Addressing Domestic Violence in Antenatal Care Environments in Nepal (ADVANCE) - study protocol for a randomized controlled trial evaluating a video intervention on domestic violence among pregnant women.

BACKGROUND: Domestic violence (DV) prior to, and during pregnancy is associated with increased risks for morbidity and mortality. As pregnant women routinely attend antenatal care this environment can be used to offer support to women experiencing DV. We have developed a video intervention that focuses on the use of behavioral coping strategies, particularly regarding disclosure of DV experiences. The effectiveness of this intervention will be evaluated through a randomized controlled trial (RCT) and a concurrent process evaluation. METHODS: All pregnant women between 12-22 weeks of gestation attending routine antenatal care at two tertiary level hospitals in Nepal are invited to participate. DV is measured using the Nepalese version of the Abuse Assessment Screen (N-AAS). Additionally, we measure participants' mental health, use of coping strategies, physical activity, and food security through a Color-coded Audio Computer Assisted Self Interview (C-ACASI). Irrespective of DV status, women are randomized into the intervention or control arm using a computer-generated randomization program. The intervention arm views a short video providing information on DV, safety improving actions women can take with an emphasis on disclosing the violence to a trusted person along with utilizing helplines available in Nepal. The control group watches a video on maintaining a healthy pregnancy and when to seek healthcare. The primary outcome is the proportion of women disclosing their DV status to someone. Secondary outcomes are symptoms of anxiety and depression, coping strategies, the use of safety measures and attitudes towards acceptance of abuse. Follow-up is conducted after 32 weeks of gestation, where both the intervention and control group participants view the intervention video after completing the follow-up questionnaire. Additionally, a mixed methods process evaluation of the intervention will be carried out to explore factors influencing the acceptability of the intervention and the disclosure of DV, including a review of project documents, individual interviews, and focus group discussions with members of the research team, healthcare providers, and participants. DISCUSSION: This study will provide evidence on whether pregnant women attending regular antenatal visits can enhance their safety by disclosing their experiences of violence to a trusted person after receiving a video intervention. TRIAL REGISTRATION: The study is registered in ClinicalTrial.gov with identifier NCT05199935.

Does treatment with bisphosphonates protect against fractures in real life? The HUNT study, Norway.

Bisphosphonates reduce fractures in randomized controlled trials (RCT); however, there is less information from real life. In our population including 14,990 women and 13,239 men, use of bisphosphonates reduced risk of fractures in hip and forearm in women. The magnitude of the effect was comparable to results from RCT. INTRODUCTION: The objective was to examine if treatment with bisphosphonates (BPs) was associated with reduced risk of fractures in the hip and forearm in women and men in the general population. METHODS: In a cohort study based on data from the third wave of the population-based HUNT Study (HUNT3), the fracture registry in Nord-Trøndelag, and the Norwegian Prescription Database, 14,990 women and 13,239 men 50-85 years were followed from the date of participating in HUNT3 (2006-2008) until the date of first fracture in the hip or forearm, death, or end of study (31 December 2012). Hazard ratios with 95% confidence intervals for hip and forearm fracture according to use of BPs were estimated using Cox proportional hazards models with time-dependent exposure. Adjustment for individual FRAX® fracture risk assessment scores was included. RESULTS: BPs, predominantly alendronate, were used by 9.4% of the women and 1.5% of the men. During a median of 5.2 years of follow-up, 265 women and 133 men had a hip fracture, and 662 women and 127 men had a forearm fracture. Compared with non-users of BPs, the hazard ratios with 95% confidence interval for a fracture among users of BPs adjusted for age and FRAX® were 0.67 (0.52-0.86) for women and 1.13 (0.50-2.57) for men. Among users of glucocorticoids, the corresponding figures were 0.35 (0.19-0.66) and 1.16 (0.33-4.09), respectively. CONCLUSIONS: Use of BPs was associated with reduced risk of fractures in hip and forearm in women, and the magnitude of effect is comparable to results from RCTs.

Proton pump inhibitors and fracture risk. The HUNT study, Norway.

