Fitting a progressive three-state colorectal cancer model to interval-censored surveillance data under outcome-dependent sampling using a weighted likelihood approach.

To optimize colorectal cancer (CRC) surveillance, accurate information on the risk of developing CRC from premalignant lesions is essential. However, directly observing this risk is challenging since precursor lesions, i.e., advanced adenomas (AAs), are removed upon detection. Statistical methods for multistate models can estimate risks, but estimation is challenging due to low CRC incidence. We propose an outcome-dependent sampling (ODS) design for this problem in which we oversample CRCs. More specifically, we propose a three-state model for jointly estimating the time distributions from baseline colonoscopy to AA and from AA onset to CRC accounting for the ODS design using a weighted likelihood approach. We applied the methodology to a sample from a Norwegian adenoma cohort (1993-2007), comprising 1, 495 individuals (median follow-up 6.8 years [IQR: 1.1 - 12.8 years]) of whom 648 did and 847 did not develop CRC. We observed a 5-year AA risk of 13% and 34% for individuals having non-advanced adenoma (NAA) and AA removed at baseline colonoscopy, respectively. Upon AA development, the subsequent risk to develop CRC in 5 years was 17% and age-dependent. These estimates provide a basis for optimizing surveillance intensity and determining the optimal trade-off between CRC prevention, costs, and use of colonoscopy resources.

Sex Differences in the Effectiveness of First-Line Tumor Necrosis Factor Inhibitors in Psoriatic Arthritis: Results From the European Spondyloarthritis Research Collaboration Network.

OBJECTIVE: Women with psoriatic arthritis (PsA) may have reduced tumor necrosis factor inhibitor (TNFi) effectiveness compared to men. We examined sex differences in treatment response and retention rates during 24 months of follow-up among patients with PsA initiating their first TNFi. METHODS: Data from patients with PsA across 13 European Spondyloarthritis Research Collaboration Network registries starting their first TNFi were pooled. Logistic regression was used to analyze the association between sex and treatment response using low disease activity (LDA) according to the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) (<3.2) at six months as the primary outcome. Analyses were adjusted for age, country, conventional synthetic disease-modifying antirheumatic drug treatment, and TNFi start year. Retention rates were explored using the Kaplan-Meier estimator. RESULTS: We analyzed the treatment response of 7,679 patients with PsA (50% women) with available data on LDA at six months. At baseline, women and men had similar characteristics, including mean DAS28-CRP (women vs men, 4.4 [SD 1.2] vs 4.2 [SD 1.2]), though patient-reported outcome measures were worse in women. At six months, 64% of women and 78% of men had LDA (relative risk [RR] 0.82; 95% confidence interval [CI] 0.80-0.84). This difference was similar after adjustment (RR 0.83; 95% CI 0.81-0.85). TNFi retention rates were evaluated in 17,842 patients with PsA. Women had significantly lower retention rates than men at all time points (women 79%, 64%, and 50% vs men 88%, 77%, and 64% at 6, 12, and 24 months, respectively). CONCLUSION: Despite comparable disease characteristics at baseline, women with PsA have reduced treatment response and retention rates to their first TNFi, highlighting the need to consider sex differences in PsA research and management.

Assessing real-world representativeness of prospective registry cohorts in oncology: insights from patients with esophagogastric cancer.

OBJECTIVES: This study aimed to explore the real-world representativeness of a prospective registry cohort with active accrual in oncology, applying a representativeness metric that is novel to health care. STUDY DESIGN AND SETTING: We used data from the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP) registry and from the population-based Netherlands Cancer Registry (NCR). We used Representativeness-indicators (R-indicators) and overall survival to investigate the degree to which the POCOP cohort and clinically relevant subgroups were a representative sample compared to the NCR database. Calibration using inverse propensity score weighting was applied to correct differences between POCOP and NCR. RESULTS: The R-indicator of the entire POCOP registry was 0.72 95% confidence interval [0.71, 0.73]. Representativeness of palliative patients was higher than that of potentially curable patients (R-indicator 0.88 [0.85, 0.90] and 0.70 [0.68, 0.71], respectively). Stratification to clinically relevant subgroups based on treatment resulted in higher R-indicators of the respective subgroups. Both after stratification and calibration weighting survival estimates in the POCOP registry were more similar to that in the NCR population. CONCLUSION: This study demonstrated the assessment of real-world representativeness of patients who participated in a prospective registry cohort and showed that real-world representativeness improved when the variability in treatment was accounted for.

A progressive three-state model to estimate time to cancer: a likelihood-based approach.

