Showing papers by "Bethesda Hospital published in 2015"

Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade.

Abstract: Targeted drug delivery with antibody-drug conjugates such as the HER2-directed ado-trastuzumab emtansine (T-DM1) has emerged as a powerful strategy for cancer therapy. We show that T-DM1 is particularly effective in eliciting antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) and in a HER2-expressing orthotopic tumor model. In the latter, despite primary resistance to immunotherapy, combined treatment with T-DM1 and anti-CTLA-4/PD-1 (cytotoxic T lymphocyte-associated protein-4/programmed cell death protein-1) was curative because it triggered innate and adaptive immunity. Tumor rejection was accompanied by massive T cell infiltration, TH1 (T helper 1) cell polarization, and, notably, a substantial increase in regulatory T cells. Depletion of regulatory T cells resulted in inflammation and tissue damage, implying their essential role in protecting the host during therapy. This study provides insights into the mechanisms of T-DM1's therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy.

Testicular function in a birth cohort of young men

Abstract: STUDY QUESTION By investigating a birth cohort with a high ongoing participation rate to derive an unbiased population, what are the parameters and influences upon testicular function for a population not selected with regard to fertility? SUMMARY ANSWER While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have no or minimal adverse impact. WHAT IS KNOWN ALREADY The majority of previous attempts to develop valid reference populations for spermatogenesis have relied on potentially biased sources such as recruits from infertility clinics, self-selected volunteer sperm donors for research or artificial insemination or once-fertile men seeking vasectomy. It is well known that studies requiring semen analysis have low recruitment rates which consequently question their validity. However, there has been some concern that a surprisingly high proportion of young men may have semen variables that do not meet all the WHO reference range criteria for fertile men, with some studies reporting that up to one half of participants have not meet the reference range for fertile men. Reported median sperm concentrations have ranged from 40 to 60 million sperm/ml. STUDY DESIGN, SIZE AND DURATION The Western Australian Pregnancy Cohort (Raine) was established in 1989. At 20-22 years of age, members of the cohort were contacted to attend for a general follow-up, with 753 participating out of the 913 contactable men. Of these, 423 men (56% of participants in the 20-22 years cohort study, 46% of contactable men) participated in a testicular function study. Of the 423 men, 404 had a testicular ultrasound, 365 provided at least one semen sample, 287 provided a second semen sample and 384 provided a blood sample. PARTICIPANTS/MATERIALS, SETTING, METHODS Testicular ultrasound examinations were performed at King Edward Memorial Hospital, Subiaco, Perth, for testicular volume and presence of epididymal cysts and varicoceles. Semen samples were provided and analysed by standard semen assessment and a sperm chromatin structural assay (SCSA) at Fertility Specialists of Western Australia, Claremont, Perth. Serum blood samples were provided at the University of Western Australia, Crawley, Perth and were analysed for serum luteinizing hormone (LH), follicular stimulating hormone (FSH), inhibin B, testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), estradiol, estrone and the primary metabolites of DHT: 5α-androstane-3α,17β-diol (3α-diol) and 5-α androstane-3-β-17-beta-diol (3β-diol). Serum steroids were measured by liquid chromatography, mass spectrometry and LH, FSH and inhibin B were measured by ELISA assays. MAIN RESULTS AND THE ROLE OF CHANCE Cryptorchidism was associated with a significant reduction in testicular (P = 0.047) and semen (P = 0.027) volume, sperm concentration (P = 0.007) and sperm output (P = 0.003). Varicocele was associated with smaller testis volume (P < 0.001), lower sperm concentration (P = 0.012) and total sperm output (P = 0.030) and lower serum inhibin B levels (P = 0.046). Smoking, alcohol intake, herniorrhaphy, an epididymal cyst, medication and illicit drugs were not associated with any significant semen variables, testicular volume or circulating reproductive hormones. BMI had a significantly negative correlation with semen volume (r = -0.12, P = 0.048), sperm output (r = -0.13, P = 0.02), serum LH (r = -0.16, P = 0.002), inhibin B (r = -0.16, P < 0.001), testosterone (r = -0.23, P < 0.001) and DHT (r = -0.22, P < 0.001) and a positive correlation with 3αD (r = 0.13, P = 0.041) and DHEA (r = 0.11, P = 0.03). Second semen samples compared with the first semen samples in the 287 participants who provided two samples, with no significant bias by Bland-Altman analysis. Testis volume was significantly correlated positively with sperm concentration (r = 0.25, P < 0.001) and sperm output (r = 0.29, P < 0.001) and inhibin B (r = 0.42, P < 0.001), and negatively correlated with serum LH (r = -0.24, P < 0.001) and FSH (r = -0.32, P < 0.001). SCSA was inversely correlated with sperm motility (r = -0.20, P < 0.001) and morphology (r = -0.16, P = 0.005). WHO semen reference criteria were all met by only 52 men (14.4%). Some criteria were not met at first analysis in 15-20% of men, including semen volume (<1.5 ml, 14.8%), total sperm output (<39 million, 18.9%), sperm concentration (<15 million/ml, 17.5%), progressive motility (<32%, 14.4%) and morphologically normal sperm (<4%, 26.4%), while all five WHO criteria were not met in four participants (1.1%). LIMITATIONS AND REASONS FOR CAUTION This was a large cohort study; however, potential for recruitment bias still exists. Men who did not participate in the testicular evaluation study (n = 282) did not differ from those who did (n = 423) with regard to age, weight, BMI, smoking or circulating reproductive hormones (LH, FSH, inhibin B, T, DHT, E2, E1, DHEA, 3α-diol, 3β-diol), but were significantly shorter (178 versus 180 cm, P = 0.008) and had lower alcohol consumption (P = 0.019) than those who did participate. WIDER IMPLICATIONS OF THE FINDINGS This study demonstrated the feasibility of establishing a birth cohort to provide a relatively unbiased insight into population-representative sperm output and function and of investigating its determinants from common exposures. While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have little adverse impact, and this study suggests that discrepancies from the WHO reference ranges are expected, due to its derivation from non-population-representative fertile populations.

Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1

Abstract: Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes, is characterized by fragile, hyperextensible skin and joint laxity. To date, vessel rupture in four unrelated classic EDS patients with a confirmed COL5A1 mutation has been reported. We describe familial occurrence of a phenotype resembling vascular EDS in a mother and her two sons, who all died at an early age from arterial ruptures. Diagnostic Sanger sequencing in the proband failed to detect aberrations in COL3A1, COL1A1, COL1A2, TGFBR1, TGFBR2, SMAD3, and ACTA2. Next, the proband's DNA was analyzed using a next-generation sequencing approach targeting 554 genes linked to vascular disease (VASCULOME project). A novel heterozygous mutation in COL5A1 was detected, resulting in an essential glycine substitution at the C-terminal end of the triple helix domain (NM_000093.4:c.4610G>T; p.Gly1537Val). This mutation was also present in DNA isolated from autopsy material of the index's brother. No material was available from the mother, but the mutation was excluded in her parents, siblings and in the father of her sons, suggesting that the COL5A1 mutation occurred in the mother's genome de novo. In conclusion, we report familial occurrence of lethal arterial events caused by a COL5A1 mutation.

In vitro maturation is associated with increased early embryo arrest without impairing morphokinetic development of useable embryos progressing to blastocysts

Abstract: STUDY QUESTIONS Does polycystic ovarian syndrome (PCOS) or in vitro maturation (IVM) treatment affect embryo development events and morphokinetic parameters after time-lapse incubation? SUMMARY ANSWER There was an increase in some abnormal phenotypic events in PCOS-IVM embryos as well as an increase in early arrest of PCOS-IVM and PCOS-ICSI embryos; however, IVM treatment or PCOS status did not alter morphokinetic development of embryos suitable for transfer of vitrification. WHAT IS KNOWN ALREADY IVM has been less successful than standard IVF in terms of clinical pregnancy, implantation and live birth rates. There is currently no information available about the development of IVM embryos according to time-lapse analysis. STUDY DESIGN, SIZE AND DURATION This article represents a prospective case-control study. The study involved 93 participants who underwent 93 treatment cycles. Cycles were completed between January 2013 and July 2014. PARTICIPANTS/MATERIALS, SETTING AND METHODS Participants were recruited for the study at Fertility Specialists of WA and Fertility Specialists South, Perth, Western Australia. Of the PCOS diagnosed patients, 32 underwent IVM treatment (PCOS-IVM) and 23 had standard ICSI treatment (PCOS-ICSI). There were 38 patients without PCOS who underwent standard ICSI treatment comprising the control group (control-ICSI). MAIN RESULTS AND THE ROLE OF CHANCE The PCOS-IVM group showed significantly more embryos with multinucleated two cells (P = 0.041), multinucleated four cells (P = 0.001) and uneven two cells (P = 0.033) compared with the control-ICSI group, but not the PCOS-ICSI group. There were no significant differences in the rates of any abnormal events between the PCOS-ICSI and control-ICSI groups. Embryo arrest between Days 2 and 3 was higher in the PCOS-IVM and PCOS-ICSI groups compared with the control-ICSI group (P < 0.001 and P = 0.001). Embryo arrest from Days 3 to 4 was higher in the PCOS-IVM group compared with both the PCOS-ICSI and control-ICSI groups (P < 0.001). There were no differences in embryo arrest rates across all three groups at the compaction or blastulation stages. Cumulative rates of embryo arrest, from the time to second polar body extrusion (tPB2) to the time to formation of a blastocyst (tB), result in a decreased proportion of useable PCOS-IVM blastocysts compared with the other two treatment groups; however, of the embryos remaining, there was no significant difference in morphokinetic development between the three groups. LIMITATIONS AND REASONS FOR CAUTION This was a small study using time-lapse analysis of embryo development as the primary end-point. Larger, randomized, clinical trials are required to clarify the implications of time-lapse incubation of IVM embryos and the effects on implantation and ongoing pregnancy. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to compare the time-lapse analysis of IVM with standard ICSI for patients with and without PCOS. This allows for a more detailed and specific timeline of events from embryos generated using this approach for patients diagnosed with PCOS and shows that embryos generated from IVM have an increased rate of early embryo arrest, however; morphokinetic development is not impaired in embryos that progress to the useable blastocyst stage. STUDY FUNDING/COMPETING INTERESTS The study was supported by the Women's and Infant's Research Foundation of Western Australia. R.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. The other authors have no competing interests.

