Yuhei Shibata

Expression of indoleamine 2,3-dioxygenase in leukemic cells indicates an unfavorable prognosis in acute myeloid leukemia patients with intermediate-risk cytogenetics

Abstract The immunomodulatory effects of indoleamine 2,3-dioxygenase (IDO) are ascribed to its ability to catalyze breakdown of the essential amino acid l-tryptophan. We applied reverse transcription-polymerase chain reaction (RT-PCR) to examine IDO mRNA expression in acute myeloid leukemia (AML) blasts, and investigated its clinical significance. We enrolled 62 patients with AML between April 2005 and March 2013. Bone marrow-derived mononuclear fractions were separated and extracted mRNA was amplified by PCR. RT-PCR showed that the bone marrow of 23 patients expressed IDO mRNA but not in 39. IDO mRNA expression did not significantly differ among cytogenetic risk profiles. The 3-year overall survival rates for patients with and without IDO mRNA expression were 39% and 74%, respectively (p < 0.005). The rates for patients with intermediate-risk cytogenetics with and without IDO mRNA expression were 16% and 70%, respectively (p < 0.005). The expression of IDO mRNA was associated with a poor prognosis of AML.

High serum concentration of L-kynurenine predicts unfavorable outcomes in patients with acute myeloid leukemia

The immunomodulatory effects of indoleamine 2,3-dioxygenase (IDO) are ascribed to its ability to catalyze the breakdown of the L-tryptophan along the L-kynurenine pathway. Because blasts from patients with acute myeloid leukemia (AML) express IDO, the goal of this study was to investigate the role of L-kynurenine as a prognostic marker for AML. We enrolled 48 AML patients. L-kynurenine concentrations were measured by high-performance liquid chromatography. The median serum L-kynurenine level was 1.67 μM. There was no significant difference in the complete remission rate between patients with L-kynurenine < 2.4 (77%) and ≥ 2.4 μM (75%). However, 3-year overall survival (OS) rates were significantly better in patients with low L-kynurenine levels (76%) than in those with high L-kynurenine levels (11%) (p < 0.0001). Furthermore, in intermediate-risk cytogenetics patients, only L-kynurenine was significantly associated with OS (p < 0.005). Multivariate analyses revealed that L-kynurenine and high leukocyte count were independent prognostic factors.

The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis

Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing intracellular enzyme of the L-kynurenine pathway, causes preneoplastic cells and tumor cells to escape the immune system by inducing immune tolerance; this mechanism might be associated with the development and progression of human malignancies. In the present study, we investigated the role of IDO in diethylnitrosamine (DEN)-induced hepatocarcinogenesis by using IDO-knockout (KO) mice. To induce hepatocellular carcinoma (HCC), hepatic adenoma, and preneoplastic hepatocellular lesions termed foci of cellular alteration (FCA), male IDO-wild-type (WT) and IDO-KO mice with a C57BL/6J background received a single intraperitoneal injection of DEN at 2 weeks of age. The mice were sacrificed to evaluate the development of FCA and hepatocellular neoplasms. HCC overexpressed IDO and L-kynurenine compared to surrounding normal tissue in the DEN-treated IDO-WT mice. The number and cell proliferative activity of FCAs, and the incidence and multiplicity of HCC were significantly greater in the IDO-WT than in the IDO-KO mice. The expression levels of the IDO protein, of L-kynurenine, and of IFN-γ, COX-2, TNF-α, and Foxp3 mRNA were also significantly increased in the DEN-induced hepatic tumors that developed in the IDO-WT mice. The mRNA expression levels of CD8, perforin and granzyme B were markedly increased in hepatic tumors developed in IDO-KO mice. Moreover, Foxp3-positive inflammatory cells had infiltrated into the livers of DEN-treated IDO-WT mice, whereas fewer cells had infiltrated into the livers of IDO-KO mice. Induction of IDO and elevation of L-kynurenine might play a critical role in both the early and late phase of liver carcinogenesis. Our findings suggest that inhibition of IDO might offer a promising strategy for the prevention of liver cancer.

Prognostic value of the combination of serum l-kynurenine level and indoleamine 2,3-dioxygenase mRNA expression in acute myeloid leukemia

Takeshi Hara, Takuro Matsumoto, Yuhei Shibata, Nobuhiko Nakamura, Hiroshi Nakamura, Soranobu Ninomiya, Junichi Kitagawa, Yasuhito Nannya, Masahito Shimizu, Hiroyasu Ito, Kuniaki Saito and Hisashi Tsurumi First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan

Association between increased serum GP88 (progranulin) concentrations and prognosis in patients with malignant lymphomas

BACKGROUND GP88 (progranulin; PGRN) is a secreted 88kDa glycosylated protein, with important functions, including inflammation and tumorigenesis. We assessed the significance of GP88 expression in survival outcomes of patients with malignant lymphoma (ML). METHODS Serum samples from 254 previously untreated ML patients were examined to measure GP88 concentrations using a sandwich human GP88 ELISA kit. Immunohistochemical analyses were performed to examine GP88 tumor tissue expression. RESULTS The median serum GP88 concentration of ML patients was 91.3ng/ml, and was significantly higher than that of the control group (median, 57.7ng/ml) (p<0.0001). Association between GP88 serum concentrations and overall survival (OS) was examined in patients with diffuse large B cell lymphoma (DLBCL) who had been stratified based on their serum GP88 concentrations. Kaplan Meier survival analysis showed that patients with serum GP88 concentrations of ≤116 and >116ng/ml, had 5-y OS rates of 70% and 50%, respectively (p=0.02). The immunohistochemical analyses of GP88 tumor expression revealed that DLBCL patients had lymphoma cells that were positive for GP88. CONCLUSIONS High serum GP88 concentrations are associated with poor prognosis in patients with DLBCL.

