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Background:Indeterminate pulmonary nodules (IPN) are a diagnostic challenge in regions where pulmonary fungal disease and smoking prevalence are high. We aimed to determine the impact of a combined fungal and imaging biomarker approach compared with a validated prediction model (Mayo) to rule out benign disease and diagnose lung cancer.Methods:Adults ages 40 to 90 years with 6–30 mm IPNs were included from four sites. Serum samples were tested for histoplasmosis IgG and IgM antibodies by enzyme immunoassay and a CT-based risk score was estimated from a validated radiomic model. Multivariable logistic regression models including Mayo score, radiomics score, and IgG and IgM histoplasmosis antibody levels were estimated. The areas under the ROC curves (AUC) of the models were compared among themselves and to Mayo. Bias-corrected clinical net reclassification index (cNRI) was estimated to assess clinical reclassification using a combined biomarker model.Results:We included 327 patients; 157 from histoplasmosis-endemic regions. The combined biomarker model including radiomics, histoplasmosis serology, and Mayo score demonstrated improved diagnostic accuracy when endemic histoplasmosis was accounted for [AUC, 0.84; 95% confidence interval (CI), 0.79–0.88; P < 0.0001 compared with 0.73; 95% CI, 0.67–0.78 for Mayo]. The combined model demonstrated improved reclassification with cNRI of 0.18 among malignant nodules.Conclusions:Fungal and imaging biomarkers may improve diagnostic accuracy and meaningfully reclassify IPNs. The endemic prevalence of histoplasmosis and cancer impact model performance when using disease related biomarkers.Impact:Integrating a combined biomarker approach into the diagnostic algorithm of IPNs could decrease time to diagnosis.

Lung cancer screening with low-dose computed tomography has demonstrated at least a 20% decrease in lung cancer-specific mortality, but it has the potential harm of unnecessary invasive procedures performed because of false-positive results. This study reports the outcomes of a structured multidisciplinary lung cancer screening program in an area of endemic histoplasmosis.A retrospective review of patients undergoing lung cancer screening from December 2012 to March 2019 was conducted. Findings suggestive of lung cancer were presented to a multidisciplinary thoracic tumor board. Patients were assigned to interval imaging follow-up, additional diagnostic imaging, or referral for an invasive procedure. Invasive procedures were then compared between benign and malignant diseases.A total of 4087 scans were performed on 2129 patients; 372 (9.1%) were suspicious and were presented to a multidisciplinary thoracic tumor board. Ultimately, 108 procedures were performed: 55 bronchoscopies, 7 percutaneous biopsies, and 46 operations. A total of 25 patients (1.2%) underwent bronchoscopy resulting in benign pathologic findings, significantly associated with an indication of an endobronchial lesion (P = .01). All percutaneous biopsy specimens revealed malignancy. Five patients (0.2%) who underwent resection had benign disease. Lung cancer was diagnosed in 67 patients (3.1% of the entire cohort), 46 of whom had stage I or II disease.Lung cancer screening in a structured, multidisciplinary program successfully identifies patients with early-stage lung cancer with limited unnecessary surgical interventions. Patients with isolated endobronchial lesions should undergo short interval imaging follow-up to avoid bronchoscopy for benign disease. Future studies to minimize unnecessary procedures could incorporate biomarkers and advanced imaging analysis into risk assessment models.

Miniaturization of multifunctional instruments is key to evolving less invasive medical procedures. The current work outlines steps towards developing a miniature motor to power a cutting tool of a millimeter-scale robot/device (target outside diameter ~2 mm) for minimally invasive procedures. Multiple motor concepts were explored and ranked using a Pugh matrix. The single-rotor hydraulic design was deemed most viable for prototyping and scale-down to the target size. Prototypes were manufactured to be progressively smaller using additive manufacturing. The smallest prototype fabricated was 2:1 scale of the desired final size with a 2 mm outside diameter (OD) rotor and a device OD of 4 mm. The scaled prototypes with an 8 mm rotor were lab tested and achieved average speeds of 5000–6000 RPM at a flowrate of 15–18 mL/s and 45 PSI water pressure. Ansys CFX was used as a design tool to explore the parameter space and 3D transient simulations were implemented using the immersed solid method. The predicted rotor RPM from the modeling matched the experimental values within 3% error. The model was then used to develop performance curves for the miniature hydraulic motor. In summary, the single-rotor hydraulic design shows promise for miniaturization to the target 2 mm size.