Paracetamol (Acetaminophen) in stroke 2 (PAIS 2): protocol for a randomized, placebo-controlled, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke and a body temperature of 36.5 °C or above.

Abstract: Rationale: In the first hours after stroke onset, subfebrile temperatures and fever have been associated with poor functional outcome. In the first Paracetamol (Acetaminophen) in Stroke trial, a randomized clinical trial of 1400 patients with acute stroke, patients who were treated with high-dose paracetamol showed more improvement on the modified Rankin Scale at three-months than patients treated with placebo, but this difference was not statistically significant. In the 661 patients with a baseline body temperature of 37·0°C or above, treatment with paracetamol increased the odds of functional improvement (odds ratio 1·43; 95% confidence interval: 1·02-1·97). This relation was also found in the patients with a body temperature of 36·5°C or higher (odds ratio 1·31; 95% confidence interval 1·01-1·68). These findings need confirmation. Aim: The study aims to assess the effect of high-dose paracetamol in patients with acute stroke and a body temperature of 36·5°C or above on functional outcome. Design: The Paracetamol (Acetaminophen) In Stroke 2 trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial. We use a power of 85% to detect a significant difference in the scores on the modified Rankin Scale of the paracetamol group compared with the placebo group at a level of significance of 0·05 and assume a treatment effect of 7%. Fifteen-hundred patients with acute ischemic stroke or intracerebral hemorrhage and a body temperature of 36·5°C or above will be included within 12h of symptom onset. Patients will be treated with paracetamol in a daily dose of six-grams or matching placebo for three consecutive days. The Paracetamol (Acetaminophen) In Stroke 2 trial has been registered as NTR2365 in The Netherlands Trial Register. Study outcomes: The primary outcome will be improvement on the modified Rankin Scale at three-months as analyzed by ordinal logistic regression. Discussion: If high-dose paracetamol will be proven effective, a simple, safe, and extremely cheap therapy will be available for many patients with acute stroke worldwide.

The importance of sonographer experience and machine quality with regards to the role of musculoskeletal ultrasound in routine care of rheumatoid arthritis patients.

Abstract: Objectives Regarding recent progress, musculoskeletal ultrasound (US) will probably soon be integrated in standard care of patient with rheumatoid arthritis (RA). However, in daily care, quality of US machines and level of experience of sonographers are varied. We conducted a study to assess reproducibility and feasibility of an US scoring for RA, including US devices of different quality and rheumatologist with various levels of expertise in US as it would be in daily care. Methods The Swiss Sonography in Arthritis and Rheumatism (SONAR) group has developed a semi-quantitative score using OMERACT criteria for synovitis and erosion in RA. The score was taught to 108 rheumatologists trained in US. One year after the last workshop, 19 rheumatologists participated in the study. Scans were performed on 6 US machines ranging from low to high quality, each with a different patient. Weighted kappa was calculated for each pair of readers. Results Overall, the agreement was fair to moderate. Quality of device, experience of the sonographers and practice of the score before the study improved substantially the agreement. Agreement assessed on higher quality machine, among sonographers with good experience in US increased to substantial (median kappa for B-mode and Doppler: 0.64 and 0.41 for erosion). Conclusions This study demonstrated feasibility and reproducibility of the Swiss US SONAR score for RA. Our results confirmed importance of the quality of US machine and the training of sonographers for the implementation of US scoring in the routine daily care of RA.

