Estimating impacts of reducing acrylonitrile exposure on lung cancer mortality in an occupational cohort with the parametric g-formula.

OBJECTIVES: To inform the potential human carcinogenicity of acrylonitrile, we estimate associations between acrylonitrile exposures and lung cancer mortality in US workers with the objectives of (1) assessing potential for healthy worker survivor bias and (2) adjusting for this bias while assessing the expected lung cancer mortality under different hypothetical occupational exposure limits on acrylonitrile exposure using the parametric g-formula. METHODS: We used data from a cohort of 25 460 workers at facilities making or using acrylonitrile in the USA. We estimated HRs to quantify associations between employment and lung cancer mortality, and exposure and leaving employment. Using the parametric g-formula, we estimated cumulative lung cancer mortality at hypothetical limits on acrylonitrile exposure. RESULTS: Recent and current employment was associated with lung cancer, and exposure was associated with leaving employment, indicating potential for healthy worker survivor bias. Relative to no intervention, reducing the historical exposure under limits of 2.0, 1.0 and 0.45 parts per million would have been expected to reduce lung cancer mortality by age 90 by 4.46 (95% CI 0.78 to 8.15), 5.03 (95% CI 0.96 to 9.11) and 6.45 (95% CI 2.35 to 10.58) deaths per 1000 workers, respectively. A larger lung cancer mortality reduction would be expected under elimination of exposure: 7.21 (95% CI 2.72 to 11.70) deaths per 1000 workers. CONCLUSIONS: Healthy worker survivor bias likely led to underestimation of excess risk. Our results corroborate previous study findings of an excess hazard of lung cancer among the highest exposed workers.

Somatic Mutational Analysis in Endoscopic Ultrasound-Guided Biopsy of Pancreatic Adenocarcinoma: Assessing Yield and Impact.

INTRODUCTION: We sought to determine the yield of somatic mutational analysis from endoscopic ultrasound (EUS)-guided biopsies of pancreatic adenocarcinoma compared with that of surgical resection and to assess the impact of these results on oncologic treatment. METHODS: We determined the yield of EUS sampling and surgical resection. We evaluated the potential impact of mutational analysis by identifying actionable mutations and its direct impact by reviewing actual treatment decisions. RESULTS: Yield of EUS sampling was 89.5%, comparable with the 95.8% yield of surgical resection. More than a quarter in the EUS cohort carried actionable mutations, and of these, more than 1 in 6 had treatment impacted by mutational analysis. DISCUSSION: EUS sampling is nearly always adequate for somatic testing and may have substantial potential and real impact on treatment decisions.

Use of a Novel Artificial Intelligence System Leads to the Detection of Significantly Higher Number of Adenomas During Screening and Surveillance Colonoscopy: Results From a Large, Prospective, US Multicenter, Randomized Clinical Trial.

INTRODUCTION: Adenoma per colonoscopy (APC) has recently been proposed as a quality measure for colonoscopy. We evaluated the impact of a novel artificial intelligence (AI) system, compared with standard high-definition colonoscopy, for APC measurement. METHODS: This was a US-based, multicenter, prospective randomized trial examining a novel AI detection system (EW10-EC02) that enables a real-time colorectal polyp detection enabled with the colonoscope (CAD-EYE). Eligible average-risk subjects (45 years or older) undergoing screening or surveillance colonoscopy were randomized to undergo either CAD-EYE-assisted colonoscopy (CAC) or conventional colonoscopy (CC). Modified intention-to-treat analysis was performed for all patients who completed colonoscopy with the primary outcome of APC. Secondary outcomes included positive predictive value (total number of adenomas divided by total polyps removed) and adenoma detection rate. RESULTS: In modified intention-to-treat analysis, of 1,031 subjects (age: 59.1 ± 9.8 years; 49.9% male), 510 underwent CAC vs 523 underwent CC with no significant differences in age, gender, ethnicity, or colonoscopy indication between the 2 groups. CAC led to a significantly higher APC compared with CC: 0.99 ± 1.6 vs 0.85 ± 1.5, P = 0.02, incidence rate ratio 1.17 (1.03-1.33, P = 0.02) with no significant difference in the withdrawal time: 11.28 ± 4.59 minutes vs 10.8 ± 4.81 minutes; P = 0.11 between the 2 groups. Difference in positive predictive value of a polyp being an adenoma among CAC and CC was less than 10% threshold established: 48.6% vs 54%, 95% CI -9.56% to -1.48%. There were no significant differences in adenoma detection rate (46.9% vs 42.8%), advanced adenoma (6.5% vs 6.3%), sessile serrated lesion detection rate (12.9% vs 10.1%), and polyp detection rate (63.9% vs 59.3%) between the 2 groups. There was a higher polyp per colonoscopy with CAC compared with CC: 1.68 ± 2.1 vs 1.33 ± 1.8 (incidence rate ratio 1.27; 1.15-1.4; P < 0.01). DISCUSSION: Use of a novel AI detection system showed to a significantly higher number of adenomas per colonoscopy compared with conventional high-definition colonoscopy without any increase in colonoscopy withdrawal time, thus supporting the use of AI-assisted colonoscopy to improve colonoscopy quality ( ClinicalTrials.gov NCT04979962).

