Phenotype-guided targeted therapy based on functional signal transduction pathway activity in recurrent ovarian cancer patients:The STAPOVER study protocol

Objective: Ovarian cancer is the fifth cause of cancer-related death among women. The benefit of targeted therapy for ovarian cancer patients is limited even if treatment is stratified by molecular signature. There remains a high unmet need for alternative diagnostics that better predict targeted therapy, as current diagnostics are generally inaccurate predictors. Quantitative assessment of functional signal transduction pathway (STP) activity from mRNA measurements of target genes is an alternative approach. Therefore, we aim to identify aberrantly activated STPs in tumour tissue of patients with recurrent ovarian cancer and start phenotype-guided targeted therapy to improve survival without compromising quality of life. Study design: Patients with recurrent ovarian cancer and either 1) have platinum-resistant disease, 2) refrain from standard therapy or 3) are asymptomatic and not yet eligible for standard therapy will be included in this multi-centre prospective cohort study with multiple stepwise executed treatment arms. Targeted therapy will be available for patients with aberrantly high functional activity of the oestrogen receptor, androgen receptor, phosphoinositide 3-kinase or Hedgehog STP. The primary endpoint of this study is the progression-free survival (PFS) ratio (PFS2/PFS1 ratio) according to RECIST 1.1 determined by the PFS on matched targeted therapy (PFS2) compared to PFS on prior therapy (PFS1). Secondary endpoints include among others best overall response, overall survival, side effects, health-related quality of life and cost-effectiveness. Conclusion: The results of this study will show the clinical applicability of STP activity in selecting recurrent ovarian cancer patients for effective therapies.</p

Selective attrition and bias in a longitudinal health survey among survivors of a disaster

BACKGROUND: Little is known about the response mechanisms among survivors of disasters. We studied the selective attrition and possible bias in a longitudinal study among survivors of a fireworks disaster. METHODS: Survivors completed a questionnaire three weeks (wave 1), 18 months (wave 2) and four years post-disaster (wave 3). Demographic characteristics, disaster-related factors and health problems at wave 1 were compared between respondents and non-respondents at the follow-up surveys. Possible bias as a result of selective response was examined by comparing prevalence estimates resulting from multiple imputation and from complete case analysis. Analysis were stratified according to ethnic background (native Dutch and immigrant survivors). RESULTS: Among both native Dutch and immigrant survivors, female survivors and survivors in the age categories 25–44 and 45–64 years old were more likely to respond to the follow-up surveys. In general, disasters exposure did not differ between respondents and non-respondents at follow-up. Response at follow-up differed between native Dutch and non-western immigrant survivors. For example, native Dutch who responded only to wave 1 reported more depressive feelings at wave 1 (59.7%; 95% CI 51.2–68.2) than Dutch survivors who responded to all three waves (45.4%; 95% CI 41.6–49.2, p < 0.05). Immigrants who responded only to wave 1 had fewer health problems three weeks post-disaster such as depressive feelings (M = 69.3%; 95% CI 60.9–77.6) and intrusions and avoidance reactions (82.7%; 95% CI 75.8–89.5) than immigrants who responded to all three waves (respectively 89.9%; 95% CI 83.4–96.9 and 96.3%; 95% CI 92.3–100, p < .01). Among Dutch survivors, the imputed prevalence estimates of wave 3 health problems tended to be higher than the complete case estimates. The imputed prevalence estimates of wave 3 health problems among immigrants were either unaffected or somewhat lower than the complete case estimates. CONCLUSION: Our results indicate that despite selective response, the complete case prevalence estimates were only somewhat biased. Future studies, both among survivors of disasters and among the general population, should not only examine selective response, but should also investigate whether selective response has biased the complete case prevalence estimates of health problems by using statistical techniques such as multiple imputation

The size of the treatment effect: do patients and proxies agree?

