Kazuo Tamura

Publications (101)248.97 Total impact

• Article: Mature T/NK-cell lymphoproliferative disease and Epstein-Barr virus infection are more frequent in patients with rheumatoid arthritis treated with methotrexate.

  Seiji Kondo, Kazuki Tanimoto, Kozue Yamada, Goichi Yoshimoto, Eiichi Suematsu, Tomoaki Fujisaki, Yumi Oshiro, Kazuo Tamura, Morishige Takeshita, Seiichi Okamura
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  ABSTRACT: We retrospectively analyzed in 54 consecutively enrolled Japanese patients with rheumatoid arthritis (RA) and lymphoproliferative disease (LPD) relevant clinicopathological characteristics, in particular paying attention to treatment with methotrexate (MTX). Between the 28 patients treated with MTX (MTX-treated group) and the 26 who were not (non-MTX group), there was no difference in age, interval between onset of RA and LPD, and lymphoma stage. Immunohistochemical analysis showed that in the MTX-treated group, 15 (53 %) patients had mature B-cell LPD, eight (29 %) mature T/NK-cell LPD, and five (18 %) had Hodgkin lymphoma. In the non-MTX group, 22 (84 %) had mature B-cell LPD, 2 (8 %) had mature T/NK-cell LPD, and 2 (8 %) had Hodgkin lymphoma. The frequency of mature T/NK-cell LPD was significantly higher in the MTX-treated group (p < 0.05). Of the eight patients in the MTX-treated group with mature T/NK-cell LPD, two had large granular lymphocytic leukemia and the other six had a variety of different histological types with frequent CD8 but not CD56 expression. Epstein-Barr virus (EBV) infection was significantly higher in the MTX-treated group (p < 0.05); evidence of latent type II EBV infection was found in four of the eight patients with mature T/NK-cell LPD. Withdrawal of MTX led to complete remission in seven patients with mature T/NK-cell LPD irrespective of EBV infection. Our findings highlight that mature T/NK-cell LPD is a frequent complication in RA patients treated with MTX. EBV infection may play a role in the pathogenesis of T/NK-cell LPD, as well as B-cell LPD and Hodgkin lymphoma in MTX-treated RA patients.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2013; · 2.49 Impact Factor
• Article: Simultaneous determination of cytosine arabinoside and its metabolite, uracil arabinoside, in human plasma using hydrophilic interaction liquid chromatography with UV detection.

  Masanobu Uchiyama, Yasushi Takamatsu, Kentaro Ogata, Taichi Matsumoto, Shiro Jimi, Kazuo Tamura, Shuuji Hara
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  ABSTRACT: A practical high-performance liquid chromatography using a Cosmosil HILIC column and UV detection was developed for determining the concentrations of cytosine arabinoside (Ara-C) and uracil arabinoside (Ara-U), which is a major metabolite of Ara-C, in human plasma. This method was used to determine the plasma concentrations of Ara-C and Ara-U in a patient treated with high-dose Ara-C therapy for end-stage renal failure. Copyright © 2013 John Wiley & Sons, Ltd.
  Biomedical Chromatography 02/2013; · 1.97 Impact Factor
• Article: Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia/lymphoma (III).

  Daisuke Nakano, Kenji Ishitsuka, Mio Kamikawa, Michika Matsuda, Ryota Tsuchihashi, Masafumi Okawa, Hikaru Okabe, Kazuo Tamura, Junei Kinjo
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  ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T lymphocytes caused by human T-cell lymphotropic virus type I (HTLV-I). In our previous paper, 214 extracts from 162 plants were screened to elucidate the anti-proliferative principles against HTLV-I-infected T-cell lines. In this study, 245 extracts from 182 plants belonging to 61 families were further tested against two HTLV-I-infected T-cell lines (MT-1 and MT-2). Potent anti-proliferative effects were exhibited against MT-1 and MT-2 cells by 52 and 60 of the 245 extracts tested, respectively. Of these, two extracts showed strong inhibitory activity (EC(50) values 0.1-1 μg/mL; +++) against both cells, 7 extracts showed moderate inhibitory activity (EC(50) values 1-10 μg/mL; ++), and 43 extracts showed weak inhibitory activity (EC(50) values 10-100 μg/mL; +), whereas the remaining extracts did not show any activity (EC(50) values >100 μg/mL; -) against MT-1 cells. On the other hand, 10 extracts showed moderate inhibitory activit and, 48 extracts showed weak inhibitory activity, whereas the remaining extracts did not show any activity against MT-2 cells. Extracts from the aerial parts of Annona reticulata and A. squamosa showed the most potent inhibitory activity and three aporphine alkaloids were isolated from their extracts as the active principles by activity-guided fractionation.
  Journal of Natural Medicines 02/2013; · 1.39 Impact Factor
• Article: [A study of the sialogogic effect of cevimeline gargle].

