Vaginal compared with intramuscular progestogen for preventing preterm birth in high-risk pregnant women (VICTORIA study): a multicentre, open-label randomised trial and meta-analysis.

OBJECTIVE: To compare the efficacy of two types of progestogen therapy for preventing preterm birth (PTB) and to review the relevant literature. DESIGN: A multicentre, randomised, open-label, equivalence trial and a meta-analysis. SETTING: Tertiary referral hospitals in South Korea. POPULATION: Pregnant women with a history of spontaneous PTB or short cervical length (<25 mm). METHODS: Eligible women were screened and randomised at 16-22 weeks of gestation to receive either 200 mg of vaginal micronised progesterone daily (vaginal group) or an intramuscular injection of 250 mg 17α-hydroxyprogesterone caproate weekly (IM group). Stratified randomisation was carried out according to participating centres and indications for progestogen therapy. This trial was registered at ClinicalTrials.gov (NCT02304237). MAIN OUTCOME MEASURE: Preterm birth (PTB) before 37 weeks of gestation. RESULTS: A total of 266 women were randomly assigned and a total of 247 women (119 and 128 women in the vaginal and IM groups, respectively) were available for the intention-to-treat analysis. Risks of PTB before 37 weeks of gestation did not significantly differ between the two groups (22.7 versus 25.8%, P = 0.571). The difference in PTB risk between the two groups was 3.1% (95% CI -7.6 to 13.8%), which was within the equivalence margin of 15%. The meta-analysis results showed no significant differences in the risk of PTB between the vaginal and IM progestogen treatments. CONCLUSION: Compared with vaginal progesterone, treatment with intramuscular progestin might increase the risk of PTB before 37 weeks of gestation by as much as 13.8%, or reduce the risk by as much as 7.6%, in women with a history of spontaneous PTB or with short cervical length. TWEETABLE ABSTRACT: Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation.

Women with threatened preterm labour followed by term delivery have an increased risk of spontaneous preterm birth in subsequent pregnancies: a population-based cohort study.

OBJECTIVES: To evaluate the association of a history of threatened preterm labour (TPL) followed by term delivery with the risk of spontaneous preterm delivery (PTD) in subsequent pregnancy. DESIGN: Population-based cohort study. SETTING: Data of the National Health Insurance Claims Database and a national health-screening programme for infants and children in South Korea. POPULATION: Women who had their first singleton delivery in 2010 and a subsequent second singleton delivery between 2011 and 2015. METHODS: Multivariable analysis adjusting for maternal age and interval between first and second deliveries was used to assess the risk of PTD based on PTD, TPL followed by term delivery, and term delivery in the first pregnancy. MAIN OUTCOME MEASURES: The risk of PTD during the second pregnancy. RESULTS: This study included 115 629 women with two consecutive deliveries during the study period. Spontaneous PTD rates in the second pregnancy were 7.71, 2.22 and 1.02% in women with PTD, TPL followed by term delivery, and term delivery in the first pregnancy, respectively. Threatened preterm labour followed by term delivery in the first pregnancy was associated with increased risk of PTD in the subsequent pregnancy after adjustment for potential confounding factors (adjusted odds ratio 2.21; 95% CI 1.76-2.78). CONCLUSION: Although women with a history of TPL followed by term delivery had a lower risk of PTD during a subsequent pregnancy compared with those with history of previous PTD, they still had a significantly increased risk of PTD compared with those who delivered at term without TPL. TWEETABLE ABSTRACT: The history of threatened preterm labour followed by term delivery is related to increased risk of subsequent spontaneous preterm delivery.

Immunologic regulatory effects of human umbilical cord blood-derived mesenchymal stem cells in a murine ovalbumin asthma model.

