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The definition of sarcopenia assessed by computed tomography (CT) varies among different reports, and few studies have examined the effect of muscle mass loss on the prognosis of post-hematopoietic cell transplantation (HCT). We retrospectively evaluated 172 patients who underwent an initial allogeneic HCT for acute leukemia at our institution. They were divided into 3 groups according to muscle mass measured at the third lumbar vertebra as assessed by CT. Patients with low muscle mass had a worse performance status, higher comorbidity index and higher disease risk. There was a significant difference in 2-year overall survival between the 3 groups, and worse overall survival (OS) was associated with lower muscle mass (

The present study compared trends in antimicrobial resistance patterns in pathogens isolated from skin and soft-tissue infections (SSTIs) in Japan with those of a nationwide survey conducted in 2013. Three organisms that caused most of the SSTIs were collected from 12 dermatology departments in medical centers and 12 dermatology clinics across Japan between April 2019 and August 2020. A total of 390 strains, including 267 Staphylococcus aureus, 109 coagulase-negative staphylococci (CNS), and 14 Streptococcus pyogenes strains were submitted to a central laboratory for antimicrobial susceptibility testing. Patient demographic and clinical information was collated. Methicillin-resistant S. aureus (MRSA) was detected in 25.8% (69/267) of the S. aureus strains. The prevalence of MRSA between the present study and the 2013 survey did not differ significantly. Furthermore, there were no significant differences in MIC values and susceptibility patterns of the MRSA strains to other agents, regardless of a history of hospitalization within 1 year or invasive medical procedures. Methicillin-resistant CNS (MRCNS) was detected in 48.6% (53/109) of CNS isolates, higher than the 35.4% prevalence in the 2013 survey. This difference could be attributed to the heterogeneity in the members of the MRCNS, which comprises multiple staphylococci species, between the 2013 and 2019 surveys. However, it was noted that the susceptibility profiles of the MRCNS to each antibiotic were not significantly different from those identified in the 2013 survey. Most strains of S. pyogenes were susceptible to each antibiotic, similar to the 2013 survey. Continuous monitoring of trends in pathogen and susceptibility profiles is important to advise local public health efforts regarding the appropriate treatment of SSTIs.

High-dose methotrexate (MTX) is widely used for the treatment of hematological malignancies. Despite the application of routine supportive care measures, such as intensive fluid hydration and urine alkalinization, nephrotoxicity is still a problem. The present study aimed to evaluate the risk factors for MTX-induced nephrotoxicity. We retrospectively reviewed 88 patients who received a regimen consisting of high-dose MTX (1000 mg/m2) and cytosine arabinoside between 2006 and 2018. Nephrotoxicity (≥ grade 2) was observed in 11 patients. Nephrotoxicity was observed only in patients with a high MTX concentration. Other than the MTX concentration, the serum uric acid level and urine pH at day 1 were associated with nephrotoxicity. A multivariate analysis revealed that urine pH was an independent risk factor for MTX-induced nephrotoxicity. Urine pH

Cardiotoxicity after allogeneic stem cell transplantation (SCT) is associated with a high rate of mortality and worsening quality of life. The relation between daunorubicin dose and post- allogeneic stem cell transplantation (SCT) cardiotoxicity remains unclear. We retrospectively evaluated 171 patients with acute myeloid leukemia (AML) who underwent their first allogeneic SCT at our institution between 2005 and 2021. High-dose daunorubicin (50 mg/m

Tumor lysis syndrome (TLS) is a metabolic disorder caused by massive tumor lysis. Hypouricemic agents are administered to prevent TLS-related hyperuricemia and renal failure. We experienced three cases of urine xanthine crystals during TLS in patients with hematologic malignancies who received prophylactic febuxostat. Yellowish and pinkish deposits were observed in urinary tract catheters and urinary bags. Urine microscopy revealed that the deposits were xanthine crystals. In rapid tumor lysis, inhibition of xanthine oxidase can cause xanthine accumulation and urine xanthine crystallization. During TLS, urine xanthine crystals may be overlooked, so careful observation and management are required to avoid xanthine nephropathy.

Gastrointestinal acute graft-versus-host disease (aGVHD) is a life-threatening complication that requires urgent and appropriate treatment. An endoscopic examination is considered the gold-standard for the diagnosis of gastrointestinal aGVHD. However, the prognostic value of endoscopy remains controversial. This study aimed to investigate the usefulness of pre-treatment macroscopic and histopathologic findings of upper and lower endoscopy with respect to predicting steroid-resistant gastrointestinal aGVHD. This retrospective study included 44 patients with gastrointestinal aGVHD who underwent endoscopy at the time of diagnosis and received systemic steroid treatment at our hospital. We graded the macroscopic and histopathologic findings using a previously validated 4-point scale. Univariate analyses of endoscopic grading revealed that a higher macroscopic grade in the ileum and higher histopathologic grades in the ileum and colon predicted a poor response to systemic steroids. In a multivariate analysis, macroscopic and histopathologic severity in the ileum were identified as significant prognostic factors that indicated resistance to steroid therapy. The presence of granulation tissue was also a strong independent predictor of resistance to steroid therapy. These findings suggest that both macroscopic and histopathologic findings in the ileum may be useful predictors of steroid-refractory gastrointestinal aGVHD and can indicate an immediate need to develop a second-line strategy.

