Reply

No abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58017/1/23350_ftp.pd

Incidence of Systemic Lupus Erythematosus in the United Kingdom, 1990-1999

Objective. To estimate the annual incidence of systemic lupus erythematosus (SLE) over a 10-year period in the UK, and to examine age-, sex-, and region-specific rates. Methods. The study was based on the UK General Practice Research Database (GPRD), which covers 5% of the UK population. We estimated SLE incidence rates, during the period 1990–1999, among persons registered with practices contributing to the GPRD, representing >33 million person-years of observation. Results. A total of 1,638 patients with incident SLE (1,374 females, 264 males) were identified. The age-standardized SLE incidence in the UK during the 1990s was 7.89 per 100,000 (95% confidence interval [95% CI] 7.46, 8.31) for females and 1.53 per 100,000 (95% CI 1.34, 1.71) for males (overall female-to-male ratio 5.2:1). Peak incidence occurred at age 50–54 years for females and 70–74 years for males. There was a small but insignificant increase of SLE incidence over the 10 years among females but not males. No clear association between latitude and SLE incidence was found, but regional variations existed, with age-standardized rates ranging from 3.56 per 100,000 (95% CI 3.00, 4.13) for the West Midlands to 7.62 per 100,000 (95% CI 5.59, 9.65) for Northern Ireland. Conclusion. This study provides updated estimates of SLE incidence in the UK. Standard methodology throughout the study period and target population allowed for comparison of rates over time and across regions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/60248/1/1_ftp.pd

Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases. We modeled oncogene-induced replication stress using inducible expression of Cyclin E1 or Cdc25A in non-transformed RPE-1 cells, either in a TP53 wild-type or TP53-mutant background. DNA fiber analysis showed Cyclin E1 or Cdc25A overexpression to slow replication speed. The resulting replication-derived DNA lesions were transmitted into mitosis causing chromosome segregation defects. Single cell sequencing revealed that replication stress and mitotic defects upon Cyclin E1 or Cdc25A overexpression resulted in genomic instability. ATR or WEE1 inhibition exacerbated the mitotic aberrancies induced by Cyclin E1 or Cdc25A overexpression, and caused cytotoxicity. Both these phenotypes were exacerbated upon p53 inactivation. Conversely, downregulation of Cyclin E1 rescued both replication kinetics, as well as sensitivity to ATR and WEE1 inhibitors. Taken together, Cyclin E1 or Cdc25A-induced replication stress leads to mitotic segregation defects and genomic instability. These mitotic defects are exacerbated by inhibition of ATR or WEE1 and therefore point to mitotic catastrophe as an underlying mechanism. Importantly, our data suggest that Cyclin E1 overexpression can be used to select patients for treatment with replication checkpoint inhibitors

The incidence and prevalence of systemic lupus erythematosus in the UK, 1999–2012

Objectives: To estimate the incidence and prevalence of systemic lupus erythematosus (SLE) in the UK over the period 1999–2012. Methods: A retrospective cohort study using the Clinical Practice Research Datalink (CPRD). The incidence was calculated per 100 000 person-years and the prevalence was calculated per 100 000 people for the period 1999–2012 and stratified by year, age group, gender, region and ethnicity. Three definitions of SLE were explored: (1) systemic lupus, (2) a fully comprehensive definition of lupus including cutaneous only lupus and (3) requiring supporting evidence of SLE in the medical record. Results: Using our primary definition of SLE, the incidence during the study period was 4.91/100 000 person-years (95% CI 4.73 to 5.09), with an annual 1.8% decline (p<0.001). In contrast, the prevalence increased from 64.99/100 000 in 1999 (95% CI 62.04 to 67.93) (0.065%) to 97.04/100 000 in 2012 (95% CI 94.18 to 99.90) (0.097%). SLE was six times more common in women. The peak age of incidence was 50–59 years. There was regional variation in both incidence and prevalence. People of Black Caribbean ethnicity had the highest incidence and prevalence. Alternative definitions of SLE increased (definition 2) or decreased (definition 3) estimates of incidence and prevalence, but similar trends were found. Conclusions: The incidence of SLE has been declining but the prevalence has been increasing in the UK in recent years. Age, gender, region and ethnicity are risk factors for SLE. This is the first study to report ethnic differences on the incidence and prevalence of SLE using the CPRD

Minimal residual disease level predicts outcome in adults with Ph-negative Bprecursor acute lymphoblastic leukemia