Background: This study examined whether MS patients and proxy respondents agreed on change in disease impact, which was induced by treatment. This may be of interest in situations when patients suffer from limitations that interfere with reliable self-assessment, such as cognitive impairment.Methods: MS patients and proxies completed the Multiple Sclerosis Impact Scale (MSIS-29) before and after intravenous steroid treatment. Analyses focused on patient-proxy agreement between MSIS-29 change scores. Transition ratings were used to measure the patient's judgement of change and whether this change was reflected in the MSIS-29 change of patients and proxies. Receiver operating characteristic (ROC) analyses were also performed to examine the diagnostic properties of the MSIS-29 when completed by patients and proxies.Results: 42 patients and proxy respondents completed the MSIS-29 at baseline and follow-up. Patient-proxy differences between change scores on the physical and psychological MSIS-29 subscale were quite small, although large variability was found. The direction of mean change was in concordance with the transition ratings of the patients. Results of the ROC analyses of the MSIS-29 were similar when completed by patients (physical scale: AUC = 0.79, 95% CI: 0.65 - 0.93 and 0.66, 95% CI: 0.48 - 0.84 for the psychological scale) and proxies (physical scale: 0.80, 95% CI: 0.72 - 0.96 and 0.71, 95% CI: 0.56 - 0.87 for the psychological scale)Conclusion: Although the results need to be further explored in larger samples, these results do point towards possible use of proxy respondents to assess patient perceived treatment change at the group level

Longitudinal proxy measurements in multiple sclerosis: patient-proxy agreement on the impact of MS on daily life over a period of two years

Background: The use of self- report measurements in clinical settings is increasing. However, in patients with limitations that interfere with reliable self- assessment such as cognitive impairment or mood disturbances, as may be the case in multiple sclerosis ( MS), data collection might be problematic. In these situations, information obtained from proxy respondents ( e. g. partners) may replace self- ratings. The aim of this study was to examine the value of proxy ratings at separate points in time and to assess patient- proxy agreement on possible changes in disease impact of MS. Methods: Fifty- six MS patients and their partners completed the Multiple Sclerosis Impact Scale ( MSIS- 29) at baseline and follow- up, two years later. Patient- proxy agreement was assessed at both time points by calculating intraclass correlation coefficients ( ICCs), exact and global agreement and the mean directional differences between groups. Agreement of change over time was assessed by calculating ICCs between change scores. In parallel, global ratings of both patients and proxy respondents of the extent to which the patient had improved or deteriorated over the past two years were collected to validate possible changes on the MSIS- 29. Results: At both time points, agreement on the physical scale was higher than agreement on the psychological scale ( ICCs at baseline were 0.81 for the physical scale and 0.72 for the psychological scale; at follow- up, the ICC values were 0.86 and 0.65 respectively). At follow- up, statistically significant mean differences between patients and proxies were noted for the physical scale (- 4.8 +/- 12.7, p = 0.006) and the psychological scale (- 8.9 +/- 18.8, p = 0.001). Agreement between change scores on the MSIS- 29 was fair ( ICC < 0.60). Our analyses suggest that the validity of measuring changes over time might be better for proxy respondents compared to patients. Conclusion: Proxy respondents could act as a reliable source of information in cross- sectional studies. Moreover, results suggested that agreement on change over time might be better for proxy respondents compared to patients. Although this remarkable finding should be interpreted cautiously because of several limitations of the study, it does plead for further investigation of this important topic

