Patient-reported quality of life after allogeneic hematopoietic cell transplantation or chemotherapy for acute leukemia.

When discussing treatment options for patients with acute leukemia, it is important to acknowledge the impact of allogeneic hematopoietic cell transplantation (allo-HCT) or chemotherapy on quality of life (QOL). We performed a cross-sectional questionnaire study that administered SF-36, FACT-Leukemia and EuroQOL5D to 524 acute leukemia survivors, to compare patient-reported QOL between chemotherapy and allo-HCT, and to elucidate predictors of QOL. Patients who received chemotherapy alone had a better physical QOL than those who received allo-HCT. On the other hand, the allo-HCT group reported a better mental QOL. In the comparison of QOL in the allo-HCT patients according to the presence of GVHD at survey, patients who had GVHD symptoms experienced statistically and clinically significantly worse QOL than those who did not. In the allo-HCT patients without GVHD, the physical QOL was comparable to that in the chemotherapy patients, and they experienced significantly better mental and general QOL than the chemotherapy patients. GVHD and immunosuppressive drugs at survey were strongly associated with worse QOL after allo-HCT. In the chemotherapy group, a shorter time between treatment completion and survey was significantly associated with worse QOL. Further evaluation of QOL by a longitudinal assessment with quantitative and qualitative analyses are warranted.

Limited sampling strategies to estimate the area under the concentration-time curve. Biases and a proposed more accurate method.

BACKGROUND: Over 100 limited sampling strategies (LSSs) have been proposed to reduce the number of blood samples necessary to estimate the area under the concentration-time curve (AUC). The conditions under which these strategies succeed or fail remain to be clarified. OBJECTIVES: We investigated the accuracy of existing LSSs both theoretically and numerically by Monte Carlo simulation. We also proposed two new methods for more accurate AUC estimations. METHODS: We evaluated the following existing methods theoretically: i) nonlinear curve fitting algorithm (NLF), ii) the trapezium rule with exponential curve approximation (TZE), and iii) multiple linear regression (MLR). Taking busulfan (BU) as a test drug, we generated a set of theoretical concentration-time curves based on the identified distribution of pharmacokinetic parameters of BU and re-evaluated the existing LSSs using these virtual validation profiles. Based on the evaluation results, we improved the TZE so that unrealistic parameter values were not used. We also proposed a new estimation method in which the most likely curve was selected from a set of pre-generated theoretical concentration-time curves. RESULTS: Our evaluation, based on clinical profiles and a virtual validation set, revealed: i) NLF sometimes overestimated the absorption rate constant Ka, ii) TZE overestimated AUC over 280% when Ka is small, and iii) MLR underestimated AUC over 30% when the elimination rate constant Ke is small. These results were consistent with our mathematical evaluations for these methods. In contrast, our two new methods had little bias and good precision. CONCLUSIONS: Our investigation revealed that existing LSSs induce different but specific biases in the estimation of AUC. Our two new LSSs, a modified TZE and one using model concentration-time curves, provided accurate and precise estimations of AUC.

Toll-like receptor 4-dependent adjuvant activity of Kakkon-to extract exists in the high molecular weight polysaccharide fraction.

Kakkon-to, a traditional herbal medicine (Kampo formula), has been used historically in China and Japan for the treatment of infectious diseases such as influenza and the common cold. However, the biological mechanism of its therapeutic action has not yet been elucidated. In this study, we investigated the immunological function of Kakkon-to and found that the high molecular weight fraction of the extract activated macrophages in vitro. This fraction was found to be composed primarily of saccharides and in vitro intensively stimulated mouse peritoneal macrophages that produce Th1 inflammatory cytokines such as tumor necrosis factor α (TNFalpha), interleukin-1beta (IL-1beta), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6). The fraction did not activate macrophages from C3H/HeJ lacking Toll-like receptor 4 (TLR4) or MyD88-deficient mice, indicating that macrophage activation by the fraction was mediated by TLR4. The route of administration of the fraction into mice regulated the kinetics of TNFalpha production in immune organs. Intravenous administration induced TNFalpha production in the four target organs of spleen, liver, lung, and Peyer’s patch; however, the most abundant production occurred in the liver and peaked at 30-60 min post administration. Peritoneal administration induced similar kinetics but the most abundant production occurred in the spleen. In contrast, oral administration induced TNFalpha production in the liver, lung, and Peyer’s patch, but not in the spleen. Although liver and lung are TNFalpha-abundant organs, production peaks in these organs occurred later than in Peyer’s patch. We also found that the fraction induced antibody production as an adjuvant against a specific antigen ovalbumin (OVA) when administered simultaneously and subcutaneously in a dose-dependent manner. Interestingly, the fraction induced IgG-class antibody in response to low doses of the antigen, which induced only IgM-class antibody when administered alone, suggesting that the fraction induces a class switch of immunoglobulin as an adjuvant in vivo. The high molecular weight fraction of Kakkon-to extract could be applicable as a potent immunostimulating drug and adjuvant.

