Publications by authors named "Kazunori Murai"

34 Publications

Second direct-acting antiviral therapy for hepatitis C virus infection after umbilical cord blood transplantation: A case report.

J Infect Chemother 2021 Aug 12;27(8):1230-1233. Epub 2021 Feb 12.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Hepatitis C virus (HCV) infection has an adverse impact on outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). It is recommended that HSCT candidates infected with HCV receive the treatment prior to transplantation. Although the recent approval of direct-acting antivirals (DAAs) has led to great advances in the treatment of HCV infection, little information is available on the efficacy and safety of DAA therapy in patients receiving allogeneic HSCT. Herein, we report the clinical course of an umbilical cord blood (UCB) recipient treated with DAAs for HCV infection. The patient achieved HCV RNA negativity with glecaprevir and pibrentasvir after consolidation therapy for acute myeloid leukemia (AML), and underwent transplantation before confirming sustained virological response (SVR) at 12 weeks. The HCV viral load became detectable on day +28 after transplantation and second HCV treatment with sofosbuvir, velpatasvir, and ribavirin was required. It is important to confirm SVR prior to transplantation, but it is often difficult. If early transplantation is required, close monitoring of HCV RNA after transplantation is needed. Further investigation is required to clarify the optimal management of HCV infection for allogeneic HSCT recipients in the DAA era.
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http://dx.doi.org/10.1016/j.jiac.2021.02.002DOI Listing
August 2021

Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial.

Lancet Haematol 2020 Mar 21;7(3):e218-e225. Epub 2020 Jan 21.

Department of Hematology and Oncology, Iwate Medical University, Morioka, Japan.

Background: A previous dasatinib discontinuation (DADI) trial showed that 31 (49%) of 63 patients with chronic-phase chronic myeloid leukaemia who were treated with second-line or subsequent dasatinib could discontinue the drug safely. However, the safety and efficacy of discontinuing first-line dasatinib remains unclear. In this trial (the first-line DADI trial) we aimed to assess molecular relapse-free survival at 6 months after discontinuation of dasatinib in patients with chronic myeloid leukaemia who had been treated with first-line dasatinib and had maintained deep molecular response for at least 1 year.

Methods: The first-line DADI trial was a single-arm, multicentre, phase 2 trial done at 23 hospitals in Japan. Patients with newly diagnosed chronic-phase chronic myeloid leukaemia without hepatosplenomegaly and extramedullary mass, who received at least 24-month dasatinib treatment and had a sustained deep molecular response (defined as BCR-ABL1/ABL1 international scale ≤0·0069% in at least four successive samples spanning a 12 month period) were enrolled. Other eligibility criteria were an age of 15 years or older, an Eastern Cooperative Oncology Group performance status score of 0-2, and no primary organ dysfunction. The primary outcome was molecular relapse-free survival (also known as treatment-free remission) after discontinuation of dasatinib at 6 months and was analysed in all patients who completed the 12-month consolidation phase. Safety was assessed in all patients who received treatment. This study closed early due to accrual and is registered with the UMIN Clinical Trials Registry (UMIN000011099).

Findings: Between Sept 20, 2013 and July 12, 2016, 68 patients who had a deep molecular response after receiving first-line dasatinib for at least 24 months were enrolled and assigned to the consolidation phase. Nine patients were excluded during the consolidation phase and one patient was excluded after study completion because of meeting exclusion criteria. 58 patients discontinued dasatinib and were assessed. 32 (55%) of 58 patients had treatment-free remission at 6 months after dasatinib discontinuation, and median follow-up was 23·3 months (IQR 11·7-31·0). Treatment-free remission at 6 months was 55·2% (95% CI 43·7-69·6). No non-haematological adverse events worse than grade 2 occurred before dasatinib discontinuation. The most common haematological adverse event was anaemia (14 [21%] of 68 treated patients); three (4%) of 68 treated patients had grade 3 neutropenia and one (1%) had grade 4 lymphopenia.

Interpretation: Our findings suggest that dasatinib could be safely discontinued after first-line treatment in patients with chronic myeloid leukaemia who had received at least 36 months of therapy and sustained deep molecular response; however, further confirmation in larger trials is needed.

Funding: Epidemiological and Clinical Research Information Network.
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http://dx.doi.org/10.1016/S2352-3026(19)30235-2DOI Listing
March 2020

[Acquired hemophilia A accompanied by immune thrombocytopenia].

Rinsho Ketsueki 2019 ;60(11):1567-1572

Department of Hematology and Oncology, Sapporo Higashi Tokushukai Hospital.

A 72-year-old man was hospitalized because of thrombocytopenia (0.5×10/µl) and anemia. The bone marrow test result revealed excessive numbers of megakaryocytes and no platelet adhesion. Furthermore, platelet-associated immunoglobulin G levels were high, and he was tested positive for Helicobacter pylori antibody. On the basis of these findings, immune thrombocytopenia was diagnosed. The patient was initially treated with eradication therapy; prednisolone, 20 mg/day (0.5 mg/kg) and a thrombopoietin receptor agonist 12.5 mg/day. During the course of treatment, the anemia worsened. Detailed examination revealed marked prolongation of activated partial thromboplastin time and inhibition of factor VIII activity. Therefore, he was diagnosed with acquired hemophilia A. Although extensive muscle hemorrhage had occurred, hemostatic therapy comprising intensification of the immunosuppressive therapy and administration of recombinant activated factor VII resulted in successful hemostasis. As the treatment progressed, inhibition of factor VIII recurred temporarily; however, immunosuppressive therapy was continued. No recurrence was observed even after 1 year of the onset of both diseases.
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http://dx.doi.org/10.11406/rinketsu.60.1567DOI Listing
December 2019

Safety and efficacy of high-dose ranimustine (MCNU) containing regimen followed by autologous stem cell transplantation for diffuse large B-cell lymphoma.

