Intermediate Subgroups Research Articles

Acute myeloid leukemia outcome: role of nucleotide excision repair polymorphisms in intermediate risk patients

In acute myeloid leukemia (AML), cytogenetics predicts treatment outcome for the favorable and poor subgroups but not for the intermediate subgroup. Polymorphisms within the nucleotide excision repair (NER) pathway may lead to interindividual differences in DNA repair capacity, influencing outcome. We studied the role of six polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, XPG Asp1104His, and CCNH Val270Ala) in overall and disease-free survival among 170 adult de novo patients with intermediate cytogenetics (diploid [n = 117]; non-diploid [n = 53]), treated with induction chemotherapy. Kaplan–Meier and Cox proportional hazards models were performed. Diploid patients with the XPD AC/CC genotype survived shorter than those with the wild-type genotype (median survival 22 vs. 40 months, p = 0.03). Diploid patients with XPC CT/TT genotype survived shorter than those with the wild-type genotype (median survival 15 vs. 30 months, p = 0.02). After adjusting for clinical and sociodemographic variables, patients carrying both XPD AC/CC and XPC CT/TT had a greater than two-fold increased risk of dying, compared to those with the wild-type genotypes (HR = 2.49; 95% CI: 1.06–5.85). No associations were observed for disease-free survival. This combined genotype may modulate treatment effect, decreasing overall survival. These findings could in the future help select treatments for patients with normal cytogenetics.

Origin of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus, China

Origin of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus, China

The Cell Polarity PTK7 Receptor Is Expressed in Myeloid Cells and Acts as a Modulator of the Chemotherapeutic Response in AML Patients.

Abstract 1571Poster Board I-596The pseudo tyrosine kinase receptor 7 (PTK7) is an orphean tyrosine kinase receptor assigned to the planar cell polarity pathway (PCP). It has been recently described and plays a major role during embryogenesis and epithelial tissue organisation. To date there is no report in the litterature considering a potential implication in hematopoiesis. In silico and in vitro analysis found that PTK7 was also expressed in normal myeloid progenitors and CD34+ CD38- bone marrow cells in humans. Preliminary results from our team showed that PTK7 was also expressed in various leukemic cell lines such Jurkat, TF-1 or KG-1a. We decided to perform a wide range multicolour immunophenotyping screen on patients with acute myeloid leukemia (AML) at diagnosis and to investigate the role of PTK7 in AML in vitro. More than 250 patient samples were evaluated and we demonstrated that PTK7 was largely expressed in AML as 72% of the samples were PTK7 positive. Its expression mostly correlates with granulocytic lineage differentiation. PTK7 expression was associated with a lower WBC count at diagnosis and a lower frequency of extramedullary disease whatever was FAB subtype. Interestingly, PTK7 expression was associated with some cytogenetic subgroups including CBF-AML and APL. There was no correlation with molecular subgroups (i.e. FLT3-ITD/NPM1/CEBPA status). Overall Survival and Relapse Free Survival were evaluated in non-APL patients treated with induction chemo (n=182). Patients with PTK7 positive AML are more resistant to anthracycline-based frontline therapy with a significantly reduced Relapse Free Survival in a multivariate analysis model integrating all pre treatment variables (2 year probability of RFS= 29% vs 66% for PTK7 negative patients, p= 0.003). Forrest plot analysis showed that the negative impact of PTK7 expression was the most significant in intermediate cytogenetic risk subgroup and when PTK7 was aberrantly expressed in M4-M5 FAB subtypes. There was no demonstrated impact on CR. In cultured cells, expression of PTK7 promotes leukemia cell migration, cell survival and resistance to anthracyclin-induced apoptosis. There was no effect of PTK7 expression on cell proliferation in tritiated thymidine assay. In the absence of known inhibitor of PTK7, we produced a soluble recombinant PTK7-Fc protein that efficiently competes for PTK7 functions in cell migration and survival assays in cell lines and primary AML samples. These data were confirmed using a shRNA strategy. We conclude that PTK7 is a PCP component expressed in the myeloid progenitor compartment that conveys promigratory and anti-apoptotic signal to leukemia cells. Its use as a potential biomarker or therapeutical target should be investigated. DisclosuresNo relevant conflicts of interest to declare.