A multifactorial conceptual model of peripheral neuromusculoskeletal predisposing factors in task-specific focal hand dystonia in musicians: etiologic and therapeutic implications

Abstract: A model is presented showing how peripheral factors may cause a process of movement adaptation that leads to task-specific focal hand dystonia in musicians (FHDM). To acquire a playing technique, the hand must find effective and physiologically sustainable movements within a complex set of functional demands and anatomic, ergonomic, and physiological constraints. In doing so, individually discriminating constraints may become effective, such as limited anatomic independence of finger muscles/tendons, limited joint ranges of motion, or (subclinical) neuromusculoskeletal defects. These factors may, depending on the instrument-specific playing requirements, compromise or exclude functional playing movements. The controller (i.e., the brain) then needs to develop alternative motions to execute the task, which is called compensation. We hypothesize that, if this compensation process does not converge to physiologically sustainable muscle activation patterns that satisfy all constraints, compensation could increase indefinitely under the pressure of practice. Dystonic symptoms would become manifest when overcompensation occurs, resulting in motor patterns that fail in proper task execution. The model presented in this paper only concerns the compensatory processes preceding such overcompensations and does not aim to explain the nature of the dystonic motions themselves. While the model considers normal learning processes in the development of compensations, neurological predispositions could facilitate developing overcompensations or further abnormal motor programs. The model predicts that if peripheral factors are involved, FHDM symptoms would be preceded by long-term gradual changes in playing movements, which could be validated by prospective studies. Furthermore, the model implies that treatment success might be enhanced by addressing the conflict between peripheral factors and playing tasks before decompensating/retraining the affected movements.

Dermatological exposure to coal tar and bladder cancer risk: a case-control study.

Abstract: Objective Coal tar ointments are used as treatment of various skin diseases, especially psoriasis and eczema. These ointments contain several carcinogenic polycyclic aromatic hydrocarbons. Metabolites of these polycyclic aromatic hydrocarbons are excreted in the urine and therefore, dermatological use of coal tar may be associated with an increased risk of bladder cancer. The objective of this study was to evaluate the association between dermatological use of coal tar ointments and bladder cancer. Material and methods A population-based case-control study was conducted including 1,387 cases diagnosed with bladder cancer and 5,182 population controls. Information on the use of coal tar, history of skin disease, and known risk factors for bladder cancer was obtained through postal questionnaires. Logistic regression analyses were performed to estimate the risk of bladder cancer after coal tar treatment, adjusted for age, gender, smoking status, duration of smoking, and intensity of smoking. Results The use of coal tar ointments was approximately equal among cases and controls (3.8% vs. 3.0%, respectively). Dermatological application of coal tar was not significantly associated with bladder cancer (adjusted odds ratio = 1.37, 95% CI: 0.93–2.01). An inverse association between bladder cancer and a history of skin disease was observed (adjusted odds ratio = 0.74, 95% CI: 0.61–0.90). Conclusion This is the first study with a specific aim to study the association between the use of coal tar preparations and bladder cancer. The results suggest that there is no reason for safety concerns with respect to the risk of bladder cancer after the use of coal tar preparations in dermatological practice.

Correlation of findings in clinical and high resolution ultrasonography examinations of the painful shoulder.

Abstract: High resolution ultrasonography is a non-painful and non-invasive imaging technique which is useful for the assessment of shoulder pain causes, as clinical examination often does not allow an exact diagnosis. The aim of this study was to compare the findings of clinical examination and high resolution ultrasonography in patients presenting with painful shoulder.Non-interventional observational study of 100 adult patients suffering from unilateral shoulder pain. Exclusion criteria were shoulder fractures, prior shoulder joint surgery and shoulder injections in the past month. The physicians performing the most common clinical shoulder examinations were blinded to the results of the high resolution ultrasonography and vice versa.In order to detect pathology of the m. supraspinatus tendon, the Hawkins and Kennedy impingement test showed the highest sensitivity (0.86) whereas the Jobe supraspinatus test showed the highest specificity (0.55). To identify m. subscapularis tendon pathology the Gerber lift off test showed a sensitivity of 1, whereas the belly press test showed the higher specificity (0.72). The infraspinatus test showed a high sensitivity (0.90) and specificity (0.74). All AC tests (painful arc II(a), AC joint tenderness(b), cross body adduction stress test(c)) showed high specificities ((a)0.96, (b)0.99, (c)0.96). Evaluating the long biceps tendon, the palm up test showed the highest sensitivity (0.47) and the Yergason test the highest specificity (0.88).Knowledge of sensitivity and specificity of various clinical tests is important for the interpretation of clinical examination test results. High resolution ultrasonography is needed in most cases to establish a clear diagnosis.