Proton pump inhibitors (PPIs) have been linked to increased risk of fracture; the data have, however, been diverging. We did not find any increased risk of fractures among users of PPIs in a Norwegian population of 15,017 women and 13,241 men aged 50-85 years with detailed information about lifestyle and comorbidity. INTRODUCTION: Proton pump inhibitors (PPIs) are widely prescribed and have been linked to increased risk of fracture. METHODS: We used data from the Nord-Trøndelag Health Study (HUNT3), The Fracture registry in Nord-Trøndelag, and the Norwegian Prescription Database, including 15,017 women and 13,241 men aged 50-85 years. The study population was followed from the date of participating in HUNT3 (2006-2008) until the date of first fracture (forearm or hip), death, or end of study (31 December 2012). The Cox proportional hazards model with time-dependent exposure to PPIs was applied, and each individual was considered as unexposed until the first prescriptions was filled. To be included, the prescription of PPIs should minimum be equivalent to 90 defined daily doses (DDD) in the period. Individuals were defined as exposed until 6 months after end of drug supply. RESULTS: The proportion of women and men using PPIs was 17.9% and 15.5%, respectively. During a median of 5.2 years follow-up, 266 women and 134 men had a first hip fracture and 662 women and 127 men, a first forearm fracture. The combined rate/1000 patient-years for forearm and hip fractures in women was 49.2 for users of PPIs compared with 64.1 among non-users; for men 18.6 and 19.8, respectively. The hazard ratios with 95% confidence interval for the first forearm or hip fracture among users of PPIs in the age-adjusted analysis were 0.82 (0.67-1.01) for women and 1.05 (0.72-1.52) for men. Adjusting for age, use of anti-osteoporotic drugs, and FRAX, the HR declined to 0.80 (0.65-0.98) in women and 1.00 (0.69-1.45) in men. CONCLUSIONS: Use of PPIs was not associated with an increased risk of fractures.

Anti-osteoporosis drug use: too little, too much, or just right? The HUNT study, Norway.

Use of anti-osteoporotic drugs (AODs) was examined in a Norwegian population 50-85 years. Among them with Fracture Risk Assessment Tool (FRAX) score for major osteoporotic fracture ≥ 20, 25% of the women and 17% of the men received AODs. The strongest predictors for AODs were high age in women and use of glucocorticoids among men. INTRODUCTION: To examine the use of anti-osteoporotic drugs (AODs) and to identify predictors for prescriptions. METHODS: Data were obtained from the Nord-Trøndelag Health Study (HUNT3) performed in 2006-2008 and the Norwegian Prescription Database, including 15,075 women and 13,386 men aged 50-85 years. Bone mineral density (BMD) in the femoral neck was measured in a subgroup of 4538 women and 2322 men. High fracture risk was defined as a FRAX score for major osteoporotic fracture (MOF) ≥ 20%; in the subgroup with BMD, high risk was in addition defined as FRAXMOF ≥ 20% or T-score ≤ - 2.5. Hazard ratios (HRs) for predictors of incident use of AODs within 2 years after HUNT3 were estimated by Cox' proportional hazards model. RESULTS: Among individuals with FRAX MOF ≥ 20%, 25% of the women and 17% of the men were treated with AODs. Among those with FRAX MOF < 20%, 3% and 1% were treated, respectively. In the subgroup with BMD measurement, 24% of the women and 16% of the men at high risk of fractures were treated, compared to 3 and 1% in women and men not fulfilling the criteria. In women, high age was the strongest predictor for treatment (HR 3.84: 95% confidence interval 2.81-5.24), followed by use of glucocorticoids (GCs) (2.68:1.84-3.89). In men, predictors were use of GCs (5.28: 2.70-10.35) followed by multimorbidity (3.16:1.31-7.63). In the subgroup with BMD, T-score ≤ - 2.5 was the strongest predictor (women 3.98:2.67-5.89; men 13.31:6.17-28.74). CONCLUSIONS: This study suggests an undertreatment of AODs in individuals at high risk of fracture.

