Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma (TUBA study).

Complete response (CR) after treatment for multiple myeloma is associated with superior progression-free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto-HCT) between 2010 and 2012. If patients did not achieve CR after auto-HCT, BD consolidation therapy was added to target CR. After the BD induction phase (n = 46), greater than or equal to CR was achieved in 4 patients (8%). After auto-HCT (n = 34), greater than or equal to CR was achieved in 9 patients (20%) and very good partial response (VGPR) was achieved in 11 (24%). Of the 24 patients who received auto-HCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses. Finally, the maximum response with or without BD consolidation was greater than or equal to CR in 19 (41%), VGPR in 7 (15%), and PR in 6 (13%). Through BD consolidation, CR was achieved in 8 of 11 patients with post-HCT VGPR and in 2 of 12 patients with post-HCT PR. In total, 4 year PFS and overall survival were 43 and 80%, respectively. After adjusting for clinical factors, there was no difference in PFS between CR patients after auto-HCT and BD consolidation, while patients with less than or equal to VGPR after consolidation had a significantly lower PFS. Patients with post-HCT CR showed good PFS, and targeting CR through BD consolidation could improve the CR rate. It would be worthwhile to prospectively compare the efficacy of consolidation only for patients who failed to achieve CR to a universal consolidation strategy.

Measurement of Proteasome Activity in Peripheral Blood Mononuclear Cells as an Indicator of Susceptibility to Bortezomib-Induced Severe Neurological Adverse Events in Patients with Multiple Myeloma.

AIMS: To explore the biomarker for predicting the occurrence of adverse events in myeloma patients treated by intravenous bortezomib, we measured proteasome activity in peripheral blood mononuclear cells. METHODS: Samples were obtained from 34 bortezomib-naïve patients. Proteasome activity was measured at pre- and postchemotherapy phase by using a synthetic substrate. RESULTS: Bortezomib injection resulted in a dramatic decrease in proteasome activity, reaching 32.4 ± 18.79% (mean ± SD) of the pretreatment level at 1 h, but it generally recovered at the end of the first course. In total, 6 patients manifested with severe bortezomib-induced peripheral neuropathy (sBIPN) in the second-third course. There was a nonsignificant trend for these patients to have lower levels of the relative proteasome activity at the end of the first course than those without sBIPN (median: 74.03 vs. 103.2%, p = 0.052). Moreover, in all of them, proteasome activity did not recover to the pretreatment level, whereas no patients with complete recovery manifested with sBIPN. Analysis with Fisher's exact test demonstrated that incomplete recovery of proteasome activity is a significant risk factor for sBIPN (p = 0.014). CONCLUSION: Patients with incomplete recovery of proteasome activity are at high risk for developing sBIPN, and the susceptible patients can be indicated by monitoring proteasome activity.

Adherence to the standard dose of imatinib, rather than dose adjustment based on its plasma concentration, is critical to achieve a deep molecular response in patients with chronic myeloid leukemia.

The correlation between imatinib (IM) trough plasma concentration (Cmin) and clinical response was assessed in patients with chronic-phase chronic myeloid leukemia. The Cmin correlated with neither the achievement of complete cytogenetic response (977 vs. 993 ng/ml, P = 0.48) nor a major molecular response (1,044 vs. 818 ng/ml, P = 0.17). Although this was significantly higher in patients with complete molecular response (CMR) than in those without (1,430 vs. 859 ng/ml, P = 0.04), the difference was not significant in the sub-population treated with a standard dose of IM (400 mg/day). Finally, multivariate analysis showed that the IM standard dose, but not Cmin, was predictive of the achievement of CMR. We thus suggest that, in practical clinics at least, adherence to the standard dose is the most important factor for the achievement of CMR.

An autopsy case of chronic active Epstein-Barr virus infection (CAEBV): distribution of central nervous system (CNS) lesions.

A 27-year-old Japanese man developed recurrent respiratory and central nervous system (CNS) symptoms, and hemophagocytic syndromes with a clinical course of 6 years. CT demonstrated multiple nodular lesions in the bilateral lungs, and MRI revealed multiple abnormal intensity areas in the brain and spinal cord. Cerebrospinal fluid (CSF) examination disclosed mild pleocytosis and the presence of Epstein-Barr virus (EBV)-DNA detected by polymerase chain reaction (PCR). The patient died of a hemorrhagic shock associated with a hemophagocytic syndrome. A postmortem study revealed massive hemorrhage in the abdominal cavity and iliopsoas muscles, as well as diffuse infiltration of lymphocytes and/or macrophages into the lungs, liver, kidneys, spleen, cardiac muscle, bone marrow, and CNS. The severe involvement was demonstrated in the CNS, especially in the spinal cord and brainstem. The CD3 positive cells of the brainstem were EBV-encoded RNA 1 positive. This is the first autopsy case of chronic active EBV infection (CAEBV) in which severe and extensive CNS involvement was demonstrated.

[Comparison of antimicrobial use density (AUD) of carbapenem antibacterial agents and investigation of the drug susceptibility of Pseudomonas aeruginosa in 3 hospitals in southern Ibaraki Prefecture, Japan].

The optimal use of anti-Pseudomonas agents is an important issue in the prevention of a tolerance against Pseudomonas aeruginosa. We evaluated the effect of antimicrobial use density (AUD) of carbapenem on drug susceptibility. The AUD of the four carbapenems, imipenem (IPM/CS), panipenem (PAPM/BP), meropenem (MEPM), and biapenem (BIPM), was examined at three hospitals in Ibaraki Prefecture, between April and September 2004. The AUD was calculated using the Defined Daily Doses (DDD) methodology developed by the WHO. A drug susceptibility test was conducted on the 306 Pseudomonas aeruginosa strains randomly collected from clinical specimens at the three hospitals between September and December 2004. In accordance with the standards set by the Clinical and Laboratory Standards Institute (CLSI), minimal inhibitory concentration (MIC) was measured using the broth microdilution method. The results showed that the AUD of carbapenem at the three hospitals tended to be higher than that in other research results in Japan. At one of the three hospitals, the AUD of the PAPM was remarkably high compared to the other carbapenems. Furthermore, P. aeruginosa strains collected at this hospital showed a low susceptibility to carbapenem, and many highly tolerant strains were also observed in this hospital. In order to maintain the susceptibility of Pseudomonas aeruginosa to carbapenem, the overall extent of carbapenem use must be optimal. The use of antimicrobial drugs should be controlled properly at each hospital, in order to prevent excessive use of PAPM/BP from being used over a long period of time.

Clinicopathological features and prognostic factors of Japanese patients with "peripheral T-cell lymphoma, unspecified" diagnosed according to the WHO classification.

Clinicopathological features of 36 patients, male: 58.3%; median: 68 years, with "peripheral T-cell lymphoma, unspecified" diagnosed by the WHO criteria were reviewed. Majority (69.4%) had stage IV disease with frequent involvements into bone marrow, spleen, liver, and skin. According to the IPI, 72.2% were categorized as high or high-intermediate risk group. CR and PR were achieved in 12 and 10 out of 31 patients treated by CHOP-based chemotherapy, respectively. One- and two-year overall survivals were 60.6 and 25.0%, respectively. Performance status, serum LDH, and B symptom were significant prognostic factors. Survival of CD4-/CD8+ cases, corresponding to cytotoxic T-cell lymphoma, was significantly worse than that of CD4+/CD8-.