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  • 1
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4947-4947
    Abstract: Introduction: The intracellular enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the metabolism of the essential amino acid tryptophan along the L-kynurenine (KYN) pathway. Some metabolites derived from tryptophan via IDO catalysis such as KYN block antigen-driven specific T-cell proliferation and induce T-cell death. IDO activity might play an important role in regulating the immune response exerted by antigen presenting cells. Indeed, we have recently reported the utility of either serum KYN or the expression of IDO mRNA as prognostic factors for acute myeloid leukemia (AML) [Leuk Lymphoma: In press, Leuk Lymphoma 56:1398-405]. Here, we investigated the value of combination of serum KYN level and expression of IDO mRNA as a prognostic factor in AML patients. Patients and Methods: AML was diagnosed according to the WHO 2008 criteria based on standard cytological and histochemical assessments of smears of cryopreserved bone marrow cells from 29 consecutive adult patients between December 2005 and March 2014. All patients in this study had been enrolled in both our serum KYN study and expression of IDO mRNA study. All follow-up data were fixed on August 1, 2014. KYN concentrations in serum samples were measured by high-performance liquid chromatography. Bone marrow-derived mononuclear fractions were separated and IDO expression was analyzed by using extracted mRNA amplified by PCR. Results: We examined expression of IDO mRNA and serum L-kynurenine in a total of 29 patients (median age, 55 years; range, 18-74 years). Among them, 11, 14 and 4 patients were classified as having favorable, intermediate and unfavorable cytogenetic risk, respectively. Twenty seven patients underwent standard intensive chemotherapy, mainly consisting of cytosine arabinoside (Ara-C) and anthracycline. All patients with acute promyelocytic leukemia (n = 5) received induction therapy containing all-trans retinoic acid. Two patients received less intensive chemotherapy [J Cancer Res Clin Oncol. 133:547-53.], because of poor performance status. The median serum KYN level was 1.63 µM (range, 0.66-5.27 µM). We set the L-kynurenine cut-off value at 2.4 µM according to our previous report. The RT-PCR results showed that bone marrow from 12 (41%) patients were IDO-positive. No significant correlation was identified between serum KYN level and IDO expression. Complete remission (CR) rates were 57% and 86% for patients with KYN levels ≥2.4 and 〈 2.4 µM, respectively. CR with initial therapy was obtained by 67% of patients with positive IDO expression, compared to 88% with negative IDO expression, respectively. Three-year OS rates were 0% and 76% for patients with KYN ≥2.4 and 〈 2.4 µM, respectively (P 〈 0.0001), and 37% and 77% for patients with IDO-positive and IDO-negative AML, respectively (P=0.0511) (Figs. 1A, B). Three-year OS rates were 83%, 50% and 0% for patients with low KYN and IDO-negative, either high KYN or IDO-positive, and high KYN and IDO-positive, respectively (P 〈 0.005; Fig. 1C.). Discussion: In the present study, we assessed the significance of serum concentration of KYN, IDO mRNA expression, and the combination of these two factors in AML patients and demonstrated their prognostic value. High serum KYN concentration was associated with poor outcomes of AML. While, expression of IDO mRNA had a tendency with poor prognosis, it did not show significant difference on the survival of AML patients. These results were due to the small sample size in this study, and will have to be confirmed in future studies with larger numbers of patients.When we compare these two factors as prognostic value, serum concentration of KYN may be more useful because measurement of serum concentration of KYN is easier than IDO mRNA expression and identifies ultra-high risk patients. In contrast, serum concentration of KYN has poor separation capacity for many other patient, which can be further subdivided by adding measurement of IDO mRNA expression. Indeed, the combination of serum concentration of KYN and IDO mRNA expression was associated with poor outcomes of AML and was able to subdivide the AML patients to three different prognostic groups clearly. Conclusion: This study clearly showed the prognostic value of the combination of serum KYN concentration and IDOm RNA expression for AML patients. Figure 1. Overall survival according to serum L-kynurenine concentration and IDO expression. Figure 1. Overall survival according to serum L-kynurenine concentration and IDO expression. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 2
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4201-4201
