Platelet Count Is an IPSS-Independent Risk Factor Predicting Survival in Refractory Anemia with Ringed Sideroblasts.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2455-2455
Author(s):  
Shanique R. Palmer ◽  
Ayalew Tefferi ◽  
David P. Steensma
Keyword(s):  
Platelet Count ◽  
Mayo Clinic ◽  
Proportional Hazards ◽  
Pearson Correlation ◽  
Univariate Analysis ◽  
Hazard Ratio ◽  
Refractory Anemia ◽  
Type I ◽  
Ringed Sideroblasts ◽  
Platelet Mass

Abstract Background: We sought to validate the International Prognostic Scoring System (IPSS) for myelodysplastic syndromes (MDS) in a well-characterized group of patients with refractory anemia with ringed sideroblasts (RARS), as well as to assess the validity of novel and easily obtained prognostic factors such as complete blood count (CBC) parameters. For instance, Bowles and colleagues (Br J Haematol2006; 135: 198) recently reported that a low platelet mass (i.e., mean platelet volume (MPV) x platelet count <0.60 mL/L) is a marker for poor survival (median, 5 months) in patients with MDS, and also asserted the MPV and platelet count do not correlate so the MPV provides independent prognostic information. Because platelet parameters have been of particular interest in RARS, especially with respect to the provisional entity RARS with thrombocytosis (RARS-T), we assessed the prognostic relevance of MPV and platelet count/mass in this MDS subtype. Methods: We analyzed all pts diagnosed with RARS by FAB criteria at Mayo Clinic between 1994 and 2002, a period chosen because it was the interval when the MPV was routinely reported along with CBCs at our center. We excluded pts who were evaluated at Mayo Clinic >6 months after initial diagnosis or were being treated for other malignancies (e.g., lymphoma or myeloma). Medical records, blood parameters, bone marrow findings, and cytogenetic results were reviewed. We performed time-to-event analysis using Kaplan-Meier estimates and Cox proportional hazards modelling, with Chi-Square statistics to assess significance (i.e., type I error rate <0.05). Results: A total of 127 pts (79 males; median age 73 years, range 51-90) were identified, with 78 verified events during the follow-up period. The median survival was 3.9 years. The correlation between MPV and platelet count was poor (Pearson correlation coefficient, -0.18). Platelet count was low in 26 pts, within the normal range in 93 pts, and elevated in 8 pts (but >600 ×109/L in only 2). In univariate analysis, lower Hb, lower MCV (but not MPV), higher total white count, lower platelet count, abnormal cytogenetics, and higher IPSS score each predicted poorer survival. In multivariate analysis using a proportional hazards model, only the platelet count (hazard ratio 0.93 for each increase in count by 25, 95% confidence interval (CI) 0.88-0.98, p=0.0055) and IPSS score (hazard ratio 7.7 for each increase in IPSS score by 1, 95% CI 4.1-14.4, p<0.0001) remained independently predictive of survival. Relatively few patients with RARS have either low platelet mass (<0.60 mL/L, 8%) or intermediate platelet mass (0.60-1.20 ml/L, 12%) as defined by Bowles et al. While the platelet mass was indeed predictive of survival (p<0.0001), this was due entirely to the platelet count, and there was no additional information from the MPV. Conclusion: The IPSS is an excellent predictor of survival in pts with RARS, and the quantitative platelet count adds independent information. The MPV has no additional effect on survival in patients with RARS.

Outcome of Refractory Anemia with Ringed Sideroblasts Associated with Marked Thrombocytosis (RARS-T) In a Large Cohort of Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4113-4113 ◽  
Author(s):  
Francois Girodon ◽  
Julien Broseus ◽  
Lourdes Florensa ◽  
Esther Zipperer ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Platelet Count ◽  
Myeloproliferative Neoplasms ◽  
Hemoglobin Concentration ◽  
Large Cohort ◽  
Refractory Anemia ◽  
White Blood Count ◽  
Employment Equity ◽  
Disease Evolution ◽  
Ringed Sideroblasts ◽  
Equity Ownership

