The Thoracic Research Evaluation and Treatment 2.0 Model: A Lung Cancer Prediction Model for Indeterminate Nodules Referred for Specialist Evaluation.

BACKGROUND: Appropriate risk stratification of indeterminate pulmonary nodules (IPNs) is necessary to direct diagnostic evaluation. Currently available models were developed in populations with lower cancer prevalence than that seen in thoracic surgery and pulmonology clinics and usually do not allow for missing data. We updated and expanded the Thoracic Research Evaluation and Treatment (TREAT) model into a more generalized, robust approach for lung cancer prediction in patients referred for specialty evaluation. RESEARCH QUESTION: Can clinic-level differences in nodule evaluation be incorporated to improve lung cancer prediction accuracy in patients seeking immediate specialty evaluation compared with currently available models? STUDY DESIGN AND METHODS: Clinical and radiographic data on patients with IPNs from six sites (N = 1,401) were collected retrospectively and divided into groups by clinical setting: pulmonary nodule clinic (n = 374; cancer prevalence, 42%), outpatient thoracic surgery clinic (n = 553; cancer prevalence, 73%), or inpatient surgical resection (n = 474; cancer prevalence, 90%). A new prediction model was developed using a missing data-driven pattern submodel approach. Discrimination and calibration were estimated with cross-validation and were compared with the original TREAT, Mayo Clinic, Herder, and Brock models. Reclassification was assessed with bias-corrected clinical net reclassification index and reclassification plots. RESULTS: Two-thirds of patients had missing data; nodule growth and fluorodeoxyglucose-PET scan avidity were missing most frequently. The TREAT version 2.0 mean area under the receiver operating characteristic curve across missingness patterns was 0.85 compared with that of the original TREAT (0.80), Herder (0.73), Mayo Clinic (0.72), and Brock (0.68) models with improved calibration. The bias-corrected clinical net reclassification index was 0.23. INTERPRETATION: The TREAT 2.0 model is more accurate and better calibrated for predicting lung cancer in high-risk IPNs than the Mayo, Herder, or Brock models. Nodule calculators such as TREAT 2.0 that account for varied lung cancer prevalence and that consider missing data may provide more accurate risk stratification for patients seeking evaluation at specialty nodule evaluation clinics.

Improving lung cancer diagnosis with cancer, fungal, and imaging biomarkers.

OBJECTIVE: Indeterminate pulmonary nodules (IPNs) represent a significant diagnostic burden in health care. We aimed to compare a combination clinical prediction model (Mayo Clinic model), fungal (histoplasmosis serology), imaging (computed tomography [CT] radiomics), and cancer (high-sensitivity cytokeratin fraction 21; hsCYFRA 21-1) biomarker approach to a validated prediction model in diagnosing lung cancer. METHODS: A prospective specimen collection, retrospective blinded evaluation study was performed in 3 independent cohorts with 6- to 30-mm IPNs (n = 281). Serum histoplasmosis immunoglobulin G and immunoglobulin M antibodies and hsCYFRA 21-1 levels were measured and a validated CT radiomic score was calculated. Multivariable logistic regression models were estimated with Mayo Clinic model variables, histoplasmosis antibody levels, CT radiomic score, and hsCYFRA 21-1. Diagnostic performance of the combination model was compared with that of the Mayo Clinic model. Bias-corrected clinical net reclassification index (cNRI) was used to estimate the clinical utility of a combination biomarker approach. RESULTS: A total of 281 patients were included (111 from a histoplasmosis-endemic region). The combination biomarker model including the Mayo Clinic model score, histoplasmosis antibody levels, radiomics, and hsCYFRA 21-1 level showed improved diagnostic accuracy for IPNs compared with the Mayo Clinic model alone with an area under the receiver operating characteristics curve of 0.80 (95% CI, 0.76-0.84) versus 0.72 (95% CI, 0.66-0.78). Use of this combination model correctly reclassified intermediate risk IPNs into low- or high-risk category (cNRI benign = 0.11 and cNRI malignant = 0.16). CONCLUSIONS: The addition of cancer, fungal, and imaging biomarkers improves the diagnostic accuracy for IPNs. Integrating a combination biomarker approach into the diagnostic algorithm of IPNs might decrease unnecessary invasive testing of benign nodules and reduce time to diagnosis for cancer.