Effects and cost-effectiveness of pharmacogenetic screening for CYP2D6 among older adults starting therapy with nortriptyline or venlafaxine : Study protocol for a pragmatic randomized controlled trial (CYSCEtrial)

Abstract: Background: Nortriptyline and venlafaxine are commonly used antidepressants for treatment of depression in older patients. Both drugs are metabolized by the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme and guidelines for dose adaptations based on the CYP2D6 genotype have been developed. The CYP2D6 Screening Among Elderly (CYSCE) trial is designed to address the potential health and economic value of genotyping for CYP2D6 in optimizing dose-finding of nortriptyline and venlafaxine. Methods/Design: In a pragmatic randomized controlled trial, patients diagnosed with a major depressive disorder according to the DSM-IV and aged 60 years or older will be recruited from psychiatric centers across the Netherlands. After CYP2D6 genotyping determined in peripheral blood obtained by finger-prick, patients will be grouped into poor, intermediate, extensive, or ultrarapid metabolizers. Patients with deviant genotype (that is poor, intermediate or ultrarapid genotype) will be randomly allocated to an intervention group in which the genotype and dosing advice is communicated to the treating physician, or to a control group in which patients receive care as usual. Additionally, an external reference group of patients with the extensive metabolizer genotype is included. Primary outcome in all groups is time needed to obtain an adequate blood level of the antidepressant drug. Secondary outcomes include adverse drug reactions measured by a shortened Antidepressant Side-Effects Checklist (ASEC), and cost-effectiveness of the screening. Discussion: Results of this trial will guide policy-making with regard to pharmacogenetic screening prior to treatment with nortriptyline or venlafaxine among older patients with depression.

Predictive role of HER2/neu, topoisomerase-II-alpha, and tissue inhibitor of metalloproteinases (TIMP-1) for response to adjuvant taxane-based chemotherapy in patients with intermediate-risk breast cancer: results from the WSG-AGO EC-Doc trial

Abstract: Taxane–anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which compared 4xEC-4xDoc versus 6xCEF/CMF. In addition to hormone receptor status and Ki-67, HER2/neu+ and topoisomerase-II-alpha status using fluorescence in situ hybridisation (FISH) and immunohistochemistry, TIMP-1 using immunohistochemistry, and aneuploidy of chromosome 17 using FISH were evaluated and correlated with outcome and taxane benefit. There was significant superiority of EC-Doc over CEF regarding 5-year DFS (90 vs. 80 %, respectively, p = 0.006) particularly in patient subgroups defined by HR+, HER2/neu+, high proliferation (i.e., Ki-67 ≥ 20 %), patient age >50 years old and normal chromosome 17 status, high TIMP-1 and low topoisomerase-II-alpha protein expression. Significant prognostic factors in multivariate analysis were EC-Doc therapy (HR = 0.61; 95 %CI 0.38–0.986), age <50 years old (HR = 1.682; 95 %CI 1.025–2.579), centrally assessed grade 3 (HR = 4.657; 95 %CI 1.809–11.989), and high Ki-67 (HR = 2.232; 95 %CI 1.209–4.121). Interestingly, we observed a significant interaction between treatment arm (EC-Doc vs. CEF) and high topoisomerase-II-alpha protein expression (HR = 0.427; 95 %CI 0.203–0.900) in multivariate interaction analysis. Despite of univariate predictive effect of HER2/neu status among other factors only topoisomerase-II-alpha protein expression was associated with significant benefit from EC-Doc compared to CEF by multivariate interaction analysis.

Efficacy of 12-weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial.

Abstract: 506 Background: Evidence suggests differential efficacy of standard neoadjuvant chemo- + targeted therapy in HER2+ early breast cancer (eBC) according to hormone-receptor (HR) status. ADAPT HER2+/H...

Employers' experiences of having a live-in domestic worker: Insights into the relationship between privilege and occupational justice

Abstract: Background: Domestic work is a common form of work in South Africa that is known to place teh workers' health at risk. Research has focused on this form of work from the worker's perspective and emphasising the changes needed in employment conditions in South Africa. Purpose: This paper explored teh phenomenon of domestic work from the employer's perspective by describing their lived experiences of employing live-in domestic workers. Method:A qualitative phenomenological study was conducted with six participants purposively selected to participate in two in-depth interviews. A thematic data nalysis was initiated between and after interviews and resulted in the first level of analysis. The second level of analysis ensured that the essence of the experience was presented with clarity. Findings: A single theme, that is "you need them, but theya re working on your nerves" and two categories - "Caught in a conundrum" and "Compelled to be benevolent" emerged. A significant aspect emphasised in the theme and categories was the way that the relationship bewteen the employers and domestic workers participation in occupations left the employer feeling weighed down. Discussion: The relationship between the occupational engagement afforded to the employers in relation to that of the domestic workers is discussed. The way that this perpetuates hegemony and thus social inequality through occupational injustice is identified. Key words: Employers experiences, Domestic workers, Microagression, Occupational justice The South African Journal of Occupational Therapy http://dx.doi.org/10.17159/2310-3833/2015/v45n1a7