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4201-4201
    Abstract: We have developed a mouse model of highly malignant lymphoma. The EL4 cell line was established from a lymphoma induced in a C57/BL6 mouse by 9,10-dimethyl-1,2-benzanthracene. Red fluorescent protein (RFP)-EL4 lymphoma cells were established. EL4-RFP cancer cells were injected in the tail vein of C57/BL6 GFP transgenic mice. EL4-RFP metastasis was observed in the lymph nodes of the superior mediastinum and in the liver 28 days later. The EL4-RFP tumors were visualized in the liver with the Olympus SZX7 microscope. Large EL4-RFP liver metastases in C57/BL6 GFP mice had GFP stromal cells derived from the host animal around the edge of EL4-RFP tumors. In addition, EL4-RFP lymphoma cells metastasis was formed in perigastric lymph node. EL4-RFP lymphoma cells circulated in the peripheral blood. Furthermore, EL4-RFP lymphoma cells were observed in bone marrow of C57/BL6 GFP transgenic mice. In summary, lymph node metastasis, liver metastasis and bone marrow metastasis were found approximately 4 weeks after transplantation. This malignant lymphoma model can be used to study early tumor development, metastasis, the role of stroma and discovery and evaluation of novel therapeuticus for this treatment-resistant disease. Citation Format: Takuro Matsumoto, Atsushi Suetsugu, Yuhei Shibata, Nobuhiko Nakamura, Hitomi Aoki, Takahiro Kunisada, Masahito Shimizu, Hisashi Tsurumi, Robert M. Hoffman. Development of a syngeneic metastatic mouse model of malignant lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4201. doi:10.1158/1538-7445.AM2015-4201
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 94, No. 12 ( 2015-12), p. 2043-2053
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 1458429-3
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  • 4
    In: Hematological Oncology, Wiley, Vol. 35, No. 2 ( 2017-06), p. 163-171
    Abstract: The CHOP regimen consisting of cyclophosphamide, doxorubicin (DOX), vincristine and prednisolone has been the most used regimen for peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS). Pirarubicin [tetrahydropyranyladriamycin (THP)], a derivative of DOX, is an anthracycline with reportedly less cardiotoxicity than DOX. Here, we confirmed the efficacy of THP‐COP using THP instead of DOX in the treatment of PTCL‐NOS. The study protocol employed a retrospective, consecutive entry design. We retrospectively analysed 56 patients with PTCL‐NOS who had received THP‐COP or CHOP. These regimens were performed every 21 days. Twenty‐nine patients received THP‐COP, and 27 received CHOP. There were no significant differences in known prognostic factors, including in the International Prognostic Index (IPI) and the prognostic index for T‐cell lymphoma (PIT), between the two groups. Complete remission rates in patients with THP‐COP and CHOP were 52% in both groups; the 3‐year overall survival (OS) rates were 67% and 52% ( p  = 0.074), and the 3‐year progression‐free survival (PFS) rates were 51% and 29% ( p  = 0.070), respectively. In patients with low IPI (low or low‐intermediate), THP‐COP had significantly better 3‐year OS (100% vs. 64%; p   〈  0.001) and 3‐year PFS (75% vs. 33%; p   〈  0.05) than CHOP. Similar differences between THP‐COP and CHOP were observed in patients with a low PIT (groups 1 or 2). Our study showed that THP‐COP produced results equivalent to CHOP regarding efficacy and safety in patients with PTCL‐NOS. In patients with low IPI or PIT, THP‐COP resulted in significantly better prognosis. Copyright © 2015 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0278-0232 , 1099-1069
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2017
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  • 5
    In: Hematological Oncology, Wiley, Vol. 35, No. 4 ( 2017-12), p. 637-644
    Abstract: Indoleamine 2,3‐dioxygenase exerts intense immunomodulatory effects due to enzymatic activities that catalyze the breakdown of the essential amino acid l ‐tryptophan. The activity of indoleamine 2,3‐dioxygenase can be estimated by measuring serum l ‐kynurenine concentrations. Here, we aimed to determine the role of l ‐kynurenine as a prognostic factor for peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) in a retrospective analysis of data derived from 31 consecutive patients between June 2000 and March 2013 who were histologically diagnosed with PTCL‐NOS according to the World Health Organization classification and treated with 6−8 cycles of cyclophosphamide, doxorubicin or pirarubicin, vincristine, and prednisolone. l ‐kynurenine concentrations in serum samples collected at admission were measured using high‐performance liquid chromatography. The median serum concentration of l ‐kynurenine was 