BACKGROUND: Mesenchymal stem cells (MSCs) have multiple immunomodulatory properties and hold therapeutic potential for inflammatory diseases. However, the therapeutic and immunologic effects of human umbilical cord blood-derived MSCs (huMSCs) remain largely unexamined for asthma. OBJECTIVE: This study was to investigate the immunomodulatory properties of huMSCs in an ovalbumin (OVA)-induced murine asthma model. METHODS: Mice were injected intraperitoneally with OVA and an aluminium hydroxide adjuvant. huMSCs were administered via the tail vein (5×105 cells/100 uL) to female BALB/c mice prior to the initial OVA challenge. The effects of huMSCs were assessed by investigating airway hyperresponsiveness, histological changes, inflammatory cell numbers, serum allergen-specific antibodies, cytokine production in spleen, lung tissue, and bronchoalveolar lavage (BAL) fluid as well as expansion of regulatory T cells. RESULTS: Administration of huMSCs significantly reduced methacholine bronchial hyperresponsiveness and eosinophil counts in BAL cells. Similarly, there was a significant decrease in serum OVA-specific IgE and IgG1 levels along with Th2 cytokine production (IL-4, IL-5, and IL-13) in the lung and spleen tissues, whereas increased percentage of regulatory T cells was observed after treatment with huMSCs. CONCLUSIONS: Our results suggest that huMSC treatment reduces OVA-induced allergic inflammation, which could be mediated by regulatory T cells.

Revisiting the diagnostic criteria of clinical chorioamnionitis in preterm birth.

OBJECTIVE: To re-evaluate the utility of the conventional criteria for clinical chorioamnionitis in the prediction of early-onset neonatal sepsis (EONS) in preterm birth. DESIGN: Retrospective cohort study. SETTING: Seoul, Republic of Korea. SAMPLE: A total of 1468 singleton births between 24 and 34 weeks due to preterm labour (n = 713) or preterm prelabour rupture of membranes (n = 755). METHOD: We evaluated three diagnostic categories of clinical chorioamnionitis: Criteria 1, conventional criteria; Criteria 2, combination of any three conventional parameters without prerequisite fever; Criteria 3, Criteria 1 plus positive maternal C-reactive protein and neutrophil left-shift into minor criteria. EONS included proven or suspected sepsis within 7 days following birth. Neonatal morbidity and mortality of EONS were also reviewed. MAIN OUTCOME MEASURES: Diagnostic performance of three combinations. RESULTS: The prevalence of EONS was 13.8%. Among 203 cases of EONS, maternal manifestation of clinical chorioamnionitis by criteria 1 was evident in only one out of seven, indicating 15.3% sensitivity for EONS prediction. However, with application of criteria 2, sensitivity significantly increased to 34.0%, while compromising specificity from 92.3% to 78.7%. Criteria 3 showed similar diagnostic performance compared with criteria 1 (sensitivity 16.7%, specificity 91.6%). Overall, neonatal mortality and neonatal composite morbidity in EONS were 14.9% and 67.8%, respectively, and there was no difference in neonatal morbidity and mortality between neonates whose mothers showed fever as a sign of clinical chorioamnionitis and those whose mothers did not. CONCLUSION: The renouncement of fever as a prerequisite for the criteria of clinical chorioamnionitis could increase sensitivity for the identification of EONS, a serious outcome of preterm birth. TWEETABLE ABSTRACT: The renouncement of fever as an essential can increase sensitivity for prediction of neonatal sepsis.

Evaluation of interface trap densities and quantum capacitance in carbon nanotube network thin-film transistors.

The interface trap density in single-walled carbon nanotube (SWNT) network thin-film transistors (TFTs) is a fundamental and important parameter for assessing the electronic performance of TFTs. However, the number of studies on the extraction of interface trap densities, particularly in SWNT TFTs, has been insufficient. In this work, we propose an efficient technique for extracting the energy-dependent interface traps in SWNT TFTs. From the measured dispersive, frequency-dependent capacitance-voltage (C-V) characteristics, the dispersive-free, frequency-independent C-V curve was obtained, thus enabling the extraction and analysis of the interface trap density, which was found to be approximately 8.2 × 10(11) eV(-1) cm(-2) at the valence band edge. The frequency-independent C-V curve also allows further extraction of the quantum capacitance in the SWNT network without introducing any additional fitting process or parameters. We found that the extracted value of the quantum capacitance in SWNT networks is lower than the theoretical value in aligned SWNTs due to the cross point of SWNTs on the SWNT network. Therefore, the method proposed in this work indicates that the C-V measurement is a powerful tool for obtaining deep physical insights regarding the electrical performance of SWNT TFTs.