The speed of neutrophil recovery following allogeneic hematopoietic cell transplantation (allo‐HCT) varies widely among patients. We retrospectively evaluated the slope of neutrophil recovery (N slope) in 120 patients who underwent a first unrelated bone marrow transplantation with granulocyte‐colony stimulating factor support between 2009 and 2018. The median N slope was 205.5 /µL/day. We classified patients into low (n = 59) and high (n = 61) N slope groups with a cut‐off value of 200 /µL/day. The high N slope group correlated with older patients, RIC regimen, high CD34+ cells and recent transplantation. The cumulative incidence of grade II to IV acute graft‐versus‐host disease (aGVHD) was significantly higher in the high N slope group than in the low N slope group (44.3% vs. 16.9%, P < 0.001). In multivariate analysis, high N slope was identified as a significant independent risk factor for grade II to IV aGVHD, irrespective of the involved organs. There were no differences in relapse, non‐relapse mortality, or overall survival between the two groups. In conclusion, the difference in N slope after allo‐HCT may predict the risk of aGVHD. Prevention and treatment of GVHD according to the changes in the neutrophil count may improve post‐transplant complications.

Background A treatment strategy is needed for hemodialysis-dependent patients with end-stage renal disease who have relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We examined the feasibility of salvage chemotherapy followed by autologous stem-cell transplantation (ASCT) and busulfan as a conditioning regimen. Patients and Methods We provided a patient with refractory DLBCL who was receiving hemodialysis with modified salvage chemotherapies that were based on the mechanism of drug pharmacokinetics and an evaluation of the pharmacokinetics of busulfan. After chemotherapy, the patient underwent ASCT. Results The regimen was successfully administered without adverse events. Conclusion Chemotherapy followed by ASCT using a conditioning regimen of reduced melphalan and pharmacokinetically targeted busulfan is a promising strategy for treating patients with relapsed or refractory DLBCL who also have end-stage renal disease and are receiving hemodialysis.

Triplet regimens, such as lenalidomide, bortezomib, and dexamethasone (RVd) or thalidomide, bortezomib, and dexamethasone (VTd), are standard induction therapies for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to RVd and VTd has been investigated in the GRIFFIN and CASSIOPEIA trials, respectively, resulting in improvement in the rate of minimal residual disease (MRD) negativity. In this study, we conducted a cost-effectiveness analysis with a 10-year time horizon to compare first-line and second-line use of daratumumab for transplant-eligible patients with NDMM. Because long-term follow-up data for these clinical trials are not yet available, we developed a Markov model that uses MRD status to predict progression-free survival. Daratumumab was used either in the first-line setting in combination with RVd or VTd or in the second-line setting with carfilzomib plus dexamethasone (Kd). Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were calculated from a Japanese and US payer perspective. In the Japanese analysis, D-RVd showed higher QALYs (5.43 vs 5.18) and lower costs (¥64 479,793 vs ¥71 287 569) compared with RVd, and D-VTd showed higher QALYs (5.67 vs 5.42) and lower costs (¥43 600 310 vs ¥49 471,941) compared with VTd. Similarly, the US analysis demonstrated dominance of a strategy incorporating daratumumab in first-line treatment regimens. Given that overall costs are reduced and outcomes are improved when daratumumab is used as part of a first-line regimen, the economic analysis indicates that addition of daratumumab to first-line RVd and VTd regimens is a dominant strategy compared with reserving its use for the second-line setting.

Aprepitant (Apr) is an effective antiemetic agent for chemotherapy-induced nausea and vomiting (CINV). Current CINV guidelines recommend the antiemetic combination of a 5-HT3 receptor antagonist, Apr, and dexamethasone (Dex) for highly emetogenic chemotherapies. Apr inhibits CYP3A4 dose-dependently. Since Dex is metabolized by CYP3A4, the combined use of Apr and Dex inhibits Dex metabolism. CINV guidelines therefore recommend dose-reduction of Dex when Apr and Dex are used together. However, there is some controversy over whether or not Dex should be reduced when administered as an antitumor agent for lymphoid malignancies. We retrospectively compared the antitumor effect of Dex-containing chemotherapy in which Dex is administered at the usual dose without Apr (group A) or administered at a half-dose in combination with Apr (group B). We analyzed 62 consecutive patients with refractory or relapsed CD20 + B cell lymphoma who received R-DHAP therapy in our hospital, including 29 and 33 cases in groups A and B, respectively. The response rate at the end of the first course of R-DHAP was 62.1% and 54.5%, respectively (P = 0.61). As another endpoint to evaluate the effect of Dex, group B tended to show greater suppression of the lymphocyte count (P = 0.05). Therefore, decreasing the dose of Dex by half appeared to be reasonable when combined with Apr.

Objective Peripherally inserted central catheters (PICCs) are widely used in patients with hematologic malignancies. However, the risks of PICC-related complications during chemotherapy for acute myeloid leukemia (AML) are not fully understood. Methods We conducted a retrospective review of 128 adult patients with AML who received induction therapy by way of PICC insertion between 2012 and 2019. Results The median duration of PICC insertion was 30 days. The incidence rate of catheter-related bloodstream infection (CRBSI) was 2.4% at 30 days, and women were more likely to suffer from CRBSI than men. Local reactions at the insertion site were observed in 56 patients; however, these events did not predict CRBSI. The incidence rates of catheter-related thrombosis (CRT) were 1.6% at 30 days. Obesity put patients at an increased risk for CRT. Unexpected PICC removal occurred in 59 patients, and women were at a higher risk of catheter removal than men. Conclusion Low PICC-related complication rates, possibly associated with high rates of catheter removal, were observed during intensive chemotherapy for AML. Women and obese patients require careful monitoring of their PICC. Procedures to achieve appropriate PICC removal without increasing the complication rate need to be considered.

The combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is used as salvage chemotherapy for relapsed or refractory lymphoma. It includes the administration of cisplatin in a single dose of 100 mg/m2, and renal toxicity is a common adverse event. In this study, we retrospectively analyzed the risk factors for renal toxicity (≥ grade 2) in 74 patients who received DHAP as salvage chemotherapy. Regarding maximal renal toxicities, 38 (51.4%), 6 (8.1%), and 1 (1.4%) patients had grade 2, 3, and 4 toxicities, respectively. Multivariate analyses revealed that overweight (body mass index ≥ 25) was an independent predictive factor for renal toxicity of ≥ grade 2 (odds ratio [OR] 4.08, P = 0.032). A subgroup analysis for patients with diffuse large B cell lymphoma treated with DHAP as second-line therapy (n = 44) confirmed that overweight was an independent risk factor (OR 5.28, P = 0.049). In conclusion, we demonstrated that overweight was an independent risk factor for renal toxicity of ≥ grade 2 in patients who received DHAP. Further clinical studies will be needed to identify a method to decrease renal toxicities after the administration of cisplatin.

Immune thrombocytopenia (ITP) can coexist with autoimmune thyroid disease. However, the detailed clinical features remain unknown. We retrospectively reviewed 248 patients with newly diagnosed ITP in our institute for whom we had thyroid function data at diagnosis between 2000 and 2019. Of the 248 patients with ITP, 74 patients also had thyroid disease, including 36 with overt thyroid disease (13 Graves' disease and 23 Hashimoto's thyroiditis) and 38 with subclinical thyroid disease (3 hyperthyroidism and 35 hypothyroidism). ITP and thyroid disease were concurrently diagnosed in 54 patients. Female sex and positivity for antinuclear antibodies (ANA) were significantly associated with thyroid diseases. Platelet-associated immunoglobulin G (PAIgG) levels in patients with Graves' disease were higher than those in patients with Hashimoto's thyroiditis. Platelet counts were similar among euthyroid patients and patients with thyroid disease. Thrombopoietin-receptor agonist was administered more frequently in patients with thyroid disease. The cumulative incidences of thrombosis and bleeding and overall survival did not differ between patients with and without thyroid disease. Treatment for thyroid disease in 22 patients improved thrombocytopenia in 21 patients, especially in 4 patients who were not treated for ITP. This study demonstrated that thyroid diseases were commonly found in patients with ITP. Treatment of the underlying thyroid disease may improve thrombocytopenia.

We retrospectively examined 57 patients with multiple myeloma who underwent autologous stem cell transplantation (ASCT) at our institution. A receiver-operating characteristic curve (ROC) analysis showed that the reduction rate of quantitative serum monoclonal protein (M-protein) before ASCT and the difference in involved and uninvolved free light chains (dFLC) 30 days after ASCT, respectively, had the greatest predictive value for all patients (area under the curve [AUC] 0.791 and 0.660, respectively). Based on the ROC curve-based cutoff values of tumor burden parameters, progression-free survival (PFS) in the high serum M-protein reduction (≥90 %) group was significantly better than that in the low serum M-protein reduction group (

We evaluated clinical outcomes of disseminated intravascular coagulation (DIC) in patients with hematological malignancies treated with synthetic protease inhibitors (SPIs) and compared the effects of gabexate mesilate (FOY) and nafamostat mesilate (FUT). We retrospectively examined 127 patients [acute myeloid leukemia (n = 48), acute lymphoblastic leukemia (n = 25), and non-Hodgkin lymphoma (n = 54)] with DIC, who were diagnosed according to Japanese Ministry of Health, Labour and Welfare criteria and treated with SPIs [FOY (n = 55) and FUT (n = 72)] at our hospital from 2006 to 2015. The DIC resolution rates on days 7 and 14 were 42.6% and 62.4%, respectively. No significant differences were observed in DIC resolution rates between the FUT and FOY groups [40.3% vs. 45.5% (day 7), P = 0.586; 56.3% vs. 69.8% (day 14), P = 0.179, respectively]. Multivariate analysis revealed that response to chemotherapy was the only independent predictor of DIC resolution on days 7 and 14 (ORR 2.81, 95% CI 1.32-5.98, P = 0.007; ORR 2.51, 95% CI 1.12-5.65, P = 0.026). Resolution of DIC was correlated with improvement of background hematological malignancies, and no significant differences were observed between the two SPIs.

The amount of infused CD34+ cells has been reported to be the strongest predictor of platelet recovery after autologous stem cell transplantation (ASCT). However, the timing of platelet recovery varies widely among patients even after the infusion of similar amounts of CD34+ cells. Therefore, we retrospectively assessed 99 patients who underwent their first ASCT for lymphoma or myeloma at our center. Thirteen patients (13%) did not achieve platelet engraftment, defined as a platelet count of at least 2.0 × 104/μL without transfusion, at day 28 after transplantation, whereas 58 of 60 patients (97%) who received at least 2.0 × 106/kg CD34+ cells achieved platelet engraftment within 28 days. Multivariate analysis identified the following significant risk factors for delayed platelet recovery: hemoglobin level and platelet count before stem cell harvest, body temperature of > 39 °C within 5 days after ASCT, and infusion of a small amount ( 39 °C within 5 days after ASCT were identified as independent factors for delayed platelet recovery. In summary, platelet recovery following ASCT was affected by insufficient hematopoietic recovery at stem cell harvest, a need for repeated apheresis, and high fever early after ASCT, particularly when the amount of infused stem cells was insufficient.