Treatment with Tumor Necrosis Factor Inhibitors in Axial Spondyloarthritis: Comparison Between Private Rheumatology Practices and Academic Centers in a Large Observational Cohort

Abstract: Objective. To evaluate the initiation of and response to tumor necrosis factor (TNF) inhibitors for axial spondyloarthritis (axSpA) in private rheumatology practices versus academic centers. Methods. We compared newly initiated TNF inhibition for axSpA in 363 patients enrolled in private practices with 100 patients recruited in 6 university hospitals within the Swiss Clinical Quality Management (SCQM) cohort. Results. All patients had been treated with ≥ 1 nonsteroidal antiinflammatory drug and > 70% of patients had a baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 before anti-TNF agent initiation. The proportion of patients with nonradiographic axSpA (nr-axSpA) treated with TNF inhibitors was higher in hospitals versus private practices (30.4% vs 18.7%, p = 0.02). The burden of disease as assessed by patient-reported outcomes at baseline was slightly higher in the hospital setting. Mean levels (± SD) of the Ankylosing Spondylitis Disease Activity Score were, however, virtually identical in private practices and academic centers (3.4 ± 1.0 vs 3.4 ± 0.9, p = 0.68). An Assessment of SpondyloArthritis international Society (ASAS40) response at 1 year was reached for ankylosing spondylitis in 51.7% in private practices and 52.9% in university hospitals (p = 1.0) and for nr-axSpA in 27.5% versus 25.0%, respectively (p = 1.0). Conclusion. With the exception of a lower proportion of patients with nr-axSpA newly treated with anti-TNF agents in private practices in comparison to academic centers, adherence to ASAS treatment recommendations for TNF inhibition was equally high, and similar response rates to TNF blockers were achieved in both clinical settings.

Efficacy of 12 weeks neoadjuvant nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple-negative breast cancer: WSG-ADAPT TN randomized phase II trial.

Abstract: 1032 Background: Pathological complete response (pCR) is associated with improved prognosis in TNBC, but optimal chemotherapy remains unclear. Neoadjuvant weekly nab-paclitaxel (Nab-Pac) has higher...

Prediction of neonatal outcome in women with gestational hypertension or mild preeclampsia after 36 weeks of gestation.

Abstract: Background: There is little knowledge about neonatal complications in GH and PE and induction at term, we aim to assess whether they can be predicted from clinical data.Methods: We used data of the HYPITAT trial and evaluated whether adverse neonatal outcome (Apgar score < 7, pH < 7.05, NICU admission) could be predicted from clinical data. Logistic regression, ROC analysis and calibration were used to identify predictors and evaluate the predictive capacity in an antepartum and intrapartum model.Results: We included 1153 pregnancies, of whom 76 (6.6%) had adverse neonatal outcome. Parity (primipara OR 2.75), BMI (OR 1.06), proteinuria (dipstick +++ OR 2.5), uric acid (OR 1.4) and creatinine (OR 1.02) were independent antepartum predictors; In the intrapartum model, meconium stained amniotic fluid (OR 2.2), temperature (OR 1.8), duration of first stage of labour (OR 1.15), proteinuria (dipstick +++ OR 2.7), creatinine (OR 1.02) and uric acid (OR 1.5) were predictors of adverse neonatal outcome. Bo...

Influence of metastatic disease on the usefulness of uracil pharmacokinetics as a screening tool for DPD activity in colorectal cancer patients.

Abstract: Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity in patients treated with a standard dose of a fluoropyrimidine such as 5-fluorouracil or capecitabine (CAP). Administration of oral uracil and subsequent measurement of uracil and dihydrouracil (DHU) plasma concentrations has been used to identify patients with DPD deficiency. Liver metastasis might influence systemic DPD activity. The aim of the study was to investigate the effect of metastatic disease on the pharmacokinetics of uracil and DHU after oral administration of uracil. 500 mg/m2 uracil was administered orally to 12 subjects with stages II–III colorectal cancer (CRC) who were treated in the adjuvant setting and to 12 subjects with stage IV metastasized CRC, all treated with CAP containing therapy. All subjects had a normal DPD activity defined as >6 nmol/mg/h determined in peripheral blood mononuclear cells. The mean uracil clearance [CL 51.7 (SD 6.4) vs. 46.7 (SD 13.0) l/h], area under the curve [AUC0–220min 20.6 (SD 6.4) vs. 21.0 (SD 5.7) h mg/l], elimination half-life [t 1/2 21 (SD 7) vs. 21 (SD 8) min], maximum concentration time [T max 27 (SD 9) vs. 25 (SD 9) min], volume of distribution [V 26.58 (SD 10.11) vs. 21.10 (SD 8.48) l] and the elimination constant [k el 2.01 (SD 0.56) vs. 2.41 (SD 0.72) h−1] did not differ significantly (p > 0.05) non-metastatic CRD versus metastatic CRC. Metastasis does not alter uracil pharmacokinetics and is similar in CRC patients with and without metastasis. Therefore, the uracil test dose could be used as a DPD phenotype test in both adjuvantly treated and metastatic CRC patients using similar cutoff criteria to identify patients with DPD deficiency.