Supplemental Figure 3. Prostate epithelial RON promotes phosphorylated and total STAT3 protein expression in TAMs.

Supplemental Figure 1. Loss of RON in the prostate epithelium does not affect prostate development.

Supplemental Table 1. Primers for Genotyping and qRT-PCR

Supplemental Figure 2. Prostate weights from mice used to evaluate metastasis.

Supplementary Methods

BACKGROUND: Indeterminate pulmonary nodules (IPNs) are a diagnostic challenge in regions where pulmonary fungal disease and smoking prevalence are high. We aimed to determine the impact of a combined fungal and imaging biomarker approach compared to a validated prediction model (Mayo) to rule out benign disease and diagnose lung cancer. METHODS: Adults aged 40-90 years with 6-30 mm IPNs were included from four sites. Serum samples were tested for Histoplasmosis IgG and IgM antibodies by enzyme immunoassay and a computed tomography based risk score was estimated from a validated radiomic model. Multivariable logistic regression models including Mayo score, radiomics score, and IgG and IgM Histoplasmosis antibody levels were estimated. The areas under the receiver-operating characteristics curves (AUC) of the models were compared among themselves and to Mayo. Bias-corrected clinical net reclassification index (cNRI) was estimated to assess clinical reclassification using a combined biomarker model. RESULTS: We included 327 patients; 157 from Histoplasmosis-endemic regions. The combined biomarker model including radiomics, Histoplasmosis serology, and Mayo score demonstrated improved diagnostic accuracy when endemic Histoplasmosis was accounted for (AUC 0.84, 95% CI 0.79-0.88, p

[Image: see text] Central Picture Legend: Ethical standards for global health initiatives.

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.

The national opioid epidemic is a public health crisis. Thoracic surgery has also been associated with high incidence of new persistent opioid use. Our purpose was to describe the incidence and predictors of opioid use after lung cancer resection. Retrospective review of lung cancer resections from 2015 to 2018 was performed using the Ohio Automated Rx Reporting System. Opioid dosing was recorded as milligram morphine equivalents (MME). Patients were stratified by preoperative opioid use. Chronic preoperative opioid users (opioid dependent) filled > 120 days supply of opioid pain medication in the 12 months prior to surgery; intermittent opioid users filled 180 days were: chronic preoperative opioid use (OR 23.8, p

Lung cancer is the leading cause of cancer deaths in the USA. Computed tomography (CT) offers the potential for early detection by screening asymptomatic high-risk patients. We aimed to review the benefits and potential harms of lung cancer screening, discuss the logistics of a screening program, and provide insight from our own experience. The National Lung Screening Trial (NLST), a large population-based study, has demonstrated mortality benefit from screening, but relatively few eligible patients currently participate. An effective screening program requires input and cooperation from multiple stakeholders. Effort should be made to actively engage patients in the process including a thorough discussion of benefits and possible harms. At our institution, this approach has resulted in a rapidly growing and sustainable program. Lung cancer screening has proven mortality benefit in high-risk patients but is underutilized. Developing and growing a screening program is a complex process requiring coordination among multiple specialties with a focus on patient autonomy.