The cost of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) is a substantial economic burden. In Japan, imatinib, dasatinib, and nilotinib are now approved as first-line treatment of CML in chronic phase. Recent “stop TKI” trials have shown that TKIs can be safely discontinued in nearly one-half of patients with sustained deep molecular response (DMR). In this study, we analyzed the cost-effectiveness of a simulated 10 years of CML treatment including stop TKI in both the United States and Japan. We constructed Markov models to compare 4 strategies in which treatment was initiated with imatinib, dasatinib, nilotinib, or any of these TKIs at the physician's discretion. Treatment was switched to another TKI in the case of intolerance or resistance to the initial TKI, and TKIs were discontinued if DMR persisted for 2 years. “Imatinib first” offered 7.34 quality-adjusted life years (QALYs) at the cost of $1 022 148 in the United States (US dollars) and ¥32 526 785 in Japan (Japanese yen). In comparison with imatinib first, the incremental cost-effectiveness ratio per QALY of “dasatinib first” (7.68 QALY, $1 236 052, ¥51 506 254), “nilotinib first” (7.64 QALY, $1 245 667, ¥39 635 598), and “physician's choice” (7.55 QALY, $1 167 818, ¥41 187 740) was $641 324, $696 717, and $666 634 in the United States and ¥54 456 325, ¥23 154 465, and ¥39 635 615 in Japan, respectively. None of the 3 strategies met the willingness-to-pay threshold. The results were robust to univariate and multivariate sensitivity analyses. Imatinib first was shown to be the most cost-effective approach even with the incorporation of stop TKI.

This study sought to investigate the impact of the soluble interleukin-2 receptor level in the relapsed or refractory phase (r/r sIL-2R) on the clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL). We determined the optimal cutoff value of r/r sIL-2R for disease progression within 6 months from salvage chemotherapy to be 861 U/mL. The high r/r sIL-2R group exhibited a significantly lower survival rate than the low r/r sIL-2R group (1-year event-free survival [EFS], 22.6% vs. 55.7%

Background: Danaparoid sodium and synthetic protease inhibitors (SPIs) have been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan. Objectives: To compare the clinical results of the treatment of DIC with danaparoid or SPIs. Methods: We retrospectively examined 188 patients with hematological malignancy-related DIC. Results: DIC resolution rate in the danaparoid group was higher than that in the SPIs group (61.5 vs. 42.6%; p = 0.031) on day 7. Multivariate analysis identified the response to chemotherapy as independent predictive factor for DIC resolution on day 7 (odds ratio, OR, 2.28; 95% confidence interval, CI, 1.21–4.31; p = 0.011). While there was no significant difference in the DIC resolution rate on day 14 (75.0 vs. 62.4%; p = 0.117), in a subgroup analysis of patients who did not show an improvement in the underlying disease, the danaparoid group showed a significantly better DIC resolution rate (OR 3.89; 95% CI 1.15–13.2; p = 0.030). There was no difference in the rate of cumulative mortality from bleeding within 28 days between the 2 groups (6.6 vs. 3.3%; p = 0.278). Conclusions: Danaparoid may be associated with more frequent resolution of DIC in patients with refractory underlying disease.

Neutropenia is a major risk factor for opportunistic infections in patients with acute myeloid leukemia (AML) who undergo chemotherapy. In the present study, we retrospectively compared the D-index, which reflects both the depth and duration of neutropenia, between two different chemotherapy regimens for AML. Sixty-seven patients with AML were included: 37 received an induction regimen of daunorubicin (DNR) and cytarabine followed by consolidation therapies consisting of standard-dose cytarabine (SDAC) and other antineoplastic agents; the remaining 30 received idarubicin (IDR) and cytarabine as remission induction therapy followed by high-dose cytarabine (HDAC). The duration of neutropenia was shorter, but the D-index was higher, with IDR than with DNR. The total D-index during the entire consolidation therapies was significantly higher with SDAC than with HDAC. In conclusion, the neutropenia profile differs between treatment regimens, and thus, physicians should plan the management of infectious complications according to the neutropenia profile for each regimen.

Introduction Cervical spinal cord injury with the C3 neurological level may cause respiratory failure and require long-term mechanical ventilation. Conventional weaning of spontaneous breathing trials is difficult to perform outside of intensive care or spinal cord units. Case presentation An 80-year-old man presented with total tetraplegia and restrictive respiratory failure that required assisted ventilation after a falling accident. Cervical spine magnetic resonance imaging showed cervical cord compression that was worst at the C3–C4 intervertebral level. He experienced unexpected cardiac arrest during the conventional weaning process of trials of intermittent spontaneous breathing in the intensive care unit. The automated weaning protocol utilizing a closed-loop ventilation mode (IntelliVent®-ASV ® ) was introduced 131 days after injury in our ward for chronically ill patients. The patient was successfully weaned 39 days after the introduction of the weaning protocol. Discussion An automated weaning protocol utilizing a closed-loop ventilation mode could be an optional procedure in patients with cervical cord injury on long-term mechanical ventilation, even in a ward for chronically ill patients where sufficient staff is not available. The efficacy and safety, and the cost-effectiveness of the procedure should be examined in larger spinal cord units.

TAFRO syndrome, a rare systemic inflammatory disease, can lead to multiorgan failure without appropriate treatment. Although thrombocytopenia is frequently seen in patients with TAFRO syndrome, little is known about its pathogenesis. Moreover, while recent studies have reported the presence of an anterior mediastinal mass in some patients, the pathological status of this remains unclear. Here, we report a case of fatal bleeding in a patient with TAFRO syndrome accompanied by an anterior mediastinal mass. A 55-year-old female was transferred to our hospital with a 2-week history of fever, epistaxis, and dyspnea. Laboratory tests revealed severe thrombocytopenia, computed tomography (CT) showed pleural effusions, and bone marrow biopsy revealed reticulin myelofibrosis. We suspected TAFRO syndrome, but the CT scan showed an anterior mediastinal mass that required a biopsy to exclude malignancy. She soon developed severe hemorrhagic diathesis and died of intracranial hemorrhage despite intensive treatment. She had multiple autoantibodies against platelets, which caused platelet destruction. An autopsy of the mediastinal mass revealed fibrous thymus tissues with infiltration by plasma cells. Our case suggests that thrombocytopenia could be attributed to antibody-mediated destruction and could be lethal. Hence, immediate treatment is imperative in cases of severe thrombocytopenia, even when accompanied by an anterior mediastinal mass.

Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic myeloid leukemia (CML). However, the effects of these agents on mature B cell lymphoma are not well known. We describe a 50-year-old man who was diagnosed with CML in the chronic phase and treated with imatinib. After 3 years of imatinib therapy that achieved a complete cytogenetic response of CML, he developed Philadelphia-negative follicular lymphoma (FL). Rituximab monotherapy induced a partial response of FL, and he subsequently achieved a major molecular response (MMR) of CML. Three years later, however, the MMR was lost, followed by the progression of FL. Imatinib was switched to nilotinib for the treatment of CML, while we chose watchful waiting for FL. He achieved MMR again under treatment with nilotinib for 8 months including one month of substitutional use of dasatinib due to adverse events, but thereafter nilotinib was switched to bosutinib due to hyperbilirubinemia. With the administration of second-generation TKIs (2G-TKIs) for a total of 18 months, he achieved a complete response to FL without antilymphoma treatment. This is the first report to suggest that 2G-TKIs may have direct or indirect effects on FL.

Background: Neutrophil recovery following allogeneic hematopoietic cell transplantation (allo-HCT) varies widely among patients. Some cases have a rapid increase in neutrophils and early engraft, while others show slow increase after neutrophils appearance and take time until engraftment. Such differences in neutrophil recovery may reflect the composition of the graft and affect the complications or prognosis after allo-SCT, though it has not been well documented in the literature. In this study, we retrospectively analyzed the influence of the slope of neutrophil recovery (N slope) following allo-HCT on post-transplant complications and prognosis. Methods: This study was a retrospective analysis of 120 patients with hematopoietic diseases who undergone first unrelated bone marrow transplantation at Jichi Medical University between January 2009 and December 2018. Patients who failed to achieve engraftment or did not receive granulocyte-colony stimulating factor were excluded. The N slope was defined as the increase of neutrophil counts from the last day of lowest neutrophil count after transplantation to the date of neutrophil engraftment. We evaluated the predictive value of N slope for acute graft-versus-host disease (GVHD) using the area under the receiver operating characteristic (ROC) curve and determined the cut-off value to maximize the sum of the sensitivity and specificity. Results: The median N slope was 205.5 /µL/day (range 26.4-7574). An ROC analysis showed that a cut-off value of N slope for grade II-IV acute GVHD was 207.5 /µL/day (sensitivity 0.73, specificity 0.6, AUC = 0.67, 95 % confidence interval (CI) = 0.59-0.79). Then, we classified patients into the low (n = 59) and high (n = 61) N slope groups according to the cut-off value of 200 /µL/day. The high N slope group correlated with older patients, RIC regimen, higher infused CD34+ cells ≥ 1.5 × 106/kg, and former transplantation between 2009 and 2013 compared with the low N slope group (p = 0.028, p = 0.003, p = 0.036 and p = 0.025, respectively). Cumulative incidence of grade II-IV acute GVHD at day 100 was significantly higher in the high N slope group than the low N slope group (44.3 % vs. 16.9%, p = 0.0007). With regard to the risk factors for grade II-IV acute GVHD, male, donor age ≥ 40 years, N slope ≥ 200 /µL/day and former transplantation between 2009 and 2013 were significant in univariate analysis. In multivariate analysis, donor age ≥ 40 years, N slope ≥ 200 /µL/day and former transplantation were identified as significant independent risk factors (hazard ratio (HR) 3.6, 95%CI 1.7-7.7, p = 0.001; HR 2.8, 95%CI 1.5-5.3, p = 0.002; HR 3.0; 95%CI 1.5-6.1, p = 0.02;, respectively). Cumulative incidence of grade III-IV acute GVHD at day 100 and chronic GVHD at 2 years did not differ in the high and low N slope groups (10.8 % vs. 5.1 %, p = 0.328; 63.3 % vs. 50.1 %, p = 0.12, respectively). In addition, there was no difference in relapse, non-relapse mortality and overall survival between the two groups (p = 0.76, p = 0.32, p = 0.65, respectively). Conclusion: The current study showed that a steeper slope of neutrophil recovery following HCT was associated with increased acute GVHD, though it did not affect relapse, NRM and OS. Early diagnosis and therapeutic intervention for acute GVHD may improve the outcome of patients with rapid neutrophil recovery. Disclosures Kanda: Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Takara-bio: Consultancy, Honoraria; CSL Behring: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Mochida: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Otsuka: Research Funding; MSD: Research Funding; Takara-bio: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Nippon-Shinyaku: Research Funding; MSD: Research Funding; Asahi-Kasei: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Celgene: Consultancy, Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Pfizer: Research Funding; Alexion: Consultancy, Honoraria; Sanofi: Research Funding; Celgene: Consultancy, Research Funding; Otsuka: Research Funding; Taiho: Research Funding; Novartis: Research Funding; Taiho: Research Funding; Taisho-Toyama: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

In this survey, the correlation between adverse drug reactions (ADRs) in human and animal toxicities was investigated for 393 medicines which were approved in Japan from September 1999 to March 2013. ADRs were collected from each Japanese package insert. Comparable animal toxicities with ADRs were collected by thorough investigation of common technical documents. The results of this survey show that hypertension and/or hypotension were mainly observed in medicines affecting the central nervous system. Hypertension was also observed in antipyretics, analgesics, anti-inflammatory agents, vasoconstrictors and agents using antibody. Concordance between human ADRs and animal toxicities was analysed. True-positive rate for hypertension and hypotension is 0.29 and 0.52, respectively. Positive likelihood ratio and inverse negative likelihood ratio are 1.98 and 1.21, respectively, in hypertension and 1.67 and 1.44, respectively, in hypotension. Concordance between human ADRs and animal toxicities is not so high in hypertension and hypotension. Identified mechanisms as on-target for hypertension and hypotension are 29.8% and 30.5%, respectively. More than half of the causative factors of hypertension and hypotension were unable to be elucidated. Our results show that the intake of medicines is often linked to blood pressure variations that are not predicted in animal toxicity studies. Improvement of drug development processes may be necessary to provide safer medicines because current animal toxicity studies are insufficient to predict all ADRs in human beings.