Int J Hematol 2018 Nov 24;108(5):510-515. Epub 2018 Jul 24.

Department of Hematology, Nephrology and Rheumatology, Akita University, 44-2 Hasunuma Hiroomote, Akita city, Akita, 010-0041, Japan.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is widely used as a salvage therapy for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL). To investigate the safety and efficacy of regimens including high-dose MCNU followed by ASCT for DLBCL, we analyzed the data from prospective multicenter trials. Twenty-nine patients were analyzed, and the median follow-up time for survival patients was 70 months. Fifteen patients received MCVC conditioning regimen, and fourteen patients received MEAM regimen. Major toxicities associated with these conditioning regimens included nausea (69%), anorexia (66%), febrile neutropenia (62%), diarrhea (59%), and mucositis (34%). One patient who developed severe sinusoidal obstructive syndrome and acute lung injury died without disease progression, and overall therapy-related mortality at 5 years was 3%. No patient developed therapy-related hematological malignancy. At 5 years, overall survival and progression-free survival in all patients were 82.8 and 58.2%, respectively. The 5-year OS in patients treated by the MCVC and MEAM regimens were 73.3 and 92.9%, respectively. These results suggest that regimens including high-dose MCNU followed by ASCT are feasible and effective for the treatment of relapsed or high-risk DLBCL. Further investigation is needed to evaluate of these regimens.
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http://dx.doi.org/10.1007/s12185-018-2508-1DOI Listing
November 2018

Pretreatment evaluation of fluorescence resonance energy transfer-based drug sensitivity test for patients with chronic myelogenous leukemia treated with dasatinib.

Cancer Sci 2018 Jul 29;109(7):2256-2265. Epub 2018 May 29.

Department of Hematology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The ΔFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the ΔFRET value and molecular response, a threshold of the ΔFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with ΔFRET value ≥0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with ΔFRET value <0.31. These results suggest that the FRET-based drug sensitivity test at diagnosis can predict early and deep molecular responses. This study is registered with UMIN Clinical Trials Registry (UMIN000006358).
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http://dx.doi.org/10.1111/cas.13625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029835PMC
July 2018

Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment.

Clin Lymphoma Myeloma Leuk 2018 05 15;18(5):353-360.e1. Epub 2018 Mar 15.

Department of Hematology, Ogaki Municipal Hospital, Gifu, Japan.

Introduction: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective.

Patients And Methods: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed.

Results: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ T-cell and CD4 regulatory T-cell (CD25CD127) counts before discontinuation correlated significantly with successful therapy discontinuation.

Conclusion: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.
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http://dx.doi.org/10.1016/j.clml.2018.03.004DOI Listing
May 2018

Rapid reduction in BCR-ABL1 transcript predicts deep molecular response in dasatinib-treated chronic-phase chronic myeloid leukaemia patients.

Eur J Haematol 2018 Jan 16;100(1):27-35. Epub 2017 Oct 16.

Division of Hematology and Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan.

Objectives: We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study).

Methods: Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post-treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT) and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL1 ) were the post-treatment factors investigated to predict the molecular response.

Results: The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL1 was the only significant landmark for predicting DMR by multivariate analysis.

Conclusions: Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR-ABL1 was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR-ABL1 IS.
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http://dx.doi.org/10.1111/ejh.12969DOI Listing
January 2018

Evaluation of the safety and efficacy of recombinant soluble thrombomodulin for patients with disseminated intravascular coagulation associated with acute leukemia: multicenter prospective study by the Tohoku Hematology Forum.

Int J Hematol 2017 May 7;105(5):606-613. Epub 2017 Feb 7.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

It has been suggested that use of recombinant soluble thrombomodulin (rTM) is superior to conventional drugs in treatment of disseminated intravascular coagulation (DIC) complicating acute leukemia. However, its safety and efficacy have not been fully examined in prospective studies. Here, we performed a multicenter prospective study to examine outcomes of rTM treatment for DIC in patients with acute leukemia. Of 33 patients registered in this study, 13 had acute myeloid leukemia (AML), three had acute lymphoblastic leukemia (ALL), and 17 had acute promyelocytic leukemia (APL). The cumulative rates of DIC resolution at day 7 and day 35 were 56 and 81% in AML/ALL and 53 and 77% in APL, respectively. The median time from the initiation of rTM to DIC resolution was 4 days in AML/ALL and 6 days in APL patients. Adverse events related to hemorrhage occurred in two AML/ALL patients (13%) and three APL patients (18%). Of these, one AML/ALL patient died with intracranial hemorrhage, and two APL patients died with intracranial hemorrhage and pulmonary hemorrhage. These results suggest that rTM may improve the survival of acute leukemia patients with DIC by inhibiting early death related to hemorrhagic events, as reported previously.
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http://dx.doi.org/10.1007/s12185-017-2190-8DOI Listing
May 2017

Causes of macrocytic anemia among 628 patients: mean corpuscular volumes of 114 and 130 fL as critical markers for categorization.

Int J Hematol 2016 Sep 28;104(3):344-57. Epub 2016 Jun 28.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-cho, Aoba-ku, Sendai, 980-8574, Japan.