Cost-effectiveness of postural exercise therapy versus physiotherapy in computer screen-workers with early non-specific work-related upper limb disorders (WRULD); a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Exercise therapies generate substantial costs in computer workers with non-specific work-related upper limb disorders (WRULD).</p> <p>Aims</p> <p>To study if postural exercise therapy is cost-effective compared to regular physiotherapy in screen-workers with early complaints, both from health care and societal perspective.</p> <p>Methods</p> <p>Prospective randomized trial including cost-effectiveness analysis; one year follow-up. Participants: Eighty-eight screen-workers with early non-specific WRULD; six drop-outs. Interventions: A ten week postural exercise program versus regular physiotherapy. Outcome measures: Effectiveness measures: Pain: visual analogous scale (VAS), self-perceived WRULD (yes/no). Functional outcome: Disabilities of Arm, Shoulder and Hand- Dutch Language Version (DASH-DLV). Quality of life outcome: EQ-5D.</p> <p>Economic measures: health care costs including patient and family costs and productivity costs resulting in societal costs. Cost-effectiveness measures: health care costs and societal costs related to the effectiveness measures. Outcome measures were assessed at baseline; three, six and twelve months after baseline.</p> <p>Results</p> <p>At baseline both groups were comparable for baseline characteristics except scores on the Pain Catastrophizing Scale and comparable for costs. No significant differences between the groups concerning effectiveness at one year follow-up were found. Effectiveness scores slightly improved over time. After one year 55% of participants were free of complaints. After one year the postural exercise group had higher mean total health care costs, but lower productivity costs compared to the physiotherapy group. Mean societal costs after one year (therefore) were in favor of postural exercise therapy [- €622; 95% CI -2087; +590)]. After one year, only self- perceived WRULD seemed to result in acceptable cost-effectiveness of the postural exercise strategy over physiotherapy; however the probability of acceptable cost-effectiveness did not exceed 60%.</p> <p>Considering societal costs related to QALYs, postural exercise therapy had a probability of over 80% to be cost-effective over a wide range of cost-effectiveness ceiling ratios; however based on a marginal QALY-difference of 0.1 over a 12 month time frame.</p> <p>Conclusion</p> <p>Although our trial failed to find significant differences in VAS, QALYs and ICERs based on VAS and QALYs at one-year follow-up, CEACs suggest that postural exercise therapy according to Mensendieck/Cesar has a higher probability of being cost-effective compared to regular physiotherapy; however further research is required.</p> <p>Trial registration</p> <p>ISRCTN 15872455</p

Shortened time interval between colorectal cancer diagnosis and risk testing for hereditary colorectal cancer is not related to higher psychological distress

Current diagnostic practices have shortened the interval between colorectal cancer (CRC) diagnosis and genetic analysis for Lynch syndrome by MSI-testing. We studied the relation of time between MSI-testing since CRC diagnosis (MSI–CRC interval) and psychological distress. We performed a cross-sectional study in 89 patients who had previously been treated for CRC. Data were collected during MSI-testing after genetic counseling. Psychological distress was measured with the IES, the SCL-90 and the POMS; social issues with the ISS, ISB and the ODHCF. The median time of MSI–CRC interval was 24 months (range 0–332), with 23% of the patients diagnosed less than 12 months and 42% more than 36 months prior to MSI-testing. In 34% of the patients cancer specific distress was high (IES scores >26). Mean psychopathology (SCL-90) scores were low, mean mood states (POMS) scores were moderate. Interval MSI–CRC was not related to psychological distress. High cancer specific distress was reported by 24% of patients diagnosed with CRC less than 12 months ago versus 39 and 35% by those diagnosed between 12 and 36 months and more than 36 months ago respectively. Distress was positively related to female gender (P = 0.04), religiousness (P = 0.01), low social support (P = 0.02) and difficulties with family communication (P < 0.001). Shortened time interval between CRC diagnosis and MSI-testing is not associated with higher psychological distress. Females, religious persons, those having low social support and those reporting difficulties communicating hereditary colorectal cancer with relatives are at higher risk for psychological distress

Distress and quality of life after autologous stem cell transplantation: a randomized clinical trial to evaluate the outcome of a web-based stepped care intervention