Summary: Purpose: Some evidence suggests that levetiracetam (LEV) possesses antiepileptogenic characteristics. The purpose of this study was to investigate the time course of seizure protection by LEV compared with that of phenytoin (PHT), phenobarbital (PB), valproate (VPA), and carbamazepine (CBZ) in the spontaneously epileptic rat (SER). The SER is a double mutant (tm/tm, zi/zi) showing both tonic convulsions and absencelike seizures. Methods: The effect of single (40, 80, and 160 mg/kg, i.p.) and 5-day (80 mg/kg/day, i.p.) administration of LEV on tonic convulsions and absence-like seizures in SERs were studied. Tonic convulsions induced by blowing air onto the animal’s head at 5-min intervals for 30 min and spontaneous absence-like seizures characterized by 5- to 7-Hz spike‐wave-like complexes in the cortical and hippocampal EEG were recorded for 30 min. In the single-administration study, observations for seizure activity were performed once before and 3 times (45, 75, and 135 min) after drug administration. In the 5-day administration study, seizure observation was performed 4 times for 30 min (once before and 3 times after drug administration) during the 5-day drug-administration period, and continued once a day until 8 days after the final administration. The antiepileptic effects of 5-day administration of conventional AEDs (PHT, PB, VPA, and CBZ) were examined by using similar methods. Results: Tonic convulsions and absence-like seizures were inhibited by a single administration of LEV at 80 and 160 mg/kg, i.p., but not significantly at 40 mg/kg, i.p. When LEV was repeatedly administered at 80 mg/kg/day, i.p., for 5 days to SERs, the inhibitory effects on seizures increased with administration time. The number of tonic convulsions and absence-like seizures were significantly reduced to 39.1% and 38.4% compared with previous values, respectively, after 5-day LEV administration. Furthermore, significant inhibition of tonic convulsions was detected ≤3 days after the final administration, and significant inhibition of absence-like seizures was still observed 8 days after the final injection of LEV. This demonstrates long-lasting seizure protection by LEV after cessation of treatment. PHT, PB, VPA, and CBZ inhibited tonic convulsions more potently compared with LEV in SERs. The maximal antiseizure effects of these drugs were reached after the initial administration, with almost the same antiseizure effects observed through day 5, despite continued drug administration. Moreover, a long-lasting treatment effect was not observed with any of these drugs except for PHT and CBZ, both of which showed moderately prolonged antiseizure effects. Conclusions: These results show that LEV is effective in the treatment of both convulsive and absence-like seizures in SERs after single- and multiple-dose administration. Interestingly, in the 5-day administration study, it was found that the antiepileptic effects for tonic convulsions and absence-like seizures were observed both during the drug-administration period and ≤8 days after the final administration of LEV. This long-lasting effect suggests that LEV may possess an antiepileptogenic effect that it does not share with PHT, PB, VPA, and CBZ. Key Words: Levetiracetam—Long-lasting effects—Spontaneously epileptic rat—Tonic convulsions—Absence-like seizures.

Many approved medicines are used with their adverse drug reactions (ADRs) appropriately managed in the clinical setting based on their risks and benefits. In this survey, the correlation between human ADR (specifically syncope/loss of consciousness and seizures/convulsions) and safety signals reported in animal studies has been investigated for 393 Japanese medicines which were approved between September 1999 and March 2013. Clinically important drug-induced ADR, syncope/loss of consciousness and seizures/convulsions are reported in this paper. Of 393 medicines, 101 (25.7%) showed syncope/loss of consciousness and 105 (26.7%) showed seizures/convulsions. Syncope/loss of consciousness and seizures/convulsions were reported for many medicines affecting the central nervous system. The animal toxicity concordance ratio with syncope/loss of consciousness and seizures/convulsions was 4.0% (4/101) and 23.8% (25/105), respectively. The underlying cases of syncope/loss of consciousness attributed to hypotension, arrhythmia, hypoglycemia or acute toxic reaction was 16.8%, 5.0%, 4.0% or 4.0%, respectively. Mechanism of seizures/convulsions for the remaining 101 medicines was not identified except for four local anesthetics. This survey suggested that the careful attention to and understanding of medicine profiles is necessary for the appropriate use of recently approved medicines in Japan.

The objective of this study was to elucidate the range of abilities of nonclinical safety assessment for predicting adverse drug reactions (ADRs) in humans. The dataset included 1256 ADRs with an incidence rate of 5% or more collected from 142 drugs approved in Japan from 2001 to 2010 (excluding anticancer agents and vaccines). Gastrointestinal, neurological and hepatobiliary ADRs were relatively common, followed by hematological, cutaneous, systemic and cardiovascular ADRs in the dataset. The analysis revealed that 48% of ADRs were predictable based on a comprehensive nonclinical safety assessment considering animal toxicity. Hematological and ocular ADRs, infection, and application site reactions showed a correlation of more than 70%, while musculoskeletal, respiratory and neurological ADRs showed a correlation of less than 30%. In addition to subjective patient perceptions, several laboratory parameters routinely monitored both in animals and humans showed a lower correlation, e.g., abnormalities in hepatobiliary and metabolic parameters, and blood pressure increase. Large molecule drugs showed lower correlation than small molecule drugs; ADRs were observed in various organs and consideration of pharmacological action did not significantly contribute to the prediction. It was also confirmed that the current standard of toxicology testing regarding dosing duration and dose level is adequate to detect concordant animal toxicity. This study collectively demonstrated a significant value of nonclinical safety assessment in predicting ADRs in humans. It also identified the subset of ADRs with poor predictability, highlighting the need for advanced testing that enables successful translation of animal toxicity to clinical settings with better accuracy and sensitivity.