  Chizuko Yoshikawa, Yasushi Takamatsu, Kentaro Ogata, Shuuji Hara, Kazuo Tamura
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  ABSTRACT: The purpose of this study was to clarify the sialogogic effect iveness of cevimeline gargle. Sequential comparison tests were conducted on healthy adult males and females who received both cevimeline and a placebo. The effect was evaluated by measuring the amount of saliva using the Saxon test and Mucus, and by recording the subjects' own perceptions of oral mucosal moisture reported according to 4 levels. First, ten subjects' measurements were taken before gargling, as well as 5 minutes, 90 minutes and 3 hours after gargling. For the cevimeline treatment, the amount of saliva reached the maximum level within 5 minutes after gargling, and a significant salivary secreting effect(p<0. 05-p<0. 001)was observed up to 90 minutes after gargling. The degree of oral moisture also reached the maximum level within 5 minutes after gargling with cevimeline, and a significant moisture effect(p<0. 05-p<0. 001)persisted up to 3 hours after gargling. After safety profiles were determined to be acceptable, an additional 19 subjects entered the study and the same results were observed. The present data, indicating that cevimeline gargle increases the saliva in healthy individuals for at least 3 hours, will be useful in clinical trials of cevimeline gargle for patients with salivary secretion disorder.
  Gan to kagaku ryoho. Cancer & chemotherapy 02/2013; 40(2):215-9.
• Article: [A case of acute respiratory distress syndrome caused by cryptococcus and cytomegalovirus co-infection after Cushing's syndrome treatment].

  Toshitaka Goto, Tohru Takata, Eiichi Sato, Kazuo Tamura, Toshihiko Yanase
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  ABSTRACT: We report a case of severe Cushing's syndrome developing into life-threatening acute respiratory distress syndrome with cryptococcus and cytomegalovirus co-infection soon after hypercortisolism treatment using metyrapone, an 11-beta-hydroxylase inhibitor. We speculate that a restored immune response would have elicited clinical symptoms of opportunistic and previously subclinical infection. The immunocompromised state and the delicate glucocorticoid balance in subjects with severe Cushing's syndrome necessitate a specific diagnostic and therapeutic approach.
  Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 01/2013; 87(1):39-43.
• Article: Expression and role of GLUT-1, MCT-1, and MCT-4 in malignant pleural mesothelioma.