Reasons for failure of prevention of mother-to-child HIV transmission in a rural South African district hospital

Abstract: Further reduction of mother-to-child transmission (MTCT) of HIV requires improved understanding of the reasons for MTCT. We reviewed maternal and infant case notes for HIV-positive infants diagnosed by polymerase chain reaction at Bethesda Hospital. Nineteen cases were analysed. Median gestation at first antenatal consultation (ANC) was 22.5 (interquartile range [IQR] 19.25-24). Eleven (57.9%) mothers were HIV positive at first ANC, whilst eight tested negative and later positive (2 antepartum, 6 postpartum). Median maternal CD4 was 408 cells/μL (IQR 318-531). Six (31.6%) received no antenatal antiretroviral therapy (ART) because they were diagnosed as HIV positive postpartum; 9 (47.3%) received antenatal ART and 3 (15.8%) were never initiated on ART. At 6 weeks postpartum, 5 infants (26.3%) were not on prophylactic nevirapine (NVP) because their mothers had not yet been diagnosed. Maternal seroconversion in pregnancy and breastfeeding, and possibly false-negative HIV tests, were important reasons for prevention of mother-to-child transmission (PMTCT) failure.

The Effects of Semantic Feature Analysis Treatment on Naming Performance in Korean Individuals with Early Dementia of the Alzheimer’s Type: Using a Familiarity of Nouns Scale

Abstract: 배경 및 목적: 초기 알츠하이머성 치매(dementia of the Alzheimer's type, DAT)환자 6명을 대상으로 친숙도를 활용한 의미자질(semantic feature analysis, SFA)중재가 중재 및 비중재 명사 이름대기, 기타 이름대기, 표준화된 언어 및 인지검사 과제에서 유의한 차이가 있는지 살펴보았다. 방법: 3명은...

Abstract OT3-2-04: ADAPT - Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early breast cancer

Abstract: Background: Early therapy response is currently not regarded for further treatment decisions as standard of care in the treatment of breast cancer (BC). Predictive markers for the success of a certain therapy could support the physician’s choice of adequate and beneficial therapies by simultaneous reduction of unnecessary toxicity. Proliferation makers as Ki-67 seem to be a suitable tool, as dynamic changes of proliferation (as result of induction therapy) have been shown to be most important for outcome of neoadjuvant chemotherapy prediction in patients with pCR in distinct BC subtypes (luminal B, TNBC, HER2+). Methods: Trial design: ADAPT combines early assessment of prognosis by conventional markers (e.g. molecular classification, nodal status) with dynamic measurement of proliferation changes during a 3-week induction therapy, using baseline diagnostic core biopsy and a second biopsy after induction therapy. ADAPT consists of an umbrella trial and five different sub-trials (HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-, Elderly) and is set up as prospective, multi-center, controlled, non-blinded, randomized phase II/III trial. Subtype-specific treatment across the sub-trials is highly innovative and involves the following treatment strategies: • HR+/HER2-: endocrine therapy (ET) vs. chemotherapy (4xPac q2w – 4xEC q2w vs. 8xNab-Pac q1w – 4xEC q2w) + ET, depending on risk classification/early response. • HER2+/HR+: T-DM1 vs. T-DM1 + ET vs. trastuzumab + ET. • HER2+/HR-: Trastuzumab + Pertzumab ± Paclitaxel q1w. • TN: Nab-Paclitaxel + Gemcitabine vs. nab-Pac + Carboplatin. • Elderly: 2xMyocet + Cyclophosphamide q3w, depending on cPR/cCR or NC/toxicity the treatment will be continued for two more cycles or changed to 6xPac q1w. Adaptation/change in therapy regimens can be made by interim analysis after n=130 in each sub-trial. Eligibility criteria: Histologically confirmed unilateral primary invasive BC with known HR-/HER2-status (central pathology) for allocation to the respective sub-trial. Pts requiring chemo- or targeted (anti-HER2) therapy must have adequate laboratory values and organ function and must have no contraindications for the planned treatment. Primary endpoints: Evaluation of dynamic test for outcome prediction/prospective comparison of 5yr EFS in responders (intermediate risk (RS 12-25) / good response to short-term ET in HR+/HER2- or pts with pCR in HER2+/TN BC) compared to low risk HR+/HER2- (RS≤11, N0-1) pts (control group). Statistical methods: Assumption across sub-protocols: adjuvant CTx can be spared in HR+/HER2- or pCR be achieved in HER2+/TN in expected 1120 (HR+/HER2-) or 170 (HER2+/TN) pts, respectively. Outcome will be compared to the control group (expected n=640 HR+/HER2- pts: low risk (by RS), i.e. no CTx). Assuming 94% 5yr survival in control group, one-sided test of non-inferiority at 95% CI will have 80% power for survival non-inferiority margin of 3.2% (i.e. 90.8% survival). Present and target accrual: By June 2014, 73 active sites have recruited 1820 pts for ADAPT HR+/HER2-. Target accrual is 4000 pts. 190 of 380 pts were successfully randomized for ADAPT HER2+/HR+. ADAPT HER2+/HR- has included 17 of 220 pts and ADAPT Triple Negative has recruited 150 of 336 pts. Citation Format: Ulrike Nitz, Oleg Gluz, Raquel von Schumann, Daniel Hofmann, Ronald E Kates, Sherko Kuemmel, Michael Braun, Claudia Schumacher, Benno Nuding, Bahriye Aktas, Helmut Forstbauer, Nicolai Maass, Mahdi Rezai, Stefan Kraemer, Mathias Warm, Rachel Wuerstlein, Nadia Harbeck. ADAPT - Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-04.