High Serum Lactate Dehydrogenase (LDH) Is An Important Prognostic Factor in the Era of Novel Agents and Adds to the Prognostic Value of the International Staging System (ISS) in Patients with Multiple Myeloma.

Abstract 1819Poster Board I-845Several older studies have shown that high serum LDH is associated with features of advanced disease and with an inferior survival of symptomatic patients with MM who require treatment. It is however unclear whether LDH may add to the prognostic value of ISS and whether it may retain its prognostic significance in patients who have been exposed to novel agent-based therapies either at diagnosis or later in the course of their disease. In order to address these issues we analyzed 996 consecutive symptomatic patients who were included in the data base of the Greek Myeloma Study Group and who received frontline treatment between January 1995 and December 2008. Elevated serum LDH to ≥300 IU/L (normal levels <225 IU/L) was observed in 11% of patients. High LDH was seen more often in patients with impaired performance status (p<0.01), with anemia (p<0.01), with thrombocytopenia (p<0.01), with renal impairment (p<0.01), with high ISS (p<0.01), and with hypercalcemia (p=0.01). The median survival of all patients was 40 months with a clear improvement for patients who started treatment after January 2000 as compared to patients who started treatment before that date (50 months versus 31 months; p<0.01). Multiple clilnical and laboratory variables correlated with the probability of survival in univariate analysis. A multivariate analysis showed that the following variables had an independent prognostic significance: LDH (p<0.001), ISS (p<0.001), performance status (p<0.001), age (p<0.001) and platelet count (p<0.001). The median survival of patients with high versus normal LDH was 15 months versus 44 months (p<0.001). High LDH was observed in 7% of patients with ISS-1, in 10% of ISS-2 and 12% of ISS-3. Within each ISS subgroup the presence of high LDH was associated with a worse median survival. In ISS-1 the median survival of patients with high LDH was 22 months (CI 95%: 10-35) while the median survival of those with normal LDH was 76 months (CI 95%: 61-91; p<0.01). Similarly in ISS-2 the median survival of patients with high and normal LDH was 11 months (CI 95%: 7-14) and 40 months (CI 95%: 32-48), respectively (p<0.001), while in ISS-3 it was 17 months (CI 95%: 11-23) and 27 months (CI 95%: 21-33), respectively (p<0.01). Subsequently, patients were separated into two groups: patients who started treatment between January 1995 and December 1999 and patients who started therapy after January 2000 i.e. patients who had access to novel agent-based therapy. In both groups the presence of high LDH was related with statistically worse survival. In patients who received treatment before January 2000, the median survival in the high LDH group was 10 months (CI 95%: 4-16) versus 36 months in the normal LDH group (CI 95%: 31-42; p<0.001). Similarly, in patients who received treatment after January 2000, the median survival in the high LDH group was 21 months (CI 95%: 12-29) versus 51 months in the normal LDH group (CI 95%: 40-63; p<0.001). We conclude that serum LDH is a readily available and inexpensive variable which has a major impact on the survival of patients with myeloma even when they belong to a low or intermediate ISS subgroup and even when they receive novel agent-based therapy. DisclosuresNo relevant conflicts of interest to declare.