Abstract Abstract 4113 Introduction: Most of the data related to RARS-T, a rare disorder, involve small cohorts of patients. We aimed to analyze more patients also considering a variety of myelodysplastic or myeloproliferative disorders. Objective: To compare a large cohort of patients with RARS-T to refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and multilineage dysplasia (RARS-MD) or essential thrombocythemia (ET) at the time of diagnosis and during disease evolution, in terms of survival and complications. Materials: Data of a European multi-center study was used including 199 cases of RARS-T 173 cases of RARS, 102 cases of RARS-MD and 431 cases of ET. Results: At baseline, compared to RARS and RARS-MD patients, RARS-T patients had similar hemoglobin concentration, but a higher white blood count. The JAK2V617F mutation was observed in 43%, 12% and 5% in RARS-T, RARS and RARS-MD patients, respectively. When separated in 2 groups (450,000<platelet count <600,000 and platelet count >600,000 × 109/l), RARS-T patients were comparable for sex, age, hemoglobin level and survival. However, patients with platelet count > 600,000 × 109/l had higher WBC (11 ×109/l versus 7.5 ×109/l, p<0.001). Similarly, no difference was noted in the survival in the JAK2 positive and negative RARS-T patients. The age and sex standardised overall survival of RARS-T patients was similar to RARS and RARS-MD patients, but lower than ET patients (p<0.001). This was despite a higher risk of transformation in acute leukemia, relative to RARS-T afflicted individuals, of 2.4 and 3.5 in RARS-MD and RARS patients, respectively. Conclusion: According to our results, the outcome in RARS-T more closely mimics myelodysplastic syndromes rather than myeloproliferative neoplasms. Our results agree with the WHO 2008 classification that considers RARS-T as a separate disorder. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Gattermann:Novartis: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Evaluation of circulating biomarkers of bone metastasis in early-stage breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10613-10613
Author(s):  
Windy Marie Dean-Colomb ◽  
Kenneth R. Hess ◽  
Elliana J. Young ◽  
Terrie Gornet ◽  
Beverly Carol Handy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Proportional Hazards ◽  
Univariate Analysis ◽  
Cox Proportional Hazards ◽  
Hazard Ratio ◽  
Stage I ◽  
Clinical Factors ◽  
Cox Proportional Hazards Regression ◽  
Proportional Hazards Regression

10613 Background: Bone is the preferred site for metastasis of breast cancer, affecting approximately 70% of women with advanced disease. N-terminal of procollagen type 1 (P1NP), c-terminal peptide crosslinks (CTX), Osteocalcin (OC) and interleukin-6 (IL-6) are markers of bone turnover that may have clinical utility as predictors of breast cancer recurrence in the bone. Methods: Serum was collected from 168 patients with stage I/II/III breast cancer prior to treatment from 09/2001 to 12/2008 and stored at -80 C. Serum levels of P1NP, CTX, OC and IL-6 were determined using the Roche’s Elecsys 2010 automated immunoassay system. Correlations of biomarker levels with time to bone metastasis (BM) development were assessed with Cox proportional hazards regression analysis and the Kaplan-Meier method. Results: Among the 168 patients analyzed, 60 patients subsequently developed BM. The biomarkers all had skewed distributions with long right tails and thus were all analyzed on the log scale. Residual analysis suggested non-linear relationships between each biomarker and risk of developing BM during follow-up. Thus, we fit Cox proportional hazards regression models for each biomarker with quadratic polynomials (on the log scale). On univariate analysis, these analyses generated p = 0.33 for IL-6, 0.26 for osteocalcin, 0.40 for CTX, and 0.032 for P1NP. Adjusting for clinical factors (stage, age, race, post menopausal, ER/PR status, HER2 status, nuclear grade) yielded p = 0.0035 for the quadratic polynomial for log P1NP. A cut-point of 75 ng/mL identified patients with a short time to development of BM. The 1, 3, and 5-year freedom-from-BM probabilities were 96%, 77% and 66% for the 150 patients with P1NP values ≤ 75 ng/mL and 88%, 45%, and 36% for the 16 patients with P1NP values > 75 ng/mL. The hazard ratio comparing patients with P1NP values ≤ 75 ng/mL to patients with P1NP values > 75 ng/mL was 3.0 (95% CI, 1.5 - 6.2) and p = 0.0075 ng/mL. After adjustment for clinical factors, the hazard ratio was 3.4 (1.5, 7.6) with p = 0.0026. Conclusions: Serum P1NP levels >75 ng/mL correlate with a shorter time to development of BM in patients with stage I-III breast cancer.