BACKGROUND: To optimize colorectal cancer (CRC) screening and surveillance, information regarding the time-dependent risk of advanced adenomas (AA) to develop into CRC is crucial. However, since AA are removed after diagnosis, the time from AA to CRC cannot be observed in an ethically acceptable manner. We propose a statistical method to indirectly infer this time in a progressive three-state disease model using surveillance data. METHODS: Sixteen models were specified, with and without covariates. Parameters of the parametric time-to-event distributions from the adenoma-free state (AF) to AA and from AA to CRC were estimated simultaneously, by maximizing the likelihood function. Model performance was assessed via simulation. The methodology was applied to a random sample of 878 individuals from a Norwegian adenoma cohort. RESULTS: Estimates of the parameters of the time distributions are consistent and the 95% confidence intervals (CIs) have good coverage. For the Norwegian sample (AF: 78%, AA: 20%, CRC: 2%), a Weibull model for both transition times was selected as the final model based on information criteria. The mean time among those who have made the transition to CRC since AA onset within 50 years was estimated to be 4.80 years (95% CI: 0; 7.61). The 5-year and 10-year cumulative incidence of CRC from AA was 13.8% (95% CI: 7.8%;23.8%) and 15.4% (95% CI: 8.2%;34.0%), respectively. CONCLUSIONS: The time-dependent risk from AA to CRC is crucial to explain differences in the outcomes of microsimulation models used for the optimization of CRC prevention. Our method allows for improving models by the inclusion of data-driven time distributions.

Short-term outcome for high-risk patients after esophagectomy.

Transthoracic esophagectomy (TTE) for esophageal cancer facilitates mediastinal dissection; however, it has a significant impact on cardiopulmonary status. High-risk patients may therefore be better candidates for transhiatal esophagectomy (THE) in order to prevent serious complications. This study addressed short-term outcome following TTE and THE in patients that are considered to have a higher risk of surgery-related morbidity. This population-based study included patients who underwent a curative esophagectomy between 2011 and 2018, registered in the Dutch Upper GI Cancer Audit. The Charlson comorbidity index was used to assign patients to a low-risk (score ≤ 1) and high-risk group (score ≥ 2). Propensity score matching was applied to produce comparable groups between high-risk patients receiving TTE and THE. Primary endpoint was mortality (in-hospital/30-day mortality), secondary endpoints included morbidity and oncological outcomes. Additionally, a matched subgroup analysis was performed, including only cervical reconstructions. Of 5,438 patients, 945 and 431 high-risk patients underwent TTE and THE, respectively. After propensity score matching, mortality (6.3 vs 3.3%, P = 0.050), overall morbidity, Clavien-Dindo ≥ 3 complications, pulmonary complications, cardiac complications and re-interventions were significantly more observed after TTE compared to THE. A significantly higher mortality after TTE with a cervical reconstruction was found compared to THE (7.0 vs. 2.2%, P = 0.020). Patients with a high Charlson comorbidity index predispose for a complicated postoperative course after esophagectomy, this was more outspoken after TTE compared to THE. In daily practice, these outcomes should be balanced with the lower lymph node yield, but comparable positive node count and radicality after THE.

The important role of cisplatin in the treatment of HPV-positive oropharyngeal cancer assessed by real-world data analysis.

OBJECTIVES: The prognostic advantage of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) resulted in the initiation of treatment de-intensification studies. Two randomized controlled trials (RCTs) reported inferior survival of HPV-positive OPSCC treated with radiotherapy plus cetuximab compared to standard of care radiotherapy plus cisplatin. In this study we investigated whether the important role of cisplatin in the treatment of HPV-positive OPSCCs would also emerge from causal inference analyses of real-world data. MATERIAL AND METHODS: A retrospective cohort of 263 advanced-stage OPSCC-patients from 5 European clinics was studied, treated with radiotherapy (RT) alone or cisplatin-based chemoradiotherapy (CRT) based on standard clinical indications. Causal inference was applied to adjust for treatment assignment, thereby simulating a randomized setting. Average treatment effect of concurrent cisplatin on overall survival (OS) probability was estimated using Bayesian Additive Regression Trees (BART) and Bayesian logistic regression. RESULTS: Significantly better survival probabilities were found for HPV-positive OPSCC treated with CRT compared to RT alone (3-year OS probability 0.961 versus 0.798, p = 0.008). CONCLUSION: This study using causal inference of retrospective patient data confirms the important role of cisplatin in the treatment of HPV-positive OPSCC. Causal inference analyses of real-world data complements the evidence from the published RCTs.