Snare Tip Soft Coagulation vs Argon Plasma Coagulation vs No Margin Treatment After Large Nonpedunculated Colorectal Polyp Resection: a Randomized Trial.

BACKGROUND & AIMS: Thermal treatment of the defect margin after endoscopic mucosal resection (EMR) of large nonpedunculated colorectal lesions reduces the recurrence rate. Both snare tip soft coagulation (STSC) and argon plasma coagulation (APC) have been used for thermal margin treatment, but there are few data directly comparing STSC with APC for this indication. METHODS: We performed a randomized 3-arm trial in 9 US centers comparing STSC with APC with no margin treatment (control) of defects after EMR of colorectal nonpedunculated lesions ≥15 mm. The primary end point was the presence of residual lesion at first follow-up. RESULTS: There were 384 patients and 414 lesions randomized, and 308 patients (80.2%) with 328 lesions completed ≥1 follow-up. The proportion of lesions with residual polyp at first follow-up was 4.6% with STSC, 9.3% with APC, and 21.4% with control subjects (no margin treatment). The odds of residual polyp at first follow-up were lower for STSC and APC when compared with control subjects (P = .001 and P = .01, respectively). The difference in odds was not significant between STSC and APC. STSC took less time to apply than APC (median, 3.35 vs 4.08 minutes; P = .019). Adverse event rates were low, with no difference between arms. CONCLUSIONS: In a randomized trial STSC and APC were each superior to no thermal margin treatment after EMR. STSC was faster to apply than APC. Because STSC also results in lower cost and plastic waste than APC (APC requires an additional device), our study supports STSC as the preferred thermal margin treatment after colorectal EMR. (Clinicaltrials.gov, Number NCT03654209.).

Through-the-scope suture closure of nonampullary duodenal endoscopic mucosal resection defects: a retrospective multicenter cohort study.

BACKGROUND: Delayed bleeding is among the most common adverse events associated with endoscopic mucosal resection (EMR) of nonampullary duodenal polyps. We evaluated the rate of delayed bleeding and complete defect closure using a novel through-the-scope (TTS) suturing system for the closure of duodenal EMR defects. METHODS: We reviewed the electronic medical records of patients who underwent EMR for nonampullary duodenal polyps of ≥ 10 mm and prophylactic defect closure with TTS suturing between March 2021 and May 2022 at centers in the USA. We evaluated the rates of delayed bleeding and complete defect closure. RESULTS: 36 nonconsecutive patients (61 % women; mean [SD] age, 65 [12] years) underwent EMR of ≥ 10-mm duodenal polyps followed by attempted defect closure with TTS suturing. The mean (SD) lesion size was 29 (19) mm, defect size was 37 (25) mm; eight polyps (22 %) involved > 50 % of the lumen circumference. Complete closure was achieved in all cases (78 % with TTS suturing alone), using a median of one TTS suturing kit. There were no cases of delayed bleeding and no adverse events attributed to application of the TTS suturing device. CONCLUSION: Prophylactic closure of nonampullary duodenal EMR defects using TTS suturing resulted in a high rate of complete closure and no delayed bleeding events.