Modeling the impact of delaying transcatheter aortic valve replacement for the treatment of aortic stenosis in the era of COVID-19.

OBJECTIVE: The aim of this study was to model the short term and 2-year overall survival (OS) for intermediate-risk and low-risk patients with severe symptomatic aortic stenosis (AS) undergoing timely or delayed transcatheter aortic valve replacement (TAVR) during the 2019 novel coronavirus (COVID-19) pandemic. METHODS: We developed a decision analysis model to evaluate 2 treatment strategies for both low-risk and intermediate-risk patients with AS during the COVID-19 novel coronavirus pandemic. RESULTS: Prompt TAVR resulted in improved 2-year OS compared with delayed intervention for intermediate-risk patients (0.81 vs 0.67) and low-risk patients (0.95 vs 0.85), owing to the risk of death or the need for urgent/emergent TAVR in the waiting period. However, if the probability of acquiring COVID-19 novel coronavirus is >55% (intermediate-risk patients) or 47% (low-risk patients), delayed TAVR is favored over prompt intervention (0.66 vs 0.67 for intermediate risk; 0.84 vs 0.85 for low risk). CONCLUSIONS: Prompt transcatheter aortic valve replacement for both intermediate-risk and low-risk patients with symptomatic severe AS results in improved 2-year survival when local healthcare system resources are not significantly constrained by the COVID-19.

Preoperative coronary artery calcifications in veterans predict higher all-cause mortality in early-stage lung cancer: a cohort study.

BACKGROUND: Lung cancer patients often have comorbidities that may impact survival. This observational cohort study examines whether coronary artery calcifications (CAC) impact all-cause mortality in patients with resected stage I non-small cell lung cancer (NSCLC). METHODS: Veterans with stage I NSCLC who underwent resection at a single institution between 2005 and 2018 were selected from a prospectively collected database. Radiologists blinded to patient outcomes graded CAC severity (mild, moderate, or severe) in preoperative CT scans using a visual estimation scoring system. Inter-rater reliability was calculated using the kappa statistic. All-cause mortality was the primary outcome. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to compare time-to-death by varying CAC. RESULTS: The Veteran patients (n=195) were predominantly older (median age of 67) male (98%) smokers (96%). The majority (68%) were pathologic stage IA. Overall, 12% of patients had no CAC, 27% mild, 26% moderate, and 36% severe CAC. Median unadjusted survival was 8.8 years for patients with absent or mild CAC versus 6.3 years for moderate and 5.9 years for severe CAC (P=0.01). The adjusted hazard ratio for moderate CAC was 1.44 (95% CI, 0.85-2.46) and for severe CAC was 1.73 (95% CI, 1.03-2.88; P for trend <0.05). CONCLUSIONS: The presence of severe CAC on preoperative imaging significantly impacted the all-cause survival of patients undergoing resection for stage I NSCLC. This impact on mortality should be taken into consideration by multidisciplinary teams when making treatment plans for patients with early-stage disease.

Validation of Histoplasmosis Enzyme Immunoassay to Evaluate Suspicious Lung Nodules.

BACKGROUND: Granulomas caused by infectious lung diseases can present as indeterminate pulmonary nodules (IPN). This study aims to validate an enzyme immunoassay (EIA) for Histoplasma immunoglobulin G (IgG) and immunoglobulin M (IgM) for diagnosing benign IPN in areas with endemic histoplasmosis. METHODS: Prospectively collected serum samples from patients at Vanderbilt University Medical Center (VUMC [n = 204]), University of Pittsburgh Medical Center (n = 71), and University of Cincinnati (n = 51) with IPN measuring 6 to 30 mm were analyzed for Histoplasma IgG and IgM with EIA. Diagnostic test characteristics were compared with results from the VUMC pilot cohort (n = 127). A multivariable logistic regression model was developed to predict granuloma in IPN. RESULTS: Cancer prevalence varied by cohort: VUMC pilot 60%, VUMC validation 65%, University of Pittsburgh Medical Center 35%, and University of Cincinnati 75%. Across all cohorts, 19% of patients had positive IgG titers, 5% had positive IgM, and 3% had positive both IgG and IgM. Of patients with benign disease, 33% were positive for at least one antibody. All patients positive for both IgG and IgM antibodies at acute infection levels had benign disease (n = 13), with a positive predictive value of 100%. The prediction model for granuloma in IPN demonstrated an area under the receiver-operating characteristics curve of 0.84 and Brier score of 0.10. CONCLUSIONS: This study confirmed that Histoplasma EIA testing can be useful for diagnosing benign IPN in areas with endemic histoplasmosis in a population at high risk for lung cancer. Integrating Histoplasma EIA testing into the current diagnostic algorithm where histoplasmosis is endemic could improve management of IPN and potentially decrease unnecessary invasive biopsies.