Preoperative geriatric assessment and tailored interventions in frail older patients with colorectal cancer: a randomized controlled trial.

AIM: Colorectal cancer (CRC) is prevalent in the older population, and surgery is the mainstay of curative treatment. A preoperative geriatric assessment (GA) can identify frail older patients at risk for developing postoperative complications. In this randomized controlled trial we wanted to investigate whether tailored interventions based on a preoperative GA could reduce the frequency of postoperative complications in frail patients operated on for CRC. METHOD: Patients > 65 years scheduled for elective CRC surgery and fulfilling predefined criteria for frailty were randomized to either a preoperative GA followed by a tailored intervention or care as usual. The primary end-point was Clavien-Dindo Grade II-V postoperative complications. Secondary end-points included complications of any grade, reoperation, length of stay, readmission and survival. RESULTS: One hundred and twenty-two patients with a mean age of 78.6 years were randomized. We found no statistically significant differences between the intervention group and the control group for Grade II-V complications (68% vs 75%, P = 0.43), reoperation (19% vs 11%, P = 0.24), length of stay (8 days in both groups), readmission (16% vs 6%, P = 0.12) or 30-day survival (4% vs 5%, P = 0.79). Grade I-V complications occurred in 76% of patients in the intervention group compared with 87% in the control group (P = 0.10). In secondary analyses adjusting for prespecified prognostic factors, there was a statistically significant difference in favour of the intervention for reducing the total number of Grade I-V complications (P = 0.05). CONCLUSION: A preoperative GA and tailored interventions did not reduce the rate of Grade II-V complications, reoperations, readmission or mortality in frail older patients electively operated on for CRC.

Validation of FRAX and the impact of self-reported falls among elderly in a general population: the HUNT study, Norway.

Fracture Risk Assessment Tool (FRAX) without bone mineral density (BMD) for hip fracture prediction was validated in a Norwegian population 50-90 years. Fracture risk increased with higher FRAX score, and the observed number of hip fractures agreed well with the predicted number, except for the youngest and oldest men. Self-reported fall was an independent risk factor for fracture in women. INTRODUCTION: The primary aim was to validate FRAX without BMD for hip fracture prediction in a Norwegian population of men and women 50-90 years. Secondary, to study whether information of falls could improve prediction of fractures in the subgroup aged 70-90 years. METHODS: Data were obtained from the third survey of the Nord-Trøndelag Health Study (HUNT3), the fracture registry in Nord-Trøndelag, and the Norwegian Prescription Database (NorPD), including 15,432 women and 13,585 men. FRAX hip without BMD was calculated, and hip fractures were registered for a median follow-up of 5.2 years. The number of estimated and observed fractures was assessed, ROC curves with area under the curve (AUC), and Cox regression analyses. For the group aged 70-90 years, self-reported falls the last year before HUNT3 were included in the Cox regression model. RESULTS: The risk of fracture increased with higher FRAX score. When FRAX groups were categorized in a 10-year percentage risk for hip fracture as follows, <4, 4-7.9, 8-11.9, and ≥12%, the hazard ratio (HR) for hip fracture between the lowest and the highest group was 17.80 (95% CI: 12.86-24.65) among women and 23.40 (13.93-39.30) in men. Observed number of hip fractures agreed quite well with the predicted number, except for the youngest and oldest men. AUC was 0.81 (0.78-0.83) for women and 0.79 (0.76-0.83) for men. Self-reported fall was an independent risk factor for fracture in women (HR 1.64, 1.20-2.24), and among men, this was not significant (1.09, 0.65-1.83). CONCLUSIONS: FRAX without BMD predicted hip fracture reasonably well. In the age group 70-90 years, falls seemed to imply an additional risk among women.

Motor development in children prenatally exposed to selective serotonin reuptake inhibitors: a large population-based pregnancy cohort study.

