[Prognostic significance of tryptophan catabolism in adult T-cell leukemia/lymphoma].

PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, and is an important micro-environmental factor suppressing antitumor immune responses. We investigated 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 volunteers. The relationships between various clinical parameters 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 in healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. There were no significant differences in serum Trp concentrations between ATL patients, HTLV-1 ACs and controls. IDO was possibly produced by ATL and/or cells in the microenvironment. Multivariate analyses demonstrated a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, to be significant independent detrimental prognostic factors in ATL and aggressive variant ATL. CONCLUSIONS: Quantification of serum Kyn and Trp is prognostically useful for individual ATL patients. Furthermore, ATL is an appropriate disease for testing novel cancer immunotherapies targeting IDO.

[Successful treatment of high-dose methotrexate-induced oliguric acute renal failure by using a combination of hemodialysis filtration and direct hemoperfusion].

A 64-year-old man with central nervous system metastases from systemic non-Hodgkin lymphoma was treated with high- dose intravenous methotrexate(MTX 3.5 g/m2). The patient subsequently developed oliguric acute renal failure 12 hours after MTX initiation, and his serum MTX level was 163 mM at 26 hours. Hemodialysis filtration(HDF)combined with direct hemoperfusion(DHP)was initiated at 45hours. Seven sessions of combined HDF and DHP and 2 courses of HDF alone were performed, and the mean MTX extraction rates were 68.2% and 74.3%, respectively. The patient experienced severe respiratory failure, febrile neutropenia, myelosuppression, and oral mucositis. However, his urine output began to improve on day 7 after MTX initiation, and his renal function gradually recovered. His serum MTX level declined to 0.04 mM on day 23 after MTX initiation. In the present case, we immediately initiated HDF and DHP and successfully treated the patient for MTX-induced renal failure.

Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma.

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.

Highly frequent and enhanced injection site reaction induced by peripheral venous injection of fosaprepitant in anthracycline-treated patients.

BACKGROUND: Fosaprepitant-associated injection site reaction (ISR) has been reported in patients treated with cisplatin, an irritant drug. We conducted this retrospective study to clarify the incidence and symptoms of fosaprepitant-associated ISR in patients treated with anthracycline. PATIENTS AND METHODS: Fifty six patients receiving 159 injections administering doxorubicin/cyclophosphamide (AC), fluorouracil/epirubicin/cyclophosphamide (FEC), or rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-)CHOP regimen through a peripheral vein at ambulatory treatment centers reviewed for this study from patients' medical records. Incidence of ISR was compared between 24 patients with fosaprepitant injection (fosaprepitant group) and 32 patients without fosaprepitant (control group). Frequency and symptoms of ISR per injection were also compared between 61 injections with fosaprepitant and 98 injections without fosaprepitant. RESULTS: Both the ISR incidence rate per patient and per injection were significantly higher in the fosaprepitant group than in the control group (67% vs. 16%; P=0.0002, 34% vs. 8.2%; P<0.0001, respectively). By multivariate analysis, fosaprepitant injection was found to be a significant independent variable correlated with ISR risk. Symptoms observed in 61 injections of fosaprepitant were pain (n=14, 23%), erythema (n=10, 16%), swelling (n=6, 10%), and delayed drip infusion (n=6, 10%). After the observation period, no ISR occurred when the administration route was changed to central venous injection or oral aprepitant was administered despite the continuation of chemotherapy. CONCLUSION: ISR occurred more frequently and severely when fosaprepitant was injected through the peripheral vein in patients treated with anthracyclines compared to those without fosaprepitant.

[A case of acute myeloid leukemia in an obese patient--determining the therapeutic dose of anticancer drugs].

Currently, there is no consensus to determine whether the therapeutic doses of anticancer drugs should be based on the actual or the ideal body weight of obese cancer patients. We performed induction and consolidation chemotherapy at doses calculated by using the actual body weight of an obese patient with acute myeloid leukemia (AML). A 47-year-old Japanese man presented with pancytopenia at our hospital, and he was diagnosed with AML (FAB classification M0). At the initial diagnosis, the patient was 170 cm tall and weighed 132 kg; therefore, his body surface area was 2.37 m(2). His performance status and organ functions were quite good. The calculations for determining doses of anticancer drugs required were based on his actual body weight. He received induction chemotherapy and achieved complete remission. Subsequently, he was treated with 4 courses of consolidation chemotherapy. Febrile neutropenia was a complication during each course, and it was relieved via myeloid recovery. Chemotherapy was administered every 4-5 weeks, except for the second course where platelet recovery was prolonged, and the prescribed treatment was completed. The guidelines of the American Society of Clinical Oncology (ASCO) recommend that physicians routinely use an obese patient's actual body weight to calculate the appropriate doses of almost all chemotherapy drugs. Therefore, the ease and compromised usage of under-dosing because of heaviness owing to obesity should be avoided.

Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma.

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients.

Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor.

Involvement of nuclear factor-kappaB (NF-kappaB) in cell survival and proliferation of multiple myeloma has been well established. In this study we observed that NF-kappaB is constitutively activated in all human myeloma cell lines, thus confirming the previous studies. In addition, we found the phosphorylation of p65 subunit of NF-kappaB in addition to the phosphorylation of IkappaBalpha and the activation of NF-kappaB DNA binding and that various target genes of NF-kappaB including bcl-x(L), XIAP, c-IAP1, cyclin D1, and IL-6 are up-regulated. We then examined the effect of a novel IkappaB kinase inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP). When myeloma cells were treated with ACHP, the cell growth was efficiently inhibited with IC(50) values ranging from 18 to 35 mumol/L concomitantly with inhibition of the phosphorylation of IkappaBalpha/p65 and NF-kappaB DNA-binding, down-regulation of the NF-kappaB target genes, and induction of apoptosis. In addition, we observed the treatment of ACHP augmented the cytotoxic effects of vincristine and melphalan (l-phenylalanine mustard), conventional antimyeloma drugs. These findings indicate that IkappaB kinase inhibitors such as ACHP can sensitize myeloma cells to the cytotoxic effects of chemotherapeutic agents by blocking the antiapoptotic nature of myeloma cells endowed by the constitutive activation of NF-kappaB.