Institut Germans Tries i PujolObjectives: Detectable minimal residual disease (MRD) after therapy for acute lymphoblastic leukemia (ALL) is the strongest predictor of hematologic relapse. This study evaluated outcomes of patients with B-cell precursor ALL with MRD of ≥10−4. Methods: Study population was from ALL study groups in Europe managed in national study protocols 2000-2014. MRD was measured by polymerase chain reaction or flow cytometry. Patients were age ≥15 years at initial ALL diagnosis. Patients were excluded if exposed to blinatumomab within 18 months of baseline or prior alloHSCT. Results: Of 272 patients in CR1, baseline MRD was ≥10−1, 10−2 to <10−1, 10−3 to <10−2, and 10−4 to <10−3 in 15 (6%), 71 (26%), 109 (40%), and 77 (28%) patients, respectively. Median duration of complete remission (DoR) was 18.5 months (95% confidence interval [CI], 11.9-27.2), median relapse-free survival (RFS) was 12.4 months (95% CI, 10.0-19.0) and median overall survival (OS) was 32.5 months (95% CI, 23.6-48.0). Lower baseline MRD level (P ≤ .0003) and white blood cell count <30,000/μL at diagnosis (P ≤ .0053) were strong predictors for better RFS and DoR. Allogeneic hematopoietic stem cell transplantation (alloHSCT) was associated with longer RFS (hazard ratio [HR], 0.59; 95% CI, 0.41-0.84) and DoR (HR, 0.43; 95% CI, 0.29-0.64); the association with OS was not significant (HR, 0.72; 95% CI, 0.50-1.05). Discussion: In conclusion, RFS, DoR, and OS are relatively short in patients with MRD-positive ALL, particularly at higher MRD levels. AlloHSCT may improve survival but has limitations. Alternative approaches are needed to improve outcomes in MRD-positive ALL

Validation and validity of diagnoses in the General Practice Research Database: a systematic review.

AIMS: To investigate the range of methods used to validate diagnoses in the General Practice Research Database (GPRD), to summarize findings and to assess the quality of these validations. METHODS: A systematic literature review was performed by searching PubMed and Embase for publications using GPRD data published between 1987 and April 2008. Additional publications were identified from conference proceedings, back issues of relevant journals, bibliographies of retrieved publications and relevant websites. Publications that reported attempts to validate disease diagnoses recorded in the GPRD were included. RESULTS: We identified 212 publications, often validating more than one diagnosis. In total, 357 validations investigating 183 different diagnoses met our inclusion criteria. Of these, 303 (85%) utilized data from outside the GPRD to validate diagnoses. The remainder utilized only data recorded in the database. The median proportion of cases with a confirmed diagnosis was 89% (range 24-100%). Details of validation methods and results were often incomplete. CONCLUSIONS: A number of methods have been used to assess validity. Overall, estimates of validity were high. However, the quality of reporting of the validations was often inadequate to permit a clear interpretation. Not all methods provided a quantitative estimate of validity and most methods considered only the positive predictive value of a set of diagnostic codes in a highly selected group of cases. We make recommendations for methodology and reporting to strengthen further the use of the GPRD in research

Characteristics of Patients with Myelodysplastic Syndromes (MDS) in the United States from 4528 Physician Surveys

Abstract The estimated incidence of MDS in the United States is 3.6 per 100,000 people, or approximately 10,000 new cases per year. Few published studies about the characteristics of incident and prevalent cases exist. This study analyzes MDS patient (pt) demographics, classification, cytopenias, and treatment options as reported in surveys of AMA-listed hematology and/or medical oncology specialists. Physicians completed 6 distinct surveys on their 4 to 10 most recently seen MDS pts. Surveys were collected in June and Oct 2005; Jan, Apr, and Sept 2006; and Jan 2007. Data included information about demographics, disease information, hematologic status, transfusion dependency, and type and rationale for treatment given. Results are presented as minimum and maximum percentages observed across surveys. Per survey, 100 specialists were contacted; 77 to 97 physicians per survey returned information for at least one MDS pt, resulting in a total of 4528 pt surveys (621 to 827 per survey). Most (67–76%) had office-based practices; others were university, community, or VA hospital-based. Across surveys, 51-57% of pts were male. The median age was 72-74 years, with no marked difference between males and females. Median duration of MDS at the time of survey was 26-36 months. Secondary MDS was seen in 8-13% of pts, most following chemo (64-81%) or radiation therapy (10-22%). Lower-risk MDS was more common in follow-up (prevalent) MDS pts than in newly-diagnosed (incident) pts (Table). Cytogenetics were available on approximately 90% of all pts, with 68-71% classified (per IPSS) as low risk, 14-21% intermediate, and 11-16% poor. The most commonly reported abnormality was 5q- (7-9% of primary MDS cases). Platelet data were collected in the final 2 surveys: 37-42% of pts had counts <100,000mm3, and 15-18% <50,000mm3; the median transfusion trigger value was 15,000mm3. Low/Int-1 MDS pts were less dependent than Int-2/High-risk pts on both red blood cell transfusions (17–29% vs 52–67%) and platelet transfusions (3–10% vs 21–34%). Erythropoiesis stimulating agents (ESAs, such as erythropoietin or darbepoetin) were used by the majority of pts (68–74%), independent of IPSS risk. Most incident pts (57–65%) received supportive care with ESAs, and there was a trend towards increased use of non-ESA therapy over time (28% in 2005 to 40% in 2007). Among all pts, lenalidomide use was similar for Low/Int-1 vs Int-2/High-risk pts (0–12% vs 0–12%), as was use of azacitidine (41–53% vs 41–57%) and decitabine (12–60% vs 0-80%). Only a minority of MDS pts (1.5–4.2%) either had or were being considered for bone marrow transplantation. The proportion of MDS pts in clinical trials was also low (0.7–3.7%), and 14–18% of pts were categorized as watch and wait. In conclusion, the majority of MDS pts have lower-risk disease, and few have secondary MDS. Transfusion needs were greater, but ESA use similar, in higher-risk MDS compared to lower-risk pts. Transplantation, and clinical trial involvement, continues to be an option for only a minority of MDS pts. Figure Figur