Novel through-the-scope suture closure of colonic EMR defects (with video).

BACKGROUND AND AIMS: Large colon polyps removed by EMR can be complicated by delayed bleeding. Prophylactic defect clip closure can reduce post-EMR bleeding. Larger defects can be challenging to close using through-the-scope clips (TTSCs), and proximal defects are difficult to reach using over-the-scope techniques. A novel, through-the-scope suturing (TTSS) device allows direct closure of mucosal defects without scope withdrawal. The goal of this study was to evaluate the rate of delayed bleeding after the closure of large colon polyp EMR sites with TTSS. METHODS: A multicenter retrospective cohort study was performed involving 13 centers. All defect closure by TTSS after EMR of colon polyps ≥2 cm from January 2021 to February 2022 were included. The primary outcome was rate of delayed bleeding. RESULTS: A total of 94 patients (52% female; mean age, 65 years) underwent EMR of predominantly right-sided (n = 62 [66%]) colon polyps (median size, 35 mm; interquartile range, 30-40 mm) followed by defect closure with TTSS during the study period. All defects were successfully closed with TTSS alone (n = 62 [66%]) or with TTSS and TTSCs (n = 32 [34%]), using a median of 1 (interquartile range, 1-1) TTSS system. Delayed bleeding occurred in 3 patients (3.2%), with 2 requiring repeated endoscopic evaluation/treatment (moderate). CONCLUSION: TTSS alone or with TTSCs was effective in achieving complete closure of all post-EMR defects, despite a large lesion size. After TTSS closure with or without adjunctive devices, delayed bleeding was seen in 3.2% of cases. Further prospective studies are needed to validate these findings before wider adoption of TTSS for large polypectomy closure.

Prognostic Factors for Non-anastomotic Biliary Strictures Following Adult Liver Transplantation: A Systematic Review and Meta-Analysis.

INTRODUCTION: The development of non-anastomotic biliary strictures (NAS) following orthotopic adult liver transplantation (OLT) is associated with significant morbidity. We performed a systematic review and meta-analysis to identify all prognostic factors for the development of NAS. METHODS: A systematic review was conducted following preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. We used the Newcastle-Ottawa scale to assess the quality of the included studies. Using the random-effects model, we calculated the weighted pooled odds ratios (OR), mean differences (MD), hazard ratios (HR), and 95% confidence intervals (CI) of the risk factors. RESULTS: Based on 19 international studies that included a total of 8269 adult LT patients, we calculated an 8% overall incidence of NAS. In this study, 7 potential prognostic factors were associated with a statistically significant hazard ratio for NAS in pooled analyses including (1) DCD donors compared to DBD donors (2) PSC as an indication for a liver transplant (3) Roux-en-Y bile duct reconstruction compared to duct-to-duct reconstruction (4) hepatic artery thrombosis (5) longer cold ischemia time (6) longer warm ischemia time (7) and total operative times. CONCLUSION: In this systematic review and meta-analysis, we identified 7 prognostic factors for the development of NAS following OLT. These findings might lay the groundwork for development of diagnostic algorithms to better risk stratify patients at risk for development of NAS.

Upper age limits for US male human papillomavirus vaccination for oropharyngeal cancer prevention: a microsimulation-based modeling study.