Regioselective 2′-O-protection of N-protected 3′,5′-O-di(t-butyl)silanediylribonucleoside derivatives with the 2-(trimethylsilyl)ethoxymethyl (SEM) group has been achieved by use of t-BuMgCl and 2-(trimethylsilyl)ethoxymethyl chloride. The former was used as a base. The 2′-O-SEM protected ribonucleoside derivatives were converted via a three-step reaction into the corresponding phosphoramidite building blocks in good overall yields.

To assess the state of thrombosis and fibrinolysis, we measured the plasma concentrations of fibrinopeptide A (FPA), fibrinopeptide Bβ15-42 (FPBβ15-42), D-dimer, protein C (PC) activity and antigen, and antithrombin III (AT III) in 17 patients of cardioembolic stroke. Patient group had significantly high concentrations of FPA and FPBβ15-42, and significantly low concentrations of PC and AT III compared with healthy control group (p

Summary: Purpose: The long-lasting antiseizure effects of levetiracetam (LEV) have been observed in the spontaneously epileptic rat (SER) that expresses both tonic and absence-like seizures. Furthermore, the antiepileptogenic effects of LEV in addition to antiseizure effects have been reported in the amygdala-kindling model in rats. This suggests that the long-lasting seizure protection of LEV may be at least partly due to its antiepileptogenic effects. Therefore this study aimed to differentiate the antiseizure and potential antiepileptogenic effects of LEV by administering LEV continuously to SERs before the appearance of any seizure expression. Methods: LEV was administered to the SERs at 80 mg/kg/day (i.p.) from postnatal weeks 5 to 8. The period of observation for tonic convulsions was from postnatal week 5 to 13. Absence-like seizures were recorded by using conventional EEG in weeks 12 and 13. Results: After age 7–8 weeks, SERs exhibit spontaneous tonic convulsions. Development of tonic convulsions was significantly inhibited in the LEV group, compared with the control group, by the middle of week 9. A significant reduction of tonic convulsions also was observed in the LEV group until week 13 (5 weeks after termination of the administration). In week 12, the absence-like seizures were significantly lower in the LEV group, compared with the control group. Conclusions: This study demonstrates a significant inhibition of seizures after prolonged treatment with LEV before the developmental expression of seizure activity in SERs. This effect is suggested to be due to an antiepileptogenic effect and not an antiseizure effect of LEV, because the half-life of the drug in plasma is short (2–3 h in rats) after single and long-term administration. Furthermore, the inhibition of seizure expression in SERs was still apparent 5 weeks after termination of LEV treatment. These results further suggest that LEV possesses not only antiseizure effects but also antiepileptogenic properties.

Background: Previous studies have shown that the absolute lymphocyte count (ALC) in peripheral blood at diagnosis may be an independent prognostic factor of IPI for patients with diffuse large B-cell lymphoma (DLBCL). In the rituximab era, the U.S. National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) was developed to improve the risk stratification of DLBCL in comparison to the existing IPI. Therefore, the aim of this study was to clarify the impact of ALC at diagnosis on event free survival (EFS) and overall survival (OS) on analysis performed with factors included in NCCN-IPI. Patients and methods: We retrospectively reviewed the ALC of 413 patients with newly diagnosed DLBCL treated with R-CHOP at our hospital between January 2005 and March 2013. Primary central nervous system lymphoma patients were excluded from this study. ALC was determined in all patients from complete blood count with differential white blood count at the time of diagnosis, and prior to therapy administration. EFS and OS were estimated according to the Kaplan-Meier method. Multivariate analysis was performed with the proportional hazard Cox model. Results: The median ALC was 1.2x10E9/L (range, 0.06-9.0). We set an ALC cut-point at 1.0x10E9/L based on previous studies. The median follow-up duration was 40 months. Baseline characteristics according to ALC (1.0x10E9/L[n=268]) are summarized in Table1. Patients with ALC1.0x10E9/L (5-year EFS, 37.0% versus 68.9%, p Conclusions: According to our results, ALC Disclosures No relevant conflicts of interest to declare.