An important role of tumor necrosis factor receptor-2 on natural killer T cells on the development of dsRNA-enhanced Th2 cell response to inhaled allergens.

BACKGROUND: Recent evidence indicates that TNF-α is a key mediator of the development of dsRNA-enhanced Th2 cell response to inhaled allergens. Natural killer T (NKT) cells may be a candidate source of Th2-polarizing cytokines. OBJECTIVE: The objective of this study was to evaluate the role of lung NKT cells on the development of TNF-α-mediated Th2 cell response. METHODS: A virus-associated asthma mouse model was generated by the administration of ovalbumin (OVA, 75 µg) and poly[I:C] (0.1 µg). Role of NKT and type I NKT cells was evaluated using CD1d- and Jα18-deficient mice. TNF-α receptors (TNFRs) were antagonized by using TNFR blocking peptides. RESULTS: The number of infiltrated NKT cells was increased in a virus-associated asthma mouse model. Increase in Th2 and Th17 cytokine levels in wild-type mice were abolished in both CD1d- and Jα18-deficient mice. In vitro co-culture experiments with alveolar macrophages and NKT cells showed that TNF-α produced by macrophages in the presence of poly[I:C] acts on NKT cells, inducing production of Th2-polarizing cytokines. Moreover, the induction of Th2-polarizing cytokines by poly[I:C] or recombinant TNF-α was impaired in both CD1d- and Jα18-deficient mice and that the above effect was reversed by a TNF-α receptor-2 (TNFR2) blocking peptide, but not by a TNFR1 blocker. CONCLUSIONS: These findings suggest that NKT cells play a key role in the development of Th2 cell response to inhaled allergens and that TNF-α produced by alveolar macrophages induces Th2 cell response, via TNFR2 on NKT cells.

Extracellular vesicles, especially derived from Gram-negative bacteria, in indoor dust induce neutrophilic pulmonary inflammation associated with both Th1 and Th17 cell responses.

BACKGROUND: Many bacterial components in indoor dust can evoke inflammatory pulmonary diseases. Bacteria secrete nanometre-sized vesicles into the extracellular milieu, but it remains to be determined whether bacteria-derived extracellular vesicles in indoor dust are pathophysiologically related to inflammatory pulmonary diseases. OBJECTIVE: To evaluate whether extracellular vesicles (EV) in indoor air are related to the pathogenesis of pulmonary inflammation and/or asthma. METHODS: Indoor dust was collected from a bed mattress in an apartment. EV were prepared by sequential ultrafiltration and ultracentrifugation. Innate and adaptive immune responses were evaluated after airway exposure of EV. RESULTS: Repeated intranasal application of indoor-dust-induced neutrophilic pulmonary inflammation accompanied by lung infiltration of both Th1 and Th17 cells. EV 50-200 nm in diameter were present (102.5 µg protein concentration/g dust) in indoor dust. These vesicles were internalized by airway epithelial cells and alveolar macrophages, and this process was blocked by treatment of polymyxin B (an antagonist of lipopolysaccharide, an outer-membrane component of Gram-negative bacteria). Intranasal application of 0.1 or 1 µg of these vesicles for 4 weeks elicited neutrophilic pulmonary inflammation. This phenotype was accompanied by lung infiltration of both Th1 and Th17 cells, which were reversed by treatment of polymyxin B. Serum dust EV-reactive IgG1 levels were significantly higher in atopic children with asthma than in atopic healthy children and those with rhinitis or dermatitis. CONCLUSION & CLINICAL RELEVANCE: Indoor dust EV, especially derived from Gram-negative bacteria, is a possible causative agent of neutrophilic airway diseases.

Association between the CD226 rs763361 polymorphism and susceptibility to autoimmune diseases: a meta-analysis.