Prognostic value of trisomy 8 in primary myelodysplastic syndrome

According to the International Prognostic Scoring System (IPSS), sole +8 is categorized as intermediate cytogenetic subgroup. But as some myelodysplastic syndrome (MDS) patients with +8 perhaps progress quickly to acute leukaemia and have shorter survival, some reports have suggested that +8 should be categorized into poor risk cytogenetic group. The aim of this study was to clarify the prognostic role of +8 in MDS patients by comparing patients with normal karyotype, 20q- and -7/7q-. The consecutive samples of 435 MDS patients in Shanghai were collected by prospective methods and diagnosed according to World Health Organization classification. Cytogenetic analysis was performed using conventional G-banding karyotyping and fluorescence in situ hybridization techniques. Prognosis was estimated by univariate Log-rank method and multivariate Cox proportional hazard models. Of 424 cases completing the cytogenetic analysis, 71 (16.7%) had +8, including 38 patients with sole +8 (9.0%). No significant difference in median survival was observed between patients with sole +8 and that with +8 and one of other abnormalities. The +8 clone size was not linked to survival. The median survival of patients with +8, normal karyotype and complex karyotype was 25months, 38.1months and 5.9months respectively. However, no significant difference was observed between patients with 20q- (21.4months) and -7/7q- (25.8months). Trisomy 8 was an independent prognostic factor by Cox regression model. There is no significant difference in prognosis between patients with +8 and patients with 20q- or -7/7q-. Trisomy 8, 20q- and -7/7q- are categorized as intermediate cytogenetic risk according to our primary study.

On the description of overgroups of E(m,R)⊗E(n,R)

The subgroups E(m,R) ⊗ E(n,R) ≤ H ≤ G = GL(mn,R) are studied under the assumption that the ring R is commutative and m, n ≥ 3. The group GL m ⊗GL n is defined by equations, the normalizer of the group E(m,R) ⊗ E(n,R) is calculated, and with each intermediate subgroup H it is associated a uniquely determined lower level (A,B,C), where A,B,C are ideals in R such that mA,A 2 ≤ B ≤ A and nA,A 2 ≤ C ≤ A. The lower level specifies the largest elementary subgroup satisfying the condition E(m, n,R, A,B,C) ≤ H. The standard answer to this problem asserts that H is contained in the normalizer N G (E(m,n,R, A,B,C)). Bibliography: 46 titles.

Bak's work on theK-theory of rings

AbstractThis paper studies the work of Bak in algebra and (lower) algebraicK-theory and some later developments stimulated by them. We present an overview of his work in these areas, describe the setup and problems as well as the methods he introduced to attack these problems and state some of the crucial theorems. The aim is to analyse in detail some of his methods which are important and promising for further work in the subject. Among the topics covered are, unitary/general quadratic groups over form rings, structure theory and stability for such groups, quadraticK2and the quadratic Steinberg groups, nonstableK-theory and localisation-completion, intermediate subgroups, congruence subgroup problem, dimension theory and surgery theory.

A comparison of the gamma-ray bursts detected by BATSE and Swift

The durations of 388 gamma-ray bursts, detected by the Swift satellite, are studied statistically in order to search for their subgroups. Then the results are compared with the results obtained earlier from the BATSE database. The standard chi^2 test is used. Similarly to the BATSE database, the short and long subgroups are well detected also in the Swift data. Also the intermediate subgroup is seen in the Swift database. The whole sample of 388 GRBs gives a support for three subgroups.

Homogeneous Metrics with Nonnegative Curvature

Given compact Lie groups H⊂G, we study the space of G-invariant metrics on G/H with nonnegative sectional curvature. For an intermediate subgroup K between H and G, we derive conditions under which enlarging the Lie algebra of K maintains nonnegative curvature on G/H. Such an enlarging is possible if (K,H) is a symmetric pair, which yields many new examples of nonnegatively curved homogeneous metrics. We provide other examples of spaces G/H with unexpectedly large families of nonnegatively curved homogeneous metrics.

The Iwasava decomposition and intermediate subgroups of the Steinberg groups over the field of fractions of a principal ideal ring

Abstract The Iwasava decomposition is proved for the Steinberg groups of types 2 A 2l−1, 2 D l , 2 E 6, 3 D 4 over the field of fractions of a principal ideal ring. By using this decomposition, it is described that subgroups exist between the Steinberg groups over the rings D and K under some restrictions on the ring D.