  Ai Mogi, Kaori Koga, Mikiko Aoki, Makoto Hamasaki, Noriko Uesugi, Akinori Iwasaki, Takayuki Shirakusa, Kazuo Tamura, Kazuki Nabeshima
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  ABSTRACT: Malignant cells supply their energy needs through increased glucose consumption, producing large quantities of lactic acid via glycolysis. Glucose transporters (GLUTs) and monocarboxylate transporters (MCTs) are therefore commonly up-regulated in human malignancies to mediate glucose influx and lactic acid efflux, respectively. However, their roles in malignant pleural mesothelioma (MPM) have not been fully elucidated. Here, we evaluated GLUT-1, MCT-1, and MCT-4 expression in human MPM and reactive mesothelial hyperplasia (RMH) and elucidated their biological role in vitro. GLUT-1, MCT-1, and MCT-4 expression was determined in human MPM (n = 35) and RMH (n = 20) specimens by immunohistochemistry and in frozen tissue, and MPM cell lines, by real-time reverse transcription-polymerase chain reaction and western blot analysis. GLUT-1, MCT-1, and MCT-4 functions in MPM were evaluated by transfection with small interfering RNA. Immunohistochemical analysis revealed higher levels of GLUT-1, MCT-1, and MCT-4 in MPM than in RMH. Additionally, GLUT-1, MCT-1, and MCT-4 mRNA levels were higher in MPM than in non-neoplastic mesothelial cell lines. The siRNA-mediated knockdown of GLUT-1 or MCT-1 significantly suppressed tumor cell proliferation, and MCT-1 silencing inhibited invasion and induced apoptosis. Taken together, these results indicate that combined application of GLUT-1, MCT-1, and MCT-4 immunohistochemistry might be useful in differentiating MPM from RMH and suggest that MCT-1plays an important biological role.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 11/2012; · 2.49 Impact Factor
• Article: Presence of both heterogeneous vancomycin-intermediate resistance and β-lactam antibiotic-induced vancomycin resistance phenotypes is associated with the outcome in methicillin-resistant Staphylococcus aureus bloodstream infection.

  Tohru Takata, Motoyasu Miyazaki, Maki Futo, Shuji Hara, Shouichi Shiotsuka, Hidetoshi Kamimura, Hisae Yoshimura, Akira Matsunaga, Takeshi Nishida, Hiroyasu Ishikura, Takahiko Ishikawa, Kazuo Tamura, Brian T Tsuji
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  ABSTRACT: Background: Although the individual expression of heterogeneous vancomycin-intermediate resistance (hVISA) and β-lactam antibiotic-induced vancomycin resistance (BIVR) phenotypes has been associated with treatment failure and recurrence in methicillin-resistant Staphylococcus aureus (MRSA) infections, the effect of the co-expression of these phenotypic profiles on clinical outcome has not been fully elucidated. The aim of this study was to determine the impact of the combination of hVISA and BIVR phenotypes on the clinical outcome in MRSA bacteremia. Methods: One hundred and sixty-two MRSA blood isolates from a 21-y period, 1987-2007, were randomly selected. Screening for hVISA was done by the macromethod Etest and confirmed by population analysis profiles. BIVR was identified using Mu3 agar containing 4 μg/ml of vancomycin. Results: Thirty (18.5%) and 39 (24.1%) of the 162 MRSA blood isolates were positive for the hVISA and BIVR phenotypes, respectively. Eighteen (11.1%) isolates possessed both hVISA and BIVR phenotypes (hVISA(+)/BIVR(+)). In a subset of patients who received initial treatment with glycopeptides, only the patients whose isolates were hVISA(+)/BIVR(+) displayed a significantly higher mortality rate in comparison to those with non-hVISA(+)/BIVR(+) (80.0% vs 31.3%, p = 0.004). The presence of both hVISA and BIVR phenotypes was a predictor of mortality using a logistic regression analysis (p = 0.025). Conclusions: The combined phenotype of hVISA and BIVR was associated with a higher probability of mortality in patients with MRSA bacteremia. Further prospective studies are warranted to delineate the clinical significance of the combined phenotype of hVISA and BIVR.
  Scandinavian Journal of Infectious Diseases 10/2012; · 1.72 Impact Factor
• Article: Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia/lymphoma (II): apoptosis of antiproliferactive principle (24,25-dihydrowithanolide D) against ATL cell lines and structure-activity relationships with withanolides isolated from solanaceous plants.

