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  • American Society of Hematology  (5)
  • Hara, Takeshi  (5)
  • Ninomiya, Soranobu  (5)
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  • American Society of Hematology  (5)
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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
    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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  • 2
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4210-4210
    Abstract: Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma and the most common lymphoid neoplasm in adults. In the pre rituximab era, the standard therapy for patients with limited stage DLBCL had been three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) followed by involved-field radiotherapy (IFRT). The addition of rituximab has revolutionized the treatment of DLBCL. Rituximab combined with CHOP (R-CHOP) has been established as the standard treatment for patients with DLBCL. However, the role of consolidative radiotherapy (RT) in the treatment of limited stage DLBCL in the rituximab era is controversial. Patients and Methods: We retrospectively analyzed 108 patients with limited stage DLBCL who received R-CHOP or R-THP-COP (rituximab plus, cyclophosphamide, pirarubicin, vincristine and prednisone) regimen between June 2004 and August 2015. We compared overall survival (OS) and progression-free survival (PFS) according to the treatment. OS was calculated from the date of initiation of chemotherapy to the date of the last follow-up or death. PFS was calculated from the date of initiation of chemotherapy to the date of progression disease, death, or last contact, whichever occurred first. Survival was estimated from Kaplan-Meier curves and compared using the log-rank test. P 〈 0.05 was considered statistically significant. Weighted Cox proportional hazards regression modeling with the inverse probability weighted (IPW) estimators method adjusting to propensity for RT was used to account for differences in baseline characteristics. Results: Median age at diagnosis was 66 years (19-88 years), with 61 males and 47 females. Forty-three patients (40%) had stage I, and 65 patients (60%) received consolidative RT after chemotherapy. Patients who received consolidative RT were significantly younger (65 vs 72, P 〈 0.01) and were more likely to have stage I disease (51% vs 23%, P 〈 0.01). The median number of chemotherapy cycles was 4 (range 3-8) in patients who received RT, and 6 (range 3-8) in patients who did not. Median follow-up was 4.3 years (0.3-10.9 years), and the 5-year OS (92% vs 63%, P 〈 0.01) and PFS (87% vs 65%, P 〈 0.01) were significantly higher for patients who received RT than those who did not. Using IPW adjustment, RT remained predictive of OS (HR 0.30, CI 0.13-0.72, P 〈 0.01) and PFS (HR 0.47, CI 0.22-0.99, P 〈 0.05). Conclusion: Our results suggest that consolidative RT improves OS and PFS in patients with limited stage DLBCL in the rituximab era. Although consolidative RT seems to be gradually phased out by chemotherapy alone, it is still an important treatment strategy. 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: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    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
    RVK:
    RVK:
    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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  • 4
    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
    Location Call Number Limitation Availability
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  • 5
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4953-4953
    Abstract: Background: The response to treatment and overall survival of patients with acute myeloid leukemia (AML) are heterogeneous. A number of prognostic factors related to patient and tumor characteristics have been described for AML, including age, performance status, and karyotype. The depletion of skeletal muscle (sarcopenia) and adipose tissue (adipopenia) are known to be associated with unfavorable prognosis in patients with some malignant diseases including lymphoma. Here, we studied the impact of sarcopenia and adipopenia on clinical outcomes of adult AML. Patients and Methods: We retrospectively analyzed 70 patients with adult AML (age ≥ 18 years) who received chemotherapy at Gifu University Hospital between December 2004 and September 2014. Skeletal muscle and adipose tissue were measured by the analysis of CT images at the L3 level before treatment. CT images were analyzed using SliceOMatic version 4.3 software (TomoVision, Montreal, QB, Canada), which enables specific tissue demarcation using previously reported Hounsfield unit (HU) thresholds. The CT HU thresholds were -29 to 150 for skeletal muscles and -190 to -30 and -50 to -150 for subcutaneous and visceral adipose tissue, respectively. These values were normalized for stature in order to calculate skeletal muscle index (SMI, cm2/m2) and adipose tissue index (ATI, cm2/m2). Results: Median age at diagnosis was 57 years (18-84 years), with 37 males and 33 females. SMI was significantly higher in male than female patients (P & lt; 0.001). ATI was significantly higher in patients aged 60 years and over than in those under 60 years (P & lt; 0.05). The sex-specific cut-offs for the SMI and ATI were determined by ROC curve analysis. Thirty-five (50%) and 31 (44%) patients were defined as sarcopenia and adipopenia, respectively. Sarcopenia and adipopenia did not significantly differ among various FAB subtypes or cytogenetic risk profiles. The rate of patients with poor performance status (ECOG ≥ 2) was significantly higher in the sarcopenic group (80% vs 45%, P & lt; 0.05), whereas not in the adipopenic group (40% vs 47%). With a median follow-up of 33.5 months, the 3-year overall survival (OS) in the sarcopeniac group was 34% compared with 74% in the non-sarcopenic group (P & lt; 0.001, Figure 1A) and 32% in the adipopenic group compared with 72% in the non-adipopenic group (P & lt; 0.005, Figure 1B). In a multivariate analysis, sarcopenia (HR = 2.84, CI = 1.08-8.08, P & lt; 0.05) and adipopenia (HR = 2.85, CI = 1.19-7.24, P & lt; 0.05) remained predictive of OS. Conclusion: Sarcopenia and adipopenia are independent prognostic factors in patients with AML. Evaluation of skeletal muscle and adipose tissue depletion by CT imaging is a useful objective tool to predict patient outcomes, but a larger prospective study is needed to confirm this effect. Figure 1. Overall survival according to sarcopenic (A) and adipopenic (B) status. Figure 1. Overall survival according to sarcopenic (A) and adipopenic (B) status. 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
    Location Call Number Limitation Availability
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