Transmission of chromosomally integrated human herpesvirsus 6 (HHV-6) variant A from a parent to children leading to misdiagnosis of active HHV-6 infection.

Only a handful of cases of chromosomally integrated human herpesvirus 6 (CI-HHV-6) have been reported, suggesting that this phenomenon is rare. We here present a familial case of HHV-6 variant A (HHV-6A) transmission through a generation, which was identified in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). A 31-year-old man with myelodysplastic syndrome underwent allogeneic HSCT from a human leukocyte antigen-identical sibling, and was found to be continuously yielding high copy numbers of HHV-6A DNA in plasma evaluated by real-time polymerase chain reaction (PCR). Antiviral therapy with ganciclovir or foscarnet failed to decrease the copy numbers. HHV-6A DNA was detected in the patient's buccal mucosa and hair follicles, and was also detected in the plasma, whole blood, and buccal mucosa of the patient's father and 2 siblings, but not in his mother. The sequences of HHV-6A DNA isolated from all family members were identical. Since monitoring of HHV-6 by PCR has been widely introduced to the field of HSCT, transplant physicians should be aware of such an alternative form of HHV-6 transmission, particularly when HHV-6A is detected.

Primary central nervous system post-transplant lymphoproliferative disorder presenting as cerebral hemorrhage after unrelated bone marrow transplantation.

We present a rare case of cerebral hemorrhage due to Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD). A 58-year-old man with myelodysplastic syndrome received allogeneic hematopoietic stem cell transplantation from an unrelated donor after being conditioned with fludarabine, melphalan, and total body irradiation. Tacrolimus and methotrexate were given for graft-versus-host disease (GVHD) prophylaxis. On day 23, he developed acute GVHD, which was successfully treated with prednisolone (PSL). The tapering of PSL failed because of extensive chronic GVHD involving the liver and lungs, and mycophenolate mofetil was added on day 244. On day 340, the patient suddenly complained of severe headache. Computed tomography confirmed subcortical hemorrhage, and he died on day 348. The autopsy revealed atypical lymphocytes infiltrating the brain and meninges, which were positive for B-cell-associated antigens and EBV-encoded RNA, and thus EBV-associated PTLD was diagnosed.

Interindividual variation of maximal blood levels of tacrolimus after its oral administration in hematopoietic cell transplant recipients.

We investigated the pharmacokinetics of oral tacrolimus in 31 hematopoietic cell transplant recipients, identifying 2 subgroups based on the differences between C(0) (trough) and C(max) (maximal) levels: group A (n = 21; 68%) with a C(max)-C(0) value of <10 ng/mL, and group B (n = 10; 32%) with a C(max)-C(0) value of >or=10 ng/mL. Although the C(0) and C(12) values were not significantly different between the 2 groups, the mean area under the concentration curve for 12 hours (AUC(0-12)) was significantly greater in group B than group A (200.9 +/- 36.3 vs 155.1 +/- 43.1 ng.h/mL; P < .05), and the mean half-life was significantly shorter in group B than group A (13.55 +/- 6.70 vs 18.17 +/- 6.30 hours; P < .05). Thus after the oral administration of tacrolimus, we observed a notably high AUC due to high peak level, which we were unable to predict simply by measuring the trough level. A pharmacokinetic analysis of each patient was essential to optimize the oral tacrolimus dose.

Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients.

Although voriconazole has been shown to interact with calcineurin inhibitors, this interaction has not been thoroughly examined. The purpose of this study was to evaluate the drug interaction between voriconazole and calcineurin inhibitors among recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-one recipients of allogeneic HSCT were evaluated. Those recipients had been on CsA (n=10) or tacrolimus (n=11) when voriconazole (400 mg per day orally, or 8 mg/kg per day, i.v.) was initiated. Trough concentrations of calcineurin inhibitors were measured before and periodically after initiating voriconazole to determine the concentration/dose (C/D) ratio of calcineurin inhibitors. Median C/D ratio significantly increased by initiating voriconazole: from 86.0 (range, 43.5-178.8) to 120.2 (range, 86.1-379.4) in CsA (P<0.05), and from 595.9 (range, 51.3-1643.3) to 890.7 (range, 94.1-4658.3) (ng/ml)/(mg/kg) in tacrolimus (P<0.01). Median increases in the C/D ratio did not differ significantly between CsA and tacrolimus (82.1%, ranging from -9.4 to 266.9% vs 115.6%, ranging from 25.4 to 307.6%). These results indicate that voriconazole alters the blood concentration of calcineurin inhibitors with a wide range of interindividual variability after allogeneic HSCT. Dose adjustment of calcineurin inhibitors on initiating voriconazole should not be decided uniformly, but determined on an individual basis by close monitoring of their blood concentrations.

Reduced efficacy of topical corticosteroid in preventing cytarabine-induced kerato-conjunctivitis in patients receiving high-dose cytarabine and total body irradiation for allogeneic hematopoietic stem cell transplantation.