OBJECTIVE: The aim of this study was to explore whether the CD226 rs763361 polymorphism confers susceptibility to autoimmune diseases. METHODS: A meta-analysis was conducted on the associations between the CD226 rs763361 polymorphism and autoimmune diseases using: 1) allele contrast, and 2) the recessive, 3) dominant and 4) additive models. RESULTS: Ten articles that included 17 comparative studies on a total of 8900 patients and 10,295 controls were included in the meta-analysis. These studies were performed on seven European, five Asian and five South American sample populations. Meta-analysis of all study subjects revealed an association between the CD226 rs763361 T allele and the susceptibility to autoimmune diseases (odds ratio; OR 1.162, 95% confidence interval; CI 1.097-1.230, p < 1.0 × 10(-8)). Stratification by ethnicity indicated an association between the CD226 rs763361 T allele and autoimmune disease in Europeans and South Americans (OR 1.134, 95% CI 1.079-1.191, p = 6.7 × 10(-7); OR 1.308, 95% CI 1.160-1.475, p = 1.1 × 10(-5)) and between the CD226 rs763361 TT genotype and autoimmune disease in Asians (OR 1.366, 95% CI 1.130-1.650, p = 0.001). Disease-specific meta-analysis showed an association between systemic lupus erythematosus (SLE) and the CD226 rs763361 T allele (OR 1.150, 95% CI 1.040-1.271, p = 0.006), but no association between rheumatoid arthritis and the CD226 rs763361 polymorphism (OR for the T allele 1.207, 95% CI 0.913-1.596, p = 0.187). On the other hand, associations were found between the CD226 rs763361 T allele and systemic sclerosis (SSc) and type 1 diabetes (T1D) (OR 1.126, 95% CI 1.020-1.244, p = 0.019; OR 1.353, 95% CI 1.102-1.660, p = 0.004). CONCLUSIONS: This meta-analysis demonstrates the CD226 rs763361 polymorphism confers susceptibility to autoimmune disease in Europeans, South Americans and Asians, and in particular, shows that the CD226 rs763361 polymorphism is associated with SLE, SSc and T1D. These results support the existence of an association between the CD226 gene and a subgroup of autoimmune diseases.

Association of a polymorphism in the intron 7 of the SREBF1 gene with osteonecrosis of the femoral head in Koreans.

Reduction or disruption of the blood supply to the bone is involved in the pathogenesis of osteonecrosis of the femoral head (ONFH). An altered lipid metabolism is one of the major risk factors for ONFH. Sterol regulatory element binding protein, SREBF1 activates genes regulating lipid biosynthesis. The aim of this study was to examine the association between the polymorphisms of the SREBF1 gene and ONFH susceptibility in the Korean population. The SREBF1 gene in 24 unrelated Korean individuals was sequenced and two polymorphisms were detected. Two variants, IVS6 - 48 C > T and IVS7 + 117 A > G, were genotyped in 423 ONFH patients and 348 controls. The genotype frequency of IVS7 + 117 A > G in ONFH patients was significantly different from that of the control group with P value < 0.0001 (Adjusted OR; 6.88, 95% CI; 3.74-12.67). Moreover, the IVS7 + 117 A > G genotype showed an association with men, and further analysis stratified by etiological factors indicated that the genotype data was significantly associated with a high risk for patients with alcohol-induced ONFH (P < 0.0001). We found that the IVS7 + 117 A > G polymorphism of the SREBF1 gene is associated with an increased risk of ONFH in the Korean population.

Vascular endothelial growth factor in allergen-induced nasal inflammation.

BACKGROUND: Increased vessel number and permeability are important features of the nasal mucosa in allergic rhinitis (AR), and are mediated in part by the cytokine vascular endothelial growth factor (VEGF). Eosinophils are the major effector cells in the nasal secretions of patients with AR during the responses to allergen challenges. To evaluate the involvement of VEGF in nasal allergic inflammation, we monitored the levels of VEGF, eosinophil cationic protein (ECP), and specific antibodies in the nasal lavage fluids (NLFs) of patients with AR in response to Dermatophagoides pteronyssinus (Dpt). METHODS: Sixty-three subjects with sensitization to Dpt were enrolled: 29 patients with AR (group I) who showed positive responses in a nasal provocation test (NPT) with Dpt; and 34 asymptomatic controls (group II) who showed sensitization to Dpt but negative NPT results. NLF samples were collected at baseline, 10, 30, and 60 min, and at 3, 6, and 24 h during the NPT. The ECP levels in the NLF samples were measured using the ImmunoCAP system. VEGF and Dpt-specific IgE, IgA, and IgG in the NLF samples were detected by ELISA. RESULTS: The eosinophil counts and ECP levels in the samples were significantly increased in group I, but not in group II, during the early and late responses. Although the baseline VEGF level was not significantly different between groups I and II, increased VEGF production was noted in group I after the NPT, especially during the early response. The level of Dpt-specific IgA was significantly increased in group I during the NPT. A relationship was found between the levels of VEGF and ECP or Dpt-specific IgA in the NLF samples collected at 10 min and at 3-6 h (P<0.05, respectively). CONCLUSION: Nasal VEGF secretion in response to allergen exposure may augment eosinophilic inflammation in the nasal mucosa of patients with AR.