There have been no studies on the distribution of causes of macrocytic anemia with respect to mean corpuscular volume (MCV) cutoff values. We retrospectively investigated the causes of macrocytic anemia (MCV ≥100 fL) among 628 patients who visited the outpatient hematology clinic in Tohoku University Hospital. To ensure data validity, we also analyzed data from 307 patients in eight other hospitals in the Tohoku district. The leading causes of macrocytic anemia (number of patients, %) were myelodysplastic syndromes (121, 19.3 %), suspected bone marrow failure syndromes (BMF; 74, 11.8 %), aplastic anemia (51, 8.1 %), plasma cell dyscrasia (45, 7.2 %), and vitamin B12 deficiency (40, 6.4 %) in Tohoku University Hospital. We made three primary findings as follows. First, the most common cause of macrocytic anemia is BMF. Second, lymphoid and solid malignancies are also common causes of macrocytosis. Third, macrocytic anemia may be classified into three groups: Group 1 (megaloblastic anemia and medications), which can exceed MCV 130 fL; Group 2 (alcoholism/liver disease, BMF, myeloid malignancy, and hemolytic anemia), which can exceed MCV 114 fL; and Group 3 (lymphoid malignancy, chronic renal failure, hypothyroidism, and solid tumors), which does not exceed MCV 114 fL. These conclusions were supported by the results from eight other hospitals.
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http://dx.doi.org/10.1007/s12185-016-2043-xDOI Listing
September 2016

High prevalence of diffuse large B-cell lymphoma in occult hepatitis B virus-infected patients in the Tohoku district in Eastern Japan.

J Med Virol 2016 12 6;88(12):2206-2210. Epub 2016 Jun 6.

Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.

Occult hepatitis B virus (HBV) infection is a clinical challenge, but its relationship to clinicopathologic features and the risk of progression to malignant lymphoma (ML) are poorly defined. We estimated the prevalence of HBV infection of 1,358 patients with newly diagnosed ML. HBV infection was more prevalent in ML than in control patients. The occult HBV infection group had a higher median onset age, no liver or spleen involvement, and higher prevalence of diffuse large B-cell lymphoma than the other groups, indicating that occult HBV infection is a distinct clinicopathologic entity. J. Med. Virol. 88:2206-2210, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jmv.24584DOI Listing
December 2016

Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial.

Lancet Haematol 2015 Dec 10;2(12):e528-35. Epub 2015 Nov 10.

Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address:

Background: First-line imatinib treatment can be successfully discontinued in patients with chronic myeloid leukaemia after deep molecular response has been sustained for at least 2 years. We investigated the safety and efficacy of discontinuing second-line or subsequent dasatinib after at least 1 year of deep molecular response.

Methods: The Dasatinib Discontinuation trial was a prospective multicentre trial done in Japan. Eligible patients taking dasatinib and with confirmed stable deep molecular response were enrolled between April 1, 2011, and March 31, 2012. All patients received dasatinib consolidation therapy for at least 1 year. In those with sustained deep molecular response, dasatinib was discontinued. Patients were followed up every month in year 1 (clinical cutoff), every 3 months in year 2, and every 6 months in year 3 for deep molecular response and immunological profiles. The primary endpoint was the proportion of patients with treatment-free remission at 6 months after discontinuation. Molecular relapse was defined as loss of deep molecular response at any assessment. This study is registered, number UMIN000005130.

Findings: 88 patients were enrolled in the consolidation phase, 24 were excluded from the discontinuation phase due to fluctuations in BCR-ABL1 transcript levels. One patient was excluded because of positive expression of major and minor BCR-ABL1 transcripts in chronic myeloid leukaemia cells and the detection of minor BCR-ABL1 transcripts during consolidation. Thus, 63 patients discontinued dasatinib treatment. The 25 patients who were excluded from discontinuation continued to receive dasatinib and none showed disease progression. Median follow-up was 20.0 months (IQR 16.5-24.0). Of the 63 patients who discontinued and were not excluded, 30 patients maintained deep molecular response while 33 patients had molecular relapses, all within the first 7 months after discontinuation. The estimated overall treatment-free remission was 49% (95% CI 36-61) at 6 months. No severe treatment-related toxic effects were seen. Treatment was restarted in the 33 patients with relapse; rapid molecular responses were seen in all 33 patients, of whom 29 (88%) regained deep molecular response within 3 months, as did the remaining four by 6 months.

Interpretation: Dasatinib discontinuation after sustained deep molecular response for more than 1 year is feasible.

Funding: Epidemiological and Clinical Research Information Network (ECRIN).
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http://dx.doi.org/10.1016/S2352-3026(15)00196-9DOI Listing
December 2015

Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia.

Eur J Clin Pharmacol 2016 Feb 27;72(2):185-93. Epub 2015 Oct 27.

Iwate Medical University School of Medicine, Morioka, Japan.

Purpose: Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients.

Methods: The dasatinib concentration required to inhibit 50 % of the CrkL (CT10 regulator of kinase like) phosphorylation in bone marrow CD34+ cells (half maximal (50 %) inhibitory concentration (IC50)CD34+cells) was calculated from each patient's dose-response curve using flow cytometry. PK parameters were obtained from the population pharmacokinetic analysis of dasatinib concentrations in plasma on day 28 after administration.

Results: Early molecular responses were not significantly associated with PK or PD (IC50 CD34+cells) parameters. However, the PK/PD parameter-time above IC50 CD34+cells-significantly correlated with BCR-ABL transcript level at 3 months (correlation coefficient (CC) = -0.292, P = 0.0375) and the reduction of BCR-ABL level at 1 or 3 months (CC = -0.404, P = 0.00328 and CC = -0.356, P = 0.0104, respectively). Patients with more than 12.6 h at time above IC50 CD34+cells achieved a molecular response of 3.0 log reduction at 3 months and those more than 12.8 h achieved a deep molecular response less than 4.0 log reduction at 6 months at a significantly high rate (P = 0.013, odds ratio = 4.8 and P = 0.024, odds ratio = 4.3, respectively).