Minority patients with lung cancer are less likely to undergo surgical resection and experience worse survival than non-Hispanic White patients. Currently, 40% of thoracic surgeons require smoking cessation before surgery, which may disproportionately affect minority patients. Our objective was to assess the risk of smoking status on postoperative morbidity and mortality among patients with lung cancer.A prospectively maintained institutional database was queried for all patients who underwent surgical resection of a primary lung malignancy between 2006 and 2020. Operative mortality, major morbidity, and a composite of morbidity and mortality were compared between current smokers and prior smokers.A total of 601 patients underwent resection, and 236 (39.3%) were current smokers. Current smokers were more likely to be younger (P .01), to have a greater pack-years history (P = .03), and to have worse pulmonary function test results (P .01). Pretreatment stage, surgical approach, and extent of resection were similar between groups. There was no difference in operative mortality (0.9% vs 1.9%, P = .49), major morbidity (12.7% vs 9.3%, P = .19), or composite major morbidity and mortality between groups (13.1% vs 9.3%, P = .14). After adjusting for pulmonary function status, current smoking status was not associated with mortality or major morbidity on multivariable logistic regression (odds ratio, 1.51; 95% confidence interval, 0.76-3.03, P = .24).Current smokers experienced similar rates of mortality and major morbidity as prior smokers. In the context of continued racial and ethnic disparities in lung cancer survival, in particular decreased resection rates among minorities, smoking cessation requirements should not delay or prevent operative intervention for lung cancer.

The national opioid epidemic is a public health crisis. Thoracic surgery has also been associated with high incidence of new persistent opioid use. Our purpose was to describe the incidence and predictors of opioid use after lung cancer resection.Retrospective review of lung cancer resections from 2015 to 2018 was performed using the Ohio Automated Rx Reporting System. Opioid dosing was recorded as milligram morphine equivalents (MME). Patients were stratified by preoperative opioid use. Chronic preoperative opioid users (opioid dependent) filled 120 days supply of opioid pain medication in the 12 months prior to surgery; intermittent opioid users filled 120 days. Chronic postoperative opioid users continued monthly use after 180 days postoperatively.137 patients underwent resection. 16.1% (n = 22) were opioid dependent preoperatively, 29.2% (n = 40) were intermittent opioid users, and 54.7% (n = 75) were opioid naïve. Opioid dependent patients had higher daily inpatient opioid use compared to intermittent users and opioid naïve (43[30.0-118.1] MME vs 17.9[3.5-48.8] MME vs 8.8[2.1-25.0] MME, p 0.001). Twenty-six percent (n = 35) of all patients were opioid users beyond 180 days postoperatively. Variables associated with opioid use 180 days were: chronic preoperative opioid use (OR 23.8, p 0.01), daily inpatient opioid requirement (1.02, p 0.01), and neoadjuvant chemotherapy (28.2, p 0.01).A quarter of patients are opioid dependent after lung cancer resection. This is due to both preexisting and new persistent opioid use. Improved strategies are needed to prevent chronic pain and opioid dependence after lung cancer resection.

Background Integrated thoracic surgery (I-6) programs have become popular over traditional general surgery (GS) pathways since their inception in 2007. However the effect of I-6 programs on GS resident training remains unknown. The purpose of this study was to evaluate the effect of I-6 programs on the thoracic operative experience of co-located GS residents. Methods Thoracic surgery cases recorded by residents in GS programs co-located with I-6 programs until 2019 were analyzed. Cases were reviewed 5 years before (TSR-5) through 5 years after (TSR-5) the matriculation of the first thoracic resident in the co-located I-6 program. To contextualize the overall trends in the field Accreditation Council for Graduate Medical Education GS resident case logs from 1990 to 2018 were analyzed and total thoracic surgery cases recorded. Statistical analysis was performed with linear regression. Results Residents in 19 GS programs with co-located I-6 programs showed an increase in total thoracic cases from 3710 to 4451 (Δ/year of +85.05 cases a year; P = .03) balanced by an increase in GS residents from 107 to 126 (Δ/year of +1.45; P = .01) with no significant overall change in the median thoracic operative case volume (31.00 at both thoracic residency before and after 5 years). Nationally from 1990 to 2018 there was no change in the total thoracic operative experience for GS graduates. Conclusions The introduction of I-6 programs did not negatively impact thoracic operative experience for residents in co-located GS programs. Adequate training of both I-6 and GS residents at the same institution is feasible.