LSD1 Inhibition with IMG7289 (bomedemstat) Rebalances Megakaryopoiesis and Erythropoiesis in a Patient with MPN/MDS with Refractory Anemia with Ringed Sideroblast and Marked Thrombocytosis with JAK2 and SF3B1 Mutations

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Abdulraheem Yacoub ◽  
Hugh Young Rienhoff
Keyword(s):  
Transcription Factor ◽  
Platelet Count ◽  
Reticulocyte Count ◽  
Refractory Anemia ◽  
Spleen Volume ◽  
Publicly Traded ◽  
Private Company ◽  
Ringed Sideroblasts ◽  
Night Sweats ◽  
Hypercellular Marrow

Lysine-specific demethylase-1 (LSD1) is a histone H3 K4 demethylase that plays a critical role in hematopoietic progenitor cell differentiation, in particular, the production of megakaryocytes and erythrocytes from their common classical bi-potent progenitor (MEP). LSD1 is recruited to chromatin by the transcription factor GFI1B to license the maturation of megakaryocyte-erythrocyte progenitor cells (MEPs). Anemia is a common and serious complication of primary myelofibrosis (PMF), which is often refractory to conventional therapy. We report here the effect of IMG-7289 (bomedemstat), an LSD1 inhibitor, on skewing the fate of MEPs favoring the production of red cells over platelets and producing a complete hematologic remission in a JAK2V617F-positive PMF patient who had developed a refractory anemia with ringed sideroblasts. A 63 year old woman presented in 2016 with a 1 year history of with fatigue significantly compromising her lifestyle. She denied fever, night sweats, or weight loss. The physical examination was unremarkable with no palpable splenomegaly. Laboratory studies showed a hemoglobin (Hb) of 11.3 g/dL, a total white blood cell count (WBC) of 20.3k/µL with leukoerythroblastosis with 1% circulating blast cells, and a platelet count of 1,192k/µL. A bone marrow biopsy (BMB) showed a hypercellular marrow with increased dysmorphic megakaryocytes but without dyserythropoiesis. There were no ringed sideroblasts with Perls stain, and silver staining showed grade 2 reticulin fibrosis. The karyotype was del(7)(q11.2) and genotyping identified a JAK2V716F allele (VAF not known). The patient was considered to have PMF. Initial treatment consisted of hydroxyurea but without any improvement in her symptoms. Financial constraints initially prevented access to ruxolitinib but the patient was eventually started on 15 mg BID in January 2018. She tolerated therapy well but discontinued therapy a year later owing to no improvement in her fatigue and opted for observation alone. Over the next year, her hemoglobin fell to the range of 9.0-9.5g/dl and she developed drenching night sweats. A BMB in August 2019 showed a hypercellular marrow with increased dysplastic megakaryocytes but now with 76% ringed sideroblasts. Reticulin stain showed grade 2-3 fibrosis. No other dysplastic features were observed. Additional genotyping was declined by insurance and the patient was considered to have an MPN/MDS overlap syndrome. Accordingly, the patient was enrolled in clinical trial IMG-7289-CTP-102 (NCT03136185), a study of the LSD1 IMG-7289. On entry, her Hb was 9.5 gm/dL with an absolute reticulocyte count of 129K/µL. The WBC was 22.7k/µL with 69% neutrophils and 11% monocytes. The platelet count was 1,585k/µL with a mean platelet volume (MPV) of 8.1 fL. Genotyping showed a JAK2V617F VAF of 27%, a new SF3B1K700E mutation with a VAF of 26%, and a DNMT3A mutation with a VAF of 95%. Spleen volume by imaging was 283.3 cm³. The starting IMG-7289 dose was 40 mg po QD. At week 12, the Hb rose to 13.8 g/dL while the absolute reticulocyte count fell to 40K/µL. The platelet count was 271k/µL with the MPV increasing to 10.5 fL. The WBC was 5.2k/µL with 58% neutrophils and 18% monocytes. The mutant JAK2 allele burden had dropped to 14%. The spleen volume was 223 cm³. The IMG-7289 dose was reduced to 35 mg QD after complaints of fatigue. At Week 24, Hb was 11.7 g/dL, WBC was 12.1k/µL and platelets were 743k/µL. The total symptom score (MPN SAF TSS) was reduced by 31% from baseline. The expected pharmacodynamic effects of LSD1 inhibition on hematopoiesis were evident in this patient: monocytosis with a decrease in neutrophils and a marked reduction in the platelet count. Most striking was the concurrent improvement in the patient's anemia which was associated with a persistent reticulocytosis present at the start of treatment but with a significant increase in red blood cells in the setting of a SF3B1 mutation. MEP fate decisions hinge on the balance between KLF1 and FLI1 with the former favoring an erythroid fate, the later, megakaryocytes. The transcription factor complex of FLI1, GATA1, FOG1 which recruits the LSD1-containing NuRD complex is essential for megakaryocyte function; IMG-7289 likely disrupts that complex favoring erythropoiesis over megakaryopoiesis. The inhibition of LSD1 may, therefore, in the setting of thrombocytosis and anemia, rebalance the fate of MEPs to ameliorate both abnormalities. Disclosures Yacoub: Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Roche: Other: Support of parent study and funding of editorial support. Rienhoff:Imago BioSciences: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Clinical Evaluation of the European LeukemiaNet Criteria for Resistance/Intolerance to Hydroxyurea In Essential Thrombocythemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4086-4086
Author(s):  
Carles Besses ◽  
Alberto Alvarez-Larrán ◽  
Montserrat Gómez ◽  
Anna Angona ◽  
Paula Amat ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Leg Ulcers ◽  
Risk Of Death