BACKGROUND: Human papillomavirus (HVP)-positive oropharyngeal cancer is the most common HPV-associated cancer in the United States. The age at acquisition of oral HPV infections that cause oropharyngeal cancer (causal infections) is unknown; consequently, the benefit of vaccination of US men aged 27-45 years remains uncertain. METHODS: We developed a microsimulation-based, individual-level, state-transition model of oral HPV16 and HPV16-positive oropharyngeal cancer among heterosexual US men aged 15-84 years, calibrated to population-level data. We estimated the benefit of vaccination of men aged 27-45 years for prevention of oropharyngeal cancer, accounting for direct- and indirect effects (ie, herd effects) of male and female vaccination. RESULTS: In the absence of vaccination, most (70%) causal oral HPV16 infections are acquired by age 26 years, and 29% are acquired between ages 27 and 45 years. Among men aged 15-45 years in 2021 (1976-2006 birth cohorts), status quo vaccination of men through age 26 years is estimated to prevent 95% of 153 450 vaccine-preventable cancers. Assuming 100% vaccination in 2021, extending the upper age limit to 30, 35, 40, or 45 years for men aged 27-45 years (1976-1994 cohorts) is estimated to yield small benefits (3.0%, 4.2%, 5.1%, and 5.6% additional cancers prevented, respectively). Importantly, status quo vaccination of men through age 26 years is predicted to result in notable declines in HPV16-positive oropharyngeal cancer incidence in young men by 2035 (51% and 24% declines at ages 40-44 years and 45-49 years, respectively) and noticeable declines (12%) overall by 2045. CONCLUSION: Most causal oral HPV16 infections in US men are acquired by age 26 years, underscoring limited benefit from vaccination of men aged 27-45 years for prevention of HPV16-positive oropharyngeal cancers.

Initial multicenter experience using a novel endoscopic tack and suture system for challenging GI defect closure and stent fixation (with video).

BACKGROUND AND AIMS: Closure of endoscopic resection defects can be achieved with through-the-scope clips, over-the-scope clips, or endoscopic suturing. However, these devices are often limited by their inability to close large, irregular, and difficult-to-reach defects. Thus, we aimed to assess the feasibility and safety of a novel through-the-scope, suture-based closure system developed to overcome these limitations. METHODS: This was a retrospective multicenter study involving 8 centers in the United States. Primary outcomes were feasibility and safety of early use of the device. Secondary outcomes were assessment of need for additional closure devices, prolonged procedure time, and technical feasibility of performing the procedure with an alternative device(s). RESULTS: Ninety-three patients (48.4% women) with mean age 63.6 ± 13.1 years were included. Technical success was achieved in 83 patients (89.2%), and supplemental closure was required in 24.7% of patients (n = 23) with a mean defect size of 41.6 ± 19.4 mm. Closure with an alternative device was determined to be impossible in 24.7% of patients because of location, size, or shape of the defect. The use of the tack and suture device prolonged the procedure in 8.6% of cases but was considered acceptable. Adverse events occurred in 2 patients (2.2%) over a duration of follow-up of 34 days (interquartile range, 13-93.5) and were mild and moderate in severity. No serious adverse events or procedure-related deaths occurred. CONCLUSIONS: The novel endoscopic through-the-scope tack and suture system is safe, efficient, and permits closure of large and irregularly shaped defects that were not possible with established devices.

Predicted Cure and Survival Among Transplant Recipients With a Previous Cancer Diagnosis.

PURPOSE: A previous cancer diagnosis is a negative consideration in evaluating patients for possible solid organ transplantation. Statistical models may improve selection of patients with cancer evaluated for transplantation. METHODS: We fitted statistical cure models for patients with cancer in the US general population using data from 13 cancer registries. Patients subsequently undergoing solid organ transplantation were identified through the Scientific Registry of Transplant Recipients. We estimated cure probabilities at diagnosis (for all patients with cancer) and transplantation (transplanted patients). We used Cox regression to assess associations of cure probability at transplantation with subsequent cancer-specific mortality. RESULTS: Among 10,524,326 patients with 17 cancer types in the general population, the median cure probability at diagnosis was 62%. Of these patients, 5,425 (0.05%) subsequently underwent solid organ transplantation and their median cure probability at transplantation was 94% (interquartile range, 86%-98%). Compared with the tertile of transplanted patients with highest cure probability, those in the lowest tertile more frequently had lung or breast cancers and less frequently colorectal, testicular, or thyroid cancers; more frequently had advanced-stage cancer; were older (median 57 v 51 years); and were transplanted sooner after cancer diagnosis (median 3.6 v 8.6 years). Patients in the low-cure probability tertile had increased cancer-specific mortality after transplantation (adjusted hazard ratio, 2.08; 95% CI, 1.48 to 2.93; v the high tertile), whereas those in the middle tertile did not differ. CONCLUSION: Patients with cancer who underwent solid organ transplantation exhibited high cure probabilities, reflecting selection on the basis of existing guidelines and clinical judgment. Nonetheless, there was a range of cure probabilities among transplanted patients and low probability predicted increased cancer-specific mortality after transplantation. Cure probabilities may facilitate guideline development and evaluating individual patients for transplantation.

