Improved False-Positive Rates and the Overestimation of Unintended Harm from Lung Cancer Screening.

BACKGROUND: Concern over high false-positive rates and the potential for unintended harm to patients is a critical component of the lack of widespread adoption of lung cancer screening. METHODS: An institutional database was used to identify patients who underwent lung cancer screening between 2/2015 and 2/2018 at Rush University Medical Center and Rush Oak Park Hospital. Reads were executed by dedicated thoracic radiologists and communicated using the Lung Imaging Reporting and Data System (Lung-RADS V.1). RESULTS: Six hundred and four patients were screened over the study period. We identified 21 primary lung cancers and 8 incidental cancers. We identified a false-positive rate of 17.5%. Only 9 patients underwent further investigative workup for benign disease (5.3%); however, only 4 (2.9%) of those patients were found to have inflammatory or infectious lesions, which are common mimickers of lung cancer. Excluding Lung-RADS category 3 for the purpose of quantifying risk of unintended harm from unnecessary procedures, we found a 6.9% false-positive rate, while diagnosing 25% of all Lung-RADS category 4 patients with primary lung cancer. CONCLUSION: False-positive rates in lung cancer screening programs continue to decline with improved radiologic expertise. Additionally, false-positive reporting overestimates the risk of unintended harm from further investigative procedures as only a percentage of positive findings are generally considered for tissue diagnosis (i.e., Lung-RADS category 4).

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.

Durability of Silicone Airway Stents in the Management of Benign Central Airway Obstruction.

PURPOSE: The literature is devoid of a comprehensive analysis of silicone airway stenting for benign central airway obstruction (BCAO). With the largest series in the literature to date, we aim to demonstrate the safety profile, pattern of re-intervention, and duration of silicone airway stents. METHODS: An institutional database was used to identify patients with BCAO who underwent rigid bronchoscopy with dilation and silicone stent placement between 2002 and 2015 at Rush University Medical Center. RESULTS: During the study period, 243 stents were utilized in 63 patients with BCAO. Pure tracheal stenosis was encountered in 71% (45/63), pure tracheomalacia in 11% (7/63), and a hybrid of both in 17% (11/63). Median freedom from re-intervention was 104 (IQR 167) days. Most common indications for re-intervention include mucus accumulation (60%; 131/220), migration (28%; 62/220), and intubation (8%; 18/220). The most common diameters of stent placed were 12 mm (94/220) and 14 mm (96/220). The most common lengths utilized were 30 mm (60/220) and 40 mm (77/220). Duration was not effected by stent size when placed for discrete stenosis. However, 14 mm stents outperformed 12 mm when tracheomalacia was present (157 vs. 37 days; p = 0.005). Patients with a hybrid stenosis fared better when longer stents were used (60 mm stents outlasted 40 mm stents 173 vs. 56 days; p = 0.05). CONCLUSION: Rigid bronchoscopy with silicone airway stenting is a safe and effective option for the management of benign central airway obstruction. Our results highlight several strategies to improve stent duration.

Effects of the Learning Curve on Efficacy of Radiofrequency Ablation for Barrett's Esophagus.

BACKGROUND & AIMS: Complete eradication of Barrett's esophagus (BE) often requires multiple sessions of radiofrequency ablation (RFA). Little is known about the effects of case volume on the safety and efficacy of RFA or about the presence or contour of learning curves for this procedure. METHODS: We collected data from the US RFA Patient Registry (from 148 institutions) for patients who underwent RFA for BE from July 2007 to July 2011. We analyzed the effects of the number of patients treated by individual endoscopists and individual centers on safety and efficacy outcomes of RFA. Outcomes, including stricture, bleeding, hospitalization, and complete eradication of intestinal metaplasia (CEIM), were assessed using logistic regression. The effects of center and investigator experience on numbers of treatment sessions to achieve CEIM were examined using linear regression. RESULTS: After we controlled for potential confounders, we found that as the experience of endoscopists and centers increased with cases, the numbers of treatment sessions required to achieve CEIM decreased. This relationship persisted after adjusting for patient age, sex, race, length of BE, and presence of pretreatment dysplasia (P < .01). Center experience was not significantly associated with overall rates of CEIM or complete eradication of dysplasia. We did not observe any learning curve with regard to risks of stricture, gastrointestinal bleeding, perforation, or hospitalization (P > .05). CONCLUSIONS: Based on analysis of a large multicenter registry, efficiency of the treatment, as measured by number of sessions needed to achieve CEIM, increased with case volume, indicating a learning curve effect. This trend began to disappear after treatment of approximately 30 patients by the center or individual endoscopist. However, there was no significant association between safety or efficacy outcomes and previous case volume.

