Kazuhito Suzuki

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study

BACKGROUND There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). RESULTS Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). CONCLUSION The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. CLINICAL TRIAL REGISTRY IDENTIFIER UMIN000004863.

Pneumocystis jiroveci pneumonia detected by FDG-PET

Dear Editor, A 57-year-old woman suffered a relapse of follicular lymphoma and underwent high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). Six months after auto-PBSCT, she developed dyspnea on exertion. Her chest X-ray findings were normal (Fig. 1a). The laboratory data revealed increased serum levels of LDH (723 IU/l) and soluble interleukin-2 receptor (3,945 U/ml). A recurrence of follicular lymphoma was suspected, and a whole-body FDG-PET was performed. FDG-PET images showed patchy increased FDG uptake in both lungs (Fig. 1b). An elevated level of β-D glucan of 2,645 pg/ml and KL-6 of 814 U/ml suggested Pneumocystis jiroveci pneumonia (PCP). Computed tomography (CT) scanning revealed patchy interstitial infiltrates in both lungs (Fig. 1c). Bronchoscopy with transbronchial lung biopsies was performed. Bronchoscopy revealed normal airways, and the biopsies demonstrated nonspecific findings. Microscopy for Pneumocystis was negative but a PCR analysis of bronchoalveolar lavage fluid revealed the P. jiroveci DNA to be positive. She was therefore administered with sulfamethoxazole-trimethoprim (ST) and prednisolone and thereafter the symptoms clinically improved. FDG-PET images after ST treatment of PCP showed complete resolution of the abnormal uptake in both lungs (Fig. 1d). A gallium scan is known to demonstrate changes resulting from Pneumosystis pneumonia even before chest X-ray changes occur [1]. The use of FDG-PET imaging has been documented in human immunodeficiency virus disease [2–4] and in infectious diseases [5]. FDG-PET may therefore also play a role in the early diagnosis of P. jiroveci pneumonia in immunocompromised patients with hematological malignancies.

Prognostic Value of C-reactive Protein, Lactase Dehydrogenase and Anemia in Recurrent or Refractory Aggressive Lymphoma

OBJECTIVE Prognostic predictors for newly diagnosed malignant lymphoma are well known. However, they have not been compared for patients with recurrent or refractory malignant lymphoma. METHODS We retrospectively analyzed biological prognostic predictors for patients with recurrent or refractory aggressive lymphoma, such as serum levels of C-reactive protein, lactate dehydrogenase, hemoglobin, β2-microglobulin and soluble interleukin-2 receptor before salvage therapy. The primary endpoint was overall survival after salvage treatment. First, univariate and multivariate analyses were performed for each of the parameters, using the log-rank test and Cox regression analysis, respectively. Secondly, we classified the patients into three risk groups on the basis of significant poor predictors. RESULTS Sixty-three patients, including 41 patients with diffuse large B-cell lymphoma, were included in this study. Overall survival was significantly worse in patients with elevated C-reactive protein level (hazard ratio 3.757; P = 0.017), elevated lactate dehydrogenase level (hazard ratio 3.948; P = 0.010) and anemia (hazard ratio 3.925; P = 0.016) by multivariate analysis. We classified patients into two groups based on these three biological parameters. The median overall survival of the high- and low-risk patients was 5.8 and 60.1 months, respectively (log-rank test; P < 0.001). The overall response rate was significantly higher among the low-risk patients than among the high-risk patients (71.4 versus 28.6%, P = 0.005). Those results were similar among all aggressive lymphoma and diffuse large B-cell lymphoma. CONCLUSIONS Elevated C-reactive protein level, elevated lactate dehydrogenase level and anemia before salvage treatment predicted poorer outcomes among patients with recurrent or refractory aggressive lymphoma.