  Daisuke Nakano, Kenji Ishitsuka, Hiroo Katsuya, Naoko Kunami, Rumiko Nogami, Yuka Yoshimura, Michika Matsuda, Mio Kamikawa, Ryota Tsuchihashi, Masafumi Okawa, Tsuyoshi Ikeda, Toshihiro Nohara, Kazuo Tamura, Junei Kinjo
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  ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is an incurable peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I. In our preceding paper, 214 extracts from 162 plants were screened to elucidate the antiproliferative principles against ATL cell lines. Several withanolides were isolated and the structure-activity relationships (SAR) examined. To extend the search for SAR, 31 further withanolides, previously isolated from solanaceous plants, were tested against ATL cell lines. The presence of a 4β-hydroxy group as well as a 5β,6β-epoxy group appeared to be essential for the activity. In contrast, the presence of a sugar moiety at either the 3- or the 27-position led to a reduction in the activity. Furthermore, 24,25-dihydrowithanolide D (13) was identified as the most potent inhibitor, showing selective toxicity against ATL cell lines by inducing apoptotic cell death.
  Journal of Natural Medicines 09/2012; · 1.39 Impact Factor
• Article: Prospective randomized study of cefepime, panipenem, or meropenem monotherapy for patients with hematological disorders and febrile neutropenia.

  Yasunori Nakagawa, Keishi Suzuki, Kensuke Ohta, Masayuki Hino, Kazuma Ohyashiki, Akihisa Kanamaru, Kazuo Tamura, Akio Urabe, Tohru Masaoka
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  ABSTRACT: The aim of this study was to evaluate the usefulness of carbapenems as initial treatment for febrile neutropenia (FN), and in patients unresponsive to this initial therapy, to evaluate the efficacy of subsequent treatment with aminoglycosides (AGs) or ciprofloxacin (CPFX). FN patients were randomized to receive cefepime (CFPM, control), panipenem/betamiprom (PAPM/BP), or meropenem (MEPM). Defervescence, an outcome endpoint, was evaluated 3 days later. Patients with minimal response were given CPFX or AGs, and their responses were reevaluated on day 7. A total of 255 patients were included. The efficacies of CFPM, PAPM/BP, and MEPM were comparable. In patients unresponsive to this initial therapy, the efficacy of subsequent CPFX and AGs treatments was also similar. There was no significant between-arm difference in cumulative efficacy on days 14 and 30. Adverse reactions were infrequent and mild. In conclusion, PAPM/BP and MEPM are as useful as CFPM as initial therapy for FN, and AGs are as efficacious as CPFX in patients unresponsive to the initial therapy.
  Journal of Infection and Chemotherapy 09/2012; · 1.80 Impact Factor
• Article: Neoadjuvant epirubicin/docetaxel (ET) concomitant chemotherapy for primary breast cancer with tumor diameter >=3.1 cm: results of the Kyushu ET therapy phase II trial.

  Reiki Nishimura, Yoshiaki Rai, Fumie Matsuo, Keisei Anan, Shinsuke Hara, Shigeru Imamura, Noriaki Itoyanagi, Masato Kato, Masayuki Okido, Manabu Kudaka, Emi Ishikawa, Yoshihiko Kamada, Ryoji Watanabe, Mitsunori Shirouzu, Shoshu Mitsuyama, Yasushi Takamatsu, Kazuo Tamura
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  ABSTRACT: Neoadjuvant epirubicin/docetaxel (ET) combination chemotherapy was administered to breast cancer patients in order to investigate their clinical and pathological response. Moreover, the breast-conserving surgery (BCS) rate, disease-free (DFS) and overall survival (OS), safety profile and the correlation of biological markers were investigated. Out of the 46 enrolled patients, 45 patients were analyzed for clinical response, and 40 patients were examined for pathological response. Estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor type2 (HER2) expression were examined immunohistologically. The median tumor size was 4.5 cm in diameter. Complete (CR) and partial responses were seen in 3 and 30 patients, respectively. A pathological CR was achieved in 4 patients and correlated with ER and PgR negativity. Moreover, BCS was performed on 16 patients. The 5-year cumulative DFS was 60.7% and OS was 91.8%. ET therapy is clinically effective with a pathological CR rate of 10% for patients with a large tumor, and should be considered as a neoadjuvant treatment option.
  Anticancer research 08/2012; 32(8):3259-65. · 1.73 Impact Factor
• Article: [A phase III study of the efficacy and safety of meropenem in patients with febrile neutropenia].