OBJECTIVES: To estimate the association between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and motor development in children considering the effect of maternal symptoms of anxiety and depression before, during and after pregnancy. DESIGN: Population-based prospective pregnancy cohort study. SETTING: The Norwegian Mother and Child Cohort study (MoBa) (1999-2008). POPULATION: A total of 51 404 singleton pregnancies. METHODS: Self-reported use of SSRIs was collected for the 6 months before pregnancy and prospectively during pregnancy. We used ordinal logistic regression as the statistical analysis. MAIN OUTCOME MEASURES: Motor development was assessed by maternal reports of fine and gross motor development at child age 3 years by items from the Ages and Stages Questionnaire (ASQ). The maternal ASQ scores were compared with data from a MoBa sub-study where clinicians assessed motor development with the Gross and Fine Motor Mullen scales of early learning. RESULTS: In all 381 women (0.7%) reported use of SSRIs during pregnancy, of these 159 reported on at least two questionnaires (prolonged use). Prolonged SSRI exposure was associated with a delay in fine motor development, odds ratio 1.42 (95% CI 1.07-1.87) compared with no SSRI exposure, after adjusting for symptoms of anxiety and depression before and during pregnancy. Severity of maternal depression seemed to explain the association only partially. Stratifying on depression after pregnancy had no impact on the estimated effect of SSRIs. CONCLUSIONS: Prolonged prenatal exposure to SSRIs was weakly associated with a delayed motor development at age 3 years, but not to the extent that the delay was of clinical importance. TWEETABLE ABSTRACT: Long-term prenatal SSRI exposure is weakly associated with delayed motor development independent of depression.

Effects of strength training on muscle cellular outcomes in prostate cancer patients on androgen deprivation therapy.

Androgen deprivation therapy (ADT) improves life expectancy in prostate cancer (PCa) patients, but is associated with adverse effects on muscle mass. Here, we investigated the effects of strength training during ADT on muscle fiber cross-sectional area (CSA) and regulators of muscle mass. PCa patients on ADT were randomized to 16 weeks of strength training (STG) (n = 12) or a control group (CG; n = 11). Muscle biopsies were obtained from m. vastus lateralis and analyzed by immunohistochemistry and western blot. Muscle fiber CSA increased with strength training (898 µm(2) , P = 0.04), with the only significant increase observed in type II fibers (1076 µm(2) , P = 0.03). There was a trend toward a difference in mean change between groups myonuclei number (0.33 nuclei/fiber, P = 0.06), with the only significant increase observed in type I fibers, which decreased the myonuclear domain size of type I fibers (P = 0.05). Satellite cell numbers and the content of androgen receptor and myostatin remained unchanged. Sixteen weeks of strength training during ADT increased type II fiber CSA and reduced myonuclear domain in type I fibers in PCa patients. The increased number of satellite cells normally seen following strength training was not observed.

Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment.

BACKGROUND: We have previously reported that the safety and efficacy of ipilimumab in real-world patients with metastatic melanoma were comparable to clinical trials. Few studies have explored health-related quality of life (HRQL) in real-world populations receiving checkpoint inhibitors. This study reports HRQL in real-world patients receiving ipilimumab and assesses the prognostic value of patient-reported outcome measures. PATIENTS AND METHODS: Ipi4 (NCT02068196) was a prospective, multicentre, interventional phase IV trial. Real-world patients (N = 151) with metastatic melanoma were treated with ipilimumab 3 mg/kg intravenously as labelled. HRQL was assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire at baseline and after 10-12 weeks. RESULTS: The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire was completed by 93% (141/151 patients) at baseline, and by 82% at 10-12 weeks. Poor performance status and elevated C-reactive protein (CRP) were associated with worse baseline HRQL. Clinically relevant and statistically significant deteriorations in HRQL from baseline to weeks 10-12 were reported (P <0.05). Baseline physical functioning [hazard ratio (HR) 1.96, P = 0.016], role functioning (HR 2.15, P <0.001), fatigue (HR 1.60, P = 0.030), and appetite loss (HR 1.76, P = 0.012) were associated with poorer overall survival independent of performance status, lactate dehydrogenase (LDH), and CRP. We further developed a prognostic model, combining HRQL outcomes with performance status, LDH, and CRP. This model identified three groups with large and statistically significant differences in survival. CONCLUSIONS: Systemic inflammation is associated with impaired HRQL. During treatment with ipilimumab, HRQL deteriorated significantly. Combining HRQL outcomes with objective risk factors provided additional prognostic information that may aid clinical decision making.