3.28 (range 0.92–8.16) μM. The l ‐kynurenine cutoff was set at 3.07 μM using receiver operating characteristics curves. The complete remission rates of patients with l ‐kynurenine 〈 3.07 and ≥3.07 μM were 69% and 51%, respectively. The 5‐year overall survival (OS) rates for patients with l ‐kynurenine 〈 3.07 and ≥3.07 μM were 80.2% and 23.4%, respectively ( p   〈  0.001). More advanced age, poor performance status, elevated lactate dehydrogenase, an unfavorable International Prognostic Index, and a poor prognostic index for T‐cell lymphoma were significantly worse factors for OS. Multivariate analyses revealed only l ‐kynurenine as an independent prognostic factor for OS. In conclusion, serum concentrations of l ‐kynurenine might comprise a novel prognostic factor with which to determine the outcomes of treatment for PTCL‐NOS. Copyright © 2016 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0278-0232 , 1099-1069
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2001443-0
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  • 6
    In: Open Journal of Internal Medicine, Scientific Research Publishing, Inc., Vol. 06, No. 04 ( 2016), p. 128-138
    Type of Medium: Online Resource
    ISSN: 2162-5972 , 2162-5980
    Language: Unknown
    Publisher: Scientific Research Publishing, Inc.
    Publication Date: 2016
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  • 7
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 57, No. 9 ( 2016-09), p. 2208-2211
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2016
    detail.hit.zdb_id: 2030637-4
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  • 8
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4210-4210
    Abstract: [Backgrounds] The controlling nutritional status (CONUT), one of the useful parameter of nutritional assessment tools, is a significant prognostic factor for various solid tumors. The CONUT score is an index calculated from the following factors; the serum albumin concentration (Alb), the total peripheral lymphocyte counts (Lymph) and total cholesterol concentration (Chol) (Table 1). Some predictive models specified the relationship between nutritional status and the prognostic value of malignant disease have been proposed. However, the role of the CONUT score in predicting clinical outcomes of diffuse large B cell lymphoma (DLBCL) patients has not been investigated. The aim of this study is to elucidate the impact of the pretreatment CONUT score on survival in patients with DLBCL who received rituximab (R) plus chemotherapy. [Patients and Methods] We retrospectively investigated 240 patients who were histologically diagnosed with DLBCL between June 2004 and November 2015. All patients received R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or R-THP-COP (cyclophosphamide, tetrahydropyranyl-adriamycin, vincristine, prednisone) regimen. We defined the best cutoff value of the CONUT score as 3 using a receiver operating characteristic curve. [Result] The mean and median of the CONUT score of all patients (median age 68, range 19 - 93, 140 male and 100 female) were 2.85 and 2 (range 0 - 12). The data of each parameter's median and range constituting CONUT (Alb, Lymph, Chol) was as follows: 4 (1.9 - 5.3), 1170 (105 - 13192), and 173 (49 - 287), respectively. Patients with High-CONUT score (≥3, n = 109) had significantly lower overall survival (OS) and progression-free survival (PFS) than those with Low-CONUT score (≤2, n = 131) (5-year OS, 63.0 vs. 83.6%, P = 0.006; 5-year PFS, 56.5 vs. 78.0%, P = 0.003). The conventional predictive factors such as International Prognostic Index (IPI; age, performance status, Ann Arbor stage, extra-nodal involvement sites and lactate dehydrogenase) were all significantly associated with a worse OS and PFS. A subsequent subgroup analysis based on age indicated that 70 years or elder patients (n = 108) with High-CONUT had a significantly worse 5-year OS and PFS as compared to Low-CONUT patients (OS, 50.0 vs. 77.2%, P = 0.008; PFS, 41.6 vs. 77.6%, P = 0.0004). In contrast, no significant differences were observed in the OS and PFS when High- and Low-CONUT patients less than 70-year-old were compared. The multivariate analysis of all of the significant parameters in patients older than 70 years indicated that High-CONUT was an independent prognostic factor for PFS (HR = 2.20, 95 % CI = 1.08-4.66, p = 0.03). [Discussion] The serum Alb concentration is a reliable indicator of nutritional status and systemic inflammation. Total peripheral Lymph, which play an important role in the immune response to the tumor, are known to indicate the immunological and nutritional status. It is also reported that Chol, an indicator of a patient's caloric reserves, increased the antigen-presenting function