  Kenji Imajo, Yasunori Ueda, Fumio Kawano, Hiroshi Sao, Tomohiko Kamimura, Yoshikazu Ito, Atuko Mugitani, Kenshi Suzuki, Naokuni Uike, Koichi Miyamura, [......], Yoshitaka Morimatsu, Nobu Akiyama, Hirokazu Nagai, Akira Ohara, Mitsune Tanimoto, Kazutaka Takaki, Kosuke Chayama, Masao Urabe, Yoshihisa Nagatoshi, Kazuo Tamura
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  ABSTRACT: Efficacy, safety and pharmacokinetics of meropenem (MEPM) were assessed when 1 g (40 mg/kg for some of the pediatric patients) t.i.d. was administered every 8hours to 101 adult and 6 pediatric patients with febrile neutropenia (FN) as diagnosed based on the Japanese guideline for FN treatment. The efficacy rate evaluated as antifebrile effect up to Day 4 of treatment was 40.0% (40/100) in adult and 66.7% (4/6) in pediatric patients. The antifebrile effect in adult patients was analyzed after stratifying them according to their neutrophil counts up to Day 4. Treatment with MEPM produced an antifebrile effect not only in patients with higher neutrophil counts (> or = 500/mm3) but also in those with lower counts (< 100/mm3), and the efficacy rate was comparable between the two groups: 38.2% in the < 100/mm3 group and 29.4 to 55.6% in the > or = 500/mm3 group. The bacteriological efficacy of MEPM evaluated as disappearance rate on Days 3 to 5 and Day 7 was both 100% (8/8 and 4/4, respectively). The time above minimal inhibitory concentration (% T > MIC) in the treatment interval was greater than 90% in 9 out of 10 patients for whom likely causative organism was isolated and identified after MEPM treatment or for whom causative organism emerging after treatment was isolated and identified. The incidence of adverse events was 93.1% in adult and 83.3% in pediatric patients. There were three deaths and one serious adverse event reported among the adult patients; however, all these cases were assessed as not related to the study medication. The incidence of adverse drug reactions was 45.5% and 66.7%, respectively. All the observed adverse drug reactions were mild or moderate in severity and none of them was severe. Adverse drug reactions which were unknown from the previous MEPM clinical studies and investigation of the results of clinical experience include 'chest discomfort', 'blood uric acid decreased', 'lymphocyte deformation', 'blood uric acid increased', 'abnormal funduscopy', 'hypesthesia' and 'hemorrhagic cystitis'. All these events were mild or moderate in severity and resolved without requiring any action or after providing symptomatic treatment. There was no unknown adverse drug reaction that resulted in treatment discontinuation. No nervous system disorders such as convulsion and impaired consciousness were reported. The results show that monotherapy of MEPM 1 g (or 40 mg/kg for some of the pediatric patients) t.i.d. every 8 hours was effective, and was also safe and well tolerated in adult and pediatric patients with FN. Therefore, MEPM monotherapy is expected to be useful as the initial treatment for Japanese patients with FN.
  The Japanese journal of antibiotics 08/2012; 65(4):271-87.
• Article: Efficacy and safety of doripenem for sepsis with neutropenia in Japanese patients with hematologic diseases.

  Nobu Akiyama, Akihisa Kanamaru, Kazuo Tamura, Mitsune Tanimoto, Kazuma Ohyashiki, Yasunori Nakagawa, Akio Urabe, Toru Masaoka
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  ABSTRACT: Doripenem (DRPM) is one of the carbapenems which has a broad-spectrum and strong activity against Pseudomonas aeruginosa. This observational study was conducted between April 2006 and March 2007 in Japan to evaluate the efficacy and safety of DRPM 0.5 g three times a day for sepsis with neutropenia in patients with hematologic diseases. One hundred-nineteen patients were enrolled from 34 medical institutes, comprising 117 patients for safety evaluation and 104 for efficacy evaluation. Monotherapy of DRPM 0.5 g three times a day (DRPM monotherapy) was evaluated in 73 patients. The response rates of DRPM monotherapy at 72 hours and at Day 7 were 31.5% (23/73) and 67.1% (49/73), respectively. The incidence of adverse reactions including abnormal changes in laboratory values was 23.1%, and hepatic toxicity was most common. All of these adverse events were judged by the investigators as non-serious and tolerable. These results suggest that DRPM is useful for sepsis with neutropenia, though further study may be warranted.
  The Japanese journal of antibiotics 08/2012; 65(4):251-62.
• Article: [A multicenter study of epirubicin-docetaxel(ET)as primary chemotherapy for patients with inflammatory breast cancer(IBC)].