Prognostic value of high thymidine kinase activity in patients with previously untreated diffuse large B-cell lymphoma treated by rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone

Abstract The purpose of this study was to investigate prognostic factors for overall survival (OS) among patients with previously untreated diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). We evaluated four biological parameters, including thymidine kinase (TK) activity. This study included 183 patients. The median level of TK was 14.0 IU/L, which we chose as the cut-off. After a median follow-up time of 50.0 months, the OS rate at 4 years in the high and low TK arm were 46.7% and 66.7%, respectively (p = 0.001). By multivariate analysis, OS was significantly inferior in the high TK arm (hazard ratio 2.705; p = 0.045). The complete response (CR) rate in the high TK arm was significantly worse than in the low TK arm. OS was significantly better in patients who had achieved CR than in those with partial response or less. In conclusion, high TK activity was a strong predictor for short OS and poor response among patients with previously untreated DLBCL treated with R-CHOP.

R-CHOP with dose-attenuated radiation therapy could induce good prognosis in gastric diffuse large B cell lymphoma

BackgroundThe treatment strategy for gastric diffuse large cell lymphoma (DLBCL) has not been standardized in such as to the cycles of chemotherapy, dose of radiation, or necessity for the surgery. Although the results of CHOP or R-CHOP treatments have demonstrated the good prognosis, the treatments have been controversial in many cases.MethodsWe retrospectively analyzed 40 gastric DLBCL patients receiving chemotherapy with or without radiation in our institute. Those in stages II-IV were treated with six cycles of R-CHOP without radiation; for those in stage I, we administered three cycles of R-CHOP with radiation.ResultsThe three-year overall survival (OS) and progression-free survival (PFS) rates were 95.2 and 91.8%, respectively. Those in stage I obtained 100% of OS. The radiation dose prescribed was 30.6 Gy for CR cases and 39.6 to 40 Gy for PR after chemotherapy. Although survival rates tended to correlate with staging groups or age-adjusted IPI classifications, multivariate statistical analysis did not show clear differences. All 14 patients with initial bleeding were successfully managed without surgery during treatment.ConclusionR-CHOP therapy was very effective for gastric DLBCL. It may be not necessary to use more than 30.6 Gy of radiotherapy in the highly chemo-sensitive cases. Less toxic treatments should be made available to gastric DLBCL patients.

Case of paraneoplastic pemphigus associated with retroperitoneal diffuse large B‐cell lymphoma and fatal bronchiolitis obliterans‐like lung disease

trauma. Smetana et al. postulated that the lipogranulomatous reaction results from the breakdown of endogenous lipids following trauma. Lee et al. reported a lipogranuloma originated from endogenous fat degeneration after a traumatic process. At the time of the accident, damaged fat tissues were destructed and degenerated. Then, lipogranuloma could have developed at the site of the trauma. In addition, there is the possibility of lymphatic migration of degenerated fat from the surgical site. Microdroplets of damaged and liquefied fat may undergo phagocytosis and be transported to other sites through lymphatics. Fat necrosis is induced by various causes, including foreign body injection, trauma, vascular insufficiency, infections and connective tissue diseases. In this case, the patient had obvious trauma history. In addition, the patient did not have a history of local injections into the skin lesions and any symptoms or signs of vascular insufficiency of the legs. In our case, we consider that posttraumatic lipogranuloma developed as a result of a combination of factors associated with trauma, including the endogenous fat degeneration and petroleum-based dressing products. Physicians should recognize the possibility of lipogranulomatous reactions associated with a traumatic process.

Antimyeloma activity of bromodomain inhibitors on the human myeloma cell line U266 by downregulation of MYCL.