Clinical and immunologic findings of methylene diphenyl diisocyanate-induced occupational asthma in a car upholstery factory.

BACKGROUND: Although methylene diphenyl diisocyanate (MDI) is widely used in many industries, there have been few immunological studies of MDI-induced occupational asthma. OBJECTIVES: We investigated the effects of MDI exposure on the clinical and immunologic condition of workers in a single car upholstery factory. METHODS: Fifty-eight MDI-exposed workers were studied. Work-related lower-respiratory symptoms (WRRS) were identified using a questionnaire. Serum-specific IgE and IgG antibodies to MDI-human serum albumin conjugate were detected by ELISA. Atopy was evaluated using a skin prick test. MDI-induced occupational asthma was confirmed in the symptomatic workers with a positive result on an MDI-specific inhalation test. RESULTS: Thirteen (22.4%) of the subjects complained of WRRS. MDI-induced occupational asthma was confirmed in five (8.6%) of the workers, and occupational eosinophilic bronchitis was confirmed in two (3.5%). The prevalence of specific IgG antibodies (20.7%) was higher than that of specific IgE antibodies (8.6%). The prevalence of MDI-induced occupational asthma/eosinophilic bronchitis was strongly associated with the presence of both WRRS and serum-specific IgG antibodies to an MDI-human serum albumin conjugate (P<0.01, <0.05, respectively). CONCLUSION: These findings suggest that MDI could be a causative agent of occupational asthma among MDI-exposed workers. The prevalence of MDI-induced occupational asthma was 8.6%, and MDI-induced eosinophilic bronchitis was confirmed in two workers. The presence of work-related lower-respiratory symptoms and serum-specific IgG antibodies to an MDI-human serum albumin conjugate may be used to predict MDI-induced occupational asthma/eosinophilic bronchitis in MDI-exposed workers.

Isolation of embryonic stem cells from enhanced green fluorescent protein-transgenic mouse and their survival in the cochlea after allotransplantation.

BACKGROUND: To study cell replacement therapy using embryonic stem (ES) cells in mice, avoiding immune rejection and tracing the fate of transplanted cells are important issues. This study was carried out to isolate ES cells ubiquitously expressing enhanced green fluorescent protein (EGFP) and test the survival of these cells in allografts in the cochlea of inbred C57BL/6 mice. METHODS: Putative ES cells were isolated from blastocysts collected from C57BL/6-green mice ubiquitously expressing EGFP. Pluripotency of these cells was tested by expression of stem cell markers and in vitro differentiation of the cells into embryoid bodies. Isolated EGFP-transgenic ES cells were injected into the cochlea of deafened inbred C57BL/6 mice, and survival of transplanted cells was identified in histologic sections of the cochlea. RESULTS: Putative ES cells expressed cellular markers for ES cells, including alkaline phosphatase, Oct-4, Nanog and stage-specific embryonic antigen-1. These cells formed embryoid bodies in suspension cultures. Incorporation of transplanted cells was found at the area of spiral ganglion neurons, auditory nerve fibers reaching the organ of Corti and stria vascularis in the scala media. Grafted cells were also found at the location of inner hair cells underneath the tectorial membrane. DISCUSSION: The isolation of ES cells from the EGFP-transgenic mouse and transplantation into allogeneic inbred mice may be a useful means of studying cell therapy with respect to the ubiquitous and stable expression of EGFP and elimination of graft rejection.

Palpable breast masses with probably benign morphology at sonography: can biopsy be deferred?