Abstract Abstract 4086 Definition of resistance/intolerance to hydroxyurea (HU) in essential thrombocythemia (ET) has been proposed by the European LeukemiaNet (ELN) however its clinical utilility has not been validated yet. We have retrospectively evaluated such criteria in 166 ET patients treated with HU for a median of 4.5 years. Response to HU treatment was categorized using the ELN criteria. The ELN definitions of resistance/intolerance to HU required the fulfillment of at least one of the following criteria: platelet count greater than 600 × 109/L after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count greater than 400 × 109/L and leukocytes less than 2.5 × 109/L or hemoglobin (Hb) less than 100 g/L at any dose of HU; presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HU; HU-related fever. Survival and time-to-event curves were estimated using the Kaplan-Meier method.Variab les attaining a significant level at the univariate analysis were included in a Cox proportional hazards model. Overall, 134 patients achieved a complete clinicohematologic response (CR) and 25 a partial response. Thirty-three patients met at least one of the ELN criteria defining resistance (n=15) or intolerance (n=21) to HU. Fifteen cases developed anemia with thrombocytosis. Other definitions of resistance were less useful. When compared with the others, resistant patients were more likely to display hyperproliferative features at ET diagnosis, such as higher levels of leukocytes (p= 0.05), platelets (p=0.004) and serum LDH (p=0.02). Eleven patients developed leg ulcers leading to a permanent discontinuation of the drug in 8 cases. No distinctive clinical profile could be ascribed to patients exhibiting leg ulcers, with the exception of a high prevalence of cardiovascular risk factors. Other unacceptable mucocutaneous manifestations occurred in 9 patients. Hematologic and mucocutaneous complications were unrelated, with only two patients presenting both types of toxicities. With a median follow-up from ET diagnosis of 7 years (range: 0.5–23), 38 patients (23%) had died, resulting in a survival probability of 65% at 10 years from HU start. The risk of death from any cause was increased by 6.2-fold (95%CI: 2.3–16.7, P<0.001) in patients who met any of the ELN criteria of resistance to HU. Anemia was in all instances the first finding qualifying for resistance to HU, with the median subsequent survival of patients with anemia being only 2.4 years (range, 0.01–4.9). A remarkable incidence of myelofibrosis was observed in patients fulfilling the ELN criteria for resistance, since this complication was recorded in 7 of 15 such cases (p>0.001). In conclusion, the best discriminating ELN criterion of resistance to HU is based on the detection of anemia. Moreover, such criterion is particularly useful since it also identifies a subset of ET patients with a poor prognosis. Disclosures: No relevant conflicts of interest to declare.

