Search

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

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.

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.

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.

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.

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.

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.

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.

Antiplatelet effects by combination therapy with aspirin and ticlopidine were investigated in comparison with single aspirin or ticlopidine therapy in 62 patients with cerebral thrombosis and transient ischemic attack. The 14, 21 and 27 patients were given orally 300mg aspirin, 200mg ticlopidine and 81mg aspirin with 100mg ticlopidine, respectively. Aspirin inhibited platelet aggregation (PA) to ADP and arachidonic acid (AA) but not to PAF, while ticlopidine inhibited PA to ADP and PAF but not to AA. In contrast, aspirin with ticlopidine inhibited PA to all the 3 agonists. Aspirin decreased plasma thromboxane (TX) B2 but not plasma β-thromboglobulin (βTG) or platelet factor (PF) 4, while ticlopidine decreased βTG and PF 4 but not TXB2. In contrast, aspirin with ticlopidine decreased TXB2 as well as βTG and PF 4. Platelet survival and lysis remained unaltered after aspirin or ticlopidine alone, whereas platelet survival was longer and percent platelet lysis was lower in 4 patients treated with both aspirin and ticlopidine than in 3 non-treated patients. Hemorrhagic complications were observed in 2, 3 and 8 patients treated with aspirin, ticlopidine and both, respectively. The results above indicate that combination therapy with aspirin and ticlopidine is a potential antithrombotic strategy, although further investigaton appeared necessary to determine optimal doses for minimizing hemorrhagic complications.

Effects of different inspiratory concentrations of sevoflurane (fluorometyl-1,1,1,3,3,3,-hexafluoro-2-propylether) on blood pressure, heart rate and efferent activities of cardiac sympathetic, cardiac parasympathetic and renal sympathetic nerves were examined using rats either under the resting condition or during noxious mechanical stimulation of a hindpaw. Under the resting condition, an increase in the inspiratory concentration of sevoflurane from 2.1% to 4.2% gradually caused a decrease in blood pressure and heart rate. With the increase in the sevoflurane concentration, cardiac sympathetic nerve activity decreased, whereas renal sympathetic nerve and cardiac parasympathetic nerve activities did not change significantly. When noxious mechanical stimulation was applied to a hind-paw by pinching, blood pressure and heart rate, renal sympathetic and cardiac sympathetic nerve activities all increased at the 2.1% concentration of sevoflurane. The responses of these parameters were attenuated at the 3.1% concentration of sevoflurane and almost disappeared at the 4.2% concentration. Cardiac parasympathetic nerve activity did not change significantly during the pinching stimulation throughout the 2.1-4.2% concentration increase.

We compared combination therapy with low-dose aspirin plus ticlopidine to therapy with aspirin alone or ticlopidine alone in patients suffering transient ischemic attack or cerebral infarction. In 17, 24, and 23 patients, respectively, 300 mg/day aspirin, 200 mg/day ticlopidine, and 81 mg/day aspirin plus 100 mg/day ticlopidine were administered orally. Aspirin alone markedly inhibited platelet aggregation induced by arachidonic acid, partially inhibited platelet aggregation induced by adenosine diphosphate, and did not inhibit platelet aggregation induced by platelet activating factor. Ticlopidine alone inhibited platelet aggregation induced by adenosine diphosphate and platelet activating factor, but did not inhibit platelet aggregation induced by arachidonic acid. Combination therapy with aspirin plus ticlopidine markedly inhibited platelet aggregation induced by all three agonists. Plasma concentrations of beta-thromboglobulin and platelet factor 4 remained unchanged by aspirin alone, were slightly reduced by ticlopidine alone, and were markedly reduced by aspirin plus ticlopidine. Plasma concentration of thromboxane B2 was reduced by aspirin alone or with ticlopidine, but not by ticlopidine alone. The level of 6-ketoprostaglandin F1 alpha was reduced only by aspirin alone. Bleeding time was significantly prolonged by aspirin alone and by ticlopidine alone, although the greatest prolongation was produced by aspirin plus ticlopidine. Our results indicate that the combination of aspirin plus ticlopidine is a potent antiplatelet strategy, although the clinical importance of the changes observed need to be determined by a properly designed and controlled prospective study.