BACKGROUND: When a palpable breast mass is detected, a biopsy is usually performed even if the mass reveals probably benign morphologic features on imaging, as there is relatively little data reporting the outcome of such breast masses. PURPOSE: To determine the negative predictive value for sonographic evaluation of palpable breast masses with probably benign morphology, and to assess whether follow-up may be an acceptable alternative to immediate biopsy. MATERIAL AND METHODS: Of the 1399 sonograms of palpable masses from January 2004 to September 2005, there were 397 patients with masses of probably benign morphology. This study included 274 of these patients (age range 12-64 years, mean age 34 years) with 312 palpable masses that were pathologically confirmed by fine-needle aspiration (n=7), ultrasound (US)-guided core needle biopsy (n=180), or surgical biopsy (n=125). The false-negative rate, negative predictive value (NPV), and 95% confidence interval (CI) were calculated using the SPSS statistical software package for Windows, version 12.0. A P value <0.05 was considered statistically significant. RESULTS: Of the 312 masses, there were 310 benign lesions and two malignancies, resulting in a false-negative rate of 0.6% (NPV 99.4%, P value=0.0432, 95% CI 0.0-1.5%). CONCLUSION: The negative predictive value of sonography for palpable breast masses with probably benign morphology is high (99.4%). Therefore, short-term imaging follow-up can be an acceptable alternative to immediate biopsy, similar to the management of nonpalpable probably benign lesions (BI-RADS category 3).

Photonic crystal lasers in InGaAsP on a SiO(2)/Si substrates and its thermal impedance.

Two-dimensional photonic crystal defect lasers in InGaAsP membranes directly bonded to a SiO(2)/Si substrate have been demonstrated. Lasing at wavelengths near 1550 nm was obtained with incident threshold pump powers as low as 1.5 mW. Good agreement between experimental data and three-dimensional finite-difference time-domain (FDTD) simulation was achieved. The thermal impedance of this laser is also characterized.

Time to first flare-up episode of GVHD can stratify patients according to their prognosis during clinical course of progressive- or quiescent-type chronic GVHD.

GVHD-specific survival (GSS) has been investigated as a potential study end point to describe the clinical course and outcome of chronic GVHD (cGVHD). However, reaching this end point requires a long observation time. We hypothesized that the time to the first flare-up (FFU) of cGVHD (TTF) can be an alternative statistical end point to GSS. This retrospective study included 96 patients with a diagnosis of cGVHD from a cohort of 119 patients with a prior history of acute GVHD. The median TTF was 73 days after the diagnosis of cGVHD. The 2-year cumulative incidences of first, second and third episodes of flare-up (FU) during courses of cGVHD were estimated as 69.5, 46.4 and 22.1%. Those patients who did not have an episode of FU of cGVHD had 96.0% of 2-years GSS rate, while those with 1 and > or =2 episodes had 50.8 and 46.8%, respectively (P=0.001). Shorter TTF was associated with poor GSS and decreased overall survival. The shorter TTF during the course of cGVHD was significantly associated with extensive cGVHD (P=0.002), Hopkins' risk category (P=0.022) and progressive-type cGVHD (P<0.001) in multivariate analysis. We propose that TTF can be an alternative end point to GSS in cGVHD trials.

Risk score model for fatal intracranial hemorrhage in acute leukemia.

To build a risk score (RS) model of fatal intracranial hemorrhage (FICH) in patients with acute leukemia, we retrospectively assessed risk factors in 792 patients newly diagnosed with acute leukemia, 41 of whom had analyzable FICH. We found that female gender (relative risk (RR) = 5.234, P<0.001), acute promyelocytic leukemia (RR = 4.057, P = 0.003), leukocytosis (RR = 3.301, P = 0.004), thrombocytopenia (RR = 3.283, P = 0.005) and prolonged prothrombin time (RR = 3.291, P = 0.016) were significantly associated with occurrence of FICH in multivariate analysis. To calculate RS for FICH, one point was assigned for each risk factor, making the RS between 0 and 5. The RS model segregated patients into three prognostic groups: a low-risk group (LRG) for RS of 0 or 1; an intermediate-risk group (IRG) for RS of 2 or 3; and a high-risk group (HRG) for RS of 4 or 5. Expectation of FICH was well correlated with risk groups (all P-values < 0.001). Overall survival was significantly shorter in the HRG compared with the LRG. The RS model we constructed to predict the occurrence of FICH will be verified through prospective studies.

