Optimal Sampling Strategy and Threshold of Serum Vancomycin Concentration in Elderly Japanese Patients Undergoing High-Flux Hemodialysis.

BACKGROUND: The optimal sampling points and thresholds for initial serum vancomycin (VCM) concentrations have not been determined in hemodialysis (HD) patients. To clarify this, multiple blood tests were performed, and the correlations between VCM concentrations at several sampling points and the area under the concentration-time curve for 24 hours (AUC24h) were analyzed. METHODS: A single-center, prospective observational study was conducted. Patients with end-stage renal failure who received VCM treatment while undergoing chronic maintenance HD were enrolled in this study. HD was performed using a high-flux membrane as the dialyzer. After VCM administration, 7 points were sampled between the first and second HD. The AUC24h after the end of the first HD (AUC0-24) and that before the end of the second HD (AUC24-48) were calculated using the linear trapezoidal method. Correlation analysis and simple regression analysis between AUC24h and serum concentrations were performed at each sampling point. RESULTS: Nine patients were evaluated. Strong correlations were found between AUC24-48 and serum concentrations at 24 hours after the initiation of VCM treatment following the first HD (C24h, R = 0.983 and P < 0.001), between AUC0-24 and C24h (R = 0.967 and P < 0.001), and between AUC24-48 and serum concentration just before the second HD (Cpre(HD2), R = 0.965 and P < 0.001). Regression equations with high coefficients of determination (R2 > 0.9) were obtained, and a C24h of ≥18.0 mg/L and a Cpre(HD2) of ≥16.5 mg/L were required to achieve an AUC24-48 value of ≥400 mg·h/L. In addition, a C24h of ≤23.3 mg/L was estimated to satisfy the AUC0-24 range of ≤600 mg·h/L. CONCLUSIONS: C24h and Cpre(HD2) are optimal sampling points for predicting VCM-AUC24h in HD patients.

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

PURPOSE: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). METHODS: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. RESULTS: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. CONCLUSIONS: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.

Generation of multivirus-specific T cells by a single stimulation of peripheral blood mononuclear cells with a peptide mixture using serum-free medium.

BACKGROUND: Restoration of virus-specific immunity by virus specific T cells (VSTs) offers an attractive alternative to conventional drugs, and can be highly effective in immunocompromised patients, including hematopoietic stem cell transplant (HSCT) recipients. However, conventional VSTs manufacture requires preparation of specialized antigen-presenting cells (APCs), prolonged ex vivo culture in serum-containing medium and antigen re-stimulation with viruses or viral vectors to provide viral antigens for presentation on APCs. METHODS: To simplify this complex process, we developed a method to generate multiple VSTs by direct stimulation of peripheral blood mononuclear cells (PBMCs) with overlapping peptide libraries in serum-free medium. RESULTS: We generated VSTs that targeted seven viruses (cytomegalovirus [CMV], Epstein-Barr virus [EBV], adenovirus [AdV], human herpesvirus 6 [HHV-6], BK virus [BKV], JC virus [JCV] and Varicella Zoster virus [VZV]) in a single line. The phenotype, growth and specificity of multiple VSTs produced in serum-free medium were equivalent to those generated in conventional serum-containing medium. DISCUSSION: The use of serum-free medium allows this approach to be readily introduced to clinical practice with lower cost, greater reproducibility due to the absence of batch-to-batch variability in serum and without concerns for infectious agents in the serum used. This simplified approach will now be tested in recipients of Human Leukocyte Antigen (HLA)-matched sibling HSCT.

Characterization of In Vitro Expanded Virus-Specific T cells for Adoptive Immunotherapy against Virus Infection.

Adoptive transfer of virus-specific T cells has emerged as a promising therapeutic approach for treatment of virus infections in immunocompromised hosts. Characterization of virus-specific T cells provides essential information about the curative mechanism of the treatment. In this study, we developed a T cell epitope mapping system for 718 overlapping peptides spanning 6 proteins of 3 viruses (pp65 and IE1 from cytomegalovirus; LMP1, EBNA1, and BZLF1 from Epstein-Barr virus; Penton from adenovirus). Peripheral blood mononuclear cells (PBMCs) from 33 healthy Japanese donors were stimulated with these peptides and virus-specific CD4+ and CD8+ T cells were expanded in vitro in the presence of interleukin (IL) 4 and IL7. A median of 13 (minimum-maximum, 2-46) peptides was recognized in the cohort. Both fresh and cryopreserved PBMCs were used for in vitro expansion. The expansion and breadth of T cell responses were not significantly different between the 2 PBMC sets. We assessed viral regions frequently recognized by T cells in a Japanese cohort that could become pivotal T cell targets for immunotherapy in Japan. We tested epitope prediction for CD8+ T cell responses against a common target region using a freely available online tool. Some epitopes were considered to be predictive.