Conclusion: These results suggest that the anti-leukemic activity of dasatinib exhibits in a time-dependent manner and that exposure for more than 12.8 h at time above IC50 CD34+cells could significantly improve prognosis.
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http://dx.doi.org/10.1007/s00228-015-1968-yDOI Listing
February 2016

Comparison of micafungin and voriconazole as empirical antifungal therapies in febrile neutropenic patients with hematological disorders: a randomized controlled trial.

Eur J Haematol 2016 Jun 26;96(6):602-9. Epub 2015 Aug 26.

Department of Hematology and Oncology, Internal Medicine, Iwate Medical University School of Medicine, Morioka City, Japan.

Objectives: In cases of hematological malignancy, patients with persistent fever and neutropenia receive antifungal empirical therapy to prevent and treat invasive fungal infections. The clinical efficacy and safety of micafungin and voriconazole were compared.

Methods: In this randomized, cooperative group, open-label trial, we assessed and compared the efficacy and safety of micafungin and voriconazole as an empirical antifungal therapy in febrile neutropenic patients with hematological malignancy. Patients were classified according to invasive fungal infection risk.

Results: There were no significant differences in clinical efficacy between the two treatments, evaluated based on (i) successful treatment of baseline fungal infection (no evaluation), (ii) absence of breakthrough fungal infection (P = 0.106), (iii) survival for ≥7 days after study completion (P = 0.335), (iv) premature study discontinuation due to poor efficacy (P = 0.424), and (v) resolution of fever during neutropenia (P = 0.756). Discontinuation due to drug-related adverse events (grades 3-4) occurred less frequently in the micafungin group (P = 0.005).

Conclusions: The clinical efficacy did not differ between micafungin and voriconazole. Micafungin was generally better tolerated than voriconazole when given as an empirical antifungal therapy in patients with persistent fever and neutropenia.
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http://dx.doi.org/10.1111/ejh.12641DOI Listing
June 2016

A prospective analysis of clinical efficacy and safety in chronic myeloid leukemia-chronic phase patients with imatinib resistance or intolerance as evaluated using European LeukemiaNet 2013 criteria.

Eur J Haematol 2015 Dec 25;95(6):558-65. Epub 2015 Mar 25.

Department of Hematology and Oncology, Iwate Medical University, Morioka, Japan.

Background: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukemia (CML).

Methods: From 2009 to 2011, 54 CML-chronic phase (CP) patients with resistance (n = 40) or intolerance (n = 25) to imatinib were registered to undergo dasatinib treatment. Eleven patients showed both resistance and intolerance to imatinib. Coincidentally, the resistance criteria in this study were the same as a non-optimal response to tyrosine kinase inhibitors (TKIs) as defined in the European LeukemiaNet (ELN) 2013 recommendations.

Results: The overall incidence rate of major molecular response (MMR) at 12 months was 62.3% (n = 47). Forty patients with resistance to imatinib who were 'warning' and 'failure' patients based on the ELN 2013 recommendations were assessed; cumulative MMR and MR(4.5) rates were 62.5% (n = 39) and 21.0% (n = 40), respectively, at 12 months. Twelve patients who showed a BCR-ABL transcript level >1% on the international scale did not achieve a MMR or discontinued dasatinib treatment because of insufficient effects. With regard to safety issues, grade 3/4 non-hematologic adverse events (AEs) were infrequent.

Conclusions: Patients with non-optimal responses (who meet ELN 2013 warning and failure criteria) to imatinib should be switched quickly to dasatinib, which is less toxic in CML-CP patients, to improve their prognoses. A BCR-ABL1 IS of <1% at 3 months of dasatinib administration is a landmark for good therapeutic outcome.
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http://dx.doi.org/10.1111/ejh.12536DOI Listing
December 2015

Platelet demand modulates the type of intravascular protrusion of megakaryocytes in bone marrow.

Thromb Haemost 2014 Oct 26;112(4):743-56. Epub 2014 Jun 26.

Yoji Ishida, Hematology and Oncology, Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan, Tel.: +81 19 651 5111, Fax: +81 19 651 5185, E-mail:

Megakaryocytes (MKs) generate platelets via intravascular protrusions termed proplatelets, which are tandem arrays of platelet-sized swellings with a beaded appearance. However, it remains unclear whether all intravascular protrusions in fact become proplatelets, and whether MKs generate platelets without forming proplatelets. Here, we visualised the sequential phases of intravascular MK protrusions and fragments in living mouse bone marrow (BM), using intravital microscopy, and examined their ultrastructure. The formation of intravascular protrusions was observed to be a highly dynamic process, in which the size and shape of the protrusions changed sequentially prior to the release of platelet progenitors. Among these intravascular protrusions, immature thick protrusions were distinguished from proplatelets by their size and the dynamic morphogenesis seen by time-lapse observation. In ultrastructural analyses, the thick protrusions and their fragments were characterised by a peripheral zone, abundant endoplasmic reticulum and demarcation membrane system, and random microtubule arrays. Proplatelets were predominant among BM sinusoids in the physiological state; however, during an acute thrombocytopenic period, thick protrusions increased markedly in the sinusoids. These results strongly suggested that BM MKs form and release two types of platelet progenitors via distinct intravascular protrusions, and that platelet demand modulates the type of intravascular protrusion that is formed in vivo.
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http://dx.doi.org/10.1160/TH14-02-0123DOI Listing
October 2014

Bortezomib induces thrombocytopenia by the inhibition of proplatelet formation of megakaryocytes.

