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PubMed | Red Cross, Hiroshima City Asa Hospital, Nippon Telegraph and Telephone, Saga University and 16 more.
Type: Journal Article | Journal: The Lancet. Haematology | Year: 2015

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.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 UMIN000005130.88 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.Dasatinib discontinuation after sustained deep molecular response for more than 1 year is feasible.Epidemiological and Clinical Research Information Network (ECRIN).


Iriyama N.,Nihon University | Fujisawa S.,Yokohama City University | Yoshida C.,National Hospital Organization Mito Medical Center | Wakita H.,Red Cross | And 14 more authors.
American Journal of Hematology | Year: 2015

To investigate the factors that affect molecular responses on dasatinib treatment in patients with chronic-phase chronic myeloid leukemia (CML-CP), we performed a clinical trial named the "D-First study." Fifty-two patients with newly diagnosed CML-CP were enrolled in this study and received 100 mg dasatinib once daily. A deep molecular response (DMR) was defined as <50 copies/μg RNA of BCR-ABL1 transcript value corrected by GAPDH, which ensures <0.01% of BCR-ABL1 transcript value according to International Scale (BCR-ABL1IS). The halving time for BCR-ABL1 transcripts was calculated using transcript levels before dasatinib treatment, transcript levels after 3 months of treatment, and the treatment time between these two points. In terms of molecular response, 38 of 51 (75%) patients reached major molecular response (MMR) by 12 months, and the rate of DMR by 18 months was 59% (30/51). While both BCR-ABL1 transcript levels before treatment and a shorter halving time of BCR-ABL1 transcripts (≤14 days) were significant factors affecting achievement of MMR by 12 months, the Sokal score at diagnosis was not associated with MMR. Importantly, the halving time was the only factor that predicted achievement of DMR by 18 months. We showed that patients with CML-CP treated with dasatinib can be stratified according to the early treatment response as determined by the halving time of BCR-ABL1 transcripts. These data emphasize the significance of the early response from dasatinib treatment in achieving a DMR. © 2014 Wiley Periodicals, Inc.


PubMed | Red Cross, Gunma Prefectural Cancer Center, Nihon University, National Hospital Organization Mito Medical Center and 13 more.
Type: Journal Article | Journal: Oncology reports | Year: 2016

Despite the efficacy and safety of dasatinib treatment for chronic-phase chronic myeloid leukemia (CML-CP), adverse effects such as pleural effusion (PE) are still a serious concern. We determined the clinical significance of PE incidence using patient data derived from the D-First clinical study. In the present study, chest radiography and quantification of specific lymphocyte subsets were performed routinely after initiation of dasatinib treatment. Among 52patients with newly diagnosed CML-CP, 17 (33%) developed PE within 18months after initial dasatinib administration, but all cases were moderate (Grade 1, 10 patients; Grade 2, 7 patients). CD56+ lymphocyte counts at 1month correlated significantly with the incidence of PE, whereas lymphocytosis did not. The major molecular response (MMR) rate at 3months (although not at later times) was significantly higher in PE-positive patients than PE-negative patients (59% versus 24%, respectively; P=0.013). Deep molecular response rates did not differ significantly between the PE groups at any time point during the observation period. Our results suggest that an immune-mediated mechanism involving natural killer cells underlies the development of PE in patients receiving dasatinib for 18months. This mechanism likely promotes transient tumor regression in patients newly diagnosed with CML-CP.


PubMed | Red Cross, National Hospital Organization, Nihon University, University of Tsukuba and 13 more.
Type: Clinical Trial, Phase II | Journal: American journal of hematology | Year: 2015

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/L for NK cells and 347/L for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.


Fujii M.,Tokyo Medical and Dental University | Takada Y.,Ohme Municipal General Hospital | Ohno K.,Tokyo Medical and Dental University | Hokari M.,Nakano General Hospital | Arai T.,Soka Municipal Hospital
Brain and Nerve | Year: 2012

We demonstrate and discuss slowly progressive expanding hematoma (SPEH) in the basal ganglia, which expands over 2 weeks. To our knowledge, there have been only 5 cases of sudden-onset SPEH of the basal ganglia. To this, we add 3 cases admitted our hospitals because of putaminal hemorrhage within 1.5 hours of onset. All hematomas exhibited "2 components of hematoma sign" on initial CT scans, which we termed the "TCH sign" characterized as an anterolateral fluid portion and a posteromedial solid portion. Follow-up CT scans revealed gradual expansion of the fluid component of the hematoma without rebleeding for the subacute phase. Two cases were treated surgically. The first case, a 47-year-old man, underwent ultrasonically guided hematoma aspiration on day 17 and the second case, a 37-year-old man, underwent hematoma removal by craniotomy on day 23 after onset. Their postoperative courses were uneventful. The third case, a 57-year-old man, improved without surgical treatment and the hematoma dissolved completely within 2 months. To an extent, the TCH sign on a CT scan can be related to SPEH. We reviewed previous reports, including those an chronic expanding intracerebral hematomas and chronic encapsulated intracerebral hematomas, and concluded that it requires approximately 1 month for encapsulation of the hematoma to emerge. We suggest a possible progressive mechanism of SPEH. At first, the hematoma is divided into a fluid and a solid portion. Local generation of osmotically active molecules by clot degradation may allow intravascular fluid to escape into the fluid portion of the hematoma. Edema fluid with leakage via the disrupted blood-brain barrier may also aggravate the fluid portion of the hematoma. The continuing inflammatory response leads to the emergence of a hematoma capsule similar to the membrane observed in cases of chronic subdural hematoma, followed by the secondary causes of hematoma expansion. We discuss feasible timing and surgical treatment methods.