Effect of reduced-intensity conditioning and the risk of late-onset non-infectious pulmonary complications in pediatric patients.

OBJECTIVE: Late-onset non-infectious pulmonary complications (LONIPCs) contribute to higher morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we investigated the risk factors of LONIPCs in pediatric patients. METHOD: Between 2001 and 2011, 74 pediatric patients (range, 7 months to 22.7 years old; median 6.5 years old), including 29 with a primary immunodeficiency, underwent 80 allo-HSCTs at our institution. Sixty-seven patients who survived more than 3 months after allo-HSCT were analyzed retrospectively. The median follow-up period was 1 973 days (range, 126-5 145 days). RESULTS: Nine patients (13.4%) developed LONIPCs between 90 and 3 578 days after allo-HSCT. A myeloablative conditioning (MAC) regimen and chronic GVHD were determined as significant risk factors of LONIPCs. None of 18 patients who received the reduced-intensity conditioning (RIC) regimen developed LONIPCs, although there was no difference in overall survival between the MAC and RIC regimen. Notably, two immunodeficient patients who received busulfan-based MAC regimen under 2 years old developed LONIPC with no history of chronic GVHD after 5 years and 10 years from SCT, respectively, suggesting the direct toxicity of busulfan. CONCLUSION: Our study's findings indicate that the RIC regimen reduces the risk of LONIPCs in pediatric patients.

Successful coil embolization of a ruptured basilar artery aneurysm in a child with leukemia: a case report.

Ruptured intracranial aneurysms are rare in the pediatric population compared to adults. This has incited considerable discussion on how to treat children with this condition. Here, we report a child with a ruptured saccular basilar artery aneurysm that was successfully treated with coil embolization. A 12-year-old boy with acute lymphoblastic leukemia and accompanying abdominal candidiasis after chemotherapy suddenly complained of a severe headache and suffered consciousness disturbance moments later. Computed tomography scans and cerebral angiography demonstrated acute hydrocephalus and subarachnoid hemorrhage caused by saccular basilar artery aneurysm rupture. External ventricular drainage was performed immediately. Because the patient was in severe condition and did not show remarkable signs of central nervous system infection in cerebrospinal fluid studies, we applied endovascular treatment for the ruptured saccular basilar artery aneurysm, which was successfully occluded with coils. The patient recovered without new neurological deficits after ventriculoperitoneal shunting. Recent reports indicate that both endovascular and microsurgical techniques can be used to effectively treat ruptured cerebral aneurysms in pediatric patients. A minimally invasive endovascular treatment was effective in the present case, but long-term follow-up will be necessary to confirm the efficiency of endovascular treatment for children with ruptured saccular basilar artery aneurysms.

Early coagulation disorder after allogeneic stem cell transplantation is a strong prognostic factor for transplantation-related mortality, and intervention with recombinant human thrombomodulin improves the outcome: a single-center experience.

We retrospectively analyzed 60 cases of pediatric patients who received allogeneic stem cell transplantation (SCT) between 2000 and 2008, using the tentative scoring system for evaluation of early (<30 days) coagulation disorders. In the 41 patients who survived, D-dimer levels showed a transient increase 2 weeks after SCT and normalized thereafter, but these levels were persistently elevated in the 19 patients who died. Of 19 patients with a positive score, 11 died of transplantation-related complications [transplantation-related mortality (TRM) = 0.579] within 1 year, while none of the 41 with a negative score died during the same period. Since 2009, 12 of 30 patients had positive scores within 30 days after SCT. Intervention with recombinant human thrombomodulin (rhTM) was introduced for patients with a positive score, and 10 of these patients survived (TRM = 0.167) along with a dramatic improvement of D-dimer level. Although the effects of this treatment were observed in a limited number of patients, our observations suggest that early coagulation disorder after allogeneic SCT is a strong prognostic factor for TRM, and that intervention with rhTM improves TRM.

Irreversible leukoencephalopathy after reduced-intensity stem cell transplantation in a dyskeratosis congenita patient with TINF2 mutation.