Features of Chromosomal Karyotype in 351 Chinese Adult Patients with Primary Myelodysplastic Syndromes: A Retrospective Analysis from a Single Institution

Myelodysplastic syndromes(MDS) are a heterogeneous group of myeloid neoplasms characterized by bone marrow failure with peripheral cytopenia and morphologic dysplasia in one or more of hematopoietic cell lineages. Chromosomal abnormalities, detected in 40–70% patients with primary MDS, are presented heterogeneous due to the disparities in race and environment. In the current study, 351 adult patients in our institution were retrospectively analyzed to clarify features of karyotype in Chinese primary MDS. There were 237 cases (67.5%) demonstrated karyotypic abnormalities including numeral changes alone(99 cases, 41.7%), structural changes alone(70 cases,29.5%) and both changes(68 cases,28.8%). Single, double and complex (more than two independent aberrations) anormaly were 130 cases(54.8%),54 cases(22.8%), 53 cases(22.4%), respectively. There were 3 cases(1.3%) with tetraploid, 1 case(0.4%)with multiploid,1 case(0.4%) with hyperdiploid and 3 cases(1.3%) with hypodiploid. Changes of aneuploid or anomaly of chromosomal arm could be detected in all of the 24 chromosomes and the aberrations frequently seen were +8, −20/20q-/del(20)(q11–13), −7/7q-/del(7)(q21–32), −5/5q-/del(5)(q13–33), −18, −11/11q-/del(11) (q23–25), +21, −Y, −21, −10, −16, −22, +9, del(12) (p12) in order. The incidence of −5/5q-/del(5)(q13–33)(5.1%)was lower than western countries(8.7–23.4%)and 5q-syndrome was even less (0.3%). The incidences of +8(19.1%) and −20/20q-/del(20)(q11–13) (9.4%) were higher than western countries(1.2–7.0%, 2.0– 3.5%, respectively). Chromosome translocations could be detected in 31 cases(13.1%) and among them 12 translocations have not been reported in MDS. In addition, i(17)(q10) could be detected in 9 cases(3.8%)in which 6 cases were single anormaly. Chromosomal duplication presented in 7 cases(3.0%) in which 4 cases involved chromosome 1. According to IPSS chromosomal prognositic classification, the incidence of poor-risk karyotypes was increasing as following orders: RA, RARS and 5q-syndrome;RCMD and RCMDRS;RAEB-I;RAEB-II and the difference was statistically significant(χ2 = 59.169, P < 0. 001). Among the 178 patients with follow-up data, the median follow-up time was 14.5(1–131)months and the median OS was 36 (95% confident interval(CI) 25–46) months with 2 and 5 year of OS 58.7% and 38.0%, respectively. According to IPSS chromosomal prognositic classification, the median OS of patients with good, intermediate and poor-risk cytogenetic subgroups were 51(95%CI 25–77),35(95%CI 5–65),13(95%CI 9–17)months respectively and the difference of OS was statistically significant by log rank test(P=0. 004). According to NN-AN-AA classification, the median OS of patients with NN, AN, AA were 51(95%CI 24–78),36(95%CI 0.3–71), 23(95%CI 10–35)month respectively and the difference of OS was statistically significant by log rank test(P =0. 039). In summary, features of chromosomal abnormalities in Chinese patients with primary MDS were not the same with that in western countries. Cytogenetical abnormalities validate vigorously malignant texture of MDS and are considered to be of great importance in revealing pathogenesis, determinating diagnosis and evaluating prognosis in MDS.

Abstract A107: Polymorphisms in nucleotide excision repair pathway and acute myeloid leukemia outcome