Eur J Haematol 2014 Oct 16;93(4):290-6. Epub 2014 May 16.

Hematology and Oncology, Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate, Japan.

Bortezomib is a potent proteasome inhibitor that has been extensively used to treat multiple myeloma. One of the most common grade 3 adverse events is cyclic thrombocytopenia. In this study, we studied the mechanism by which bortezomib induces thrombocytopenia in a mouse model. After the intravenous administration of bortezomib (2.5 mg/kg) via tail vein, platelet counts significantly decreased on days 2-4 and recovered to the normal range on day 6. Bortezomib (2.5 mg/kg) injected into mice in vivo did not affect colony-forming unit-megakaryocytes (CFU-Mk) or megakaryocytes in the bone marrow. However, proplatelet formation (PPF) significantly decreased on days 2 and 4, after bortezomib administration to mice. Meanwhile, CFU-Mk formation and the ploidy distribution of cultured megakaryocytes in vitro were not affected by bortezomib used at concentrations of ≤ 1 ng/mL. The PPF of megakaryocytes in vitro significantly decreased with 0.1, 1, 10, and 100 ng/mL bortezomib. Considering the bortezomib concentration in clinical studies, these data strongly suggest that decreased PPF activity induces thrombocytopenia. To elucidate the mechanism behind decreased PPF, Western blot was performed. Activated Rho expression increased after the incubation of murine platelets with bortezomib. Decreased PPF activity was eliminated by the addition of Y27632, a Rho kinase inhibitor, in vitro. Given that the Rho/Rho kinase pathway is a negative regulator of PPF, bortezomib increases activated Rho, inducing decreased PPF, which results in decreased platelet count.
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http://dx.doi.org/10.1111/ejh.12342DOI Listing
October 2014

Successful use of cyclophosphamide as an add-on therapy for multiple myeloma patients with acquired resistance to bortezomib or lenalidomide.

Case Rep Hematol 2013 28;2013:651902. Epub 2013 Mar 28.

Hematology & Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.

Novel agents such as thalidomide, lenalidomide, and bortezomib have been shown to possess potent activity against multiple myeloma. However, the treatment strategy for patients who acquired resistance to these agents has not been established. In addition to switching drug classes, intensified treatment strategy, including increase in the dosage of current agents and addition of other agents, may be considered for these patients. We here describe 2 myeloma patients with acquired resistance to bortezomib or lenalidomide, in whom add-on therapy with low-dose cyclophosphamide was effective and tolerable. These cases suggest that add-on therapy with cyclophosphamide is one of the treatment options to overcome resistance to novel agents in patients with multiple myeloma. A larger prospective study is needed to clarify the efficacy and safety of this strategy for novel agent-resistant multiple myeloma.
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http://dx.doi.org/10.1155/2013/651902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625568PMC
April 2013

Safety and feasibility of high-dose ranimustine (MCNU), carboplatin, etoposide, and cyclophosphamide (MCVC) therapy followed by autologous stem cell transplantation for malignant lymphoma.

Int J Hematol 2012 Nov 1;96(5):624-30. Epub 2012 Oct 1.

Department of Hematology, Akita University Graduate School of Medicine, Akita, Japan.

High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is widely used as a salvage therapy in the treatment of refractory malignant lymphoma. To investigate the safety and feasibility of a high-dose MCNU, carboplatin, etoposide and cyclophosphamide (MCVC) regimen, we conducted a prospective multicenter trial. Thirty patients with relapsed/refractory/poor-risk non-Hodgkin lymphoma (NHL n = 27) or Hodgkin lymphoma (HD n = 3) were uniformly treated with an MCVC regimen and underwent auto-SCT. The median follow-up duration of the surviving patients was 67 months (56-133 months). The major toxicities were anorexia (94 %), diarrhea (80 %), nausea (79 %), febrile neutropenia (70 %), alopecia (67 %) and mucositis (60 %). Three patients developed severe left ventricular dysfunction, and two patients developed severe sinusoidal obstructive syndrome (SOS). Of these patients, two died without disease progression. Treatment-related mortality was 6.6 %. Late-onset adverse events including two cases of cytomegalovirus pneumonia and one of interstitial pneumonia were observed. In DLBCL (n = 13) and transformed FL (n = 2) patients, OS and EFS at 3 years were 72 and 46 %, respectively. These results suggest that the MCVC regimen followed by auto-SCT is a feasible and tolerable therapy for relapsed/refractory malignant lymphoma. However, cardiac toxicity due to high-dose cyclophosphamide and development of SOS can occur and should be carefully monitored. Further follow-up is needed to evaluate the long-term efficacy and safety of this regimen.
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http://dx.doi.org/10.1007/s12185-012-1186-7DOI Listing
November 2012

T-cell prolymphocytic leukemia in Japan: is it a variant?

Int J Hematol 2012 Jun 24;95(6):660-7. Epub 2012 Apr 24.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-cho, Aoba-ku, Sendai 980-8574, Japan.