Risk-factor analysis for predicting progressive- or quiescent-type chronic graft-versus-host disease in a patient cohort with a history of acute graft-versus-host disease after allogeneic stem cell transplantation.

This study attempts to identify variables that can predict the development of progressive- or quiescent-type chronic GVHD (pq cGVHD) and transplant outcomes after the diagnosis of cGVHD in 99 patients who experienced acute GVHD (aGVHD) after allogeneic SCT. The prognostic significance of various clinical parameters at diagnosis of cGVHD was examined to determine the prognostic factors for GVHD-specific survival (GSS) in patients with pq cGVHD. Among 118 patients who experienced any degree of aGVHD, 99 were evaluated for cGVHD. The incidence of overall and extensive pq cGVHD at 2 years was estimated as 84.4 and 63.1%, respectively. A multivariate analysis showed that severe aGVHD (grade 3, 4) (P=0.022), primary treatment failure (P=0.009) and elevated alkaline phosphatase (P=0.001) were all significant independent factors predicting a higher overall incidence of pq cGVHD. The GSS and probability of systemic immunosuppressive treatment at 2 years after diagnosis of cGVHD were estimated as 55.9 and 51.9%. GVHD-specific survival was significantly associated with performance status (P=0.004) and lymphocytopenia (

Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

Clinical impact of imatinib was evaluated in 20 patients (median age, 37 years; range, 15-67 years) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), who were administered with induction chemotherapy of daunorubicin, vincristine, prednisolone, and L-asparaginase, along with imatinib 600 mg/day during remission induction and 400 mg/day during consolidation courses. One patient died on day 14 from septic shock, while the remaining 19 achieved complete remission (CR). In total, 15 patients underwent allogeneic hematopoietic cell transplantation (HCT) during first CR. After median follow-up period of 799 days, six patients experienced recurrence; two with early recurrence within 100 days, one with leptomeningeal recurrence at 11 month, and three with post-HCT recurrence. Eight patients died. Median CR duration (821 days) and median patient survival (894 days) in the study were significantly longer by 2.9- and 2.3-fold, respectively, when compared to those of 18 historical patients treated with same regimen of combination chemotherapy without imatinib. Toxicities of the combined treatment were manageable and included grade 4 myelosuppression (n = 20) and reversible > or = grade 3 hyperbilirubinemia (n = 4). Beneficial clinical effects were observed when imatinib was added to combination chemotherapy in patients with newly diagnosed Ph+ ALL. Further studies with larger number of patients are necessary.

Severe metabolic abnormalities after allogeneic hematopoietic cell transplantation.

Severe metabolic abnormalities occurring within 100 days after allogeneic hematopoietic cell transplantation (HCT) were investigated in 311 patients. The metabolic abnormalities included hyper- and hypocalcemia, hypophosphatemia, hyper- and hypokalemia, hyper- and hyponatremia, hyper- and hypomagnesemia, hypercholesterolemia, hyper- and hypoglycemia, and hyperuricemia. Severe abnormalities, defined as grades III-V by NCI CTCAE v3.0, occurred in 269 patients (86.5%). Multivariate analysis revealed that patients with moderate-to-severe hepatic veno-occlusive disease had significantly higher risk for the occurrence of severe metabolic abnormalities. Grades III-IV acute graft-versus-host disease was the most frequently associated with individual metabolic abnormalities. Patients with at least one severe metabolic abnormality had significantly higher day 100 nonrelapse mortality (P=0.015) and lower 5-year overall survival (P=0.002) than those without severe abnormalities. The number of metabolic abnormalities also stratified the patients with different clinical outcomes. In conclusion, severe metabolic abnormalities occurring within 100 days after allogeneic HCT were common, and their occurrence was significantly associated with inferior clinical outcomes. These results indicate that metabolic parameters should be monitored in patients undergoing allogeneic HCT and that the occurrence of severe metabolic abnormalities should be considered an important toxicity parameter in prospective clinical trials regarding allogeneic HCT.