Preparing for Bundled Payments: Impact of Complications Post-Coronary Artery Bypass Grafting on Costs.

BACKGROUND: Bundled payments for coronary artery bypass grafting (CABG) provide a single reimbursement for care provided from admission through 90 days post-discharge. We aim to explore the impact of complications on total institutional costs, as well as the drivers of high costs for index hospitalization. METHODS: We linked clinical and internal cost data for patients undergoing CABG from 2014 to 2017 at a single institution. We compared unadjusted average variable direct costs, reporting excess cost from an uncomplicated baseline. We stratified by The Society of Thoracic Surgeons preoperative risk and quality outcome measures as well as value-based outcomes (readmission, post-acute care utilization). We performed multivariable linear regression to evaluate drivers of high costs, adjusting for preoperative and intraoperative characteristics and postoperative complications. RESULTS: We reviewed 1789 patients undergoing CABG with an average of 2.7 vessels (SD 0.89). A significant proportion of patients were diabetic (51.2%) and obese (mean body mass index 30.6, SD 6.1). Factors associated with increased adjusted costs were preoperative renal failure (P = .001), diabetes (P = .001) and body mass index (P = .05), and postoperative stroke (P < .001), prolonged ventilation (P < .001), rebleeding requiring reoperation (P < .001) and renal failure (P < .001) with varying magnitude. Preoperative ejection fraction and insurance status were not associated with increased adjusted costs. CONCLUSIONS: Preoperative characteristics had less of an impact on costs post-CABG than postoperative complications. Postoperative complications vary in their impact on internal costs, with reoperation, stroke, and renal failure having the greatest impact. In preparation for bundled payments, hospitals should focus on understanding and preventing drivers of high cost.

Modeling the Impact of Delaying the Diagnosis of Non-Small Cell Lung Cancer During COVID-19.

BACKGROUND: The novel coronavirus (COVID-19) pandemic has led surgical societies to recommend delaying diagnosis and treatment of suspected lung cancer for lesions less than 2 cm. Delaying diagnosis can lead to disease progression, but the impact of this delay on mortality is unknown. The COVID-19 infection rate at which immediate operative risk exceeds benefit is unknown. We sought to model immediate versus delayed surgical resection in a suspicious lung nodule less than 2 cm. METHODS: A decision analysis model was developed, and sensitivity analyses performed. The base case was a 65-year-old male smoker with chronic obstructive pulmonary disease presenting for surgical biopsy of a 1.5 to 2 cm lung nodule highly suspicious for cancer during the COVID-19 pandemic. We compared immediate surgical resection to delayed resection after 3 months. The likelihood of key outcomes was derived from the literature where available. The outcome was 5-year overall survival. RESULTS: Immediate surgical resection resulted in a similar but slightly higher 5-year overall survival when compared with delayed resection (0.77 versus 0.74) owing to the risk of disease progression. However, if the probability of acquired COVID-19 infection is greater than 13%, delayed resection is favorable (0.74 vs 0.73). CONCLUSIONS: Immediate surgical biopsy of lung nodules suspicious for cancer in hospitals with low COVID-19 prevalence likely results in improved 5-year survival. However, as the risk of perioperative COVID-19 infection increases above 13%, a delayed approach has similar or improved survival. This balance should be frequently reexamined at each health care facility throughout the curve of the pandemic.

Early Outcomes of Multivisceral Transplant Using Hepatitis C-Positive Donors.