Upper-extremity deep vein thrombosis related to central venous port systems implanted in cancer patients.

The purpose of the current study was to evaluate the incidence and course of upper-extremity deep vein thrombosis (UEDVT) related to an implanted central venous port (CV-port) system in cancer patients. From July 2007 to July 2008, 92 consecutive patients who underwent implantation of a CV-port for chemotherapy for colorectal cancer were prospectively enrolled in the study. All patients were examined at prescribed intervals by ultrasonography (US) to estimate the incidence of catheter-related venous thrombosis. We categorised ultrasound diagnosis into three types: Type 0, no thrombus; Type I, thrombi around catheter without obstruction of venous flow; Type II: thrombi with obstruction of venous flow. Upon initial ultrasound examination, 25 cases (27%) were categorised as Type 0, 64 (70%) as Type I and III (3%) as Type II. Of the 64 Type-I cases, 4 cases worsened to Type II within a month, and 3 others (including 1 patient who developed pulmonary embolism) became Type II after 1 month. Of the other Type-I cases, 12 cases improved to Type 0 and 45 cases remained Type I. All 10 patients categorised as Type II underwent anticoagulant therapy and resumed their chemotherapy without exacerbations of thrombosis. In cancer patients undergoing long-term chemotherapy, there is an unexpectedly high prevalence of catheter-related UEDVT, which can be detected by ultrasound at an early stage after implantation of a CV-port. Given that cancer patients with UEDVT may have worse outcomes than those without, clinicians should consider careful monitoring for UEDVT and introducing anticoagulant therapy.

Clinicopathological manifestations and treatment of intestinal transplant-associated microangiopathy.

Intestinal transplant-associated microangiopathy (i-TAM) is an important complication after allogeneic hematopoietic SCT. From 1997 to 2006, 87 of 886 patients with diarrhea after transplantation received colonoscopic biopsy. i-TAM, GVHD and CMV colitis were diagnosed histopathologically. The median duration from transplantation to the onset of diarrhea was 32 days (range: 9-130 days) and that from the onset of diarrhea to biopsy was 12 days (range: 0-74 days). The median maximal amount of diarrhea was 2 l/day (range: 130-5600 ml/day). Histopathological diagnosis included i-TAM (n=80), GVHD (n=26), CMV colitis (n=17) and nonspecific findings (n=2) with overlapping. Among 80 patients with i-TAM, abdominal pain was a major symptom, and only 11 patients fulfilled the proposed criteria for systemic TAM. Non-relapse mortality (NRM) among patients without resolution of diarrhea was 72% and i-TAM comprised 57% of NRM. NRM was 25% among patients without intensified immunosuppression, but was 52, 79 and 100% among those with intensified immunosuppression before diarrhea, after diarrhea, and before and after diarrhea, respectively. In conclusion, i-TAM is a major complication presenting massive refractory diarrhea and abdominal pain, which causes NRM. Avoiding intensified immunosuppression that damages vascular endothelium until the resolution of i-TAM may improve transplant outcome.

Clinical characteristics of chronic graft-versus-host disease following umbilical cord blood transplantation for adults.

Chronic GVHD is a significant complication following allogeneic hematopoietic stem cell transplantation; however, the clinical characteristics of chronic GVHD following cord blood transplantation (CBT) in adults have not been well described. Between March 2001 and November 2005, a total of 77 patients underwent CBT at eight transplantation centers of the Nagoya Blood and Marrow Transplantation Group. Of 77 patients, 29 survived without graft failure or progression of underlying diseases for at least 100 days after transplantation. The median age of the 29 patients was 42 years (range, 18-67 years). Seven patients developed chronic GVHD (extensive, n=4; limited, n=3) disease. The cumulative incidence of chronic GVHD 1 year after day 100 was 24% (95% confidence interval (CI), 11-41%), and the organs involved were the skin (n=6), oral cavity (n=4), liver (n=1) and gastrointestinal tract (n=1). In three patients, chronic GVHD was resolved with supportive care. The remaining four were successfully treated with additional immunosuppressive therapy. Event-free survival rates of the 29 patients with and without chronic GVHD 3 years after day 100 were 83 (95% CI, 27-97%) and 36% (95% CI, 17-56%), respectively (P=0.047). These results suggest that chronic GVHD following CBT is mild and has a graft-versus-malignancy effect.