This study aimed to retrospectively evaluate the incidence of kerato-conjunctivitis in patients receiving TBI followed by high-dose cytarabine, and to clarify how effectively topical corticosteroid eye drops prevent kerato-conjunctivitis in these patients. Fifty-three patients who received cytarabine at a dose of 3 g/m2 every 12 h for 4 days after receiving TBI (12 Gy) as a conditioning for allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated. For the prophylaxis of kerato-conjunctivitis, all patients received betamethasone sodium phosphate eye drops every 6 h, starting 1 day before the first dose of cytarabine and continuing until 1 day after the last dose of cytarabine or the complete resolution of ocular symptoms. For grading of kerato-conjuncitivitis, the National Cancer Institute-Common Toxicity Criteria were used. Among the 53 patients, the grades of kerato-conjunctivitis were grade 0 in 13 patients, grade 1 in 6 patients (11.3%), grade 2 in 10 patients (18.9%) and grade 3 in 25 patients (47.2%). These results strongly suggest that topical corticosteroid eye drops could not effectively prevent the development of cytarabine-induced kerato-conjunctivitis in HSCT recipients who receive high-dose cytarabine following TBI. Further investigation into a more effective prophylaxis for cytarabine-induced kerato-conjunctivitis in this setting is required.

Tacrolimus and methotrexate for the prophylaxis of graft-versus-host disease after unrelated donor cord blood transplantation for adult patients with hematologic malignancies.

Eighteen patients with hematologic malignancies underwent cord blood transplantation (CBT) from unrelated donors after being conditioned with myeloablative or reduced-intensity regimens, and received tacrolimus and methotrexate (15 mg/m(2) on day 1, 10 mg/m(2) on days 3 and 6) as graft-versus-host disease (GVHD) prophylaxis. The median number of nucleated cells in infused cord blood was 2.66 x 10(7)/kg (range 1.90 to 4.15 x 10(7)/kg). Engraftment was achieved in 16 of 18 patients. The median time to absolute neutrophil count >0.5 x 10(9)/L was 21.5 days (range 17 to 32), and the median time to platelet count >2.0 x 10(9)/L was 36 days (range 26 to 57). Of the 16 evaluable patients, five and eight had grades I and II acute GVHD, respectively, and none had grades III/IV acute GVHD. The cumulative incidence of grade II acute GVHD was 44.4%. Chronic GVHD occurred in 7 of 15 evaluable patients: limited type in three patients, extensive type in four patients. Of the 18 patients, 14 were alive and disease-free between 173 and 1514 days after CBT (median 746 days). The probability of disease-free survival at 2 years was 79.1%. These results, although in a retrospective study, suggested that tacrolimus and short-term methotrexate effectively prevented the occurrence of severe acute GVHD after unrelated CBT, and may contribute to a high survival rate.

Total body irradiation and granulocyte colony-stimulating factor-combined high-dose cytarabine as a conditioning regimen in allogeneic hematopoietic stem cell transplantation for advanced myelodysplastic syndrome: a single-institute experience.

In this study, we retrospectively evaluated the efficacy and safety of total body irradiation (TBI) and granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with advanced myelodysplastic syndrome (MDS). We evaluated 22 patients with advanced MDS, including refractory anemia with excess blasts (RAEB; n=10), RAEB in transformation (n=2), acute myelogenous leukemia transformed from MDS (n=6) and chronic myelomonocytic leukemia (n=4). The conditioning regimen consisted of 12 Gy of TBI and high-dose cytarabine (3 g/m(2)) every 12 h for 4 days, and the cytarabine was combined with continuous administration of G-CSF. The stem cell sources were bone marrow or peripheral blood stem cells from human leukocyte antigen (HLA)-identical siblings (n=12) and bone marrow from HLA serologically matched unrelated donors (n=10). Three patients experienced disease relapse, two of whom died of disease progression. Of 22 patients, 16 are currently alive and disease-free. The 5-year estimated overall survival, disease-free survival, relapse and non-relapse mortality rates are 76.7, 72.2, 16.6 and 14.1%, respectively. These results suggest that G-CSF-combined high-dose cytarabine could be a promising component of the conditioning regimen of allogeneic HSCT for advanced MDS, providing a low incidence of both relapse and treatment-related mortality.

Polymyositis, pulmonary fibrosis and malignant lymphoma associated with hepatitis C virus infection.

Polymyositis has been associated with various viral infections, and a spectrum of immune-related diseases may occur with hepatitis C (HCV) infection. Both polymyositis and HCV infection may be accompanied by pulmonary fibrosis. An association between polymyositis and malignancy has also been reported. We report a 55-year-old woman accompanied cryoglobulinemia with HCV infection and manifesting polymyositis, pulmonary fibrosis and malignant lymphoma. Steroid therapy was effective to improve interstitial pneumonia, polymyositis, and liver function.