Topographic distribution of cerebral infarct probability in patients with acute ischemic stroke: mapping of intra-arterial treatment effect.

BACKGROUND: Since proof emerged that IA treatment (IAT) is beneficial for patients with acute ischemic stroke, it has become the standard method of care. Despite these positive results, recovery to functional independence is established in only about one-third of treated patients. The effect of IAT is commonly assessed by functional outcome, whereas its effect on brain tissue salvage is considered a secondary outcome measure (at most). Because patient and treatment selection needs to be improved, understanding the treatment effect on brain tissue salvage is of utmost importance. OBJECTIVE: To introduce infarct probability maps to estimate the location and extent of tissue damage based on patient baseline characteristics and treatment type. METHODS: Cerebral infarct probability maps were created by combining automatically segmented infarct distributions using follow-up CT images of 281 patients from the MR CLEAN trial. Comparison of infarct probability maps allows visualization and quantification of probable treatment effects. Treatment impact was calculated for 10 Alberta Stroke Program Early CT Score (ASPECTS) and 27 anatomical regions. RESULTS: The insular cortex had the highest infarct probability in both control and IAT populations (47.2% and 42.6%, respectively). Comparison showed significant lower infarct probability in 4 ASPECTS and 17 anatomical regions in favor of IAT. Most salvaged tissue was found within the ASPECTS M2 region, which was 8.5% less likely to infarct. CONCLUSIONS: Probability maps intuitively visualize the topographic distribution of infarct probability due to treatment, which makes it a promising tool for estimating the effect of treatment.

Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3.

BACKGROUND: Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive. RESULTS: MethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p ≤ 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear. CONCLUSIONS: We identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV-positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population-based cohorts.

DNA methylation analysis in self-sampled brush material as a triage test in hrHPV-positive women.

BACKGROUND: Primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening shows relatively low specificity, which makes triage testing necessary. In this study, DNA methylation analysis was compared with cytology for triage testing in hrHPV-positive women. Moreover, feasibility of DNA methylation analysis directly on brush-based self-sampled specimens was assessed. METHODS: Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV-positive women were referred to a physician for triage liquid-based cytology. DNA methylation analysis was performed on 128 hrHPV-positive physician-collected triage samples and 50 matched brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT. RESULTS: In physician-taken triage material, DNA methylation analysis of JAM3 showed the highest combined specificity (88%) and sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false-positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. Agreement between DNA methylation analysis performed directly on the matched self-sampled material and physician-taken samples was 88% for JAM3 (κ=0.75, P<0.001) and 90% for C13ORF18 (κ=0.77; P<0.001). CONCLUSIONS: DNA methylation analysis as a triage test in hrHPV-positive women is an attractive alternative to cytology. Furthermore, DNA methylation is feasible directly on brush-based self-samplers and showed good correlation with matched physician-taken samples. Direct molecular triage on self-collected specimens could optimise the screening program, especially for non-responders, as this would eliminate the need for an additional physician-taken scraping for triage testing.

Disease-modifying anti-rheumatic drug usage, prescribing patterns and disease activity in rheumatoid arthritis patients in community-based practice.

AIMS: Our aim was to examine the spectrum of disease activity and usage of disease-modifying anti-rheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients seen over a period of 12 months in community-based rheumatology practice. METHODS: Data were prospectively collected on 1059 consecutive RA patients who attended two private, community-based rheumatology clinics from 1 May 2007 to 1 May 2008. Information on patient demographics, medication history and disease activity was collected. Life table graphs were developed to track medication retention over time. Statistical significance was determined by log-rank tests. RESULTS: One thousand and fifty-nine patients with RA were entered into the database over a 12-month period. Eight hundred and twenty-six patients (85%) were treated with single or combination conventional DMARD compared with 159 patients (15%) on a biologic DMARD either alone or in combination. Methotrexate monotherapy was the most commonly prescribed DMARD, used in 41% of patients studied. Almost half (47%) were on combination DMARD therapy. Methotrexate and tumour necrosis factor inhibitors had the highest retention rate over 12 and 30 months since first prescription. A large proportion of patients (47%) had moderate disease activity. CONCLUSION: Rates of biologic DMARD usage were similar to other studies and the predominance of methotrexate use was also in keeping with current recommendations for management of RA. There appears to be a significant unmet need for improved disease control among RA patients with moderate disease activity, which requires further investigation.

Ankylosing spondylitis: an Australian experience.

BACKGROUND: The purpose of this study was to characterize an Australian cohort of ankylosing spondylitis (AS) patients and examine predictors of important disease outcomes. METHODS: Cross-sectional study of first visit data among patients referred to the Austin Spondylitis Clinic from rheumatology or general practices. We obtained clinical and laboratory data and validated composite indices through self-reported questionnaire. RESULTS: Delay in AS diagnosis averaged 8.1 years and was higher among women and younger-onset disease. Cervicothoracic mobility was better in women although they showed more entheseal tender points and greater impairment of quality of life. Those with long-standing AS had similar disease activity to recent onset disease but had greater functional disability. Current smoking was associated with worse outcomes although there was no association between cumulative exposure and AS outcomes. CONCLUSION: The clinical expression of AS in this first-described Australian cohort is similar to previously described cohorts. We observed greater cervicothoracic mobility and a higher enthesitis index among women perhaps contributing to longer delay to diagnosis.

Final height and hormonal function after bone marrow transplantation in children.

AIM: To analyze final height and hormonal function in long-term survivors of bone marrow transplantation (BMT). PATIENTS: Group 1 consisted of 16 patients (10 boys) with a hematologic malignancy, mostly leukemia, conditioned for BMT with total body irradiation (TBI), 7.5 to 12 Gy, and cyclophosphamide. Group 2 consisted of 14 patients (9 boys) with severe aplastic anemia, conditioned with chemotherapy only. RESULTS: In group 1, patients achieved a reduced final height after BMT. The difference between the height standard deviation score (SDS) at BMT and the height SDS at final height was -1.96 (0.82) SDS in boys and -0.92 (0.71) SDS in girls (p = 0.0001, and p = 0.02 respectively). Final height was also lower than target height (boys, p = 0.01; girls, p = 0.03). Prepubertal growth in the first 3 years after BMT was normal but pubertal height gain was decreased. The patients in group 2 achieved normal height. Thyroid function and adrenal function were normal in all patients, and no growth hormone deficiency was detected. Serum follicle-stimulating hormone values after BMT were increased in all group 1 patients, with return to normal in two patients. Serum luteinizing hormone values were increased in all group 1 girls, with recovery in one girl. Normal serum luteinizing hormone values and spontaneous puberty were found in all group 1 boys. In group 2, disturbances in gonadotropins were seen only in three boys and two girls. CONCLUSION: In patients treated in childhood with BMT after chemotherapy and TBI with 7.5 Gy or more, final height is compromised because of blunted growth in puberty. Patients who had not received TBI suffered no height loss. In the majority of patients, the combination of chemotherapy and TBI also resulted in irreversible disturbances of gonadal function.