Importance of Geriatric Syndromes in Older Patients with Diabetes with de novo Insulin Treatment: The VEGAS Study

Abstract: Aims The VEGAS study was conducted to evaluate representative data of de novo insulin-treated older patients with type 2 diabetes in the outpatient setting in Germany.

Economic and clinical benefits of radiofrequency ablation versus hysterectomy in patients suffering from menorrhagia: a retrospective analysis with German health claims data.

Abstract: Objective: To assess clinical and economic benefits of radiofrequency ablation (RFA) compared to hysterectomy when treating patients suffering from menorrhagia. Methods: Based on German health claims data, a retrospective, longitudinal, observational analysis was performed. Patients having continuously statutory health insurance coverage during the study and being coded for menorrhagia and a relevant treatment option were included in the analysis. The control group was created using propensity score matching. Results: We discovered that using RFA generates cost savings of €1844 during the quarter of performance. As direct costs during a 2-year follow-up show similar levels in both groups, these initial savings can be preserved. This is partly because even if more patients in the RFA group were re-coded for menorrhagia after initial therapy, just a small proportion of these patients required another surgical intervention. Conclusion: RFA should more often be considered a relevant treatment option both from...

Intraluminal Volume Dose Alteplase for the Clearance of Occluded Peripherally Inserted Central Catheter Lines at a Long-Term Acute Care Hospital: Efficacy and Economic Impact

Abstract: Purpose: To evaluate the efficacy and economic impact of a maximum of 2 doses of intraluminal volume 1 mg/1 mL dose alteplase for the clearance of occluded peripherally inserted central cath- eter (PICC) lines at a long-term acute care hospital (LTACH) Methods: Open-label, nonrandomized quasi-experimental trial taking place over a 3-month period from December 2013 to March 2014 Patients had a standing order of either standard (2 mg/2 mL) or intraluminal volume (1 mg/1 mL) dose alteplase entered for any potential occlu- sions The primary efficacy outcome was restored line patency after a maximum of 2 doses of alteplase Secondary efficacy outcomes included restored patency after 1 dose of alteplase, reocclu - sion rate, mean time to reocclusion, and mean number of occlusions per patient Results: A total of 168 patients were enrolled into the study (intraluminal volume, n = 54; stand- ard, n = 114) and a total of 270 occlusions were recorded; 90 received intraluminal volume dose alteplase and 180 received the standard dose The primary efficacy endpoint was 933% for the intraluminal volume dose group and 944% for the standard dose group Secondary outcomes were similar between groups The average cost per dose was $12377 and $6062 for the standard and intraluminal volume dose alteplase groups, respectively Conclusion: For the clearance of occluded PICC lines at our LTACH, there was no statistical differ- ence in the efficacy of a maximum of 2 doses of intraluminal volume dose alteplase versus the stand - ard dose Use of intraluminal volume dose alteplase was found to be significantly more cost-effective

Assessing HER2 testing quality in breast cancer (BC): Variables that influence HER2-positivity from a large, multicenter, observational study in Germany.

Abstract: 11062 Background: Despite > 10 years of routine HER2 testing in BC, quality is still an issue. It is often assumed that inter- and intra-laboratory variations in testing quality can be assessed by ...