High incidence of secondary failure of platelet recovery after autologous and syngeneic peripheral blood stem cell transplantation in acute promyelocytic leukemia.

Secondary failure of platelet recovery (SFPR), which is a delayed decline in platelet count after primary recovery following myeloablative hematopoietic SCT, is a significant problem in allogeneic SCT. However, its clinical characteristics have not been well described in autologous SCT for acute myeloid leukemia. We reviewed 11 consecutive patients who had received autologous or syngeneic SCT for acute promyelocytic leukemia. Seven of 11 patients (64%) had SFPR, which is defined as a decline in the platelet count to less than 30,000/microl for more than 7 days. The median onset of SFPR was day 36 (range, 25-51 days) and the median duration of thrombocytopenia was 13 days (range, 4-25 days). Of nine patients who received busulfan-containing preparative regimens, seven (78%) had SFPR and one had delayed primary platelet count recovery. Neither patient who received cyclophosphamide and total body irradiation as preparative regimens had SFPR. The clinical courses of SFPR were transient and self-limited. SFPR was not associated with relapse of underlying diseases, graft failure or other fatal morbidities. The unexpectedly high prevalence and the characteristics of SFPR may provide additional information on management following autologous SCT for acute myeloid leukemia.

Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults.

Post transplant immune disorders are problematic in cord blood transplantation (CBT) for adult patients, and optimal prophylaxis has not been established. We investigated whether intensive graft-versus-host disease (GVHD) prophylaxis using short-term methotrexate (MTX) has a prognostic impact on CBT. Post-CBT immune reactions were classified according to time course as pre-engraftment immune reaction (PIR), engraftment syndrome (ES) or acute GVHD. Between March 2001 and November 2005, a total of 77 patients underwent CBT at eight transplantation centers. Median age was 48 years (range, 18-69 years). Preparative regimens comprised myeloablative (n=31) or reduced-intensity (n=46). Acute GVHD prophylaxis included cyclosporine alone (n=23), tacrolimus alone (n=12), cyclosporine plus MTX (n=17), tacrolimus plus short-term MTX (n=23) or cyclosporine plus methylprednisolone (n=2). Cumulative incidences of PIR, ES and grade II-IV GVHD were 36, 12 and 23%, respectively. Short-term MTX exerted significant favorable effects on post-CBT immune reactions (hazard ratio, 0.55; 95% confidence interval (95% CI), 0.31-0.98; P=0.04) in multivariate analysis. Overall survival rates for patients with and without short-term MTX at day 180 were 59% (95% CI, 42-73%) and 16% (95% CI, 6.6-30%) (P=0.0001), respectively. Short-term MTX could offer one optimal regimen to reduce immune reactions and improve outcomes in CBT.

Risk and prognostic factors for Japanese patients with chronic graft-versus-host disease after bone marrow transplantation.

The incidence and prognostic factors for chronic graft-versus-host disease (cGVHD) were evaluated for 255 Japanese patients who survived more than 100 days after bone marrow transplantation, and of whom 119 (47%) developed cGVHD. Prior acute GVHD (grade 2-4) and use of an unrelated donor were significantly associated with the onset of cGVHD. Presence of cGVHD did not have an impact on mortality (hazard ratio (HR) = 0.89; 95% confidence interval (CI), 0.59-1.3). Three factors at diagnosis were associated with cGVHD-specific survival: presence of infection (HR = 4.1; 95% CI, 1.6-10.3), continuing use of corticosteroids at the onset of cGVHD (HR = 3.9; 95% CI, 1.7-9.1), and a Karnofsky performance score <80 (HR = 4.7; 95% CI, 2.0-11.3). The probability of cGVHD-specific survival at 4 years was 79% (95% CI, 70-86%). The severity and death rate of Japanese patients with cGVHD was lower than those for populations in Western countries, which might be the result of greater genetic homogeneity of Japanese ethnics. Our patients could not be accurately classified when the proposed prognostic models from Western countries were used, thus indicating the need for a different model to identify high-risk patients.

Solid tumors after hematopoietic stem cell transplantation in Japan: incidence, risk factors and prognosis.