Effective treatment of advanced prostate cancer persists as a significant clinical need as only 30% of patients with distant disease survive to 5 years after diagnosis. Targeting signaling and tumor cell–immune cell interactions in the tumor microenvironment has led to the development of powerful immunotherapeutic agents, however, the prostate tumor milieu remains impermeable to these strategies highlighting the need for novel therapeutic targets. In this study, we provide compelling evidence to support the role of the RON receptor tyrosine kinase as a major regulator of macrophages in the prostate tumor microenvironment. We show that loss of RON selectively in prostate epithelial cells leads to significantly reduced prostate tumor growth and metastasis and is associated with increased intratumor infiltration of macrophages. We further demonstrate that prostate epithelial RON loss induces transcriptional reprogramming of macrophages to support expression of classical M1 markers and suppress expression of alternative M2 markers. Interestingly, our results show epithelial RON activation drives upregulation of RON expression in macrophages as a positive feed-forward mechanism to support prostate tumor growth. Using 3D coculture assays, we provide additional evidence that epithelial RON expression coordinates interactions between prostate tumor cells and macrophages to promote macrophage-mediated tumor cell growth. Taken together, our results suggest that RON receptor signaling in prostate tumor cells directs the functions of macrophages in the prostate tumor microenvironment to promote prostate cancer.Implications:Epithelial RON is a novel immunotherapeutic target that is responsible for directing the macrophage antitumor immune response to support prostate tumor growth and progression.

Malignant solitary fibrous tumors (MSFT) are rare neoplasms, and typically exhibit an aggressive course. While complete surgical resection is the primary treatment modality, the role of adjuvant radiation treatment in larger tumors is not well-established. Despite limited reported cases which demonstrated extended disease-free periods with adjuvant radiation, its utilization is conflictingly both recommended or discouraged across the literature due to the absence of high-quality published data. This is a report to add to the slowly growing body of literature to support the use of adjuvant radiation in these tumors. Specifically, a case of a 64-year-old man who developed rash and mild back pain after a total hip arthroplasty. He was found to have a large paravertebral MSFT, and was treated with surgical resection followed by adjuvant radiation due to size and focally positive margins. He has continued to have no evidence of disease 21 months after treatment. This case of successful treatment and continued disease-free interval with resection and adjuvant radiation contributes valuable supporting data to the management of this rare disease entity. Furthermore, a review of available literature on MSFT treatment is conducted to illustrate the inconsistency in post-surgical management, and demonstrate the necessity of additional detailed reports from a radiation treatment perspective.

Human beings have evolved their modes of communication continually through the ages. Over the last decade, social media in their various forms have become the preferred mode among younger generations, and their use has increased among older generations as well. Worldwide users of social media are expected by 2021 to number over 3 billion, which is approximately a third of the world’s population.1 The region with the highest penetration rate of social networks is North America, wherein around 60% of the population has more than one social media account, and 78% of the US population has a social networking profile.2 Social media offer enormous potential benefits for both care providers and patients, as the platform allows for the dissemination and gathering of information and has the innate ability to network globally. In fact, in a recent survey, 70% of surgeons indicated that they believe social media benefited professional development, while 22% preferred social media as their primary modality of networking and communication with colleagues.3 In using social media, care providers, particularly physicians and surgeons, must pay close attention to professionalism, specifically within the framework of professional ethics.