PubMed | Ohme Municipal General Hospital
Type: Case Reports | Journal: Endocrine journal | Year: 2015

A 32-year-old Chinese woman with rapid weight gain and progressive edema was found to have typical Cushingoid features. Her endocrine data were consistent with a diagnosis of ACTH-dependent Cushings syndrome. To differentiate ectopic ACTH syndrome (EAS) from Cushings disease (CD), various dynamic endocrine and imaging tests were performed. Her ACTH response was negative to corticotropin-releasing hormone (CRH) and positive to desmopressin. Magnetic resonance imaging of the pituitary showed no mass lesion. Computed tomography scan of the chest revealed a large mass (21 15 mm) in the anterior mediastinum, where positron emission tomography showed accumulation of [(18)F] fluorodeoxyglucose. Selective venous sampling showed marked step-up in ACTH level in the internal thoracic vein but not in the cavernous sinus after CRH stimulation. These data are compatible with the diagnosis of EAS. The resected tumor was pathologically consistent with thymic neuroendocrine tumor (NET) positive for ACTH by immunohistochemistry and abundant V1b receptor gene expression by RT-PCR. Postoperatively, her circulating ACTH/cortisol levels became normalized, and responded to stimulation with CRH but not with desmopressin. Her Cushingoid appearance gradually disappeared, and she was free from recurrence 5 years after surgery. This is a rare case of desmopressin-responsive EAS caused by thymic NET with predominant V1b gene expression, which was successfully localized by imaging modalities combined with selective venous sampling.


PubMed | Ohme Municipal General Hospital
Type: Journal Article | Journal: Clinical laboratory | Year: 2013

The aim of the present study was to examine the usability of procalcitonin (PCT) for severity assessment in patients with acute cholangitis (AC).Serum PCT concentrations were measured on admission in patients with AC. Patients were classified with mild, moderate, or severe AC based on severity assessment guidelines.We included 159 treatment-nave patients with AC (95 males, 64 females) in this study. The median PCT concentrations were 0.08 ng/mL (interquartile range (IQR) 0.04 - 0.18 ng/mL), 0.37 ng/mL (IQR 0.15 - 1.85 ng/mL), and 5.56 ng/mL (IQR 3.59 - 25.89 ng/mL) in patients with mild, moderate and severe AC, respectively. PCT concentrations were significantly higher in patients with severe AC than in patients with moderate AC (p < 0.0001), and in patients with moderate AC than in patients with mild AC (p < 0.0001). The areas under the receiver operating characteristic curves for PCT to discriminate patients with moderate and severe AC were 0.84 (95% CI 0.77 to 0.92, p < 0.001) and 0.86 (95% CI 0.78 to 0.92, p < 0.001), respectively.Serum PCT concentrations were elevated in patients with AC and may be a useful parameter for the severity assessment of AC.


PubMed | Ohme Municipal General Hospital
Type: Case Reports | Journal: [Rinsho ketsueki] The Japanese journal of clinical hematology | Year: 2015

A 42-year-old female was admitted to our hospital because of continuous fever, anemia, and immature myeloid cells in peripheral blood. Bone marrow biopsy revealed severe myelofibrosis (MF). We performed computed tomography and identified several swollen mediastinal lymph nodes and nodules in the right upper lung. Lymph node biopsy showed an infection with Mycobacterium intracellulare (M. intracellulare), a nontuberculous mycobacterium (NTM). Antituberculosis drugs led to remission of the NTM infection. Bone marrow biopsy revealed marked improvement in MF and red blood cell infusion was not required after therapy. No prior cases of concomitant NTM with M. intracellulare and MF have been reported. This is thus the first reported case showing improvement of myelofibrosis after NTM treatment. This case report offers valuable insights into the pathology of MF.


PubMed | Ohme Municipal General Hospital
Type: Journal Article | Journal: International journal of hematology | Year: 2014

Lymphocytosis in response to dasatinib for chronic myelogenous leukemia (CML) may be associated with favorable response. However, it occurs at varying times and in a limited subset of patients. To identify early clinical markers for favorable responses applicable to all patients with or without lymphocytosis, we prospectively analyzed lymphocyte profiles of 50 Japanese CML patients treated with dasatinib after intolerance/resistance to imatinib. Although absolute lymphocyte counts did not differ significantly until 3 months between patients with complete molecular response (CMR) at 12 months and those without it, relative increases in lymphocyte compared with baselines differed significantly from 1 month. Patients with relative lymphocyte counts >150 % at 1 month or >200 % at 3 months had higher CMR rates at 12 months than others (57.9 vs. 23.3 %, P = 0.015, and 76.5 vs. 16.1 %, P < 0.0001, respectively). A relative increase in lymphocyte subset of CD57(+)CD14(-), CD8(+)T, or NK cells >200 % at 1 month was also significantly associated with a higher CMR rate. There were significant negative correlations between relative lymphocyte increases and BCR/ABL transcript levels. CD57(+)CD14(-) cells were a highly specific focus of proliferation. Relative increases in lymphocyte count and its subsets from 1 month are reliable early markers of favorable responses to dasatinib.


PubMed | Ohme Municipal General Hospital
Type: Case Reports | Journal: Internal medicine (Tokyo, Japan) | Year: 2013

Bilateral internal carotid artery dissection (ICAD) is a rare but important cause of stroke in young adults. Anticoagulant and/or antiplatelet agents are usually recommended for stroke prevention;however, such treatments remain highly controversial, and there are inadequate data to compare the efficacy of anticoagulation and antiplatelet therapy. We herein report the case of 30-year-old man presenting with progressive bilateral ICAD during antiplatelet treatment. This report suggests the possibility that intramural hematomas are enlarged by antiplatelet and anticoagulant agents and draws attention to the medications associated with ICAD.

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