BACKGROUND: In the era of direct-acting antiviral therapies, hepatitis C-positive organs offer a strategy to expand the donor pool. Heart failure patients with concomitant renal insufficiency benefit from combined heart/kidney transplant. In 2017, we began utilizing organs from hepatitis C donors for heart/kidney transplants. METHODS: Characteristics and outcomes of heart/kidney transplants were collected at our institution from 2012 through 2019. We determined patient cohorts by donor hepatitis C antibody status, antibody positive (HCV+) vs antibody negative (HCV-). Outcomes of interest include survival, postoperative allograft function, and waitlist time. Summary and descriptive statistics, as well as survival analyses, were performed. RESULTS: Thirty-nine patients underwent heart/kidney transplantation from 2012-2019. Twelve patients received HCV+ organs, and 27 patients received HCV- organs with minimal differences in donor and recipient cohort characteristics. Recipients who consented to receive HCV+ organs had a shorter median waitlist time. HCV+ and HCV- groups had similar perioperative and early postoperative cardiac function and similar rates of delayed renal graft function. HCV+ recipients demonstrated higher creatinine levels at 3 months posttransplant compared with HCV- recipients, but by 1-year post-transplant, creatinine levels in both groups were similar. The groups had similar 30-day and 1-year survival. CONCLUSIONS: This study is a single-center series of heart/kidney transplant using HCV+ donors. When the potential increased risk of early postoperative renal dysfunction is balanced against similar survival and decreased waitlist time, the results suggest that HCV+ donors are an important source of transplantable organs for heart/kidney transplantation.

Modeling the impact of delaying surgery for early esophageal cancer in the era of COVID-19.

BACKGROUND: Surgical society guidelines have recommended changing the treatment strategy for early esophageal cancer during the novel coronavirus (COVID-19) pandemic. Delaying resection can allow for interim disease progression, but the impact of this delay on mortality is unknown. The COVID-19 infection rate at which immediate operative risk exceeds benefit is unknown. We sought to model immediate versus delayed surgical resection in a T1b esophageal adenocarcinoma. METHODS: A decision analysis model was developed, and sensitivity analyses performed. The base case was a 65-year-old male smoker presenting with cT1b esophageal adenocarcinoma scheduled for esophagectomy during the COVID-19 pandemic. We compared immediate surgical resection to delayed resection after 3 months. The likelihood of key outcomes was derived from the literature where available. The outcome was 5-year overall survival. RESULTS: Proceeding with immediate esophagectomy for the base case scenario resulted in slightly improved 5-year overall survival when compared to delaying surgery by 3 months (5-year overall survival 0.74 for immediate and 0.73 for delayed resection). In sensitivity analyses, a delayed approach became preferred when the probability of perioperative COVID-19 infection increased above 7%. CONCLUSIONS: Immediate resection of early esophageal cancer during the COVID-19 pandemic did not decrease 5-year survival when compared to resection after 3 months for the base case scenario. However, as the risk of perioperative COVID-19 infection increases above 7%, a delayed approach has improved 5-year survival. This balance should be frequently re-examined by surgeons as infection risk changes in each hospital and community throughout the COVID-19 pandemic.

Modeling the Impact of Delaying Bariatric Surgery due to COVID-19: a Decision Analysis.

We developed a decision analysis model to evaluate risks and benefits of delaying scheduled bariatric surgery during the novel coronavirus disease (COVID-19) pandemic. Our base case was a 45-year-old female with diabetes and a body mass index of 45 kg/m2. We compared immediate with delayed surgery after 6 months to allow for COVID-19 prevalence to decrease. We found that immediate and delayed bariatric surgeries after 6 months resulted in similar 20-year overall survival. When the probability of COVID-19 infection exceeded 4%, then delayed surgery improved survival. If future COVID-19 infection rates were at least half those in the immediate scenario, then immediate surgery was favored and local infection rates had to exceed 9% before surgical delay improved survival. Surgeons should consider local disease prevalence and patient comorbidities associated with increased mortality before resuming bariatric surgery programs.

Cost-Effectiveness Analysis of Fibrinolysis vs Thoracoscopic Decortication for Early Empyema.