Salvage and delayed esophagectomy after chemoradiation therapy (CRT) have been associated with increased morbidity and mortality, but recent series have shown similar outcomes compared to timely esophagectomy. We aim to evaluate outcomes for delayed and salvage esophagectomy for esophageal adenocarcinoma utilizing a large national database.The National Cancer Database for 2004 to 2014 was queried for patients with clinical stage II or III esophageal adenocarcinoma who underwent preoperative CRT and esophagectomy. Patients who underwent surgery90 days after CRT were defined as the timely esophagectomy group (n = 7822), and those who underwent surgery ≥90 days after CRT were defined as the delayed esophagectomy group (n = 667).A total of 8489 patients met our inclusion criteria. The median post-CRT interval was 49 days (range, 40-61 days) for the timely esophagectomy group and 109 days (range, 97-132 days) for the delayed esophagectomy group. The delayed group was more likely to be of black race (2.3% vs 1.2%; P .01) and more likely to have Medicare (47.9% vs 39.8%; P .001). There were no significant between-group differences in chemotherapy regimens (P = .17), radiation dose (P = .18), or surgical approach (P = .48). The delayed esophagectomy group had higher rates of pathological complete response (22.2% vs 18.6%; P = .043) and 90-day postoperative mortality (10.4% vs 7.8%; P .01). On multivariate analysis, delayed esophagectomy was not independently associated with decreased overall survival.In this large retrospective database study, despite increased perioperative mortality, delayed and salvage esophagectomy for adenocarcinoma appear to have similar long-term survival as timely esophagectomy. Delayed and salvage esophagectomy may be offered to patients who do not receive timely esophagectomy after CRT.

Carbon nanotube (CNT) technology is improving around the world to the point where new types of devices can be made. Spinning millimeter-length CNT into yarn and drawing ribbon and twisting into yarn have been demonstrated, and the yarn is being used as electric and thermal conductors. It is also becoming feasible to use carbon nanotube hybrid conductive tapes and yarn to make tiny electromechanical components such as wires, coils, transformers, and electric motors. These components further enable the manufacturing of precision medical devices, such as biomedical wires, sensors, actuators, manipulators, and millirobots for minimally invasive in vivo diagnosis and treatment. Precision biomedical microdevices promise to improve disease diagnosis and treatment, improve health-care delivery, and spur novel medical system development. Treatments for heart disease, cancer, neural repair, drug delivery, probing, reconstruction, and healing might be advanced using miniature precision devices. The concept of CNT-based precision medical devices is a new area of research, and the state of the art in their development and potential applications are discussed in this chapter.

e16067 Background: Management of locally advanced esophageal and gastroesophageal junction (E/GEJ) adenocarcinoma is typically managed with neoadjuvant treatment followed by surgery. Clinical outcomes remain suboptimal and a considerable proportion of patients develop recurrence. However, prognostic and predictive factors are not well-defined. We thus aimed to identify any factors that were associated with disease recurrence and decreased overall survival (OS) among patients with E/GEJ adenocarcinoma treated with curative intent. Methods: A retrospective study spanning 2011-2020 was performed, which identified 56 patients who underwent esophagectomy for E/GEJ adenocarcinoma at the University of Cincinnati. Data on baseline demographic and clinical characteristics, treatment details, pathologic outcomes, recurrence patterns, and survival were extracted from the electronic medical record. Predictors of recurrence and OS, using multivariable logistic regression and Cox proportional hazards analyses, respectively, were identified using all potential predictors and parsimonious modeling. The study was approved by the UC IRB; statistical analyses were performed using SAS 9.2; 95% confidence intervals and two-sided p-values were calculated. Results: Of the 56 patients included, 50 (89%) were White and 6 (11%) were Black; 46 (82%) were male and 48 (85%) were current or former smokers. Tumor location was E in 37 (66%) and GEJ in 19 (34%) patients; 30 (64%) had cT3 or cT4 tumors and 27 (55%) had node-positive disease. Neoadjuvant treatment included platinum-based chemotherapy for 43 (77%) and radiation for 40 (71%) patients; all patients underwent esophagectomy. Median OS for the entire cohort was 4.2 (95% CI 1.8-NR) years and 23(41%) had recurrence after resection. Multivariable modeling showed body mass index (BMI) < 25 (OR vs. BMI ≥ 25: 5.41, 95% CI 1.4-20.4, p = 0.01) to be associated with recurrence; a higher pathologic T stage showed a trend toward increased risk (pT stages 1, 2, and 3 patients (vs. pT 0) were 0.2, 1.1, and 2.5 times more likely to have recurrent disease, respectively. OS was inferior for patients with recurrence (HR for death, vs. no recurrence: 5.42, 95% CI 2.1-13.8, p < 0.001) and a baseline ECOG PS ≥2 (HR vs. ECOG PS < 2: 2.36, 95% CI 0.87-6.4, p = 0.09). Conclusions: In this dataset of patients with E/GEJ adenocarcinoma treated with curative-intent resection, baseline clinical parameters of lower BMI and worse ECOG PS (rather than disease characteristics such as T and N stage) were the main predictors of recurrence and decreased OS. These findings suggest that improving clinical outcomes may at least partly depend on prehabilitation targeting nutrition and physical therapy for patients undergoing curative treatment for E/GEJ adenocarcinoma.