Outcome of mismatch repair deficient metastatic colorectal cancer (CRC): The Mayo Clinic Experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15030-e15030
Author(s):  
Zhaohui Jin ◽  
Cristobal T. Sanhueza ◽  
Benny Johnson ◽  
Thomas C. Smyrk ◽  
David W. Larson ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Metastatic Disease ◽  
Mayo Clinic ◽  
Proportional Hazards ◽  
Immune Therapy ◽  
Univariate Analysis ◽  
Disease Diagnosis ◽  
Cox Proportional Hazards ◽  
Rank Test ◽  
Primary Tumors

e15030 Background: Deficiencies in the DNA mismatch repair (dMMR) system cause errors during DNA replication, which in turn give rise to microsatellite instability (MSI-H). MSI-H in mCRC is rare and its prognostic and predictive impact on outcome is unclear. This cohort study aims to investigate the prognostic and predictive value of MSI-H in metastatic CRC prior to the immune therapy era. Methods: 75 MSI-H mCRC patients (pts) and 75 matched (age, gender, disease sidedness, metachronous) MSS mCRC pts were identified from 1268 mCRC who had MSI/MMR test results at Mayo Clinic Rochester between 1/1992 and 7/2016. A retrospective review was conducted by using data from electronic medical records (EMR). Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: In the MSI-H group, there were 39 male (52%) and 36 female (48%) pts. Median age at metastatic disease diagnosis was 54.7 years. 35 patients presented with stage IV CRC. Primary tumors location: 38 right side, 11 transverse colon, 15 left side, 11 rectum. The MSS group was well matched (3 mismatches for gender and 1 mismatch for metachronous metastatic disease). Median overall survivals (OS) were 28.1 and 37.4 months for MSI-H and MSS pts, respectively ( p= 0.098). 98.7% MSS pts and 94.7% MSI-H pts had Fluoropyrimidine-based chemotherapy for metastatic disease and there was no median OS difference between these two groups (37.4 vs. 32.3 months p= 0.91). 43 MSI-H and 39 MSS pts had metastasectomy including ablation ( p= 0.51) with longer median OS (82.0 and 69.9 months, p= 0.90) compared to pts without metastasectomy (13.9 and 19.7 months, p= 0.15). Age < 65, metastasectomy, asymptomatic metastatic lesions, BRAF wild type, and multiple metastasectomy were associated with better survival in univariate analysis. Only metastasectomy remained statistically significant in multivariate analysis ( p< 0.0001). Conclusions: MSI-H mCRC do not appear to have improved prognosis compared with MSS cancers, in fact, there is a trend toward inferior outcome. In both groups, metastasectomy including multiple metastasectomy should be considered to optimize OS.

Survival Is Poorer in Patients with Secondary Core Binding Factor Acute Myelogenous Leukemia Compared with De Novo Core Binding Factor Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2856-2856
Author(s):  
Gautam Borthakur ◽  
Nitin Jain ◽  
Hagop Kantarjian ◽  
E. Lin ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Platelet Count ◽  
Univariate Analysis ◽  
Patient Characteristics ◽  
Hazard Ratio ◽  
Myelogenous Leukemia ◽  
P Value ◽  
Core Binding Factor ◽  
Secondary Aml ◽  
Binding Factor