T-cell prolymphocytic leukemia (T-PLL) is characterized by a post-thymic immunophenotype, salient chromosome abnormalities, and an aggressive clinical course. However, cases in which these features are absent have been occasionally reported in Japan. Here, clinical and biological features of 13 T-PLL cases, diagnosed between 1992 and 2009 in the Tohoku region of Japan, were compared with three Western series. Median age was 64 (range 40-78) years old, and the male to female ratio (12:1) was higher than that of the Western series (P < 0.04). Presented manifestations were similar to those of Western cases, but central nervous system involvement, which is rare in Western cases, was observed in 3 of 13 cases (23 %) (P < 0.04). Immunophenotypic patterns were similar to those of Western cases, but HLA-DR was positive in 6 of 9 cases (67 %), which is distinct from Western cases (0-9 %) (P < 0.002). By chromosome analyses, 14q11 abnormality and trisomy 8q, which are common among Western cases (70-80 %), were not observed in any cases (P < 0.002). Morphologically, seven were classified as typical type, five as a small-cell variant, and one as a cerebriform variant. Seven cases experienced an aggressive course, whereas six experienced an indolent course over a median follow-up of 50 months. In contrast to Western cases, clinical courses were closely correlated with morphological types; 86 % of typical types were aggressive, whereas 83 % of small-cell types were indolent (P = 0.025). On the basis of these observations, together with previous Japanese cases in the literature, we propose that Japanese cases of T-PLL may constitute a variant.
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http://dx.doi.org/10.1007/s12185-012-1077-yDOI Listing
June 2012

Comparison of long-term clinical outcomes of CHOP chemotherapy between Japanese patients with nodal peripheral T-cell lymphomas and those with diffuse large B-cell lymphoma in the study group of the Tohoku Hematology Forum.

J Clin Exp Hematop 2011 ;51(1):29-35

Department of Hematology, Aomori Prefectural Hospital, Japan.

To clarify the clinical outcome of peripheral T-cell lymphomas (PTCLs), we conducted a retrospective review comparing the outcomes of patients with PTCL (nodal peripheral T-cell lymphoma, unspecified, n=34 ; angioimmunoblastic T-cell lymphoma, n=12) to those with diffuse large B-cell lymphoma (DLBCL, n=48). All patients received CHOP-based chemotherapy without rituximab. PTCL patients presented at a more advanced clinical stage (91% vs. 65%, P<0.002) with a poorer performance status (26% vs. 17%, P<0.002) than DLBCL patients. The complete response rate among PTCL patients was significantly lower than among DLBCL patients (39% vs. 67%, P<0.008), as was the 3-year overall survival rate (26% vs. 50%, P=0.005), and Cox multivariate analysis revealed immunophenotype, performance status, and extranodal site involved to be significantly associated with shorter overall survival (P=0.045, P=0.007, and P=0.034, respectively). Our findings suggest that PTCL patients tend to have a poor prognosis associated with several initial risk factors. Moreover, the T-cell phenotype itself appears to have a significant impact on overall survival. Thus, standard CHOP chemotherapy may be inadequate for PTCLs, especially in patients with high-risk factors. The development of newly stratified therapies for the treatment of PTCLs would be highly desirable.
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http://dx.doi.org/10.3960/jslrt.51.29DOI Listing
October 2011

Low concentration of serum haptoglobin has impact on understanding complex pathophysiology in patients with acquired bone marrow failure syndromes.

Int J Hematol 2010 May 8;91(4):602-10. Epub 2010 Apr 8.

Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.

To clarify whether measurement of serum haptoglobin (Hp) has impact on understanding pathophysiology in bone marrow failure (BMF) syndromes, we investigated concentrations of serum Hp by nephelometric procedure in 156 Japanese patients with BMF, including 54 aplastic anemia (AA), 50 paroxysmal nocturnal hemoglobinuria (PNH), and 52 myelodysplastic syndromes (MDS) patients. The frequencies with low concentrations of serum Hp (<42 mg/dL) in PNH patients (98.0%) were significantly higher than those in AA (27.8%; P < 0.0001) and MDS (38.5%; P < 0.0001) patients. In AA patients, white blood cell (WBC), absolute neutrophil, and platelet counts were significantly decreased in the group (n = 15) with low concentrations of serum Hp than in that (n = 39) with normal concentrations of it, and WBC counts were positively correlated with concentrations of serum Hp, suggesting that WBC counts may affect the concentrations. In MDS patients, hemoglobin concentrations and serum iron were significantly decreased and increased, respectively, in the group (n = 20) with low concentrations of serum Hp than in that (n = 32) with normal concentrations of it, and the values of serum iron were inversely correlated with concentrations of serum Hp, suggesting that ineffective erythropoiesis may affect the concentrations. Several AA and MDS patients with low concentrations of serum Hp had Coombs-negative autoimmune hemolytic anemia determined by immunoradiometric assay. In conclusion, several factors in conjunction with pathophysiology contribute to decrease of serum Hp in BMF.
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http://dx.doi.org/10.1007/s12185-010-0559-zDOI Listing
May 2010

Factor XII Ofunato: Lys346Asn mutation associated with blood coagulation factor XII deficiency causes impaired secretion through a proteasome-mediated degradation.

Thromb Res 2010 May 22;125(5):438-43. Epub 2009 Dec 22.

Department of Laboratory Medicine, Iwate Medical University School of Medicine, Morioka, Iwate, Japan.

Introduction: Congenital blood coagulation factor XII (FXII) deficiency is a rare coagulation disease and an autosomal recessive trait. It is found by chance in many cases. We identified a novel mutation (Lys346Asn) in the FXII gene of a patient with FXII deficiency, designated as Factor XII Ofunato.

Methods: The proband was a 75-year-old Japanese woman with a prolonged activated partial thromboplastin time (52.8s). The FXII activity and antigen were greatly reduced (activity, 5%; antigen, 4.5%). We analyzed FXII gene of this patient using a direct sequencing method and characterized mutant FXII through in vitro expression studies.