Abstract A107 Acute myeloid leukemia (AML), the most common leukemia in adults is frequently associated with genetic abnormalities. Based on pre-treatment cytogenetics, AML patients are classified into favorable, intermediate and poor subgroups. Cytogenetics are good predictors of treatment outcome for the favorable and poor subgroups. However, for patients with intermediate cytogenetics, optimal treatment is uncertain. For these patients incorporating genetic markers to the existing prognostic factors might be helpful to identify subgroups of patients. Variants in genes within the nucleotide excision repair (NER) pathway may lead to inter-individual differences in DNA repair capacity which could eventually influence AML outcome. We studied the role of 5 polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, and CCNH Val270Ala) within this pathway on overall and disease-free survival among 170 adult de-novo AML patients with intermediate cytogenetics [diploid karyotypes (n = 117) and non-diploid karyotypes (n = 53)], treated with induction chemotherapy. Kaplan-Meier methods and Cox proportional hazards models were performed. After a median follow-up of 16 months, 56% of diploid patients died compared to 71% among the non-diploid group (Log Rank p= 0.03). Among patients with diploid karyotypes, after adjusting for clinical and socio-demographic characteristics (age, sex, ethnicity, WBC, performance status, and smoking), XPD Lys751Gln and XPC Ala499Val were found to be independently associated with overall survival. Patients with the XPD Lys751Gln/Gln751Gln genotype were twice more likely to have died than those with the wild genotype (HR: 1.97; 95% CI: 1.09 - 3.55). XPC Ala499Val/Val499Val patients had a 75% increased mortality compared to those with the wild genotype (HR: 1.75; 95% CI: 1.02 - 2.98). Patients carrying both (XPD Lys751Gln/Gln751Gln and XPC Ala499Val/Val499Val) had significantly shorter survival compared to those with the wild genotype (HR: 3.49; 95% CI: 1.58 - 7.68). 21% of the AML patients with diploid cytogenetics carried both risk variants. No significant associations were observed for disease-free survival in AML patients. Our results suggest that polymorphic variants in NER repair enzymes may modulate AML outcome in patients with diploid cytogenetics. Patients with the high risk genotype combination could have diminished DNA repair capacity, which in turn, could result in greater susceptibility to genotoxic effects of treatment decreasing overall survival. These findings could in the future be used in selecting treatment strategies for patients with normal cytogenetics. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A107.

Is the European System for Cardiac Operative Risk Evaluation model valid for estimating the operative risk of patients considered for percutaneous aortic valve replacement?

The European System for Cardiac Operative Risk Evaluation has been used to define a particularly high-risk group of patients for aortic valve replacement in whom alternative procedures, such as stent-mounted percutaneous valve procedures, may be appropriate. Our objective was to assess the validity of this risk assessment at a large-volume, tertiary cardiac surgical center. From January 1, 2000, to December 30, 2006, a total of 1177 patients underwent isolated aortic valve replacement at the Mayo Clinic. Patient and operative demographics were recorded in a prospective database. Early mortality (< or = 30 days) was obtained. Additive and logistic European System for Cardiac Operative Risk Evaluations were calculated for each patient. The mean patient age was 68.0 years (+/-14.7 years) at the time of surgery, and 36.8% were female. Variables used in the calculation of the European System for Cardiac Operative Risk Evaluation included chronic lung disease (15% of our cohort), extracardiac arteriopathy (13.8%), neurologic dysfunction (0.2%), previous cardiac surgery (23.2%), renal failure (6.5%), active endocarditis (3.1%), recent myocardial infarction (1.1%), unstable angina (0.1%), and severe pulmonary hypertension (6.5%). The ejection fraction was severely reduced (< or = 30%) in 4.9% of patients and moderately reduced (< or = 50%) in 12.7% of patients. One percent of patients were in a critical state, and operation was performed urgently in 3.4% of patients. Although mean mortality estimates were 6.9% +/- 3.4% (additive European System for Cardiac Operative Risk Evaluation) and 10.9% +/- 12.7% (logistic European System for Cardiac Operative Risk Evaluation), actual overall operative mortality in our patients was 2.5%. Additive and logistic European System for Cardiac Operative Risk Evaluations overestimated operative mortality in low, intermediate, and high-risk subgroups by up to 17.8%. The European System for Cardiac Operative Risk Evaluation should not be used to determine the operability of patients for isolated aortic valve replacement. Elevated European System for Cardiac Operative Risk Evaluations alone do not appropriately define a population for use of a percutaneous aortic valve.

Prognostic predictors for non-small cell lung cancer patients with brain metastasis after radiotherapy.