A compilation of research working groups on drug utilisation across Europe

BACKGROUND: The assessment of the benefit-risk of medicines needs careful consideration concerning their patterns of utilization. Systems for the monitoring of medicines consumption have been established in many European countries, and several international groups have identified and described them. No other compilation of European working groups has been published. As part of the PROTECT project, as a first step in searching for European data sources on the consumption of five selected groups of medicines, we aimed to identify and describe the main characteristics of the existing collaborative European working groups. FINDINGS: Google and bibliographic searches (PubMed) of articles containing information on databases and other sources of drug consumption data were conducted. For each working group the main characteristics were recorded.Nineteen selected groups were identified, focusing on: a) general drug utilisation (DU) research (EuroDURG, CNC, ISPE'S SIG-DUR, EURO-MED-STAT, PIPERSKA Group, NorPEN, ENCePP, DURQUIM), b) specific DU research: b.1) antimicrobial drugs (ARPAC, ESAC, ARPEC, ESGAP, HAPPY AUDIT), b.2) cardiovascular disease (ARITMO, EUROASPIRE), b.3) paediatrics (TEDDY), and b.4) mental health/central nervous system effects (ESEMeD, DRUID, TUPP/EUPoMMe). Information on their aims, methods and activities is presented. CONCLUSIONS: We assembled and updated information on European working groups in DU research and in the utilisation of five selected groups of drugs for the PROTECT project. This information should be useful for academic researchers, regulatory and health authorities, and pharmaceutical companies conducting and interpreting post-authorisation and safety studies. European health authorities should encourage national research and collaborations in this important field for public health

Characteristics of US Patients with Myelodysplastic Syndromes: Results of Six Cross-sectional Physician Surveys

Background Myelodysplastic syndromes (MDS) comprise a group of pathologically and cytogenetically distinct bone marrow disorders. Little is known about the characteristics of MDS patients, including their pathological and prognostic classifications, cytopenias, transfusion and supportive care needs, and treatment regimens. We describe these characteristics in a large group of recently diagnosed and existing (ie, established) MDS patients. Methods We conducted six consecutive cross-sectional surveys among US hematology and medical oncology specialists (identified from an American Medical Association [AMA] database of physicians who administer chemotherapy) between June 2005 and January 2007. A questionnaire collected data on the characteristics and treatment patterns of the 4–10 most recently seen MDS patients for each physician, including demographic data, transfusion needs, treatment approaches, and consideration for clinical trials or bone marrow transplantation. Results A panel of 101 physicians who were geographically representative of physicians registered with the AMA characterized 614–827 patients per survey, for a total of 4514 responses. Among recently diagnosed patients, 55% were male (95% confidence interval [CI] = 52% to 59%), the median age at diagnosis was 71 years (range = 65–80 years), and 10% (95% CI = 8% to 12%) had MDS secondary to chemotherapy, radiation therapy, or environmental exposure. The median duration of MDS in established patients ranged from 13 to 16 months over the six surveys. Among recently diagnosed MDS patients, fewer patients with lower-risk disease than with higher-risk disease were dependent on either red blood cell transfusions (22% vs 68%) or platelet transfusions (6% vs 33%). More than 50% of all newly diagnosed and established patients used erythropoiesis-stimulating agents. A small percentage of all patients either had had or were being considered for bone marrow transplantation (recently diagnosed: 4%; established: 4% or less) or were being treated on clinical trials (recently diagnosed: 1%; established: 4% or less). Conclusions MDS patients in the United States have substantial transfusion needs, and use of erythropoiesis-stimulating agents and are seldom considered for bone marrow transplantation or clinical trials. These data may be useful in characterizing the health care resource use and pharmacoeconomic impact of MDS in the United States