Interest and preferences for exercise counselling and programming among Norwegian cancer survivors.

To be able to make suitable exercise intervention programmes for cancer survivors, we need more information about exercise preferences. The primary aim of the study was to investigate the interest and preferences for exercise among Norwegian cancer survivors. A secondary aim was to identify demographic and medical characteristics associated with interest in exercise counselling. A questionnaire was completed by 1284 cancer survivors. Overall, 76% of participants were interested or maybe interested in receiving exercise counselling at some point during their cancer experience. Logistic regression analyses indicated that the interest in exercise counselling in men was associated with younger age, presence of comorbidity and having received chemotherapy. In women, the interest was associated with younger age, higher education and change in physical activity level. The participants preferred face-to-face exercise counselling with an exercise specialist from a cancer centre, at a hospital, immediately after treatment. Most cancer survivors were interested in an exercise programme, walking as activity, at moderate intensity and they wanted to start immediately after treatment. The knowledge from this study can contribute to make suitable physical rehabilitation available to cancer patients in the future.

The use of real-world data in cancer drug development.

Excitement about the dramatic increase in potential successful anticancer medicines in recent years is hampered by the high costs involved as well as the length of time traditional pathways take for regulatory approval. The translation of experimental clinical data into real-world evidence is also problematic. While the randomised controlled trial remains the gold standard for assessing efficacy and safety, there is increasing interest in the use of observational data to enable more rapid, informed and widespread availability and access to important anticancer medicines. Taking real-world evidence into account in regulatory and health technology assessment in a thoughtful and balanced fashion will enrich and justify sound decision-making.

TP53 and long-term prognosis in colorectal cancer: mutations in the L3 zinc-binding domain predict poor survival.

In a consecutive series of 222 colorectal carcinomas from patients with a median follow-up time of 56.8 months (range, 0.5-92.2) treated with surgery, the TP53 gene was screened for mutations. Exons 5-8 were analyzed using constant denaturant gel electrophoresis followed by sequencing, and mutations were found in 102 cases (45.9%). Mutations were found more frequently in rectal tumors versus other locations (P = 0.029) and in aneuploid compared to diploid tumors (P < 0.001). Presence of a TP53 mutation was also significantly associated with absence of microsatellite instability (P = 0.028), as well as with loss of heterozygosity at 17p13 (P < 0.001). The TP53 mutations in the left-sided and rectal tumors were more often transversions than transitions, indicating a different etiology in the development of these tumors. The tendency for shorter cancer-related survival among patients with mutations in their tumors was only statistically significant for patients with left-sided tumors (P = 0.003). All patients with mutations affecting the L3 domain of the protein involved in zinc binding had a significantly shorter cancer-related survival (P = 0.036), indicating that mutations affecting this domain have biological relevance in terms of colorectal cancer disease course. These results suggest that knowledge of a patient's TP53 status, with respect to both the presence and the localization of the mutation, may be important in prognosis evaluation, particularly when selecting patients for more aggressive postoperative therapeutic intervention.

Inflammatory markers in bronchoalveolar lavage fluid from human volunteers 2 hours after hydrogen fluoride exposure.

Fluoride has been in focus as a possible causal agent for respiratory symptoms amongst aluminium potroom workers for several decades. Previously, using bronchoalveolar lavage (BAL), we demonstrated airway inflammation in healthy volunteers 24 hours after exposure to hydrogen fluoride (HF). The objective of the present study was to examine early lung responses to HF exposure. Bronchoscopy with BAL was performed 2 hours after the end of 1-hour exposure to HE Significant reductions in the total cell number and the number of neutrophils and lymphocytes were observed in bronchoalveolar portion (BAP), whereas there were no significant changes in the bronchial portion (BP). Significantly decreased concentrations of beta2-MG, IL-6 and total protein were found in both BAP and BP. Additionally, IL-8 was significantly reduced in BP, and ICAM-1 and albumin were present in lower concentrations in BAP. Lung function measurements were not affected by HF exposure. These reported effects are presumably transitory, as many were not present in the airways 24 hours after a similar HF exposure.