  Michiyo Saimura, Keisei Anan, Shoshu Mitsuyama, Satoshi Toyoshima, Koji Ikejiri, Tetsufumi Ohchi, Yoshiaki Rai, Tatsuji Oikawa, Manabu Kudaka, Reiki Nishimura, Shoji Kuroki, Kiyoshi Namba, Yuji Nakafusa, Kazuo Tamura
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  ABSTRACT: We evaluated the efficacy and safety of the epirubicin plus docetaxel(ET)regimen, which is a combination of active agents given to patients with inflammatory breast cancer(IBC)as a primary therapy. Nineteen patients received ET(60, 60mg/m2) every 3 weeks for 4 courses, and appropriate surgery was offered unless disease progression occurred. Seventeen patients completed the ET regimen and 1 patient was excluded because of no diffuse erythema, leaving 18 patients evaluable for the response and safety profile of this regimen. Grade 3/4 hematological toxicities were neutropenia in 15 patients(79%), febrile neutropenia in 8 patients(42%)and anemia in 3 patients(16%). Six patients(63%)received granulocyte colony-stimulating factor for febrile neutropenia. Febrile neutropenia was observed only for 1 course in all 6 patients and progression to apparent infection was not observed. Grade 3/4 non-hematological toxicities were constipation in 3, nausea in 2, anorexia in 2, fatigue in 1, vomiting in 1, diarrhea in 1, and stomatitis in 1 patient. The ET regimen was given to 16 patients(89%)as planned. The median number of courses was 4(range: 2-4). The clinical response rate was 44%. The median time to progression was 9 months, and median overall survival was 26 months. It is concluded that the ET regimen was well tolerated and effective as a primary chemotherapy for IBC.
  Gan to kagaku ryoho. Cancer & chemotherapy 07/2012; 39(7):1075-9.
• Article: First reported case of hemoglobin lansing in Asia detected by false low oxygen saturation on pulse oximetry.

  Kenji Ishitsuka, Junji Uchino, Junko Kato, Mikihiro Ikuta, Kentaro Watanabe, Akira Matsunaga, Kazuo Tamura
  International journal of hematology 05/2012; 95(6):731-2. · 1.17 Impact Factor
• Article: [Docetaxel in combination with epirubicin as the first-line chemotherapy for advanced and recurrent breast cancer: a multicenter phase II study].

  Keisei Anan, Maki Tanaka, Shoshu Mitsuyama, Shigeru Imamura, Shinji Ohno, Shinsuke Hara, Tatsuji Oikawa, Teruhiko Fujii, Reiki Nishimura, Emi Ishikawa, Hiroshi Yano, Hideki Taniguchi, Masayuki Ohkido, Tetsufumi Ohchi, Kazuo Chijiiwa, Ichirou Arime, Kazuo Shimada, Hiromichi Inoue, Kazuo Tamura
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  ABSTRACT: This study examined the efficacy and tolerability of docetaxel(DOC)in combination with epirubicin(EPI)as the first-line treatment for patients with advanced and recurrent breast cancer. A total of 56 female patients with metastatic breast cancer not previously treated for metastatic disease received DOC(60mg/m²)and EPI(60mg/m2)on day 1 every 3 weeks. The patient characteristics included a median age of 53 years. Advanced disease was present in 86% of patients, and recurrent disease was found in 14%; 3 or more metastatic sites had been diagnosed in 38% of patients, and 59% patients were ER+. The median number of courses administered was 6. The median dose intensity was 18. 7mg/m²week for DOC and EPI, and the relative dose intensities were 93. 5%and 93. 3%, respectively. The clinical responses included a complete response in 5%, a partial response in 54%, and stable disease in 33% of patients, with a disease control rate of 92%. The progression-free survival was 78. 3%, and the overall survival was 91. 9% at 1 year. Grade 3/4 toxicities included neutropenia in 82%, leukopenia in 71%, febrile neutropenia in 16%, anorexia in 9%, and anemia in 7%of the patients. Neither congestive heart failure nor toxic death occurred. The D and E combination with doses of 60mg/m2 is an active and generally well-tolerated regimen that can be used as first-line chemotherapy for patients with metastatic breast cancer.
  Gan to kagaku ryoho. Cancer & chemotherapy 05/2012; 39(5):747-52.
• Article: Phase I study of the combination of irinotecan hydrochloride, carboplatin, and dexamethasone for the treatment of relapsed or refractory malignant lymphoma

