An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics.

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale.

RECeUS: Ratio estimation of censored uncured subjects, a different approach for assessing cure model appropriateness in studies with long-term survivors.

The need to model a cure fraction, the proportion of a cohort not susceptible to the event of interest, arises in a variety of contexts including tumor relapse in oncology. Existing methodology assumes that follow-up is long enough for all uncured subjects to have experienced the event of interest at the time of analysis, and researchers have demonstrated that fitting cure models without sufficient follow-up leads to bias. Few statistical methods exist to evaluate sufficient follow-up, and they can exhibit poor performance and lead users to falsely conclude sufficient follow-up, leading to bias, or to falsely claim insufficient follow-up, possibly leading to additional, costly data collection. We propose a new quantitative statistic (RECeUS) to evaluate whether cure models may be appropriate to apply to censored data. Specifically, we propose that the estimated proportion of censored uncured subjects in a study can be used to evaluate cure model appropriateness. We evaluated the performance of RECeUS against existing methods via simulation and with two data examples, and we observe that RECeUS displays superior performance. In simulated and real-world settings, RECeUS correctly identifies both situations in which data appear appropriate for cure modeling and when data seem inappropriate for fitting cure models.

Quantification of follow-up time in oncology clinical trials with a time-to-event endpoint: Asking the right questions.

For the analysis of a time-to-event endpoint in a single-arm or randomized clinical trial it is generally perceived that interpretation of a given estimate of the survival function, or the comparison between two groups, hinges on some quantification of the amount of follow-up. Typically, a median of some loosely defined quantity is reported. However, whatever median is reported, is typically not answering the question(s) trialists actually have in terms of follow-up quantification. In this paper, inspired by the estimand framework, we formulate a comprehensive list of relevant scientific questions that trialists have when reporting time-to-event data. We illustrate how these questions should be answered, and that reference to an unclearly defined follow-up quantity is not needed at all. In drug development, key decisions are made based on randomized controlled trials, and we therefore also discuss relevant scientific questions not only when looking at a time-to-event endpoint in one group, but also for comparisons. We find that different thinking about some of the relevant scientific questions around follow-up is required depending on whether a proportional hazards assumption can be made or other patterns of survival functions are anticipated, for example, delayed separation, crossing survival functions, or the potential for cure. We conclude the paper with practical recommendations.

Evaluation of pelvic floor muscle function (PFMF) in cervical cancer patients with Querleu-Morrow type C hysterectomy: a multicenter study.

INTRODUCTION: To evaluate the pelvic floor muscle function (PFMF) of cervical cancer patients after type QM-C hysterectomy and to explore the relationship between decreased PFMF and related factors. METHODS: This was a multi-centered retrospective cohort study. 181 cervical cancer patients who underwent type QM-C hysterectomy were enrolled from 9 tertiary hospitals. Strength of PFMF were measured using neuromuscular apparatus (Phenix U8, French). Risk factors contributing to decreased PFMF were analyzed by univariate and multivariate ordinal polytomous logistic regression. RESULTS: Totally 181 patients were investigated in this study. 0-3 level of type I muscle fibre strength (MFSI) was 52.6% (95/181), 0-3 level of type IIA muscle fibre strength (MFSIIA) was 50% (91/181). Subjective stress urinary incontinence was 46% (84/181), urinary retention was 27.3% (50/181), dyschezia was 41.5% (75/181), fecal incontinence was 9% (18/181). ① MFSI: Multivariate ordinal polytomous logistic regression shows that the follow-up time (p < 0.05), chemotherapy and radiotherapy (p = 0.038) are independent risk factors of MFSI's reduction after type QM-C hysterectomy. ② MFSIIA: multivariate ordinal polytomous logistic regression shows that the follow-up time (p < 0.05) are independent risk factors of MFSIIA's reduction after type QM-C hysterectomy. The pelvic floor muscle strength (PFMS) increased after 9 months than in 9 months after operation, which showed that the PFMS could be recovered after operation. CONCLUSIONS: We advocate for more attention and emphasis on the PFMF of Chinese female patients with cervical cancer postoperation. PEKING UNIVERSITY PEOPLE'S HOSPITAL: PFMF after QM-C hysterectomy has not been analyzed by current study. The contribution is that patients with radical hysterectomy should do pelvic floor rehabilitation exercises in 3 months after operation. Clinical Trails NCT number of this study is 02492542.

Variations in pathways and resource use in follow-up after abnormal mammography screening: a nationwide register-based study.