Results: Sequence analysis of the FXII gene revealed a G-->C point mutation at nucleotide 9845, resulting in Lys346 (AAG)-->Asn (AAC) replacement in the catalytic domain. Expression studies in Chinese hamster ovary cells demonstrated that mutant FXII (346N-FXII) showed a lower level of accumulation in the cells than wild-type. Secretion of 346N-FXII was greatly reduced in culture medium. We also investigated mRNA expression levels of wild-type and 346N-FXII in transfected cells using quantitative RT-PCR. Both mRNA expressions were equivalent levels. Pulse-chase experiments showed that 346N-FXII was extensively degraded intracellularly compared to wild-type. Using membrane-permeable inhibitors, we observed that degradation occurred in the pre-Golgi compartment and that proteasome apparently plays a central role in this process.

Conclusions: These results show that most 346N-FXII is degraded intracellularly through endoplasmic reticulum-associated degradation as the protein quality control system, resulting in an insufficient secretion phenotype.
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http://dx.doi.org/10.1016/j.thromres.2009.12.004DOI Listing
May 2010

Deguelin suppresses cell proliferation via the inhibition of survivin expression and STAT3 phosphorylation in HTLV-1-transformed T cells.

Leuk Res 2010 Mar 24;34(3):352-7. Epub 2009 Sep 24.

Hematology & Oncology, Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan.

Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of aggressive ATL patients remains poor because of its resistance to conventional chemotherapy. We examined the effect of deguelin, a naturally occurring rotenoid, on HTLV-1-transformed T-cell lines, KUT-1 and MT-2 cells. We found that deguelin suppressed cell proliferation and induced cell death in these cells. Immunoblot analysis showed the inhibition of survivin expression and signal transducers, and activators of transcription (STAT) 3 phosphorylation of both cells. We also observed the cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP) in deguelin-treated cells, indicating that deguelin induces caspase-dependent apoptosis in these cells. Furthermore, proteasome inhibitor MG132 prevented the down-regulation of survivin expression and STAT3 dephosphorylation by deguelin, suggesting that the action mechanism of deguelin involves the degradation of survivin and phosphorylated STAT3 through the ubiquitin/proteasome pathway. Our data indicate that deguelin presents a potent anti-proliferative effect in part via the down-regulation of survivin expression and STAT3 phosphorylation in HTLV-1-transformed cells. Deguelin merits further investigation as a potential chemotherapeutic agent for ATL.
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http://dx.doi.org/10.1016/j.leukres.2009.09.003DOI Listing
March 2010

Clinical significance of high-Km 5'-nucleotidase (cN-II) mRNA expression in high-risk myelodysplastic syndrome.

Leuk Res 2007 Oct 12;31(10):1343-9. Epub 2007 Mar 12.

Department of Hematology/Oncology, Iwate Medical University, Japan.

We analyzed cytosolic high-Km 5'-nucleotidase (cN-II) and deoxycytidine kinase (dCK) mRNA expression in bone marrow mononuclear cells (BMMNC) of patients with high-risk myelodysplastic syndrome (MDS) using quantitative real-time polymerase chain reaction (rt-PCR). At diagnosis, the cN-II mRNA expression of patients was higher than that of healthy volunteers, but the dCK mRNA expression showed no significant difference. Patients with ara-C-containing chemotherapies whose BMMNC showed a high level of cN-II expression (greater than the median value) had shorter median overall survival (15 months versus 22 months, p<0.01) and shorter median post-chemotherapy survival (10 months versus 16 months, p=0.012). These data suggest that the expression level of cN-II mRNA might be a prognostic factor of high-risk MDS.
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http://dx.doi.org/10.1016/j.leukres.2007.01.018DOI Listing
October 2007

Discrepancy between the percentage of hypochromic erythrocytes and the reticulocyte hemoglobin content in hemodialysis patients with recombinant human erythropoietin therapy.

Lab Hematol 2005 ;11(2):124-30

Department of Clinical Laboratory, Internal Medicine, San-ai Hospital, 1-31-31 Tsukigaoka, Morioka, Iwate, Japan.

The percentage of hypochromic erythrocytes (%HYPO) and the reticulocyte hemoglobin content (CHr) have been used for the diagnosis of iron deficiency (ID). However, we found a discrepancy between %HYPO and CHr values in some hemodialysis patients. Hemodialysis patients receiving recombinant human erythropoietin (rHuEPO) with ID were defined as patients with a %HYPO value exceeding 5%. Five ID patients with a high CHr (group A) and 3 ID patients with a low CHr (group B) received 120 mg/week iron intravenously for 8 to 12 weeks. Changes in %HYPO, CHr, percentage of macrocytic erythrocytes (%MACRO), absolute reticulocyte count, immature reticulocyte fraction, and soluble transferrin receptor level were investigated over a 20-week period. CHrs were measured with 2 hematology analyzers: the Bayer HealthCare Technicon H*3 and the ADVIA 120. Patients in group A showed a significantly greater mean %MACRO (P < .01) and a lower mean red blood cell number (P < .05) than patients in group B. Even the mean CHr at baseline in group A was significantly higher than the mean CHr in the healthy subjects (P < .01), and hemoglobin levels increased in association with the reduction in rHuEPO dose following iron administration (P < .01). We found a group with high CHr, %HYPO, and %MACRO values among hemodialysis patients. Iron administration enables the rHuEPO dose to be reduced.
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http://dx.doi.org/10.1532/LH96.04072DOI Listing
October 2005

Successful treatment with cyclosporine and high-dose gamma immunoglobulin for persistent parvovirus B19 infection in a patient with refractory autoimmune hemolytic anemia.

