Purpose: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important microenvironmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL).Experimental Design: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients.Results: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL.Conclusions: Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/ Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO.

Reactivation of hepatitis B virus (HBV) infection may occur in adult T-cell leukemia-lymphoma (ATL) patients with resolved HBV infection who receive monotherapy with the anti-CC chemokine receptor 4 monoclonal antibody, mogamulizumab. However, there is little evidence regarding the incidence and characteristics of HBV reactivation in ATL patients receiving systemic chemotherapy, including the use of this antibody. We conducted a retrospective study for 24 ATL patients with resolved HBV infection underwent regular HBV DNA monitoring to assess HBV reactivation in Nagoya City University Hospital between January 2005 and June 2013. With median HBV DNA follow-up of 238 days (range 57-1420), HBV reactivation (defined as the detection of HBV DNA) was observed in three (12.5 %) of 24 patients with resolved HBV infection. No hepatitis due to HBV reactivation occurred in those patients who were diagnosed with HBV DNA levels below 2.1 log copies/mL and who received antiviral drugs. Mogamulizumab was administered prior to HBV reactivation in two of three HBV-reactivated patients. In the mogamulizumab era, further well-designed prospective studies are warranted to estimate the incidence of HBV reactivation and to establish regular HBV DNA monitoring-guided preemptive antiviral therapy for such patients.

We report an adult T-cell leukemia-lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy.

Serous ovarian cancer is the most frequent type of epithelial ovarian cancer. Despite the use of surgery and platinum‐based chemotherapy, many patients suffer from recurrence within 6 months, termed platinum resistance. Currently, the lack of relevant molecular biomarkers for the prediction of the early recurrence of serous ovarian cancers is linked to the poor prognosis. To identify an effective biomarker for early recurrence, we analyzed the genome‐wide DNA methylation status characteristic of early recurrence after treatment. The patients in The Cancer Genome Atlas (TCGA) dataset who showed a complete response after the first therapy were categorized into 2 groups: early recurrence serous ovarian cancer (ERS, recurrence ≤12 months, n = 51) and late recurrence serous ovarian cancer (LRS, recurrence >12 months, n = 158). Among the 12 differently methylated probes identified between the 2 groups, we found that ZNF671 was the most significantly methylated gene in the early recurrence group. A validation cohort of 78 serous ovarian cancers showed that patients with ZNF671 DNA methylation had a worse prognosis (P < .05). The multivariate analysis revealed that the methylation status of ZNF671 was an independent factor for predicting the recurrence of serous ovarian cancer patients both in the TCGA dataset and our cohort (P = .049 and P = .021, respectively). Functional analysis revealed that the depletion of ZNF671 expression conferred a more migratory and invasive phenotype to the ovarian cancer cells. Our data indicate that ZNF671 functions as a tumor suppressor in ovarian cancer and that the DNA methylation status of ZNF671 might be an effective biomarker for the recurrence of serous ovarian cancer after platinum‐based adjuvant chemotherapy.

Bortezomib (Btz) is an active agent used to treat multiple myeloma (MM). Not all patients who receive Btz-containing therapy show a favorable response. Interaction of cellular adhesion molecules with MM and bone marrow stromal cells is crucial for the survival of MM cells. However, little is known about the role of these molecules in the sensitivity of MM to Btz-containing therapy. Thus, we evaluated the correlation between the level of cellular adhesion molecules in MM cells and the efficacy of Btz plus dexamethasone (Bd) therapy. The expression of the neural cell adhesion molecule gene (NCAM, also known as CD56), ITGA4, CXCR4, and other genes were analyzed in 74 samples of primary MM cells collected from patients before they received Bd therapy. Of the eight genes tested, expression of NCAM was lower among patients who responded poorly to Bd therapy. In vitro expression of NCAM induced by transfection of MM cells enhanced their sensitivity to Btz treatment by causing accumulation of polyubiquitinated proteins. Our results indicate that expression of NCAM is associated with better response to Btz treatment and is a promising candidate biomarker for predicting response to therapies involving Btz.