Expert consensus on endoscopic papillectomy using a Delphi process.

BACKGROUND AND AIMS: Consensus regarding an optimal algorithm for endoscopic treatment of papillary adenomas has not been established. We aimed to assess the existing degree of consensus among international experts and develop further concordance by means of a Delphi process. METHODS: Fifty-two international experts in the field of endoscopic papillectomy were invited to participate. Data were collected between August and December 2019 using an online survey platform. Three rounds were conducted. Consensus was defined as ≥70% agreement. RESULTS: Sixteen experts (31%) completed the full process, and consensus was achieved on 47 of the final 79 statements (59%). Diagnostic workup should include at least an upper endoscopy using a duodenoscope (100%) and biopsy sampling (94%). There should be selected use of additional abdominal imaging (75%-81%). Patients with (suspected) papillary malignancy or over 1 cm intraductal extension should be referred for surgical resection (76%). To prevent pancreatitis, rectal nonsteroidal anti-inflammatory drugs should be administered before resection (82%) and a pancreatic stent should be placed (100%). A biliary stent is indicated in case of ongoing bleeding from the papillary region (76%) or concerns for a (micro)perforation after resection (88%). Follow-up should be started 3 to 6 months after initial papillectomy and repeated every 6 to 12 months for at least 5 years (75%). CONCLUSIONS: This is the first step in developing an international consensus-based algorithm for endoscopic management of papillary adenomas. Surprisingly, in many areas consensus could not be achieved. These aspects should be the focus of future studies.

External validation of blue light imaging (BLI) criteria for the optical characterization of colorectal polyps by endoscopy experts.

BACKGROUND AND AIM: Recently, the BLI Adenoma Serrated International Classification (BASIC) system was developed by European experts to differentiate colorectal polyps. Our aim was to validate the BASIC classification system among the US-based endoscopy experts. METHODS: Participants utilized a web-based interactive learning system where the group was asked to characterize polyps using the BASIC criteria: polyp surface (presence of mucus, regular/irregular and [pseudo]depressed), pit appearance (featureless, round/non-round with/without dark spots; homogeneous/heterogeneous distribution with/without focal loss), and vessels (present/absent, lacy, peri-cryptal, irregular). The final testing consisted of reviewing BLI images/videos to determine whether the criteria accurately predicted the histology results. Confidence in adenoma identification (rated "1" to "5") and agreement in polyp (adenoma vs non-adenoma) identification and characterization per BASIC criteria were derived. Strength of interobserver agreement with kappa (k) value was reported for adenoma identification. RESULTS: Ten endoscopy experts from the United States identified conventional adenoma (vs non-adenoma) with 94.4% accuracy, 95.0% sensitivity, 93.8% specificity, 93.8% positive predictive value, and 94.9% negative predictive value using BASIC criteria. Overall strength of interobserver agreement was high: kappa 0.89 (0.82-0.96). Agreement for the individual criteria was as follows: surface mucus (93.8%), regularity (65.6%), type of pit (40.6%), pit visibility (66.9%), pit distribution (57%), vessel visibility (73%), and being lacy (46%) and peri-cryptal (61%). The confidence in diagnosis was rated at high ≥4 in 67% of the cases. CONCLUSIONS: A group of US-based endoscopy experts have validated a simple and easily reproducible BLI classification system to characterize colorectal polyps with >90% accuracy and a high level of interobserver agreement.

Solid Organ Transplantation and Survival among Individuals with a History of Cancer.