Single tube multiplex polymerase chain reaction genotype analysis of GSTM1, GSTT1 and GSTP1: relation of genotypes to TP53 tumor status and clinicopathological variables in breast cancer patients.

Glutathione S-transferases are involved in the conjugation of a number of human carcinogens. The frequencies of the deletion alleles coding for GSTM1, and GSTT1, related to deficient conjugation of xenobiotics, as well as a recently reported variant in the exon 5 of GSTP1 were investigated in this study. A multiplex polymerase chain reaction based method for a rapid and high throughput genotype analysis of all three GSTM1, GSTT1 and GSTP1 genes in a single tube was developed. Leukocyte DNA from two hundred and thirty-nine (n = 239) breast cancer patients were genotyped. Tumors from a subset of these breast cancer patients (n = 131) have previously been investigated for mutations in the TP53 gene, levels of p53 protein accumulation and loss of heterozygosity at several loci on chromosome 17. When genetic alterations in the tumors were analyzed with respect to glutathione S-transferase genotypes, a significantly higher proportion of the patients with a G allele (GG + AG) of the GSTP1 had loss of heterozygosity at the TP53 gene locus mapping to 17p, compared with non-G allele carriers (74% versus 29%) (P = 0.018). The patients carrying the G allele of GSTP1 also had more frequently mutations in the TP53 gene in their tumor (38%), compared with patients with the AA genotype (21%) (P = 0.055). G allele carriers had predominantly deletion or transversion mutations in the TP53 gene (5 of 7 and 5 of 6 respectively). A higher frequency of the G allele carriers was observed among patients with negative lymph node status (P = 0.0004). A higher proportion of the patients with positive lymph node status at the time of diagnosis had a combined GSTM1 null/GSTT1 null genotype (P = 0.05). Patients who were homozygous for the deleted GSTM1 allele were found to have a significantly shorter overall survival (P = 0.036).

Combining diclofenac with acetaminophen or acetaminophen-codeine after oral surgery: a randomized, double-blind single-dose study.

In a randomized double-blind study, 120 patients with moderate to strong pain after surgical removal of wisdom teeth were given the following in single oral doses: 100-mg enteric-coated diclofenac tablets; 1 g acetaminophen (INN, paracetamol); 1 g acetaminophen plus 60 mg codeine; 100-mg enteric-coated diclofenac tablets plus 1 g acetaminophen; or 100-mg enteric-coated diclofenac tablets plus 1 g acetaminophen plus 60 mg codeine. Patients recorded pain intensity and pain relief for 8 hours. Upside assay sensitivity was confirmed because acetaminophen plus codeine was superior to acetaminophen. Diclofenac plus acetaminophen with and without codeine had superior analgesic effect compared with diclofenac, acetaminophen, or acetaminophen plus codeine. Addition of 60 mg codeine increased the degree of side effects. These results support the clinical practice of combining diclofenac with acetaminophen for acute pain. Of clinical importance are superior and prolonged analgesia and fewer side effects after enteric-coated diclofenac tablets plus acetaminophen compared with acetaminophen plus codeine.

Quality of life during radiotherapy for rectal cancer.