BACKGROUND: Surgical decortication is recommended by national guidelines for management of early empyema, but intrapleural fibrinolysis is frequently used as a first-line therapy in clinical practice. This study compared the cost-effectiveness of video-assisted thoracoscopic surgery (VATS) decortication with intrapleural fibrinolysis for early empyema. METHODS: A decision analysis model was developed. The base clinical case was a 65-year-old man with early empyema treated either by VATS decortication or intrapleural tissue plasminogen activator and deoxyribonuclease. The likelihood of key outcomes occurring was derived from the literature. Medicare diagnosis-related groups and manufacturers' drug prices were used for cost estimates. Successful treatment was defined as complete or nearly complete resolution of empyema on imaging. Effectiveness was defined as health utility 1 year after empyema. RESULTS: Intrapleural tissue plasminogen activator and deoxyribonuclease were more cost-effective than VATS decortication for treating early empyema for the base clinical case. Surgical decortication had a slightly lower cost than fibrinolysis ($13,345 vs $13,965), but fibrinolysis had marginally higher effectiveness at 1 year (health utility of 0.80 vs 0.71). Therefore, fibrinolysis was the more cost-effective option. Sensitivity analyses found that fibrinolysis as the initial therapy was more cost-effective when the probability of success was greater than 60% or the initial cost was less than $13,000. CONCLUSIONS: Surgical decortication and intrapleural fibrinolysis have nearly equivalent cost-effectiveness for early empyema in patients who can tolerate both procedures. Surgeons should consider patient-specific factors, as well as the cost and effectiveness of both modalities, when deciding on an initial treatment for early empyema.

Exploring patient willingness to accept hepatitis C-infected kidneys for transplantation.

BACKGROUND: As organs infected with Hepatitis C virus (HCV) provide an opportunity to expand the donor pool, the primary aim of this study is to explore patient willingness to accept a kidney from HCV-infected donors compared to other high-risk donors. METHODS: An anonymous, electronic survey was sent to all active kidney transplant waitlist patients at a single large volume transplant center. Patients were asked to respond to three hypothetical organ offers from the following: 1) HCV-infected donor 2) Donor with active intravenous drug use and 3) Donor with longstanding diabetes and hypertension. RESULTS: The survey was sent to 435 patients of which 125 responded (29% response rate). While 86 out of 125 patients (69%) were willing to accept an HCV-infected kidney, only a minority of respondents were willing to accept a kidney from other high-risk donors. In contrast to other studies, by multivariable logistic regression, age and race were not associated with willingness to accept an HCV-infected kidney. CONCLUSIONS: In this exploratory study, utilization of kidneys from HCV-infected donors to expand the donor pool appears to be an acceptable option to patients.

Developing prediction models for clinical use using logistic regression: an overview.

Prediction models help healthcare professionals and patients make clinical decisions. The goal of an accurate prediction model is to provide patient risk stratification to support tailored clinical decision-making with the hope of improving patient outcomes and quality of care. Clinical prediction models use variables selected because they are thought to be associated (either negatively or positively) with the outcome of interest. Building a model requires data that are computer-interpretable and reliably recorded within the time frame of interest for the prediction. Such models are generally defined as either diagnostic, likelihood of disease or disease group classification, or prognostic, likelihood of response or risk of recurrence. We describe a set of guidelines and heuristics for clinicians to use to develop a logistic regression-based prediction model for binary outcomes that is intended to augment clinical decision-making.

Optimizing Surgical Treatment of Internationally Adopted Children With Cleft Lip and/or Palate: Understanding the Family Experience.

OBJECTIVE: To understand the experience of families with children undergoing cleft surgery following adoption from a country outside the United States. To identify factors, including the timing of surgery, that influence family function throughout the surgical experience. DESIGN: Semistructured qualitative interviews were conducted with parents of internationally adopted children postrepair of cleft lip and/or cleft palate and coded by a multidisciplinary study team. Mixed methods were used to contextualize themes derived from the parent interviews. RESULTS: Twenty parent interviews were conducted, and four core themes were identified: (1) parental anxieties prior to surgery, (2) considerations for the timing of surgery, (3) impact of the surgical experience on the child and family, and (4) modifiable sociocontextual factors. Parents considered a strong child bond with at least one parent and the ability of the child to communicate basic needs to be important before undergoing surgery. In retrospect, parents generally felt that the surgical experience did not have a negative impact on their child or their families and that the surgical experience may have even facilitated bonding and attachment with their child. Acceleration of family bonding was expressed more often by parents of children who were adopted at older than 2 years. CONCLUSIONS: In our study, parents reported that cleft surgery soon after international adoption did not appear to impair child bonding or adjustment. Specific family and provider factors that could optimize the experience for families were identified.