Kentaro Ogata

Intravenous cyclosporine and tacrolimus caused anaphylaxis but oral cyclosporine capsules were tolerated in an allogeneic bone marrow transplant recipient

A Japanese female patient with angioimmunoblastic T cell lymphoma underwent allogeneic bone marrow transplantation (BMT) from her brother. Cyclosporine at a dose of 3 mg/kg was started by continuous infusion over 24 h on day −1 of BMT. Within a couple of minutes after the infusion was begun, she developed diffuse pruritic erythema on her whole body and tachycardia. The infusion was immediately stopped and corticosteroid was given, resulting in disappearance of the erythema gradually. She was then switched to intravenous tacrolimus. However, she suffered urticalial erythema again. Since polyoxyethylated castor oil, a solubilizer used in the injective formulation of both cyclosporine and tacrolimus, is considered to be responsible for the reaction, she was given oral capsules of cyclosporine (Sandimmun) in which polyoxyethylated castor oil was not contained. No further anaphylactic reaction was observed. The BM cells were successfully engrafted without causing severe GVHD. She was discharged on cyclosporine capsules without any further adverse effects. Anaphylaxis to intravenous cyclosporine and tacrolimus is a very rare but a serious complication. Our present case indicates that oral capsule of Sandimmun is a safe alternative to prevent GVHD in such a case of anaphylactic reaction against intravenous formulation. Bone Marrow Transplantation (2001) 28, 421–423.

Individual dose adjustment of oral busulfan using a test dose in hematopoietic stem cell transplantation.

Maintaining the appropriate average steady-state plasma concentrations (Css) of busulfan (BU) is critical for both successful engraftment and minimizing toxicity in hematopoietic stem cell transplantation (HST). We therefore performed a prospective trial with 50 adult Japanese patients that involved adjusting the BU dose in accordance with individual BU phar-macokinetics (PK). After administering a 0.5-mg/kg test dose of oral BU, we analyzed individual BU PK parameters and calculated an adjusted BU dose that would achieve a target BU Css of 850 ng/mL. Thirty-nine patients (78%) required a BU dose decrease, and the median adjusted BU dose was 0.81 mg/kg (range, 0.51–1.29 mg/kg). All patients who underwent allogeneic HST received the adjusted BU dose. After administering the sixth BU dose, we measured the plasma BU concentration. The actual BU concentration was significantly correlated with the expected BU concentration, and the predictability of the BU Css was 103% ± 19%. The incidence of toxicity excluding oral mucositis was low, and there was no regimen-related toxicity-associated mortality. Engraftment was achieved in 98% of the patients. This study showed that our method for adjusting the BU dose facilitated reliable prediction of the actual BU Css and that individualized BU dose adjustment was able to improve clinical outcomes in HST recipients treated with a BU-containing conditioning regimen.

Interferon-α and zidovudine for relapsed/refractory adult T cell leukemia/lymphoma: case reports of Japanese patients

Combination therapy with interferon-α and zidovudine (IFN/AZT) has been regarded as standard care for acute and indolent (i.e., chronic and smouldering) ATL based on reports involving a limited number of patients. This treatment approach has not been evaluated in Japan, a major endemic area of this disease in the world. This is the first Japanese report of IFN/AZT for ATL. It is impossible to draw any definitive conclusion from this small study; however, IFN/AZT showed clear anti-ATL effects for refractory/relapsed ATL patients. This report would contribute for developing future ATL treatment in Japan.

Simultaneous determination of cytosine arabinoside and its metabolite, uracil arabinoside, in human plasma using hydrophilic interaction liquid chromatography with UV detection

A practical high-performance liquid chromatography using a Cosmosil HILIC column and UV detection was developed for determining the concentrations of cytosine arabinoside (Ara-C) and uracil arabinoside (Ara-U), which is a major metabolite of Ara-C, in human plasma. This method was used to determine the plasma concentrations of Ara-C and Ara-U in a patient treated with high-dose Ara-C therapy for end-stage renal failure.