Brain metastasis (BM) is often found in the patients with lung cancer. Radiotherapy is regular and effective means of therapy and it aims at palliating symptoms and prolonging survival time. However, now there are different viewpoints on protocols of radiotherapy and prognostic factors. A retrospective analysis is used to evaluate the results of treatment for 82 cases with brain metastasis from non-small cell lung cancer (NSCLC) and explore the prognostic factors to establish a prognostic index (PI) model. From Feb.1995 to Oct. 2006, 82 patients irradiated for BM from NSCLC, with both complete medical charts and follow-up data available, were eligible for this retrospective analysis. A number of potential factors which might affect prognosis after irradiation were evaluated. The significance of prognostic variables in the survival resulted from both univariate analysis by Kaplan-Meier combining with log-rank test and multivariate Cox regression model. The prognostic index (PI) was established based on Cox regression analysis and subgrouping values. The follow-up time was 1-120 months. For the entire cohort, the median survival from the start of radiation for BM was 10.5 months, and the actuarial overall survival rate was 50.8%, 23.7% and 5.1% at 0.5, 1 and 2 years respectively. Univariate analysis showed KPS, control of primary tumor, interval from the beginning of diagnostic to BM, extracranial systemic metastasis, counts of lymphocyte and solitary BM were predictors of prognosis. However, in the Cox multivariate analysis, only KPS, control of primary tumor, interval from the beginning of diagnostic to BM and solitary BM were significant prognostic factors. The prognostic index was established based on Cox regression analysis and 82 patients were stratified good, intermediate and poor prognostic sub-groups. The difference of survival rate among 3 subgroups is significant (P <0.001). Radiotherapy is proved to be effective for NSCLC patients with BM. KPS, control of primary tumor, interval from the beginning of diagnostic to BM and solitary BM are independent prognostic factors. PI model can well predict the prognostic of patients with BM from NSCLC.

The geometry of compact homogeneous spaces with two isotropy summands

We give a complete list of all homogeneous spaces M = G/H where G is a simple compact Lie group, H a connected, closed subgroup, and G/H is simply connected, for which the isotropy representation of H on T p M decomposes into exactly two irreducible summands. For each homogeneous space, we determine whether it admits a G-invariant Einstein metric. When there is an intermediate subgroup H < K < G, we classify all the G-invariant Einstein metrics. This is an extension of the classification of isotropy irreducible spaces, given independently by Manturov (Dokl. Akad. Nauk SSSR 141, (1961), 792–795 1034–1037, Tr. Semin. Vector Tensor Anal. 13, (1966), 68–145) and J Wolf (Acta Math. 120, (1968), 59–148 152, (1984) 141–142).

Influence of Local Tumor Control on Distant Metastases and Cancer Related Mortality After External Beam Radiotherapy for Prostate Cancer

We report local control outcomes, as assessed by posttreatment biopsies in patients who underwent 3-dimensional conformal radiotherapy for clinically localized prostate cancer. In addition, we report the influence of local tumor control on long-term distant metastases and cause specific survival outcomes. Posttreatment prostate biopsies were performed in 339 patients who underwent 3-dimensional conformal radiotherapy for clinically localized prostate cancer. The histological outcome of prostate biopsy was classified as positive-prostatic adenocarcinoma without typical radiation induced changes or negative-no evidence of carcinoma or severe treatment effect. Median followup in this group of 339 patients was 10 years after the completion of treatment and 6.25 years after posttreatment biopsy. Overall biopsy outcomes in these patients were positive in 32%, severe treatment effect in 21% and negative in 47%. A higher radiation dose in the intermediate and high risk subgroups was associated with a lower incidence of positive biopsy. Of patients at intermediate risk who received a dose of 75.6 or greater 24% had a positive biopsy compared to 42% who received 70.2 Gy or less (p = 0.03). In the high risk group positive treatment biopsies were noted in 51% of patients who received 70.2 Gy or less, 33% of those who received 75.6 Gy and 15% of those who received 81 Gy or greater (70.2 or less vs 75.6 Gy p = 0.07 and 75.6 vs 81 Gy or greater p = 0.05). Short course neoadjuvant androgen deprivation therapy before 3-dimensional conformal radiotherapy had a significant impact on the posttreatment biopsy outcome. Of patients who did not receive androgen deprivation therapy 42% had a positive biopsy compared to 16% who received androgen deprivation therapy (p <0.0001). Patients with negative and severe treatment effect biopsies had similar 10-year prostate specific antigen relapse-free survival outcomes that were markedly different from outcomes in those with positive treatment biopsies. Multivariate analysis indicated that the strongest predictor of biochemical failure was posttreatment biopsy status (positive vs severe treatment effect or negative p <0.001), followed by pretreatment prostate specific antigen (p = 0.05) and clinical T stage (p = 0.09). Similarly multivariate analysis revealed that a positive posttreatment biopsy was one of the strongest predictors of distant metastasis and prostate cancer death in this cohort of patients. As assessed by posttreatment prostate biopsies, local control is improved with higher radiation doses. Long-term biochemical outcomes in patients with posttreatment biopsies demonstrating severe treatment effect changes were not different than those in patients with negative biopsies. We also noted that local tumor control was associated with a decrease in distant metastases and prostate cancer mortality, further highlighting the importance of achieving optimal tumor control in patients with clinically localized disease.