  Junji Suzumiya, Hitoshi Suzushima, Kouichi Maeda, Seiichi Okamura, Atae Utsunomiya, Tunefumi Shibuya, Kazuo Tamura, Kyushu Hematology Organization for Treatment Study Group
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  ABSTRACT: A phase I study of irinotecan hydrochloride (CPT-11), carboplatin, and dexamethasone treatment in 7 patients with relapsed lymphoma and 7 patients with refractory lymphoma was conducted to evaluate the maximal tolerated dose. The 6 female and 8 male patients had a median age of 63 years (range, 45-73 years), a median performance status of 0 (range, 0-2), and a median disease stage of IV.This study included patients with diffuse large B-cell lymphoma (n = 5), adult T-cell leukemia/ lymphoma (n = 2), mantle cell lymphoma (n = 2), follicular lymphoma (n = 2), angioimmunoblastic T-cell lymphoma (n = 1), anaplastic large cell lymphoma (n = 1), and Hodgkin’s lymphoma (n = 1). All patients had received anthracycline-containing combination chemotherapy prior to this therapy.The starting dosage of CPT-11 was 15 mg/m2 per day (days 1–3 and 8–10), and dosage-escalation increments of 5 mg/m2 per day were planned, with fixed dosages of carboplatin (250 mg/m2 per day, day 1) and dexamethasone (40 mg/body, days 1–3 and days 8–10). Five patients were enrolled at level 1, 3 at level 2, 4 at level 3, and 2 at level 4. Ten patients (71%) and 11 patients (79%) experienced grade 3 or 4 hematologic toxicities of leukocytopenia and neutropenia, respectively.Three patients (29%) and 9 patients (64%) experienced grade 3 or 4 thrombocytopenia and anemia, respectively.Two patients who received 30 mg/m2 (level 4) of CPT-11 developed sepsis.We concluded that the recommended dose of CPT-11 with carboplatin and dexamethasone is 25 mg/m2. No deaths were related to this chemotherapy, and no patient developed liver dysfunction.The overall response rate was 36%.We conclude that the combination therapy of CPT-11, carboplatin, and dexamethasone is effective as salvage therapy but that the duration of response is too short.
  International Journal of Hematology 04/2012; 79(3):266-270. · 1.27 Impact Factor
• Article: Prognostic index for acute- and lymphoma-type adult T-cell leukemia/lymphoma.

