinical oncology group study, JCOG 9301.

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.

Prognostic significance of CD7+CD56+ phenotype and chromosome 5 abnormalities for acute myeloid leukemia M0.

Myeloid/natural killer (NK) cell precursor acute leukemia is an entity of acute leukemia characterized by poor prognosis and a CD7+CD56+ myeloid antigen+ phenotype without light-microscopic myeloperoxidase reactivity. This disease shares several clinical characteristics with acute myeloid leukemia (AML) M0. To clarify the relationship between these 2 leukemias, we analyzed 105 cases of AML M0. Among them, 17 were CD7+ and CD56+, 77 were negative for either antigen, and 11 could not be determined. CD7+CD56+ AML M0 showed onset at significantly lower patient age (median 46 versus 63 years, P = .004). The disease localization and the hematological manifestations were significantly different: CD7+CD56+ AML showed more frequent extramedullary involvement, fewer circulating leukemic blasts, less anemia, and less thrombocytopenia than did AML M0. The cytogenetic aberrations were also unique, because no 5q abnormalities were found in CD7+CD56+ M0. The prognosis of CD7+CD56+ M0 was poor in patients younger than 46 years (P = .03). Multivariate analysis showed that the CD7+CD56+ phenotype was a significant prognostic factor for AML M0, as well as age, circulating blast percentage, and chromosome 5 abnormalities These findings suggest that AML M0 consists of heterogeneous subgroups to be managed separately, and CD7+CD56+ M0 constitutes a distinct subtype of AML M0.