of monocytes. Organ function decreases with aging, and many elderly patients have comorbidities that compromise their capacity to tolerate standard dose chemotherapy. In addition, intensive chemotherapy is often complicated by deterioration of nutritional status as the elderly. Hence, elderly patients are an extremely heterogeneous population and optimal treatment strategy should be adapted in consid eration of comorbidities. On the other hand, DLBCL is a curable disease even in the elderly population. Therefor prognostic stratification in older population should be focused on the real biological age of patients and on primary variables that reflect tumor aggressiveness, immune interaction and nutritional status. In this respect, the pretreatment CONUT score is considered suitable for prognostic model of elderly patients. Previously, we have reported that sarcopenia is an independent poor prognostic factor for PFS in male patients with DLBCL (Ann Hematol, 2015). In this cohort, sarcopenia has no effect on PFS in elderly patients. [Conclusion] The pretreatment CONUT score is easily able to predict the prognosis of elderly patients with DLBCL. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1515-1515
    Abstract: BACKGROUND: Bowel perforation after chemotherapy is a serious life-threatening complication of diffuse large B cell lymphoma (DLBCL) involving gastrointestinal tract. R Vaidya et al reported that 9 % of patients with gastrointestinal lymphoma developed a perforation, of which 55% occurred after chemotherapy, and DLBCL was the most common lymphoma associated with perforation (R Vaidya et al Ann Oncol 2013). We assume that the dose reduction of chemotherapy may have advantages to reduce the risk of gastrointestinal perforation and shorten the duration of neutropenia. This study aimed to investigate the incidence of gastrointestinal perforation after chemotherapy, whether reduced dose intensity chemotherapy could reduce the risk of the bowel perforation and how therapeutic modalities influence on the prognosis. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 348 consecutive patients who were diagnosed as having DLBCL at the Gifu University Hospital between August 2004 and April 2015. Eighty-six patients (86/348, 24.7%) were identified to have gastrointestinal involvement of DLBCL by biopsy. The prognosis of DLBCL patients with GI involvement was retrospectively investigated regarding treatments. RESULTS: The involved sites were gastric (51 patients, 48.1%), duodenal (7 patients, 6.6%), colorectal (6 patients, 5.7%), small intestine (36 patients, 34.0%) with duplicate counts permitted. Fourteen patients (14/86, 16.3%) were provided surgical treatment prior to chemotherapy since many of them had already suffered from serious complications such as ileus, perforation and bleeding. Sixty-five patients (65/86, 75.5%) received R-CHOP or CHOP like regimen ± radiation therapy as a first-line chemotherapy. As for remaining patients, two patients received R-hyperCVAD regimen because their histology were Burkitt like, and another patients received Rituximab ± other low dose chemotherapy for their frailness. The 45 patients (45/65, 69.2%) of them received reduced dose intensity (RDI) chemotherapy at the first course because increased risk of gastrointestinal perforation with chemotherapy was concerned about by endoscopic findings. The reduction rates of chemotherapy determined by the attending physician were approximately from 10% to 50%. Six patients (6/65, 9.23%) developed gastrointestinal perforation after chemotherapy (stomach 1, duodenum 0, small intestine 5, colon 0). Three of them received full dose chemotherapy at the time of small intestinal perforation including 2 patients who developed grade 4 neutropenia after the perforation. One of them died of infection after the perforation. The perforation rate was 15.0% in full dose chemotherapy group and 6.67% in the RDI chemotherapy group (p=0.361). The median day of perforation after initiation of chemotherapy was 21 days (range; 5-63 days). The small intestine was the most common site of perforation and 4 patients (4/5, 80%) had the ulcerative type lesions in their perforation site. CONCLUSIONS: Prior to chemotherapy, risk of GI perforation should be evaluated. We consider that small intestinal ulcerative lesion is high risk of GI perforation. The RDI chemotherapy may be an optimal therapy for patients with primary GI DLBCL with high risk. Further and larger prospective study should be required to confirm this. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 57, No. 1 ( 2016-01-02), p. 92-98
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2016
    detail.hit.zdb_id: 2030637-4
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