Abstract Translocation (8;21)(q22;q22) and inversion of chromosome 16 [inv(16) (p13q22)] are considered good-risk cytogenetic abnormalities in acute myeloid leukemia (AML) accounting for 15% of primary AML cases (Blood. 2002 Dec 15;100(13):4325–36) and are characterized at the molecular level by disruption of genes encoding subunits of core binding factor (CBF). Increasing age, increasing peripheral blast percentage and complex cytogenetics are associated with poor overall survival in these patients (Br J Haematol. 2006 Oct;135(2):165–73). Here we assess differences in patient characteristics and outcomes between the primary and secondary core binding factor AML. One hundred eighty nine CBF AML patients treated at our institution were studied; 18 (9.5%) had secondary AML. Patients with secondary CBF AML were older (p= 0.02, median ages 57 vs. 44 years) and had lower WBC counts (p=0.03) (Table1). Overall survival (OS) was worse in the secondary AML patients (94 weeks versus 621 weeks, p=0.0016) (Figure 1). Age, hemoglobin, platelet count, and bilirubin were significantly associated with OS in the univariate analysis. In the multivariate analysis, after adjusting for age, hemoglobin, WBC, and bilirubin, secondary CBF AML was marginally significantly associated with worse OS (hazard ratio 1.884, CI95% 0.979–3.625, p=0.058) but not worse PFS (p= 0.15) (Table 2). These data suggest that the secondary CBF AML has much poorer prognosis than the primary CBF AML, further indicating that “CBF AML” is not a homogeneous entity with a uniformly good prognosis. Table 1: Summary statistics of patients’ continuous characteristics by abnormality status Patient characteristics Total patients Primary AML (n=171, male=96) Secondary AML (n=18, male=8) p-value (primary vs secondary AML) Median (range) Median (range) Median (range) Age (years) 44 (16–88) 44 (16–88) 57 (31–75) 0.02 WBC (103/mm3) 14.7 (0.6–387) 16.4 (0.6–387) 6.6 (0.8–103.8) 0.03 Hemoglobin (g/dl) 8.1 (2.5–14.3) 8.2 (2.5–14.3) 7.8 (4.8–10.8) 0.33 Platelet count (103/mm3) 38 (5–350) 38 (5–350) 39 (9–139) 0.88 Bilirubin (mg/dl) 0.6 (0.0–15.3) 0.6 (0.0–5.0) 0.6 (0.1–15.3) 0.94 Creatinine (mg/dl) 0.9 (0.5–2.9) 0.9 (0.5–2.9) 0.9 (0.5–1.8) 0.66 Table 2: Multivariate Cox proportional hazards model in estimating the association between covariates and patients’ survival Variable Hazard ratio (95% CI) p-value Abnormality (secondary vs primary) 1.884 (0.979–3.625) 0.058 Age (1 year increase) 1.028 (1.012–1.044) 0.0004 Hemoglobin (1gm/dl increase) 0.864 (0.769–0.970) 0.014 WBC (103/mm3 increase) 1.003 (1.000–1.007) 0.061 Bilirubin (1 mg/dl increase) 1.179 (1.044–1.332) 0.008 Figure Figure

Factors that contribute to urban–rural gradients in risk of schizophrenia: Comparing Danish and Western Australian registers

2021 ◽  
pp. 000486742110096
Author(s):  
Oleguer Plana-Ripoll ◽  
Patsy Di Prinzio ◽  
John J McGrath ◽  
Preben B Mortensen ◽  
Vera A Morgan
Keyword(s):  
Confidence Interval ◽  
Western Australia ◽  
Urban Areas ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Hazard Ratio ◽  
Indigenous Status ◽  
Increased Risk ◽  
The Relationship ◽  
Western Australian