Hematopoietic stem cell transplantation (HSCT) for dyskeratosis congenita (DC) is challenging due to severe treatment-related adverse effects. Development of pulmonary fibrosis or veno-occlusive disease is well described in DC. However, neurological complication after HSCT has not been reported. A 9-year-old Japanese male with DC harboring the TINF2 mutation received reduced-intensity HSCT. Unfortunately, patient developed posterior reversible encephalopathy syndrome-like symptoms plausibly result by combination of thrombotic microangiopathy, graft-versus-host disease, and persistent hypertension and has been persisted mental retardation. Therefore, to decrease risk in DC cases after HSCT, strict control of hypertension, graft-versus-host disease, and thrombotic microangiopathy is required.

Impact of influenza A(H1N1) in pediatric patients with cancer and hematologic disorders: establishment of information sharing system for swine influenza.

In Japan, we encountered a pandemic expansion of novel influenza A(H1N1) in September 2009, but the impact on patients with underlying disease remained unclear. The Tokyo Children Cancer Study Group (TCCSG) established a "novel influenza information-sharing system" to share real time information on how the novel influenza affects pediatric patients with cancer or other hematologic disorders. To facilitate reporting, we limited the items to only the basic data (underlying disease, age, sex), influenza-associated data (diagnostic method, therapy and outcome) and allowed space for free comments. We could share the information promptly, and found that this system worked well. One hundred and fifteen patients were reported between September 2009 and February 2010. Although eight patients needed to be hospitalized, none of the patients died, were admitted to intensive care units or demonstrated sequelae. The novel influenza A(H1N1) did not have a strong impact on pediatric patients with cancer or hematologic disorder at least during the 2009-2010 season.

[Assessment of chemotherapy-induced nausea and vomiting(CINV)using MASCC antiemesis tool].

Chemotherapy-induced nausea and vomiting (CINV) is one of the side effects causing significant psychological and physical suffering in patients receiving chemotherapy. Because CINV often impairs patients' quality of life and leads to cessation of treatments, antiemetic therapy has been thought important. Recently, the development of new antiemetic agents and the antiemetic guidelines provided by ASCO, NCCN, and MASCC etc. allow us to palliate CINV with appropriate antiemetic therapy. For appropriate antiemetic therapy, the patient must obtain accurate CINV information, particularly regarding whether it will be acute or delayed. MASCC first developed and posted the MASCC Antiemesis Tool (MAT) in 2004. The MAT is an eight-term scale for the assessment of acute and delayed nausea and vomiting, and is completed once per chemotherapy course. Although it is now validated in the US and UK and used worldwide, few reports have been available in Japan to use assessment tools including the MAT for acute and delayed CINV. We prospectively investigated the utility of the MAT. Fifteen ambulatory patients with breast cancer were subjected to evaluation, aged 29 to 73(median 58)years. In the results, the MAT allowed us to easily find patients treated with inappropriate antiemetic therapy. At the same time, it was easy to determine acute or delayed CINV, resulting in more appropriate treatment. The scale questions were unfamiliar to patients, but they clearly understood by means of a detailed explanation. Thus, it was suggested that the MAT is useful to assess antiemetic therapy. Consequently, it could contribute to completion of the chemotherapy.

Factors of thoracic cage deformity that affect pulmonary function in adolescent idiopathic thoracic scoliosis.

STUDY DESIGN: This clinical study examined the association between pulmonary function and thoracic cage deformities in scoliosis. OBJECTIVE: To determine the factors in spinal and thoracic cage deformities that affect pulmonary function in scoliosis. SUMMARY OF BACKGROUND DATA: Pulmonary function in scoliosis has generally been evaluated in terms of lateral spinal curvature. No previous report has evaluated changes in pulmonary function taking into consideration measurements reflecting not only spinal curvature but also thoracic cage deformities, although scoliosis is a three-dimensional deformity. METHODS: A total of 109 patients (mean age, 14.2 years) with adolescent idiopathic right thoracic scoliosis (mean lateral spinal curvature, 37.7 degrees) had full assessment of pulmonary function and a radiographic evaluation from radiographs of the whole spine, Moiré topography, and thoracic computed tomography. RESULTS: Multiple regression analysis (stepwise method) was performed at each vertebral level from T3-T12 to identify the factor that most strongly affects %VC. The correlation coefficient was highest at T9 and next highest at T8, with values of 0.641 (r2 = 0.411, P < 0.0001) and 0.625 (r2 = 0.390, P < 0.0001), respectively. At T9, multiple regression analysis showed that the sagittal diameter of the thoracic cage and the total lung area were identified as factors that most strongly affect %VC. Similarly, the sagittal diameter of the thoracic cage and the rotation angle to the sagittal plane were identified at T8. CONCLUSIONS: The factors that reduced %VC were the sagittal diameter of the thoracic cage, total lung area and vertebral rotation at the T8 and T9 levels.