Background Psychological distress (i.e. depression and anxiety) is a strong predictor of functional status and other aspects of quality of life in autologous stem cell transplantation following high-dose chemotherapy. Treatment of psychological distress is hypothesized to result in improvement of functional status and other aspects of quality of life. The aim is to evaluate the outcome of stepped care for psychological distress on functional status and other aspects of quality of life in patients with hematological malignancy treated with autologous stem cell transplantation. Methods/Design The study is designed as a randomized clinical trial with 2 treatment arms: a stepped care intervention program versus care as usual. Patients are randomized immediately pre transplant. Stepped care and care as usual are initiated after a 6 weeks buffer period. Outcome is evaluated at 13, 30, and 42 weeks post transplant. In the experimental group, the first step includes an Internet-based self-help program. If psychological distress persists after the self-help intervention, the second step of the program is executed, i.e. a diagnostic evaluation and a standardized interview, yielding a problem analysis. Based on this information, a contract is made with the patient and treatment is provided consisting of individual face-to-face counseling, medication, or referral to other services. Care as usual comprises an interview with the patient, on ad hoc basis; emotional support and advice, on ad hoc basis; if urgent problems emerge, the patient is referred to other services. Primary outcome variables are psychological distress and functional status. Data are analyzed according to the intention to treat-principle. Discussion This study has several innovative characteristics. First, the outcome of the intervention for psychological distress in patients with hematological malignancy treated with autologous stem cell transplantation is evaluated in a randomized controlled study. Second, the impact of the intervention on functional status is evaluated: it is hypothesized that reduction of psychological distress results in improved functional status. Furthermore, the intervention concerns an Internet-based treatment in the first step. Finally, the intervention is characterized by an emphasis on self-management, efficiency, and a multi-disciplinary approach with nurses taking up a central role

False Heart Rate Feedback and the Perception of Heart Symptoms in Patients with Congenital Heart Disease and Anxiety

Background Little is known about the mechanisms explaining an increased perception of heart symptoms in congenital heart disease (ConHD). In the present study, it was suggested that a combination of high trait anxiety and disease history increases the perception of heart symptoms. Purpose It was tested whether false heart cues will result in an increased perception of heart symptoms in patients with ConHD and anxiety. Method Thirty-six patients with ConHD and 44 healthy controls performed two exercise tasks. During one of the exercise tasks, participants were exposed to a false heart cue consisting of false heart rate feedback (regular or irregular). Perceived heart symptoms were assessed and heart rate, arterial partial pressure of CO2, and respirator rate were monitored continuously. Results In line with the predictions, false heart rate feedback resulted in an increased perception of heart symptoms in high trait anxious patients with ConHD that could not be explained by acute heart dysfunction. However, unexpectedly, this effect was not observed immediately after the false heart rate feedback task but after a second exercise task without false feedback. Conclusion The results suggest that not the sole presence of ConHD but ConHD in combination with high trait anxiety results in a vulnerability to overperceive heart symptom

Association between physical activity and metabolic syndrome: a cross sectional survey in adolescents in Ho Chi Minh City, Vietnam

<p>Abstract</p> <p>Background</p> <p>The emerging epidemic of overweight/obesity in adolescents in Ho Chi Minh City, Vietnam underlines the importance of studying the metabolic syndrome in Vietnamese adolescents who are becoming progressively more inactive. No study in Vietnam has examined the association of metabolic syndrome with moderate to vigorous physical activity (PA) levels among adolescents. We aimed to examine this association in a sample of urban adolescents from Ho Chi Minh City.</p> <p>Methods</p> <p>A cross-sectional assessment was conducted in 2007 on a representative sample of 693 high-school students from urban districts in Ho Chi Minh City. Metabolic syndrome was defined according to the International Diabetes Federation criteria and physical activity was measured with Actigraph accelerometers. The association between physical activity and metabolic syndrome was assessed by using multiple logistic regression models.</p> <p>Results</p> <p>Overall 4.6% of the adolescents and 11.8% of the overweight/obese adolescents had metabolic syndrome. Elevated BP was the most common individual component of the metabolic syndrome (21.5%), followed by hypertriglyceridemia (11.1%). After adjusting for other study factors, the odds of metabolic syndrome among youth in the lowest physical activity group (<43 minutes of physical activity/day) were five times higher than those in the highest physical activity group (>103 minutes/day) (AOR = 5.3, 95% CI: 1.5, 19.1). Metabolic syndrome was also positively associated with socioeconomic status (AOR = 9.4, 95% CI: 2.1, 42.4).</p> <p>Conclusions</p> <p>A more physically active lifestyle appears to be associated with a lower odds of metabolic syndrome in Vietnamese adolescents. Socio-economic status should be taken into account when planning interventions to prevent adolescent metabolic syndrome.</p