Patient perceptions of symptoms and concerns during cancer chemotherapy: ‘affects my family’ is the most important

BackgroundCancer chemotherapy is associated with a variety of side effects/adverse events. It is very important that patients adhere to the planned chemotherapy regimen, which necessitates a minimum of side effects and that these side effects be kept under control. We have investigated patients’ concerns and symptoms during chemotherapy with the aim to seek solutions that will improve patients’ quality of life during chemotherapy.MethodsForty-nine patients with malignant diseases on parenteral antineoplastic agents were sequentially enrolled in this study. These patients completed a questionnaire consisting of 42 items related to non-physical concerns and 52 items of physical symptoms related to chemotherapy. Each patient was also asked to select the three items among these 94 items which affected him/her the most. ResultsThe median age of the cancer patients was 62 years and the male-to-female ratio was 18:31. Among the non-physical concerns, the most frequently chosen concern was ‘affects my family or partner,’ followed by anxiety related to treatment. Regarding the physical symptoms, the most frequent complaints were fatigue, alopecia and constipation, while the most troublesome symptoms were nausea, poor taste and paresthesia. Overall, the most frequently expressed concerns were ‘affects my family or partner’ and anxiety related to treatment. Male patients suffered most from fever, fatigue and nausea, and female patients complained more of poor taste and gastrointestinal problems.ConclusionPatient perceptions of adverse events associated with cancer chemotherapy apparently have changed from physical symptoms to non-physical concerns. In our patient cohort ‘affects my family or partner’ was the most important concern. One important point to note is that female patients often complained of poor taste because this meant they were unable to cook well.

The small molecule STF-62247 induces apoptotic and autophagic cell death in leukemic cells

Adult T cell leukemia/lymphoma (ATL) is an aggressive malignant T cell disease caused by human T cell leukemia virus-I (HTLV-1). Treatment outcomes for aggressive subtypes of ATL remain poor, with little improvement in overall survival since HTLV-1 was discovered. Therefore, new therapeutic strategies for ATL are required. STF-62247 induces autophagy and selectively kills renal cell carcinoma without apoptotic cell death. Here, we demonstrate that STF-62247 reduced cell viability and resulted in autophagosome accumulation and autophagy in leukemic cell lines (S1T, MT-2, and Jurkat). Interestingly, STF-62247 induced apoptosis in HTLV-1-infected cell lines (S1T and MT-2), as indicated by DNA fragmentation and caspase activation, but not in non-HTLV-1-infected Jurkat cells; a caspase inhibitor did not prevent this caspase-associated cell death. STF-62247 also increased nuclear endonuclease G levels. Furthermore, STF-62247 reduced cell viability and increased the number of apoptotic cells in peripheral blood mononuclear cells collected from patients with acute ATL, which has a poor prognosis. Therefore, STF-62247 may have novel therapeutic potential for ATL. This is the first evidence to demonstrate the cell growth-inhibitory effect of an autophagy inducer by caspase-dependent apoptosis and caspase-independent cell death via autophagy and endonuclease G in leukemic cells.

1608PCHEMOTHERAPY FOR DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENT PATIENT

ABSTRACT Aim: 5-FU is metabolized by thymidine phosphorylase and orotate phosphoribosyl transferase and is principally degraded in the blood or liver by dihydropyrimidine dehydrogenase (DPD). DPD, the catalyzing enzyme in the first and rate-limiting step of the degradation process, degrades approximately 85% of the administered 5-FU. DPD activity in peripheral blood mononuclear cells has been reported to correlate inversely with 5-FU clearance. In reports of DPD deficiency, the prognosis is poor, and approximately 60% patients die. With a reported high mortality rate, chemotherapy is generally contraindicated for patients with DPD deficiency, and there have been no reports of continued chemotherapy in patients with a DPD activity level of Methods: Chemotherapy for a 73-year old man with jejunal cancer was initiated. Capecitabine was administered in incrementally increasing doses, beginning with a single pill (dose-escalation method), while monitoring plasma 5-FU concentration, leukocyte, neutrophil, and platelet counts. Results: DPD protein measurement in the peripheral blood mononuclear cells yielded a level of 2.35 U/mg using the ELISA method (the same method yielded DPD measurements ranging from 33.6 to 183.6 U/mg in peripheral blood mononuclear cells from 10 healthy individuals). Ultimately, after increasing the Capecitabine dose to 1800 mg, oxaliplatin and bevacizumab were added and XELOX+bevacizumab treatment was initiated. Subsequent DPD protein measurement showed that the level had increased to approximately 10-fold the level before chemotherapy. Furthermore, the peritoneal metastases disappeared following chemotherapy. Conclusions: Because of serious adverse events, the chemotherapy-associated mortality rate among DPD-deficient patients is high, and there have been no reports of continuous chemotherapy in patients with DPD activity levels of Disclosure: All authors have declared no conflicts of interest.