Introduction: An association between schizophrenia and urbanicity has long been observed, with studies in many countries, including several from Denmark, reporting that individuals born/raised in densely populated urban settings have an increased risk of developing schizophrenia compared to those born/raised in rural settings. However, these findings have not been replicated in all studies. In particular, a Western Australian study showed a gradient in the opposite direction which disappeared after adjustment for covariates. Given the different findings for Denmark and Western Australia, our aim was to investigate the relationship between schizophrenia and urbanicity in these two regions to determine which factors may be influencing the relationship. Methods: We used population-based cohorts of children born alive between 1980 and 2001 in Western Australia ( N = 428,784) and Denmark ( N = 1,357,874). Children were categorised according to the level of urbanicity of their mother’s residence at time of birth and followed-up through to 30 June 2015. Linkage to State-based registers provided information on schizophrenia diagnosis and a range of covariates. Rates of being diagnosed with schizophrenia for each category of urbanicity were estimated using Cox proportional hazards models adjusted for covariates. Results: During follow-up, 1618 (0.4%) children in Western Australia and 11,875 (0.9%) children in Denmark were diagnosed with schizophrenia. In Western Australia, those born in the most remote areas did not experience lower rates of schizophrenia than those born in the most urban areas (hazard ratio = 1.02 [95% confidence interval: 0.81, 1.29]), unlike their Danish counterparts (hazard ratio = 0.62 [95% confidence interval: 0.58, 0.66]). However, when the Western Australian cohort was restricted to children of non-Aboriginal Indigenous status, results were consistent with Danish findings (hazard ratio = 0.46 [95% confidence interval: 0.29, 0.72]). Discussion: Our study highlights the potential for disadvantaged subgroups to mask the contribution of urban-related risk factors to risk of schizophrenia and the importance of stratified analysis in such cases.

scholarly journals Anhedonia as a Potential Risk Factor of Alzheimer’s Disease in a Community-Dwelling Elderly Sample: Results from the ZARADEMP Project

2021 ◽  
Vol 18 (4) ◽  
pp. 1370
Author(s):  
David Vaquero-Puyuelo ◽  
Concepción De-la-Cámara ◽  
Beatriz Olaya ◽  
Patricia Gracia-García ◽  
Antonio Lobo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Potential Risk ◽  
Proportional Hazards ◽  
Univariate Analysis ◽  
Population Sample ◽  
Public Health Problem ◽  
Cox Proportional Hazards ◽  
Community Dwelling ◽  
Major Public Health Problem

(1) Introduction: Dementia is a major public health problem, and Alzheimer’s disease (AD) is the most frequent subtype. Clarifying the potential risk factors is necessary in order to improve dementia-prevention strategies and quality of life. Here, our purpose was to investigate the role of the absence of hedonic tone; anhedonia, understood as the reduction on previous enjoyable daily activities, which occasionally is underdetected and underdiagnosed; and the risk of developing AD in a cognitively unimpaired and non-depressed population sample. (2) Method: We used data from the Zaragoza Dementia and Depression (ZARADEMP) project, a longitudinal epidemiological study on dementia and depression. After excluding subjects with dementia, a sample of 2830 dwellers aged ≥65 years was followed for 4.5 years. The geriatric mental state examination was used to identify cases of anhedonia. AD was diagnosed by a panel of research psychiatrists according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. A multivariate survival analysis and Cox proportional hazards regression model were performed, and the analysis was controlled by an analysis for the presence of clinically significant depression. (3) Results: We found a significant association between anhedonia cases and AD risk in the univariate analysis (hazard ratio (HR): 2.37; 95% CI: 1.04–5.40). This association persisted more strongly in the fully adjusted model. (4) Conclusions: Identifying cognitively intact individuals with anhedonia is a priority to implement preventive strategies that could delay the progression of cognitive and functional impairment in subjects at risk of AD.

scholarly journals Characterization of alternative splicing events and prognostic signatures in breast cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Pihua Han ◽  
Jingjun Zhu ◽  
Guang Feng ◽  
Zizhang Wang ◽  
Yanni Ding
Keyword(s):  
Breast Cancer ◽  
Alternative Splicing ◽  
Proportional Hazards ◽  
Pearson Correlation ◽  
Original Data ◽  
Cox Proportional Hazards ◽  
Prognostic Indicators ◽  
Splicing Factors ◽  
Rna Seq