Int J Hematol 2004 Oct;80(3):250-3

Department of Hematology/Oncology, Iwate Medical University School of Medicine, Morioka, Iwate, Japan.

We describe a patient with persistent pure red cell aplasia due to human parvovirus B19 (HPVB19) infection during immunosuppressive therapy for refractory autoimmune hemolytic anemia (AIHA). The patient had been given corticosteroid (CS) and/or azathioprine for AIHA. During the course of treatment, reticulocyte count and hemoglobin levels decreased suddenly. Bone marrow aspirate showed erythroid lineage-specific aplasia with a few giant proerythroblasts, suggesting the presence of HPVB19 infection. The diagnosis of aplastic crisis due to HPVB19 infection was based on positive test results by polymerase chain reaction for HPVB19 immunoglobulin M (IgM) antibody and B19 DNA. Although splenectomy followed by administration of high-dose gamma globulin (HDIG) and plasma exchange were performed, the crisis and hemolysis recurred. Aplastic crises occurred several times when the B19 IgG result became negative and the CD4+ lymphocyte count was less than 300/microL. The patient showed complete recovery from anemia after CS was switched to cyclosporin A (CsA) and intermittent administration of HDIG. The result for B19 IgG antibody was continuously positive, and the DNA result became negative after these treatments. The results in this case indicated that concomitant administration of CsA and intermittent administration of HDIG can lead to cure of chronic anemia due to HPVB19 infection in patients with refractory AIHA.
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http://dx.doi.org/10.1532/ijh97.04017DOI Listing
October 2004

Clinical and biological significance of CD56 antigen expression in acute promyelocytic leukemia.

Leuk Lymphoma 2004 Sep;45(9):1783-9

Department of Hematology/Oncology, Iwate Medical University School of Medicine, Morioka, Japan.

The biological significance of CD56 antigen expression in patients with acute promyelocytic leukemia (APL) has been under investigation. We investigated the clinical and biologic features of CD56+APL. In our series, CD56 antigen was positive in 4 of 28 (14%) APL patients. No differences were found regarding age, gender, performance status (PS), initial leukocyte and platelet counts, lactate dehydrogenase (LDH) and fibrinogen (Fbg) levels according to CD56 expression. CD34 antigen was co-expressed in 3 of the 4 patients with CD56+ APL, in contrast to 2 of the 24 patients with CD56- APL (P = .01). Extramedullary relapse occurred in 3 of the 4 patients with CD56+ APL, in contrast to none of the 24 patients with CD56- APL (P = .001). Median remission duration was 4 months in CD56+ APL and was not reached in CD56- APL. The CD56+ population had a shorter remission duration (P < .0001) and disease-free survival (P < .0001). In contrast, no difference was found in overall survival. These results suggested that CD56 expression was associated with the leukemogenetic mutation at the primitive hematopoietic progenitor cell level and extramedullary relapse in APL patients treated with ATRA and chemotherapy.
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http://dx.doi.org/10.1080/10428190410001683624DOI Listing
September 2004

[Refractory germ cell cancer of testis treated by salvage high-dose chemotherapy: report of three cases].

Hinyokika Kiyo 2004 Feb;50(2):77-80

Department of Urology, Iwate Medical University School of Medicine.

We reported three cases (42, 20 and 18-year-old men) of advanced nonseminomatous testicular germ cell cancer treated by salvage high-dose chemotherapy (HDC) supported by peripheral blood stem cell autotransplantation. Two cases which had been refractory to (B) EP (bleomycin, etoposide, cisplatin) and VIP (etoposide, ifosfmide, cisplatin) chemotherapies received one course of high-dose CEI (carboplatin 1,250 mg/m2, etoposide 1,500 mg/m2 and ifosfamide 7.5 g/m2), and the other case had been refractory to PVB (cisplatin, vinblastine, bleomycin) and VIP chemotherapies received one course of high-dose CEI and high-dose CCT (carboplatin 800 mg/m2, cyclophosphamide 6 g/m2 and thiotepa 720 mg/m2). Only one case achieved an incomplete remission by HDC, which was verified as a pathological complete response at the following salvage surgery, and has been alive with no evidence of disease for 68 months. The others achieved no change of disease following HDC and died from cancer progression. Hepatotoxicity, neurotoxicity and severe depression occurred, but not fatal in 2 cases.
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February 2004

Uncommon karyotypic abnormality, t(11;19)(q23;p13.3), in a patient with blastic phase of chronic myeloid leukemia.

Cancer Genet Cytogenet 2004 Apr;150(2):159-63

Department of Hematology/Oncology, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan.

We describe unusual cytogenetic findings in a 33-year-old male with blastic phase of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia. In addition to the t(9;22)(q34;q11), which was detected in all metaphases, a t(11;19)(q23;p13.3) was also identified as an evolutional change in all 20 metaphases. Fluorescence in situ hybridization (FISH) analysis showed that fusion signals of the ABL/BCR probes were found in 95% of blastic cells. Southern blotting and FISH analysis also revealed involvement of the MLL gene on 11q23. Clinical course was aggressive and the patient responded poorly to therapy. These findings suggest an association between Ph and 11q23 with poor prognosis, and that t(11;19)(q23;p13.3) was the essential pathogenic factor in our case.
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http://dx.doi.org/10.1016/j.cancergencyto.2003.09.005DOI Listing
April 2004
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