Bendamustine-120 plus rituximab therapy for relapsed or refractory follicular lymphoma: a multicenter phase II study.

The optimal dose, schedule, and other aspects of bendamustine plus rituximab treatment remain unclear for patients with relapsed or refractory follicular lymphoma (FL). Herein, we analyzed the efficacy of bendamustine combined with rituximab (RB-120) treatment for Japanese patients with relapsed or refractory FL. This phase II clinical trial included patients with relapsed or refractory FL who received 375 mg/m2 rituximab on day 1 and 120 mg/m2 bendamustine on days 2 and 3 every 28 days for up to 6 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included the complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Thirty-seven patients were enrolled in the trial (median age 62 years, range 42-75 years). All patients were previously treated with rituximab-containing chemotherapy, and 83.8% were previously treated with the R-CHOP regimen. A median of 5 cycles (range 1-6) and 48.6% of patients completed 6 cycles. The ORR was 91.9% (95% confidence interval [CI] 78.1-98.3%), with a CR rate of 86.5% (95% CI 71.2-95.5%). The 3-year PFS and OS were 70.9% (95% CI 52.3-83.3%) and 88.9% (95% CI 73.1-95.7%), respectively, with the median 39.5 months follow-up duration. The most-frequently observed grade 3/4 adverse events were hematologic: lymphopenia (95%) and neutropenia (70%). No treatment-related deaths were observed. RB-120 showed a good efficacy with equivalent toxicities, compared with the bendamustine 120 mg/m2 monotherapy. However, the problem of high drop-out incidences cannot be ignored.

Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL).

BACKGROUND: Central nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach. PATIENTS AND METHODS: A total of 608 patients (median age, 67 years; range 22-92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis. RESULTS: None of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2-141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9-19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5-39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4-4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.

Phytohemagglutinin-induced IL2 mRNA in whole blood can predict bortezomib-induced peripheral neuropathy for multiple myeloma patients.

The proteasome inhibitor bortezomib has revolutionized the treatment of multiple myeloma. However, bortezomib-induced peripheral neuropathy (BiPN) is a serious complication that compromises clinical outcome. If patients with a risk of developing BiPN could be predicted, physicians might prefer weekly, reduced-dose, or subcutaneous approaches. To seek biomarkers for BiPN, we conducted a multicenter prospective study using a simple and unique system. Multiple myeloma patients received twice-weekly or weekly 1.3 mg/m(2) bortezomib intravenously, and a 2-ml sample of whole blood was obtained before treatment and 2-3 days and 1-3 weeks after the first dose. Induction of gene expression was then quantified by real-time PCR. Of a total of 64 enrolled patients, 53 patient samples qualified for mRNA analysis. The BiPN grade was associated with phytohemagglutinin-induced IL2, IFNG and TNFSF2, as well as with lipopolysaccharide-induced IL6 levels. More importantly, of the 19 patients showing a 3-fold increase in phytohemagglutinin-induced IL2, 14 did not suffer from BiPN (73.7% prediction), whereas of the 34 patients with a <3-fold increase, 23 experienced BiPN (67.6% prediction). Therefore, we concluded that pretreatment of phytohemagglutinin-induced IL2 mRNA levels in whole blood serve as a promising biomarker for predicting BiPN, and this finding warrants validation in a larger study.

Phase III trial of CHOP-21 versus CHOP-14 for aggressive non-Hodgkin's lymphoma: final results of the Japan Clinical Oncology Group Study, JCOG 9809.

BACKGROUND: CHOP-21 has remained the standard chemotherapy for aggressive non-Hodgkin's lymphoma (NHL), and dose intensification is a potential strategy for improving therapeutic results. We conducted a phase III trial to determine whether dose-dense strategy involving interval shortening of CHOP (CHOP-14) is superior to CHOP-21. PATIENTS AND METHODS: A total of 323 previously untreated patients (aged 15-69 years) with stages II-IV aggressive NHL were randomized. The primary end point was progression-free survival (PFS). RESULTS: Treatment compliance was comparable in both study arms. At 7-year follow-up, no substantial differences were observed in PFS and overall survival (OS) between CHOP-21 (n = 161) and CHOP-14 (n = 162) arms. Median PFS was 2.8 and 2.6 years with CHOP-21 and CHOP-14, respectively (one-sided log-rank P = 0.79). Eight-year OS and PFS rates were 56% and 42% [95% confidence interval (CI) 47% to 64% and 34% to 49%], respectively, with CHOP-21 and 55% and 38% (95% CI 47% to 63% and 31% to 46%), respectively, with CHOP-14. Subgroup analyses showed no remarkable differences in PFS or OS for patients stratified as per the International Prognostic Index or by age. CONCLUSION: Dose-intensification strategy involving interval shortening of CHOP did not prolong PFS in advanced, aggressive NHL.

Multivariate analysis of risk factors for hemorrhagic cystitis after hematopoietic stem cell transplantation.