Abstract Background Breast cancer (BRCA) is one of the most common cancers worldwide. Abnormal alternative splicing (AS) frequently observed in cancers. This study aims to demonstrate AS events and signatures that might serve as prognostic indicators for BRCA. Methods Original data for all seven types of splice events were obtained from TCGA SpliceSeq database. RNA-seq and clinical data of BRCA cohorts were downloaded from TCGA database. Survival-associated AS events in BRCA were analyzed by univariate COX proportional hazards regression model. Prognostic signatures were constructed for prognosis prediction in patients with BRCA based on survival-associated AS events. Pearson correlation analysis was performed to measure the correlation between the expression of splicing factors (SFs) and the percent spliced in (PSI) values of AS events. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted to demonstrate pathways in which survival-associated AS event is enriched. Results A total of 45,421 AS events in 21,232 genes were identified. Among them, 1121 AS events in 931 genes significantly correlated with survival for BRCA. The established AS prognostic signatures of seven types could accurately predict BRCA prognosis. The comprehensive AS signature could serve as independent prognostic factor for BRCA. A SF-AS regulatory network was therefore established based on the correlation between the expression levels of SFs and PSI values of AS events. Conclusions This study revealed survival-associated AS events and signatures that may help predict the survival outcomes of patients with BRCA. Additionally, the constructed SF-AS networks in BRCA can reveal the underlying regulatory mechanisms in BRCA.

Abstract P098: Slower Gait Speed is Associated with Increased Mortality Risk in Chronic Kidney Disease.

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Baback Roshanravan ◽  
Cassiane Robinson-Cohen ◽  
Kushang V Patel ◽  
Greg Levin ◽  
Ian H de Boer ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gait Speed ◽  
Proportional Hazards ◽  
Prognostic Significance ◽  
Continuous Variable ◽  
Hazard Ratio ◽  
Risk Of Death ◽  
Social Security Death Index

Objective: Skeletal muscle dysfunction (sarcopenia) is an under-recognized complication of chronic kidney disease (CKD) that may have important clinical consequences. Gait speed is associated with sarcopenia and comorbid disease burden among older adults; however, little is known about the prognostic significance of gait speed in CKD. We determined the association of gait speed with all-cause mortality in a prospective cohort of non-dialysis CKD patients. Methods: We measured usual gait speed over 4-meters in 309 participants from a prospective study of non-dialysis CKD. Included subjects had an estimated glomerular filtration rate (eGFR ckdepi ) <90mL/min/1.73m 2 , were stroke-free and did not require a wheelchair for ambulation. Study coordinators assessed mortality during follow-up by phone contacts, medical record review, and the social security death index. We evaluated gait speed continuously, and using a cut point of 0.8 m/s, consistent with previous studies. We used Cox's proportional hazards to estimate the association of gait speed with mortality after adjustment for age, sex, race, smoking, diabetes, pre-existing CAD, BMI, eGFR and hemoglobin. Results: Median follow-up time was 2.7 years; range 27 days to 4.8 years. The mean age was 58.9 ± 13 years and mean eGFR by cystatin C (eGFR cysc ) was 48.5 ± 23mL/min/1.73m 2 . There were a total of 31 deaths (10.4%) during follow-up. Unadjusted mortality rates were 23 and 80 deaths per 1,000 person-years among participants who had a gait speed of >0.8m/s versus ≤0.8m/s, respectively. After full adjustment, gait speed ≤0.8m/s was associated with a 2.8-fold greater risk of death compared to a gait speed >0.8 m/s. Gait speed was also strongly associated with mortality when analyzed as a continuous variable ( Table ) and a stronger predictor of death than age, history of CAD, or diabetes. No. Deaths (%) Model 1 + Model 2 # Hazard Ratio 95% CI Hazard Ratio 95% CI Gait speed * 32(10) 0.74 (0.64-0.86) 0.75 (0.64-0.87) >0.8m/s 13 (6) Reference Reference ≤0.8m/s 19(19) 3.49 (1.54-7.95) 2.84 (1.25-6.48) * Gait speed analyzed continuously per 10cm/s increase in speed. +Model 1: Adjusted for age, sex, race, study site #Model 2: adds smoking, BMI, eGFR cysc , diabetes, prevalent coronary disease. Conclusion: Gait speed is strongly associated with death in a cohort of middle-aged CKD patients.

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