Prognostic Analysis of Refractory Anemia in Adult Patients with Myelodysplasric Syndrome in China.

Several reports indicated a striking difference in age, chromosome abnormalities and prognosis between Western and Eastern MDS patients, even in the same subtype. The prognostic factors in Chinese MDS patients remain unclear. To investigate the prognostic factors and survival rate in Chinese cases with refractory anemia (RA) in adult MDS based on FAB classification, and to evaluate the applicability of international prognostic scoring system (IPSS) for Chinese MDS-RA patients by comparing with the clinical features of Western cases, Three hundred and seven MDS-RA cases were registered and followed-up in Shanghai, Suzhou and Beijing from 1995 to 2006. The longest follow-up duration was 103 months, and the median follow-up duration was 26.7 months. Kaplan-Meier curve, Log-rank and COX regression model were used to analyze the prognostic factors and survival rate. The median age of 307 MDS-RA cases was 52 years. The frequency of 2 or 3 lineage cytopenias was 85.6%. Abnormal karyotype occurred in 35.7% of all MDS-RA patients. By IPSS cytogenetic risk groups, 165 cases (70.2%) were in the good IPSS cytogenetic subgroup, 44 cases (18.7%) in the intermediate IPSS cytogenetic subgroup and 26 cases (11.1%) in the poor IPSS cytogenetic subgroup. According to IPSS, 20 cases (8.5%) were categorized as low risk, 195 cases (83.0%) as intermediate–I risk and 20 cases (8.5%) as intermediate–II risk. The 1–year, 2–year, 3–year, 4–year and 5–year survival rate were 90.8%, 85.7%, 82.9%, 74.9% and 71.2%, respectively. Fifteen cases (4.9%) transformed to acute myeloid leukemia and the median transformation time was 15.9 months (range 3–102 months). Lower white blood cells count (<1.5 × 109/L), platelet count (<30 × 109/L) and cytogenetic abnormalities were identified as independent prognostic factors by multivariate analysis, while the age (≥65 years), hemoglobin level(<60g/L), IPSS cytogenetic subgroup and IPSS risk subgroup were not independent prognostic factors associated with survival time by COX regression analysis. In summary, Chinese patients were younger and had lower incidence of cytogenetic abnormalities and more severe cytopenias than that of the Western patients. However, the Chinese patients have more favorable prognosis than Western patients do. WBC count, platelet count and karyotype are major prognostic factors for prediction of survival and can be helpful in identifying patients with different prognosis and consequently designing the optimal therapeutic strategies. The present IPSS scores based on conditions of western patients may not be perfectly applicable to MDS-RA patients in Asia and need to be modified.