Background Individualized prediction of outcomes may help with therapy decisions for patients with non-small cell lung cancer. We developed a nomogram by analyzing 17 clinical factors and outcomes from a randomized study of sublobar resection for non-small cell lung cancer in high-risk operable patients. The study compared sublobar resection alone with sublobar resection with brachytherapy. There were no differences in primary and secondary outcomes between the study arms, and they were therefore combined for this analysis. Methods The clinical factors of interest (considered as continuous variables) were assessed in a univariate Cox proportional hazards model for significance at the 0.10 level for their impact on overall survival (OS), local recurrence-free survival (LRFS), and any recurrence-free survival (RFS). The final multivariable model was developed using a stepwise model selection. Results Of 212 patients, 173 had complete data on all 17 risk factors. Median follow-up was 4.94 years (range, 0.04 to 6.22). The 5-year OS, LRFS, and RFS were 58.4%, 53.2%, and 47.4%, respectively. Age, baseline percent diffusing capacity of lung for carbon monoxide, and maximum tumor diameter were significant predictors for OS, LRFS, and RFS in the multivariable model. Nomograms were subsequently developed for predicting 5-year OS, LRFS, and RFS. Conclusions Age, baseline percent diffusing capacity of lung for carbon monoxide, and maximum tumor diameter significantly predicted outcomes after sublobar resection. Such nomograms may be helpful for treatment planning in early stage non-small cell lung cancer and to guide future studies.

Background Sublobar resection (SR) in high-risk operable patients may result in a long-term decrease in pulmonary function. We previously reported 3-month pulmonary function outcomes from a randomized phase III study of SR alone compared with SR with brachytherapy in patients with non-small cell lung cancer. We now report long-term pulmonary function after SR. Methods Pulmonary function was measured at baseline and at 3, 12, and 24 months. A decline of 10% or more from baseline in the percentage predicted forced expiratory volume of 1 percentage or in the diffusion capacity of the lung for carbon monoxide was considered clinically meaningful. The effect of study arm, tumor location, size, approach (video-assisted thoracoscopic surgery vs thoracotomy), and SR type (wedge vs segmentectomy) on pulmonary function was assessed using a Wilcoxon rank sum test. A generalized estimating equation model was used to assess the effect of each factor on longitudinal data, including all four time points. Results Complete pulmonary function data at all time points was available in 69 patients. No significant differences were observed in pulmonary function between SR and SR with brachytherapy, thus the study arms were combined for all analyses. A decline of 10% or more ( p = 0.02) in the percentage predicted forced expiratory volume in 1 second was demonstrated for lower-lobe resections at 3 months but was not at 12 or 24 months. A decline of 10% or more ( p = 0.05) in the percentage predicted diffusion capacity of the lung for carbon monoxide was seen for thoracotomy at 3 months but was not at 12 or 24 months. Conclusions Clinically meaningful declines in pulmonary function occurred after lower lobe resection and after thoracotomy at 3 months but subsequently recovered. This study suggests that SR does not result in sustained decreased pulmonary function in high-risk operable patients.