Development of a multiomics database for personalized prognostic forecasting in head and neck cancer: The Big Data to Decide EU Project.

BACKGROUND: Despite advances in treatments, 30% to 50% of stage III-IV head and neck squamous cell carcinoma (HNSCC) patients relapse within 2 years after treatment. The Big Data to Decide (BD2Decide) project aimed to build a database for prognostic prediction modeling. METHODS: Stage III-IV HNSCC patients with locoregionally advanced HNSCC treated with curative intent (1537) were included. Whole transcriptomics and radiomics analyses were performed using pretreatment tumor samples and computed tomography/magnetic resonance imaging scans, respectively. RESULTS: The entire cohort was composed of 71% male (1097)and 29% female (440): oral cavity (429, 28%), oropharynx (624, 41%), larynx (314, 20%), and hypopharynx (170, 11%); median follow-up 50.5 months. Transcriptomics and imaging data were available for 1284 (83%) and 1239 (80%) cases, respectively; 1047 (68%) patients shared both. CONCLUSIONS: This annotated database represents the HNSCC largest available repository and will enable to develop/validate a decision support system integrating multiscale data to explore through classical and machine learning models their prognostic role.

Estimating adjuvant treatment effects in Stage II colon cancer: Comparing the synthesis of randomized clinical trial data to real-world data.

There is an ongoing discussion regarding the impact of adjuvant chemotherapy in Stage II colon cancer. We therefore estimated adjuvant treatment effect in Stage II colon cancer using pooled disease-free survival (DFS) data from randomized clinical trials (RCT approach) and compared this to real-world data (RWD approach) estimates. First, we estimated the treatment effect in RCTs by (i) searching relevant trials reporting DFS data, (ii) generating patient-level data from reported DFS data and (iii) estimating treatment effect in the patient-level data. Second, the treatment effect was estimated in an observational cohort of 1,947 patients provided by the Netherlands Cancer Registry using three propensity score methods; matching, weighting and stratification. In the RCT approach, patient-level data of 4,489 patients (events: 853) were generated from seven trials which compared two of the following treatment arms: control, 5FU/LV or FOLFOX. A Cox model was used to estimate a hazard ratio (HR) of 0.77 (0.43;1.10) for 5FU/LV vs. control and 0.93 (0.72;1.15) for FOLFOX vs. 5FU/LV. In the RWD approach, HRs for any adjuvant treatment vs. control were 0.95 (0.50;1.80), 0.88 (0.24;3.21) and 1.05 (0.04;2.06) using matching, weighting and stratification, respectively. There was no significant difference with the estimates from the RCT approach (interaction test, p > 0.10). The RCT data suggest a clinically relevant benefit of adjuvant chemotherapy in terms of DFS, but the estimate did not reach statistical significance. Stratified analyses are required to evaluate whether treatment effect differs in specific subgroups.

Wound dehiscences following pre-implant bone augmentation with autogenous iliac crest bone grafts: A retrospective cohort study.

PURPOSE: To evaluate possible risk factors associated with wound dehiscences following pre-implant alveolar bone augmentation with autologous anterior iliac crest bone grafts covered with resorbable collagen membranes or human demineralised bone laminae. MATERIALS AND METHODS: Data of 161 patients who underwent bone augmentation prior to the insertion of dental implants were analysed. The preoperative dental status, locations of alveolar bone augmentation sites and location of wound dehiscences were recorded. Gender, age, smoking, alcohol exposure, and dental and medical histories were reviewed. Information was also collected on the surgeons, augmentation technique, application of a collagen membrane, fixation screw type and suture material. Univariate logistic regression analysis was used to evaluate pre- and perioperative variables as predictors of dehiscences. RESULTS: A total of 42 (26.1%) of the 161 augmented patients developed a wound dehiscence following surgery. Most commonly affected sites were the anterior maxilla, followed by the anterior mandible. Males developed wound dehiscences with higher probability than females (odds ratio female = 0.444; P = 0.025; 95% CI: 0.214 to 0.903). Furthermore, marginal associations (P < 0.10) are found for smoking and an anterior location of the augmentation. Smokers were found to have higher probability of a wound dehiscence (odds ratio 2.089; P = 0.064; 95% CI: 0.957 to 4.500) compared to non-smokers. A posterior location of the augmentation was associated with lower probability of a wound dehiscence (odds ratio 0.188; P = 0.076; 95% CI: 0.035 to 0.802) compared to an anterior location. CONCLUSIONS: Based on this study population, smoking in males seems to be the most important risk factor for the development of wound dehiscences after pre-implant alveolar bone augmentation procedures.