Risk Stratification Using Stress Echocardiography: Incremental Prognostic Value over Historic, Clinical, and Stress Electrocardiographic Variables Across a Wide Spectrum of Bayesian Pretest Probabilities for Coronary Artery Disease

We sought to evaluate the risk stratification ability and incremental prognostic value of stress echocardiography over historic, clinical, and stress electrocardiographic (ECG) variables, over a wide spectrum of bayesian pretest probabilities of coronary artery disease (CAD). Stress echocardiography is an established technique for the diagnosis of CAD. However, data on incremental prognostic value of stress echocardiography over historic, clinical, and stress ECG variables in patients with known or suggested CAD is limited. We evaluated 3259 patients (60 +/- 13 years, 48% men) undergoing stress echocardiography. Patients were grouped into low (<15%), intermediate (15-85%), and high (>85%) pretest CAD likelihood subgroups using standard software. The historical, clinical, stress ECG, and stress echocardiographic variables were recorded for the entire cohort. Follow-up (2.7 +/- 1.1 years) for confirmed myocardial infarction (n = 66) and cardiac death (n = 105) was obtained. For the entire cohort, an ischemic stress echocardiography study confers a 5.0 times higher cardiac event rate than the normal stress echocardiography group (4.0% vs 0.8%/y, P < .0001). Furthermore, Cox proportional hazard regression model showed incremental prognostic value of stress echocardiography variables over historic, clinical, and stress ECG variables across all pretest probability subgroups (global chi2 increased from 5.1 to 8.5 to 20.1 in the low pretest group, P = .44 and P = .01; from 20.9 to 28.2 to 116 in the intermediate pretest group, P = .47 and P < .0001; and from 17.5 to 36.6 to 61.4 in the high pretest group, P < .0001 for both groups). A normal stress echocardiography portends a benign prognosis (<1% event rate/y) in all pretest probability subgroups and even in patients with high pretest probability and yields incremental prognostic value over historic, clinical, and stress ECG variables across all pretest probability subgroups. The best incremental value is, however, in the intermediate pretest probability subgroup.

Leukocytosis and clinical outcomes in acute inferior myocardial infarction

An elevated white blood cell count (WBC) on hospital admission has been shown by numerous studies to be associated with increased mortality and morbidity in patients with acute coronary syndromes [1–4]. For patients with anterior wall acute myocardial infarction (AMI), neutrophil counts on admission were associated with infarct size and left ventricular systolic function in the chronic phase [5]. However, the association between initial WBC count and clinical outcomes specifically for acute inferior MI remains unclear. We retrospectively reviewed the clinical characteristics and in-hospital outcomes of 406 patients (295 men, 111 women, mean age 64.8±12.9 years) with the diagnosis of acute inferior MI at our institution from January 1997 to March 2004. Patients were stratified into three subgroups based on initial WBC recorded at the time of hospital admission .The baseline WBC count ranged from 3.1 to 32.4×10 cells/mm. The mean WBC count was 11.37± 3.9×10 cells/mm and the 25th and 75th percentiles were, 8.67×10 cells/mm and 13.12×10 cells/mm respectively. The three subgroups consisted of low WBC subgroup: WBC ≤8.67×10 cells/mm, intermediate WBC subgroup: WBC 8.68–13.12×10 cells/mm and high WBC subgroup: WBC N13.12×10 cells/mm. Baseline clinical characteristics are shown in Table 1. Patients in the uppermost WBC subgroup were more often men, had a history of smoking and had a higher hemoglobin level.

NMR structure of the first Ig module of mouse FGFR1.

Fibroblast growth factor (FGF) receptors (FGFRs) regulate a multitude of cellular processes during embryogenesis and in the adult. The extracellular part of the prototypical FGFR consists of three Ig modules (Ig1 - Ig3), in which Ig2 and Ig3 determine affinity and specificity for FGF and heparin, while the Ig1 module is thought to have a regulatory function. The crystal structures of the Ig2 and Ig3 modules alone and in complex with FGF have previously been reported. The structure of the Ig1 module is unknown, and very little is known about the structural determinants for the regulatory function of this module. We describe here the NMR structure of the Ig1 module of mouse FGFR1. The three-dimensional fold of the module belongs to the intermediate Ig subgroup and can be described as a beta-barrel consisting of two beta-sheets. One sheet is formed by A', G, F, C, and C', and the other by A, B, B', E, and D beta-strands. The overall strand topology of the Ig1 module is similar to that of the Ig2 and Ig3 modules. However, the A/A' loop of the Ig1 module is much longer than that of the Ig2 and Ig3 modules. It contains eight extra residues compared to the Ig3 module, and five extra residues compared to Ig2.