To evaluate the incidence, risk factors and prognosis for solid tumors after hematopoietic stem cell transplantation (HSCT) in Japan, 809 patients who had received HSCT between 1981 and 2000 were retrospectively analyzed. In all, 19 newly diagnosed secondary cancers were observed. The risk for cancer development was 2.8 times as high as that for expected cases. The cumulative incidence ratios at 5 and 10 years were 1.9 and 4.2%, respectively. The risk was significantly elevated for buccal cavity cancer (standard incidental ratio (SIR), 44.42: 95% confidence interval (CI) 17.86-91.51), esophageal cancer (SIR, 22.36: 95% CI 6.09-57.25), and cervical cancer (SIR, 8.58: 95% CI 1.04-31.01). Of 15 patients who developed solid cancers following allografting, 12 had chronic graft-versus-host disease (GVHD), and all 10 patients with squamous cell carcinoma of the buccal cavity or esophagus had chronic GVHD. On multivariate analysis, extensive chronic GVHD and age over 45 years at the time of transplantation were associated with a higher risk for solid cancers. In all, 17 patients received therapy for secondary cancers, nine of whom are still alive and the 5-year probability of survival from the diagnosis is 42.8%. Our data suggest that early detection of secondary cancers is very important in prolonging overall survival.

Clinical value of multidetector row computed tomography in detecting lymph node metastasis of early gastric cancer.

AIMS: To evaluate the clinical value of multidetector row computed tomography (MDCT) as a pre-operative staging tool for lymph node metastasis in patients with early gastric cancer (EGC). METHODS: In 278 consecutive patients with EGC, lymph node metastasis was evaluated pre-operatively with MDCT at a slice thickness of 2.5mm (n=57), 5.0mm (n=188), or 7.5mm (n=33). RESULTS: Overall accuracy of nodal category from N0 to N3 was 86% for MDCT and 95% for operative assessment. Regarding accuracy in detecting at least one metastatic lymph node, area under curves (AUC) of receiver operating characteristics for 2.5, 5.0, and 7.5-mm slices and assessment during surgery were 0.87, 0.67 and 0.47, and 0.70, which were significantly different (P<0.0001). MDCT image with 2.5-mm could discriminate the presence of lymph node metastasis with diagnostic accuracy: sensitivity 80%; specificity 92%; positive predictive value (PPV) 50%; negative predictive value (NPV) 98%, whereas assessment during surgery was as follows: sensitivity 65%; specificity 98%; PPV 72%; and NPV 97%. CONCLUSIONS: These results suggest that pre-operative assessment with MDCT using thinner slices may detect at least one lymph node metastasis as accurately as assessment during surgery for patients with EGC.

Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation.

CMV disease remains a major infectious complication after allogeneic hematopoietic stem cell transplantation (HSCT). To investigate the relationship between CMV antigenemia, treatment with ganciclovir (GCV), and outcome, we retrospectively analyzed 241 consecutive patients at risk for CMV infection who underwent allogeneic HSCT. Antigenemia-guided pre-emptive strategy with GCV was used for all patients. CMV antigenemia developed in 169 patients (70.1%), and CMV disease in 18 patients (7.5%). Multivariate analysis showed that acute GVHD (grades II-IV) was the only risk factor for developing antigenemia, and acute GVHD and advanced age for CMV disease. GCV use, as well as acute GVHD and advanced age, significantly increased the risk for bacterial and fungal infection after engraftment. Those who developed CMV antigenemia had a poorer outcome than those who did not (log-rank, P=0.0269), although the development of CMV disease worsened the outcome with only borderline significance (log-rank, P=0.0526). In conclusion, detection of antigenemia proved to be a poor prognostic factor for HSCT patients, which may be attributed to a combination of factors, including CMV disease itself, the effect of treatment, and a host status that allows for reactivation of CMV. Optimal pre-emptive strategy needs to be determined.

Acute promyelocytic leukemia with apparently normal karyotype: molecular findings and response to all-trans retinoic acid.

Acute promyelocytic leukemia (APL) is specifically associated with a reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of a fusion of the retinoic acid receptor-alpha (RARA) gene and the promyelocytic leukemia (PML) gene. However, there are several reports describing APL cases lacking the t(15; 17). Many such cases are those bearing variant translocations involving chromosomes 15 or 17, and those with no chromosomal aberrations have rarely been reported. We have studied a patient with APL showing an apparently normal karyotype which was confirmed by spectral karyotyping (SKY). A submicroscopic PML-RARA fusion was identified by reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescent in situ hybridization (FISH). All-trans retinoic acid (ATRA) was effective as the initial therapy for remission induction and as the reinduction therapy after a relapse. The present study shows the key role of the fusion of PML-RARA in the responsiveness to ATRA as well as in the leukemogenesis of APL.