To establish the most appropriate prophylactic therapy and risk factors for predicting hemorrhagic cystitis (HC) after stem cell transplantation (SCT), we retrospectively analyzed the clinical records of 450 transplant patients treated from 1982 to 2002. In all, 81 patients developed early- and/or late-onset HC (early=29, late=48, both=4). For the incidence of early-onset HC, administration of cyclophosphamide (CY) (p=0.0079, odds ratio (OD)=5.109, 95% confidence interval (CI)=1.533-17.030), busulfan (BU) (p=0.0015, OD=3.336, 95% CI=1.584-7.027), BU+CY (p=0.0001, OD=4.369, 95% CI=2.055-9.292), antithymocyte globulin (p=0.0009, OD=3.368, 95% CI=1.642-6.911), nonradiation (p=0.0163, OD=2.564, 95% CI=0.181-0.841), 2-mercaptoethane sodium sulfonate (Mesna) (p=0.0001, OD=7.519, 95% CI=2.847-19.858), and bladder irrigation (p=0.0001, OD=4.950, 95% CI=2.328-10.523) were risk factors. By Fisher's exact test, the combination of BU and Mesna was a more significant risk factor (P<0.001) than Mesna alone (p=0.008) compared to the administration of neither agent. By multivariate analysis, prophylactic administration of Mesna (p=0.0105, OD=5.301, 95% CI=1.477-19.026) and bladder irrigation (p=0.0001, OD=9.469, 95% CI=3.872-23.156) were significant risk factors of early-onset HC. We conclude that (i). high-dose BU as well as CY is a cause of HC, (ii). protective bladder irrigation has an opposite effect, and (iii). Mesna possibly has a toxic effect on bladder mucosa.

[Secondary eosinophilia in a patient with hypereosinophilic syndrome after allogeneic bone marrow transplantation from a sibling donor].

A 23-year-old man first visited a local hospital in 1998 because of exertional dyspnea. Peripheral blood examination revealed mild leukocytosis with 82% eosinophils, and he was treated with prednisolone. As the eosinophilia did not improve, he was referred to Tokai University Hospital in March 1999 for further diagnosis and treatment. The patient was diagnosed as having hypereosinophilic syndrome (HES) because of unexplained hypereosinophilia persisting for more than 6 months, resulting in cardiac dysfunction. His disease was progressive in spite of immunosuppressive therapy, interferon-alpha and cytotoxic chemotherapy. Since he had an HLA-identical brother, allogeneic bone marrow transplantation (BMT) was performed in October 1999. After completion of the immunosuppressive therapy on day 79 after BMT, the number of eosinophils gradually increased again. Although we suspected recurrence of the disease, DNA fingerprinting revealed that the peripheral granulocytes were 100% donor type. An increase of interleukin-5 (IL-5) produced by peripheral lymphocytes and a decrease of the Th1/2 ratio suggested that the eosinophilia was related to GVHD. The eosinophilia was eventually controlled by cyclosporin. We conclude that DNA fingerprinting and examination of the IL-5 level and Th1/2 ratio are useful for differentiating between relapse and GVHD in cases of eosinophilia occurring after BMT for HES.

Determination of 18alpha-glycyrrhizin and 18beta-glycyrrhizin in dog plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed for the separation and determination of 18alpha-glycyrrhizin (alpha-GZ) and 18beta-glycyrrhizin (beta-GZ) in dog plasma. The two compounds were separated on a reversed-phase column and detected by UV absorption at 254 nm. The mobile phase was a mixture of water-methanol-60% perchloric acid (45:55:0.5, v/v) and was adjusted to pH 8.0 with 25% ammonia solution. Indomethacin was added to the plasma as an internal standard. Methanol was selected for the extraction of both the compounds and internal standard. Alpha-GZ and beta-GZ could be precisely determined in concentration of 1 mg/ml in a 0.1 ml sample.

Results of a dental fear survey in Japan: implications for dental public health in Asia.

The purpose of this investigation was to initiate the study of dental fear in Japan. 415 college students, aged 18-22 yr were surveyed. A standardized questionnaire which has been used in the United States was translated into Japanese and was administered to the students. More than 80% of those surveyed reported some dental fear. Six to 14% of the students reported extreme fear of the dentist. The majority of the subjects admitted that they delayed making dental appointments due to fear. Muscle tension was the most common physiological symptom reported. The dental drill and needle were the most fear-provoking stimuli.

[Application of PIXE (particle-induced x-ray emission) method to the cytolytic test of tumor cells].

Immunological studies have often been based on the results of cytolytic assay in which cells labelled with radioactive 51Cr are usually employed. The replacement of the radioactive isotope by a stable one is obviously desirable in order to eliminate the problem of radiation hazard and to prevent environmental contamination. We applied PIXE (particle induced X-ray emission) method for the detection of stable chromium (Cr). MM46 cells labelled with natural Cr were treated with anti-MM46 serum and a rabbit complement. The remaining Cr was filtered. The released Cr was precipitated with ethanol and deposited on the filter. The specimens were bombarded with proton beams from a Van de Graaff accelerator and the X-rays produced were detected with a Si(Li) detector. The Cr peaks appeared clearly. One of the main advantages of the application of the PIXE method is its high sensitivity. Another merit of the present method is that it can easily compare the remaining ratio of several elements in cellular materials after lytic treatment. This information may be used as a parameter indicating differences in the process of cytolysis.