The aim of this study was to assess symptoms and health-related quality of life (HRQL) during (neo)adjuvant radiotherapy for rectal cancer. Patients receiving pelvic radiotherapy 50 Gy for rectal cancer, were studied prospectively (n=42). The European Organization for Research and Treatment of Cancer (EORTC) questionnaires quality of life-core 30 QLQ-C30 and QLQ-CR38 and a 5-day symptom diary were completed at the start and end of radiotherapy and 4-6 weeks later. At the end of radiotherapy, mean scores of diarrhoea, fatigue and appetite loss had significantly increased (P<0.01) compared with pretreatment scores, but this was not observed for scores for nausea or pain. At the end of radiotherapy, diarrhoea, fatigue, appetite loss, physical function, social function and global quality of life (QL) were significantly worse than the population-based norms. 64% of the patients reported an increase in fatigue and 52% an increase in diarrhoea during radiotherapy. HRQL scores had returned to pre-treatment levels 4-6 weeks after radiotherapy. Thus, diarrhoea, fatigue and appetite loss increased transiently during pelvic radiotherapy.

Computed tomography/magnetic resonance based volume changes of the primary tumour in patients with prostate cancer with or without androgen deprivation.

BACKGROUND AND PURPOSE: To evaluate changes of the volume of the cancerous prostatic gland during androgen deprivation (AD) started immediately after diagnosis (IAD). Hypothetically, these data would assist the radiotherapist to determine the appropriate duration of pre-radiotherapy downsizing neoadjuvant luteinizing hormone releasing hormone (LHRH) treatment. A second aim was to assess any increase of the prostatic volume during the 1st year of diagnosis in patients who were allocated to a deferred treatment policy (DAD). METHODS AND MATERIALS Thirteen patients in the IAD cohort and 13 patients in the DAD group, all with T1-3pN1-2M0 prostate cancer, had regular computed tomography/magnetic resonance (CT/MR) examinations during the 1st year after randomization within the EORTC-GU trial 30846. Pre-treatment prostate specific antigen (PSA) values were available in only 12 patients. RESULTS: In the IAD group the prostate gland decreased with significant difference as compared with the DAD patients (P=0.033). As compared with the pre-treatment situation the prostate gland in the IAD group was reduced in size by 18, 35, and 46% at 1, 6, and 12 months, respectively. In four of six evaluable IAD patients the prostatic volume continued to shrink after achievement of the nadir PSA level (at 3 months). In three of the 13 DAD patients the prostate volume increased by >25% during the 1st 3 months after randomization. CONCLUSION: If neoadjuvant androgen deprivation is applied before local treatment to downsize the volume of the cancerous prostate gland, our limited data suggest that such treatment should last at least 6 months in order to achieve a maximal effect in the majority of patients. In about 1/4 of untreated patients an increase in the prostate volume by >25% may occur within 3 months of diagnosis. If no AD is given, radiotherapy should start within this period.

Repeated significance tests on accumulating survival data.

The aim of the study was to compare the properties of two well-known group sequential methods and to demonstrate the effect of performing interim analyses on accumulating survival data without making appropriate adjustments of the nominal significance level. The properties of a group sequential method with fixed nominal significance level (Pocock stopping boundaries) and a method with increasing nominal level with each interim analysis (O'Brien-Fleming boundaries) were compared by stochastic simulation. Simulation experiments with survival times sampled from a breast cancer trial and from exponential distributions were performed. The true overall significance level with unplanned interim analyses increased from 5% to 14% when a maximum of five tests were performed. Both group sequential methods maintained the desired overall significance level. The O'Brien-Fleming method had higher power than Pocock's method. It also reduced the risk of early stopping based on immature data and should usually be preferred.

Sequential or fixed sample trial design? A case study by stochastic simulation.

The properties of Wilcoxon's rank sum test for fixed sample size and a Wilcoxon-type two-sample sequential test have been illustrated and compared by means of stochastic simulation. Data from a real fixed sample trial have been used, both for resampling from the original data, and for construction of an idealized theoretical distribution. The sequential and the fixed sample test obtain equal power, but the sequential test mostly includes considerably fewer patients to reach a conclusion, i.e. the mean and median number of patients included are both much lower than the fixed sample size. Under the hypotheses only a small fraction of the simulation runs exceed the fixed sample size. These findings exemplify results obtained in theoretical analyses and simulation studies covering a wide range of distributions. In our opinion sequential tests have obvious advantages and are in many cases better alternatives than fixed sample tests in clinical trials.