BACKGROUND: The success of immunotherapy highlights a possible role for immunity in controlling cancer during remission for patients with cancer in the general population. A prior cancer diagnosis is common among solid organ transplant candidates, and immunosuppressive medications administered to transplant recipients may increase recurrence risk. METHODS: Using linked data from the United States solid organ transplant registry and 13 cancer registries, we compared overall and cancer-specific survival among patients with cancer who did versus did not receive subsequent transplantation. We used Cox regression in cohort and matched analyses, controlling for demographic factors, cancer stage, and time since cancer diagnosis. RESULTS: The study included 10,524,326 patients with cancer, with 17 cancer types; 5,425 (0.05%) subsequently underwent solid organ transplantation. The median time from cancer diagnosis to transplantation was 5.7 years. Transplantation was associated with reduced overall survival for most cancers, especially cervical, testicular, and thyroid cancers [adjusted hazard ratios (aHR) for overall mortality, 3.43-4.88]. In contrast, transplantation was not associated with decreased cancer-specific survival for any cancer site, and we observed inverse associations for patients with breast cancer (aHRs for cancer-specific mortality, 0.65-0.67), non-Hodgkin lymphoma (0.50-0.51), and myeloma (0.39-0.42). CONCLUSIONS: Among U.S. patients with cancer, subsequent organ transplantation was associated with reduced overall survival, likely due to end-stage organ disease and transplant-related complications. However, we did not observe adverse associations with cancer-specific survival, partly reflecting careful candidate selection. IMPACT: These results do not demonstrate a detrimental effect of immunosuppression on cancer-specific survival and support current management strategies for transplant candidates with previous cancer diagnoses.

The perils of using predicted values in place of observed covariates: an example of predicted values of body composition and mortality risk.

BACKGROUND: Several studies have assessed the relation of body composition to health outcomes by using values of fat and lean mass that were not measured but instead were predicted from anthropometric variables such as weight and height. Little research has been done on how substituting predicted values for measured covariates might affect analytic results. OBJECTIVES: We aimed to explore statistical issues causing bias in analytical studies that use predicted rather than measured values of body composition. METHODS: We used data from 8014 adults ≥40 y old included in the 1999-2006 US NHANES. We evaluated the relations of predicted total body fat (TF) and predicted total body lean mass (TLM) with all-cause mortality. We then repeated the evaluation using measured body composition variables from DXA. Quintiles and restricted cubic splines allowed flexible modeling of the HRs in unadjusted and multivariable-adjusted Cox regression models. RESULTS: The patterns of associations between body composition and all-cause mortality depended on whether body composition was defined using predicted values or DXA measurements. The largest differences were observed in multivariable-adjusted models which mutually adjusted for both TF and TLM. For instance, compared with analyses based on DXA measurements, analyses using predicted values for males overestimated the HRs for TF in splines and in quintiles [HRs (95% CIs) for fourth and fifth quintiles compared with first quintile, DXA: 1.22 (0.88, 1.70) and 1.46 (0.99, 2.14); predicted: 1.86 (1.29, 2.67) and 3.24 (2.02, 5.21)]. CONCLUSIONS: It is important for researchers to be aware of the potential pitfalls and limitations inherent in the substitution of predicted values for measured covariates in order to draw proper conclusions from such studies.

Is group testing ready for prime-time in disease identification?

Large-scale disease screening is a complicated process in which high costs must be balanced against pressing public health needs. When the goal is screening for infectious disease, one approach is group testing in which samples are initially tested in pools and individual samples are retested only if the initial pooled test was positive. Intuitively, if the prevalence of infection is small, this could result in a large reduction of the total number of tests required. Despite this, the use of group testing in medical studies has been limited, largely due to skepticism about the impact of pooling on the accuracy of a given assay. While there is a large body of research addressing the issue of testing errors in group testing studies, it is customary to assume that the misclassification parameters are known from an external population and/or that the values do not change with the group size. Both of these assumptions are highly questionable for many medical practitioners considering group testing in their study design. In this article, we explore how the failure of these assumptions might impact the efficacy of a group testing design and, consequently, whether group testing is currently feasible for medical screening. Specifically, we look at how incorrect assumptions about the sensitivity function at the design stage can lead to poor estimation of a procedure's overall sensitivity and expected number of tests. Furthermore, if a validation study is used to estimate the pooled misclassification parameters of a given assay, we show that the sample sizes required are so large as to be prohibitive in all but the largest screening programs.

