What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

A framework for identifying treatment-covariate interactions in individual participant data network meta-analysis.

BACKGROUND: Stratified medicine seeks to identify patients most likely to respond to treatment. Individual participant data (IPD) network meta-analysis (NMA) models have greater power than individual trials to identify treatment-covariate interactions (TCIs). Treatment-covariate interactions contain "within" and "across" trial interactions, where the across-trial interaction is more susceptible to confounding and ecological bias. METHODS: We considered a network of IPD from 37 trials (5922 patients) for cervical cancer (2394 events), where previous research identified disease stage as a potential interaction covariate. We compare 2 models for NMA with TCIs: (1) 2 effects separating within- and across-trial interactions and (2) a single effect combining within- and across-trial interactions. We argue for a visual assessment of consistency of within- and across-trial interactions and consider more detailed aspects of interaction modelling, eg, common vs trial-specific effects of the covariate. This leads us to propose a practical framework for IPD NMA with TCIs. RESULTS: Following our framework, we found no evidence in the cervical cancer network for a treatment-stage interaction on the basis of the within-trial interaction. The NMA provided additional power for an across-trial interaction over and above the pairwise evidence. Following our proposed framework, we found that the within- and across-trial interactions should not be combined. CONCLUSION: Across-trial interactions are susceptible to confounding and ecological bias. It is important to separate the sources of evidence to check their consistency and identify which sources of evidence are driving the conclusion. Our framework provides practical guidance for researchers, reducing the risk of unduly optimistic interpretation of TCIs.

What impact do assumptions about missing data have on conclusions? A practical sensitivity analysis for a cancer survival registry.

BACKGROUND: Within epidemiological and clinical research, missing data are a common issue and often over looked in publications. When the issue of missing observations is addressed it is usually assumed that the missing data are 'missing at random' (MAR). This assumption should be checked for plausibility, however it is untestable, thus inferences should be assessed for robustness to departures from missing at random. METHODS: We highlight the method of pattern mixture sensitivity analysis after multiple imputation using colorectal cancer data as an example. We focus on the Dukes' stage variable which has the highest proportion of missing observations. First, we find the probability of being in each Dukes' stage given the MAR imputed dataset. We use these probabilities in a questionnaire to elicit prior beliefs from experts on what they believe the probability would be in the missing data. The questionnaire responses are then used in a Dirichlet draw to create a Bayesian 'missing not at random' (MNAR) prior to impute the missing observations. The model of interest is applied and inferences are compared to those from the MAR imputed data. RESULTS: The inferences were largely insensitive to departure from MAR. Inferences under MNAR suggested a smaller association between Dukes' stage and death, though the association remained positive and with similarly low p values. CONCLUSIONS: We conclude by discussing the positives and negatives of our method and highlight the importance of making people aware of the need to test the MAR assumption.

Prepartum nutrition and solar radiation in beef cattle: II. Residual effects on postpartum milk yield, immunoglobulin, and calf growth.

Residual effects of nutrition and solar radiation during the last two-thirds of gestation on postpartum milk yield, immunoglobulin (Ig) G and M in both colostrum and calf serum, and calf growth were determined in beef cattle. Nineteen mature, multiparous crossbred cows (Bos taurus) at d 90 of pregnancy were assigned to either low (LO, 70% NRC total energy intake) or high (HI, 110% NRC total energy intake) nutritional level (sudangrass hay) and to either shade (S) or no shade (NS) treatments in a 2 x 2 factorial experiment. After parturition, all cows were moved into a large paddock and managed uniformly. Calf weights and calf serum were collected within 1 d postpartum, thereafter at 2-wk intervals for the next 12 wk, and then at 4-wk intervals until weaning. Colostrum samples were taken from the cow and milk yields were determined by the "weigh-suckle-weigh" technique. Neither prepartum nutrition nor environment influenced lactational performance of the dam. Concentrations of IgG were elevated in the colostrum of LO cows (15.3 vs 7.8 g/100 mL, LO vs HI, respectively; P < or = .05) but were not affected by shading. The patterns of IgG concentration in the calf serum were not altered by prepartum nutrition or environment; however, the pattern of IgM concentrations was greater (P < or = .01) in calves from S cows than in those from NS cows. This difference in IgM profile did not seem to be due to any residual effect from prepartum treatments. Postnatal growth of calves from birth until weaning were similar across all prepartum treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Prepartum nutrition and solar radiation in beef cattle: I. Relationships of body fluid compartments, packed cell volume, plasma urea nitrogen, and estrogens to prenatal development.

Adaptations in body fluid pools during pregnancy were monitored in cows (n = 19) assigned to either low (LO, 70% NRC total feed intake) or high (HI, 110% NRC total feed intake) nutritional level (sudangrass hay) and to either shade (S) or no shade (NS) treatments in a 2 x 2 factorial experiment. Body water distribution (empty body water [EBW] by urea dilution; extracellular water [ECW] by thiosulfate dilution; intracellular water [ICW] by difference; plasma volume by Evans Blue dilution; interstitial water [ISW] by difference) was measured at 4-wk intervals beginning at 3 mo of pregnancy until birth and then immediately after birth. Both EBW and ICW in LO cows showed a steady decline (P < or = .05), whereas HI cows tended to maintain these body pools throughout gestation. Shading did not affect the pattern of change in EBW; however, it did produce a greater (P < or = .05) ICW in the S than in the NS cows throughout gestation. Generally, other body fluid pools (ECW, ISW, and plasma) were either not affected, or were just slightly affected, by shading or nutrition. Most of the body fluid pools (EBW, ECW, ICW, and ISW) inversely followed the seasonal changes in solar radiation. Calf birth weights were not affected by treatments but were moderately correlated to EBW (r = .49; P < or = .05) and ICW (r = .50; P < or = .05). Plasma urea nitrogen change, although not affected by nutrition, was affected (P < or = .05) by shading.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrasound evaluation of the popliteal space. Comparison with arthrography and physical examination.

Ultrasound scanning techniques were used to examine the popliteal space in 102 knees. In 30 of 34 knees in which arthrograms were also obtained, the information obtained from both tests was the same. In two instances in which there were different results, the presence of palpable popliteal cysts was confirmed by ultrasound scans but not by arthrography, and in two other cases, small asymptomatic cysts were seen on arthrograms but not on ultrasound scans. In the 68 other knees, ultrasound scans were helpful in the differential diagnosis of popliteal cysts, popliteal artery aneurysms, thrombophlebitis, and a solid poplitieal mass. The results indicate that ultrasound scanning is a valuable, rapid, safe, accurate technique in evaluating patients with symptoms or findings related to the popliteal space.