R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial

Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracyclin with less cardiotoxicity than doxorubicin (DOX). We previously reported the efficacy and safety of R‐THP‐COP consisting of rituximab (R), THP, cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL) for diffuse large B cell lymphoma (DLBCL) in phase 2 studies. Here, we prospectively compared the efficacy and safety of the R‐THP‐COP and standard R‐CHOP regimen (consisting of R, CPA, DOX, VCR, and PSL) in a noninferiority phase 3 trial. This prospective, randomized phase 3 study included patients younger than 70 years of age with previously untreated DLBCL. The regimen consisted of R (day 1), DOX, or THP (day 3), CPA (day 3), VCR (day 3), and PSL for 5 days every 3 weeks for 6 to 8 cycles. Between July 5, 2006 and June 11, 2013, 81 patients were randomly assigned to the treatment groups (R‐CHOP group, 40 patients; R‐THP‐COP group, 41 patients). R‐THP‐COP was noninferior to R‐CHOP, as assessed by the primary endpoint of complete response rate (85% vs 85% respectively). With a median follow‐up of 75.2 months, the 5‐year overall survival was 87% in the R‐CHOP group and 82% in the R‐THP‐COP group (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.31‐2.49; P = .82). The 5‐year progression‐free survival was 74% in the R‐CHOP group and 79% in the R‐THP‐COP group (HR: 1.37, 95% CI: 0.56‐3.55; P = .49). No grade 3 cardiac side effects were observed in either group. No serious late adverse reactions were observed in either group, with the exception of therapy‐related acute myeloid leukemia in the R‐THP‐COP group. These data indicate that R‐THP‐COP is noninferior to R‐CHOP with regard to clinical response, and has an acceptable safety profile. Thus, this regimen may be an alternative therapy to R‐CHOP.

A salvage chemotherapy of R‐P‐IMVP16/CBDCA consisting of rituximab, methylprednisolone, ifosfamide, methotrexate, etoposide, and carboplatin for patients with diffuse large B cell lymphoma who had previously received R‐CHOP therapy as first‐line chemotherapy

We have reported the efficacy of the salvage chemotherapy P‐IMVP16/CBDCA for patients with diffuse large B cell lymphoma (DLBCL) who had previously received CHOP before the availability of rituximab (R). Here, we confirmed the efficacy of R combined with P‐IMVP16/CBDCA as a salvage chemotherapy for patients with DLBCL, who had previously received R‐CHOP. We retrospectively analysed 59 patients with relapse or refractory DLBCL (38 male patients and 21 female patients) presenting between June 2004 and June 2013. The patients received R 375 mg/m2 on day 1, methylprednisolone 1000 mg/body for 3 days (from day 3 to day 5), ifosfamide 1000 mg/m2 for 5 days (from day 3 to day 7), methotrexate 30 mg/m2 on day 5 and day 12, etoposide 80 mg/m2 for 3 days (from day 3 to day 5), and carboplatin 300 mg/m2 on day 3 every 21 days. Patients aged 70 years or older were given 75% of the standard dose. The overall response rate (complete response + partial response) was 64.4%. The 2‐year overall survival rate was 55.3%. The 2‐year progression free survival rate was 34.7%. The 2‐year overall survival rate was 61.5% for the relapse patients, and 15.6% for the refractory patients (p < 0.0001). One patient died because of sepsis related to the treatment regimen. Non‐hematological adverse effects were mild and tolerable. The R‐P‐IMVP‐16/CBDCA regimen displayed a significant activity in relapsed DLBCL, with acceptable toxicity, and should be considered a candidate for salvage chemotherapy. Copyright

CHOP or THP-COP regimens in the treatment of newly diagnosed peripheral T-cell lymphoma, not otherwise specified: a comparison of doxorubicin and pirarubicin.

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

Peripheral T-Cell Lymphoma, Not Otherwise Specified and Concurrent Seminoma in Testis

Concurrent seminoma and malignant lymphoma of the testis is rare. We present a case of concurrent seminoma and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in a 54-year-old man who complained of painless left testicular enlargement. Radical left orchiectomy was performed. Macroscopically, the tumor (4.0 × 3.0 cm) was creamy, soft, and homogeneous, and microscopic evaluation revealed an alveolar structure of large cells that formed sheets, as well as colonization by other abnormal cells in a 1.0 × 1.0 cm area. The portion of the tumor comprising large abnormal cells was diagnosed as a seminoma, which was positive for c-kit by immunohistochemistry; the other portion was diagnosed as CD3/CD8, TIA, and granzyme B-positive PTCL-NOS. These two portions were clearly differentiated from one another. The patient received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy and achieved complete response for 50 months. To our knowledge, this is the first reported case of synchronous advanced seminoma and PTCL.

Serum concentrations of l‐kynurenine predict clinical outcomes of patients with peripheral T‐cell lymphoma, not otherwise specified

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