  Hiroo Katsuya, Takeharu Yamanaka, Kenji Ishitsuka, Atae Utsunomiya, Hidenori Sasaki, Shuichi Hanada, Tetsuya Eto, Yukiyoshi Moriuchi, Yoshio Saburi, Masaharu Miyahara, [......], Naokuni Uike, Shinichiro Yoshida, Kiyoshi Yamashita, Kunihiro Tsukasaki, Hitoshi Suzushima, Yuju Ohno, Hitoshi Matsuoka, Tatsuro Jo, Junji Suzumiya, Kazuo Tamura
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  ABSTRACT: The prognosis of acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL) is poor, but there is marked diversity in survival outcomes. The aim of this study was to develop a prognostic index (PI) for acute- and lymphoma-type ATL (ATL-PI). In a retrospective review, data from 807 patients newly diagnosed with acute- and lymphoma-type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed a PI using a multivariable fractional polynomial model. Median overall survival time (MST) for the 807 patients was 7.7 months. The Ann Arbor stage (I and II v III and IV), performance status (0 to 1 v 2 to 4), and three continuous variables (age, serum albumin, and soluble interleukin-2 receptor [sIL-2R]) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (P < .001; χ(2) = 89.7, 2 df; log-rank test). We also simplified the original ATL-PI according to dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and developed an easily calculable PI with prognostic discrimination power (P < .001; χ(2) = 74.2, 2 df; log-rank test). The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks.
  Journal of Clinical Oncology 04/2012; 30(14):1635-40. · 18.37 Impact Factor
• Article: Importance of inducible multidrug resistance 1 expression in HL-60 cells resistant to gemtuzumab ozogamicin.

  Taichi Matsumoto, Shiro Jimi, Shuuji Hara, Yasushi Takamatsu, Junji Suzumiya, Kazuo Tamura
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  ABSTRACT: Resistance to gemtuzumab ozogamicin (GO) hampers the effective treatment of refractory acute myeloid leukemia (AML). To clarify the mechanism of resistance to GO, HL-60 cells were persistently exposed to GO in order to establish GO-resistant HL-60 (HL-60/GOR) cells. Multidrug resistance 1 (MDR-1) was strongly expressed in HL-60/GOR cells, but not in HL-60 cells. Although withdrawal of GO after the chronic exposure of HL-60/GOR cells to this compound gradually decreased MDR-1 expression to trace levels, reintroducing GO restored high MDR-1 expression in HL-60/GOR cells, but not in HL-60 cells. These results indicate that HL-60/GOR cells acquired the ability to induce MDR-1 expression in response to GO. U0126, a MEK1/2 inhibitor, prevented GO-inducible MDR-1 expression and abrogated GO resistance in HL-60/GOR cells. These results suggest that in the clinical use of GO, inducible MDR-1 expression in tumor cells should be investigated before treatment with GO. If the cells are positive then MEK1/2 inhibitors may be effective in overcoming resistance to GO.
  Leukemia & lymphoma 02/2012; 53(7):1399-405. · 2.40 Impact Factor
• Article: Prognostic impact of extranodal involvement in diffuse large B-cell lymphoma in the rituximab era.

  Hiroyuki Takahashi, Naoto Tomita, Masahiro Yokoyama, Saburo Tsunoda, Takahiro Yano, Kayoko Murayama, Chizuko Hashimoto, Kazuo Tamura, Kazuya Sato, Yoshiaki Ishigatsubo
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  ABSTRACT: Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated. The authors retrospectively analyzed 1221 patients treated uniformly with standard R-CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax-associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15-91 years). Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04). Extranodal involvement affects the prognosis of patients undergoing R-CHOP therapy for DLBCL.
  Cancer 12/2011; 118(17):4166-72. · 4.77 Impact Factor
• Article: Targeting Bcl-2 family proteins in adult T-cell leukemia/lymphoma: in vitro and in vivo effects of the novel Bcl-2 family inhibitor ABT-737.

  Kenji Ishitsuka, Naoko Kunami, Hiroo Katsuya, Rumiko Nogami, Chie Ishikawa, Fusanori Yotsumoto, Hiroe Tanji, Naoki Mori, Morishige Takeshita, Shingo Miyamoto, Kazuo Tamura
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  ABSTRACT: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). ABT-737, a small molecule inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, significantly induced apoptosis in HTLV-1 infected T-cell lines as well as in fresh ATLL cells, and synergistically enhanced the cytotoxicity and apoptosis induced by conventional cytotoxic drugs. Moreover, ABT-737 significantly inhibited the in vivo tumor growth of an ATLL mouse model. These results suggest that the use of an agent targeting anti-apoptotic bcl-2 family proteins, either alone or in combination with other conventional drugs, represents a novel promising approach for ATLL.
  Cancer letters 12/2011; 317(2):218-25. · 4.86 Impact Factor