Outcomes of a hybrid technique using EMR and endoscopic full-thickness resection for polyps not amenable to standard techniques (with video).

BACKGROUND AND AIMS: The full-thickness resection device (FTRD) offers a safe and effective approach for resection of complex colorectal lesions but is limited to lesions <2 cm in size. A hybrid approach-combining EMR with the FTRD-significantly expands the pool of lesions amenable to this technique; however, its safety and efficacy has not been well established. METHODS: We report a single-center retrospective study of consecutive patients who underwent full-thickness resection (FTR) of colorectal lesions, either with a standalone FTRD or a hybrid (EMR + FTRD) approach. Outcomes of technical success, clinical success (macroscopically complete resection), R0 resection, and adverse events (AEs) were evaluated. RESULTS: Sixty-nine FTR procedures (38 standalone FTR and 31 hybrid EMR + FTR) were performed on 65 patients. The most common indications were nonlifting polyp (43%) or suspected high-grade dysplasia or carcinoma (38%). Hybrid EMR + FTR permitted resection of significantly larger lesions (mean, 39 mm; range, 15-70 mm) compared with standalone FTR (mean, 17 mm; range, 7-25 mm; P < .01). Clinical success (91%), technical success (83%), and R0 resection (81%) rates did not differ between standalone and hybrid groups. Most patients (96%) were discharged home on the day of the procedure. Three AEs occurred, including 2 patients who developed acute appendicitis. CONCLUSIONS: A hybrid approach combining EMR and FTRD maintains safety and efficacy while permitting resection of significantly larger lesions than FTRD alone.

Bias due to Berkson error: issues when using predicted values in place of observed covariates.

Studies often want to test for the association between an unmeasured covariate and an outcome. In the absence of a measurement, the study may substitute values generated from a prediction model. Justification for such methods can be found by noting that, with standard assumptions, this is equivalent to fitting a regression model for an outcome variable when at least one covariate is measured with Berkson error. Under this setting, it is known that consistent or nearly consistent inference can be obtained under many linear and nonlinear outcome models. In this article, we focus on the linear regression outcome model and show that this consistency property does not hold when there is unmeasured confounding in the outcome model, in which case the marginal inference based on a covariate measured with Berkson error differs from the same inference based on observed covariates. Since unmeasured confounding is ubiquitous in applications, this severely limits the practical use of such measurements, and, in particular, the substitution of predicted values for observed covariates. These issues are illustrated using data from the National Health and Nutrition Examination Survey to study the joint association of total percent body fat and body mass index with HbA1c. It is shown that using predicted total percent body fat in place of observed percent body fat yields inferences which often differ significantly, in some cases suggesting opposite relationships among covariates.

Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy.

BACKGROUND: Quantifying associations between genetic mutations and loss of ambulation (LoA) among males diagnosed with childhood-onset dystrophinopathy is important for understanding variation in disease progression and may be useful in clinical trial design. METHODS: Genetic and clinical data from the Muscular Dystrophy Surveillance, Tracking, and Research Network for 358 males born and diagnosed from 1982 to 2011 were analyzed. LoA was defined as the age at which independent ambulation ceased. Genetic mutations were defined by overall type (deletion/duplication/point mutation) and among deletions, those amenable to exon-skipping therapy (exons 8, 20, 44-46, 51-53) and another group. Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Mutation type did not predict time to LoA. Controlling for corticosteroids, Exons 8 (HR = 0.22; 95% CI = 0.08, 0.63) and 44 (HR = 0.30; 95% CI = 0.12, 0.78) were associated with delayed LoA compared to other exon deletions. CONCLUSIONS: Delayed LoA in males with mutations amenable to exon-skipping therapy is consistent with previous studies. These findings suggest that clinical trials including exon 8 and 44 skippable males should consider mutation information prior to randomization.