Bromodomain and extraterminal protein (BET) inhibitors suppress the expression of c-MYC. U266, a human myeloma cell line, expresses the MYCL gene, but not the c-MYC gene. Our aim was to analyse the antimyeloma activity of BET inhibitors on U266 cells. Two BET inhibitors, I-BET151 and JQ1, were tested. U266 cell proliferation decreased to 61.5 and 54.0% of the control after incubation with 500 nmol/l I-BET151 for 72 and 96 h and to 53.5 and 56.4% of control after incubation with 500 nmol/l JQ1 for 72 and 96 h by MTS tetrazolium, respectively. BET inhibitors induced cell cycle arrest at the G1 phase in U266 cells, but did not induce apoptosis by flow cytometry. According to Gene Set Enrichment Analysis, MYC-related genes were significantly downregulated in U266 cells treated with I-BET151 similar to KMS11 cells that expressed c-MYC. The MYCL1 was expressed in U266 cells, whereas c-MYC and MYCN were not by quantitative real-time reverse-transcription-PCR. Incubation with I-BET151 induced downregulation of MYCL1 in U266 cells. BET inhibitors decreased the cell proliferation in U266 cells with overexpression of MYCL less than those without overexpression of MYCL. BET inhibitors induce G1 arrest without apoptosis and interfere with the proliferation of U266 myeloma cells, which express MYCL, but not c-MYC. BET inhibitors might be active in cancers that express MYCL, but not c-MYC.

High thymidine kinase activity is a strong predictive factor for poor prognosis in peripheral T-cell lymphoma treated with cyclophosphamide, adriamycin, vincristine and prednisone

Abstract The prognosis of patients with peripheral T-cell lymphoma (PTCL) treated with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP) is poor, but their laboratory prognostic parameters had not previously been evaluated. We retrospectively reviewed 55 patients with newly diagnosed PTCL treated with CHOP from August 1999 to May 2009 at our institution. We analyzed six laboratory parameters, including thymidine kinase (TK) activity, to evaluate overall survival, which was the primary end-point. In multivariate analysis, the overall survival was significantly worse in patients with high TK activity (hazard ratio 34.8, 95% confidence interval [CI] 1.03–1176.23). The overall response rate among patients with high TK activity was 21.4%, significantly poorer compared with other parameters (p = 0.001). High TK activity predicts poor overall survival among patients with newly diagnosed PTCL treated with CHOP. Response to CHOP treatment is significantly decreased in patients with PTCL with high TK activity.

Epstein-Barr Virus-associated Lymphoproliferative Disorder with Encephalitis Following Anti-thymocyte Globulin for Aplastic Anemia Resolved with Rituximab Therapy: A Case Report and Literature Review

Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) sometimes occur following Anti-thymocyte globulin (ATG) administration for allogenic stem cell transplantation but are rare in aplastic anemia (AA) patients. A 55-year-old woman with AA following ATG developed refractory fever and was diagnosed with EBV-LPD. She was successfully treated with weekly rituximab monotherapy; however, she developed EBV encephalitis. She was admitted to the intensive care unit and finally recovered from unconsciousness. EBV-LPD should be considered after ATG for AA when symptoms appear. Because EBV-LPD following ATG for AA can rapidly progress, weekly monitoring of EBV-DNA and early intervention may be necessary.

Clinical significance of cancer-related fatigue in multiple myeloma patients

Cancer-related fatigue (CRF) is one of the adverse events in multiple myeloma (MM) patients treated with cytotoxic agents, proteasome inhibitors (PIs), and immunomodulatory drugs (IMiDs) such as bortezomib, lenalidomide, and thalidomide. The aims of our study were to prospectively analyze the clinical significance of CRF, and to evaluate the cumulative incidence of CRF and the survival rates of 16 MM patients who were treated with PIs and IMiDs. Reactivation of salivary human herpes virus (HHV)-6 and HHV-7 was analyzed using real-time quantitative polymerase chain reaction (qPCR). CRF was evaluated using a visual analog scale (VAS). Eleven newly diagnosed multiple myeloma (NDMM) and five relapsed or refractory MM patients were enrolled in this study. The cumulative incidence of CRF was 54.9%. The treatment types were not associated with the CRF incidence. The cumulative incidence of reactivation of HHV-6 and HHV-7 was 73.1% and 45.6%, respectively. However, the reactivation of HHV-6 and HHV-7 was not related to CRF. The overall survival (OS) and progression-free survival (PFS) in NDMM patients with CRF was significantly shorter than in those without CRF. In conclusion, CRF was one of the major symptoms in MM patients, and predicted shorter OS and PFS in NDMM patients.