PURPOSE: Mammography screening reduces breast cancer mortality, but a successful screening programme depends on both high participation and a sufficient follow-up of abnormalities. This study investigated patterns of follow-up after abnormal screening mammography in Denmark, and whether the variation was associated with health care resource use. METHODS: We included 19,458 women aged 50-69 years with an abnormal screening mammography during a 3-year period of 2014-2016. Women were followed until the end of 2018. Their follow-up pathway was categorized in terms of the timeliness, appropriateness (i.e. whether all recommended diagnostic tests were utilized), and the ratio of benign vs. malignant surgeries. Further, we estimated health care resource use including post-diagnostic imaging and surgery procedures. RESULTS: Ninety-seven percent of women had a diagnostic follow-up test within 6 months and 94% of those had diagnostic procedures in accordance with the recommendations. The proportion with timely follow-up (i.e. within 1 month) was 83%, but varied significantly between administrative regions (p < 0.001), and also between women with a screen-detected cancer and those with a false-positive mammogram (87% vs. 81%, p < 0.001). The ratio between having a benign versus a malignant surgery was 1:8, but it varied depending on which tests were used for diagnosis. The average number of procedures was, generally, in accordance with the recommendations. CONCLUSION: In most cases, follow-up after abnormal screening mammography followed national recommendations. We nevertheless found that this was not always the case in certain subgroups and administrative regions.

Readmission After Emergency General Surgery: NSQIP Review of Risk, Cause and Ideal Follow-Up.

BACKGROUND: The Emergency General Surgery (EGS) population is particularly at high risk for readmission. Currently, no system exists to predict which EGS patients are most at risk. We hypothesized that a subset of EGS patients could be identified with increased 30-day unplanned readmission. We also hypothesized that a majority of readmissions occur sooner than the conventional 2-week follow-up period. METHODS: National Surgical Quality Improvement Program (NSQIP) nonelective general surgery patients were analyzed. Multivariable logistic regression identified factors with increased odds of unplanned readmission. AAST EGS Diagnosis Categories were used to categorize postop ICD-9 codes, and the top 10 CPT codes in each group were analyzed. Readmission rate, the reason for unplanned readmission, and time to readmission were analyzed. RESULTS: A total of 383,726 patients were identified with a readmission rate of 8.1% within 30 d of their primary procedure. The top 50 CPT codes accounted for 84% of EGS readmissions. Increased readmission risk was demonstrated for underweight patients (OR = 1.15, P < 0.05). High-risk hospital characteristics were LOS >2 d, any inpatient pulmonary complications, and discharge to any facility or rehab (all P < 0.05). Surgical site infections cause nearly 25% of readmissions. Intestinal procedures are most frequently readmitted (22% of EGS readmissions), with colorectal procedures having the higher odds of readmission. Most readmissions occur <10 d after discharge. CONCLUSIONS: A high-risk subpopulation exists within EGS, and most readmissions occur sooner than a typical 2-week follow-up. Early interventions for high-risk EGS subpopulations may allow for early intervention and reduction of unnecessary healthcare utilization.

The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis.

PURPOSE: Breast cancer is the most common cancer in females and the leading cause of death worldwide. The effects of statins on breast cancer prognosis have long been controversial; thus, it is important to investigate the relationship between statin type, exposure time, and breast cancer prognosis. This study sought to explore the effect of statins, as well as the different effects of statin solubility and variable follow-up times, on breast cancer prognosis. METHODS: We searched the MEDLINE (via PubMed), EMBASE (via OvidSP), Cochrane Library, and ISI Web of Knowledge databases using combinations of the terms "breast neoplasms[MeSH]," "statins" or "lipid-lowering drug," "prognosis" or "survival," or "mortality" or "outcome" with no limit on the publication date. We searched the databases between inception and October 15, 2016. Reference lists of the included studies and relevant reviews were also manually screened. The initial search identified 71 publications, and 7 of these studies, which included a total of 197,048 women, met the selection criteria. Two authors independently screened each study for inclusion and extracted the data. The data were analyzed using Stata/SE 11.0. RESULTS: Overall statin use was associated with lower cancer-specific mortality and all-cause mortality, although the benefit appeared to be constrained by statin type and follow-up time. Lipophilic statins were associated with decreased breast cancer-specific and all-cause mortality; however, hydrophilic statins were weakly protective against only all-cause mortality and not breast cancer-specific mortality. Of note, one group with more than 4 years of follow-up did not show a significant correlation between statin use and cancer-specific mortality or all-cause mortality, whereas groups with less than 4 years of follow-up still showed the protective effect of statins against cancer-specific mortality and all-cause mortality. CONCLUSIONS: Although statins can reduce breast cancer patient mortality, the benefit appears to be constrained by statin type and follow-up time. Lipophilic statins showed a strong protective function in breast cancer patients, whereas hydrophilic statins only slightly improved all-cause mortality. Finally, the protective effect of statins could only be observed in groups with less than 4 years of follow-up. These findings are meaningful in clinical practice, although some conclusions contradict conventional wisdom and will thus require further exploration.