Background: A consensus is yet to be reached on therole of interim fluorine-18 fluorodeoxyglucose (18F-FDG) position emission tomography-computed tomography (PET-CT) for prognosis in diffuse large B-cell lymphoma (DLBCL), but it has been recently reported that maximum standardized uptake value (SUV max) reduction between baseline and midtherapy may be a better predictor of overall survival (OS) and event free survival (EFS). Patients and Method: 456 patients were newly diagnosed with DLBCL in our institute between February 2007 and January 2013. Primary central nervous system lymphoma or primary effusion lymphoma patients were excluded from this study. All patients who were not perfomed PET were also excluded. In order to determine the predictive value of interim PET-CT and SUV max reduction criteria on OS and EFS for patients with DLBCL, we retrospectively analyzed the PET-CT and SUV max data of 104 first-line DLBCL patients treated with 6 to 8 courses of R-CHOP or R-THPCOP therapy. PET-CT was performed at diagnosis (baseline), and after 2 to 4 courses (interim PET). Interim PET was scheduled two weeks after the second to fourth cycle of immunochemotherapy. A visual analysis of interim PET was done with the use of the Deauville criteria, and an analysis of the SUV max reduction criteria was calculated by [(SUV max reduction from baseline to interim PET)/SUV max at baseline]. For each PET image, the tumor with the most intense 18F-FDG uptake was identified among all foci with the use of a graded color scale. The hottest volumetric region was determined, and the SUV max was calculated. To assess the SUV max, the hottest tumor in any region or organ on interim PET was used for comparison, even if its location differed from the initial hottest tumor in baseline PET. Survival curves were estimated with Kaplan–Meier analysis and compared using the log-rank test. Results: One hundred and four patients were enrolled in this study, and their characteristics are detailed in Table 1. With a median follow-up of 38.5 months, the two-year overall survival and EFS were 83.3% and 73.6%. The results forinterim PET were 66.3% (69/104) negative and 33.7% (35/104) positive, respectively. Interim PET negative versus positive two-year OS was 85.0% (95%CI 0.739-0.917) versus 79.9% (95%CI 0.624-0.899) (P value 0.58), and the two-year EFS was 77.7% (95%CI 0.658-0.860) versus 65.7% (0.476-0.789) (P value 0.24), respectively (Figure 1). The SUV max cutoff values 66% estimated by receiver-operating-characteristic (ROC) analysis to distinguish treatment response were similar to other independent cohort studies at 2 to 4 cycles of induction treatment, and this threshold was chosen to analyze our series. For SUV max data, the two-year OS was 84.4% (95%CI 0.750-0.904) for a SUV max reduction ≥66.0% compared with 75.0% (95%CI 0.408-0.912) for a reduction of Conclusions: Analysis of the data in our study was unable to demonstrate the predictive value of interim PET for OS and EFS, but SUV max reduction criteria may improve the prognostic value of interim PET. However, the 66% cutoff value must be validated in a larger-scale prospective trial, and further investigation and the standardization of SUV max reduction criteria are needed. Disclosures No relevant conflicts of interest to declare.

Background Angioma serpiginosum is a rare, acquired vascular lesion simulating purpura, and should be differentiated from purpuric dermatoses such as Henoch-Schonlein purpura. Observations We report 2 cases of angioma serpiginosum examined using epiluminescence microscopy. Characteristic findings of angiomas ("red lagoons") were observed entirely or focally in these 2 cases, but not in 4 cases of Henoch-Schonlein purpura and a case of senile purpura. Conclusion Epiluminescence microscopy is beneficial in distinguishing angioma serpiginosum from purpuric dermatoses.

Anti-atheromatous effects of fenofibrate were studied in cholesterol-fed rabbits. Rabbits in the control group (HCD) and fenofibrate group (F-HCD) were fed the 0.5% cholesterol diet and the 0.5% cholesterol plus 0.11% fenofibrate diet (corresponding to ca. 30 mg/kg/day), respectively, for 2, 4 or 10 weeks. Fenofibrate did not change serum levels of total cholesterol, HDL-cholesterol and triglyceride during the feeding period. The percentage of plaque area (PPA) formation in the thoracic aorta was time-dependently increased. PPA values were reduced in the rabbits treated with fenofibrate for 2 and 4 weeks, but not in those treated for 10 weeks. Fenofibrate had no effect on the plaque thickness. The percentage of circulating free platelets in the HCD group was reduced at the 4th week of feeding, but that in the F-HCD group was not. The anti-platelet effect of fenofibrate might cause the anti-atheromatous effect. Fenofibric acid, an active metabolite of fenofibrate, had no inhibitory effect on LDL peroxidation in vitro. From these results, we conclude that fenofibrate manifests an anti-atheromatous effect independent of the hypolipidemic effect in cholesterol-fed rabbits and that it may inhibit an early event in the atherogenesis.

Anti-atheromatous effects of fenofibrate were studied in KHC rabbits with a hereditary deletion in LDL receptors, a defect similar to that in Watanabe heritable hyperlipidemic rabbits. KHC rabbits (10-weeks-old) were given a dietary admixture of fenofibrate (ca. 30 or ca. 100 mg/kg/day) for 20 weeks. Fenofibrate did not change serum total cholesterol, high density lipoprotein and triglyceride levels. Fenofibrate decreased the percent of plaque area formation in the thoracic aorta, but not the degree of foam cell formation, fibrosis and edematous change, and thickness of the intima. Furthermore, fenofibrate markedly inhibited the medial damage with foam cell formation in the aorta at week 20. From these results, we conclude that fenofibrate manifested the anti-atheromatous effect in KHC rabbit and also the previous model of cholesterol-fed rabbits, particularly against the medial damage in KHC rabbits, independent of the hypolipidemic effect.

To the Editor. —Milk-borne transmission of human T-lymphotropic virus type 1 (HTLV-1) has been well established both epidemiologically and experimentally. Switching from breastfeeding to bottle-feeding reduced the virus infection rate to approximately one tenth, but a few bottle-fed infants still became infected with HTLV-1 through an as yet unidentified route. 1 Transplacental or intrauterine transmission of HTLV-1 has been a controversial subject because detection of HTLV-1 antigen or proviral DNA in umbilical cord blood does not necessarily lead to seroconversion of the children. 2-4 We now report that perinatal infection of HTLV-1 may account for the rare cases of seroconversion not related to breast-feeding. We studied 17 HTLV-1 antibody—positive carrier mothers and their newborn infants: 10 of them were delivered by the vaginal route and the other seven by cesarean section at term. During pregnancy, the presence of HTLV-1 antibodies was checked by the particle agglutination method (titers 1:64 to

Regioselective 2′-O-protection of N-protected 3′,5′-O-di(t-butyl)silanediylribonucleoside derivatives with the 2-(trimethylsilyl)ethoxymethyl (SEM) group has been achieved by use of t-BuMgCl and 2-(trimethylsilyl)ethoxymethyl chloride. The former was used as a base. The 2′-O-SEM protected ribonucleoside derivatives were converted via a three-step reaction into the corresponding phosphoramidite building blocks in good overall yields.