Low-intensity fetal lungs on MRI may suggest the diagnosis of pulmonary hypoplasia.

BACKGROUND: Pulmonary hypoplasia is a common cause of neonatal death. Despite the recent advances in prenatal diagnosis with US, the diagnosis of pulmonary hypoplasia is difficult. The recent application of fast MR imaging may provide additional valuable information. OBJECTIVE: To evaluate pulmonary hypoplasia in the fetus with MRI. MATERIALS AND METHODS: The subjects comprised 23 fetuses (18-40 weeks' gestation), including major anomalies diagnosed on fetal ultrasonography (n = 20), maternal abnormality (n = 2) and one normal twin. MRI was performed with a 1.5-T magnet and half-Fourier acquisition single-shot turbo spin-echo (HASTE) sequences. MR images were interpreted by three radiologists with special attention to the intensity of the lungs. The lung-to-liver intensity ratio was calculated by means of region-of-interest (ROI) analysis. The diagnosis of pulmonary hypoplasia depended on clinical, surgical and autopsy findings. RESULTS: All fetuses with normal pulmonary development showed high intensity in the lung except for one fetus at 24 weeks' gestational age. All fetuses with pulmonary hypoplasia showed lung of low intensity. CONCLUSIONS: Low-intensity fetal lung on MRI imaging indicates pulmonary hypoplasia after 26 weeks' gestation.

Remineralization across the resin-dentin interface: in vivo evaluation with nanoindentation measurements, EDS, and SEM.

OBJECTIVE: The purpose of this study was to evaluate the in vivo remineralization of the possible non-resin infiltrated hybridoid layer between the hybrid layer and the subjacent dentin substrate using nanoindentation, energy dispersive x-ray spectroscopy microanalyses (EDS), and scanning electron microscopy (SEM) technologies. METHOD AND MATERIALS: Twenty Class V cavities were placed in healthy adult monkey teeth. Each cavity was total etched with 37% phosphoric acid for 60 seconds, rinsed, and air dispersed, and SA-Primer was applied to the collagen layer. Cavities were divided into two groups: In group 1, Protect Liner (low-viscosity resin) and Clearfil AP-X (resin composite) were placed per manufacturer's directions, and no bonding agent was placed on the acid-etched interface. In group 2, Clearfil Photobond (bonding agent) was applied, and Protect Liner and Clearfil AP-X were placed as in group 1. Teeth were observed at 7 days (control) and 6 months by nanoindentation, EDS, and SEM. RESULTS: Six-month data showed an increased nanohardness in areas 5 pm adjacent to the demineralized or partially demineralized dentin interface. Following treatment with a conventional adhesive system on the acid-etched interface (group 2), there were increased nanohardness and calcium EDS measurements in the substrate just below the resin-dentin impregnated layer. CONCLUSION: Our 6-month in vivo nanoindentation and EDS data demonstrate that the non-resin infiltrated zone becomes remineralized following adhesive resin treatment.

Specific gravity of whole blood in cynomolgus monkeys (Macaca fascicularis), squirrel monkeys (Saimiri sciureus), and tamarins (Saguinus labiatus) and total blood volume in cynomolgus monkeys.

Blood collection is a common laboratory procedure in animal experiments. The purpose of this study is to establish baseline data for two essential hematologic parameters, total blood volume (TBV) and specific gravity of blood (SGB), of nonhuman primates. The SGB was determined by dropping samples of whole blood into cupric sulfate solution. The values for the mean SGB +/- 1 standard deviation are: cynomolgus monkeys, 1.0526 +/- 0.0019 [males (n = 39), 1.0531 +/- 0.0017; females (n = 48), 1.0522 +/- 0.001]; squirrel monkeys, 1.0555 +/- 0.0037 [males (n = 56), 1.0581 +/- 0.0027; females (n = 76), 1.0536 +/- 0.0032]; and tamarins, 1.0582 +/- 0.0020 [males (n = 13), 1.0582 +/- 0.0023; females (n = 17), 1.0581 +/- 0.0018]. To determine the TBV, blood was collected in tubes containing 1.5 mg EDTA after intravenous injection of Evans Blue solution. The TBV was obtained after correcting for the hematocrit and the dilution factor of the Evans Blue solution. The formulae were established to estimate TBV by referring to body weight (BW). There was no significance between TBV and BW in male monkeys weighing more than 6 kg.