Longitudinal clinical trials with adaptive choice of follow-up time.

In longitudinal studies comparing two treatments with a maximum follow-up time there may be interest in examining treatment effects for intermediate follow-up times. One motivation may be to identify the time period with greatest treatment difference when there is a non-monotone treatment effect over time; another motivation may be to make the trial more efficient in terms of time to reach a decision on whether a new treatment is efficacious or not. Here, we test the composite null hypothesis of no difference at any follow-up time versus the alternative that there is a difference at at least one follow-up time. The methods are applicable when a few measurements are taken over time, such as in early longitudinal trials or in ancillary studies. Suppose the test statistic Z(t(k)) will be used to test the hypothesis of no treatment effect at a fixed follow-up time t(k). In this context a common approach is to perform a pilot study on N1 subjects, and evaluate the treatment effect at the fixed time points t1,…,t(K) and choose t* as the value of t(k) for which Z(t(k)) is maximized. Having chosen t* a second trial can be designed. In a setting with group sequential testing we consider several adaptive alternatives to this approach that treat the pilot and second trial as a seamless, combined entity and evaluate Type I error and power characteristics. The adaptive designs we consider typically have improved power over the common, separate trial approach.

Development of postoperative velopharyngeal function in patients with cleft palate.

OBJECTIVE: Patients with a cleft palate often experience a velopharyngeal dysfunction known as velopharyngeal insufficiency (VPI). The purpose of this study was to examine the development of velopharyngeal function (VPF) following primary palatoplasty and the factors that are linked to it. METHODS: A retrospective study was conducted to examine the medical records of patients who had cleft palate, with or without cleft lip (CP ± L) and underwent palatoplasty at a Tertiary Affiliated Hospital between 2004 and 2017. Postoperative evaluation of VPF was conducted at two follow-up times (T1, T2) and was classified as either normal VPF, mild VPI, or moderate/severe VPI. The consistency of VPF evaluations between the two time points was then assessed, and patients were categorized into either the consistent or inconsistent group. The study collected and analyzed data on gender, cleft type, age at operation, follow-up duration, and speech records. RESULTS: The study included 188 patients with CP ± L. Out of these, 138 patients (73.4%) showed consistent VPF evaluations, while 50 patients (26.6%) showed inconsistent VPF evaluations. Among those with VPI at T1 (91 patients), 36 patients (39.6%) had normal VPF at T2. The rate of VPI decreased from 48.40% at T1 to 27.13% at T2, whereas the rate of normal VPF increased from 44.68% at T1 to 68.09% at T2. The consistent group had a significantly younger age at operation (2.90 ± 3.82 vs 3.68 ± 4.02), a longer duration of T1 (1.67 ± 0.97 vs 1.04 ± 0.59), and a lower comprehensive score of speech performance (1.86 ± 1.27 vs 2.60 ± 1.07) than the inconsistent group. CONCLUSIONS: It has been verified that there are changes in the development of VPF over time. Patients who underwent palatoplasty at a younger age were more likely to have confirmed VPF diagnosis at the first evaluation. The duration of follow-up was identified as a critical factor that affects the confirmation of VPF diagnosis.

Long Follow-Up Times Weaken Observational Diet-Cancer Study Outcomes: Evidence from Studies of Meat and Cancer Risk.

For years, prospective cohort studies of diet and cancer incidence have reported smaller effects than do retrospective case-control (CC) studies. The differences have been attributed to problems with CC studies, including dietary recall bias, poor matching of cases and controls, and confounding. The hypothesis evaluated here is that long follow-up periods between ascertainment of diet and cancer incidence weaken the findings. Prospective studies of cancer incidence with respect to serum 25-hydroxyvitamin D concentration have already shown reduced benefit of higher concentrations for longer follow-up periods. Evaluating that hypothesis for dietary factors involved searching the journal literature for meta-analyses of red meat and processed meat and cancer incidence. I used findings from observational studies for bladder, breast, colorectal, and gastric cancers. To evaluate the effect of duration of follow-up time, I used two approaches. First, I plotted the relative risks for CC studies for gastric cancer with respect to consumption of 100 g/day of red meat and for bladder cancer for 50 g/day of processed meat against the interval between the dietary data and cancer incidence. Second, I compared nested CC studies of meat and cancer incidence for five breast cancer studies and one colorectal cancer study. Both approaches yielded an inverse correlation between interval or follow-up time and relative risk. My findings strongly suggest that diet near time of cancer diagnosis is more important than for longer intervals, that results from meta-analyses should be revised when possible with appropriate adjustments for duration of follow-up, and that dietary guidelines be revised accordingly.