Incidence of Esophageal Adenocarcinoma and Causes of Mortality After Radiofrequency Ablation of Barrett's Esophagus.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) is commonly used to treat Barrett's esophagus (BE). We assessed the incidence of esophageal adenocarcinoma (EAC) after RFA, factors associated with the development of EAC, and EAC-specific and all-cause mortality. METHODS: We collected data for outcomes of patients who underwent RFA for BE from July 2007 through July 2011 from US multicenter RFA Patient Registry. Patients were followed until July 2014. Kaplan-Meier curves of EAC incidence were stratified by baseline histology. Crude EAC incidence and mortality (all-cause and EAC-specific) were calculated, and adjusted all-cause mortality was assessed. Logistic regression models were constructed to assess predictors of EAC and all-cause mortality. RESULTS: Among 4982 patients, 100 (2%) developed EAC (7.8/1000 person-years [PY]) and 9 patients (0.2%) died of EAC (0.7/1000 PY) in a mean 2.7 ± 1.6 years. The incidence of EAC in nondysplastic BE was 0.5/1000 PY. Overall, 157 patients (3%) died during follow-up (all-cause mortality, 11.2/1000 PY). On multivariate logistic regression, baseline BE length (odds ratio, 1.1/ cm) and baseline histology (odds ratios, 5.8 and 50.3 for low-grade dysplasia and high-grade dysplasia [HGD] respectively) predicted EAC incidence. Among 9 EAC deaths, 6 (67%) had baseline HGD, and 3 (33%) had baseline intramucosal EAC. The most common causes of death were cardiovascular (15%) and extraesophageal cancers (15%). No deaths were associated with RFA. CONCLUSIONS: Based on analysis of a multicenter registry of patients who underwent RFA of BE, less than 1% died from EAC. The incidence of EAC was markedly lower in this study than in other studies of disease progression, with the greatest absolute benefit observed in patients with HGD.

Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects.

Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo-fetal death was observed more often in the rabbit. Discordance across species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (i.e. embryo-fetal death, growth retardation, and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone.

Number of Ribs Resected is Associated with Respiratory Complications Following Lobectomy with en bloc Chest Wall Resection.

PURPOSE: Pulmonary lobectomy with en bloc chest wall resection is a common strategy for treating lung cancers invading the chest wall. We hypothesized a direct relationship exists between number of ribs resected and postoperative respiratory complications. METHODS: An institutional database was queried for patients with non-small cell lung cancer that underwent lobectomy with en bloc chest wall resection between 2003 and 2014. Propensity matching was used to identify a cohort of patients who underwent lobectomy via thoracotomy without chest wall resection. Patients were propensity matched on age, gender, smoking history, FEV1, and DLCO. The relationship between number of ribs resected and postoperative respiratory complications (bronchoscopy, re-intubation, pneumonia, or tracheostomy) was examined. RESULTS: Sixty-eight patients (34 chest wall resections; 34 without chest wall resection) were divided into 3 cohorts: cohort A = 0 ribs resected (n = 34), cohort B = 1-3 ribs resected (n = 24), and cohort C = 4-6 ribs resected (n = 10). Patient demographics were similar between cohorts. The 90-day mortality rate was 2.9 % (2/68) and did not vary between cohorts. On multivariate analysis, having 1-3 ribs resected (OR 19.29, 95 % CI (1.33, 280.72); p = 0.03), 4-6 ribs resected [OR 26.66, (1.48, 481.86); p = 0.03), and a lower DLCO (OR 0.91, (0.84, 0.99); p = 0.02) were associated with postoperative respiratory complications. CONCLUSIONS: In patients undergoing lobectomy with en bloc chest wall resection for non-small cell lung cancer, the number of ribs resected is directly associated with incidence of postoperative respiratory complications.

Micro-CT imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report.

During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventional skeletal evaluations; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology.

Durability and predictors of successful radiofrequency ablation for Barrett's esophagus.

BACKGROUND & AIMS: After radiofrequency ablation (RFA), patients may experience recurrence of Barrett's esophagus (BE) after complete eradication of intestinal metaplasia (CEIM). Rates and predictors of recurrence after successful eradication have been poorly described. METHODS: We used the US RFA Registry, a nationwide registry of BE patients receiving RFA, to determine rates and factors that predicted recurrence of intestinal metaplasia (IM). We assessed recurrence by Kaplan-Meier analysis for the overall cohort and by worst pretreatment histology. Characteristics associated with recurrence were included in a logistic regression model to identify independent predictors. RESULTS: Among 5521 patients, 3728 had biopsies 12 months or more after initiation of RFA. Of these, 3169 (85%) achieved CEIM, and 1634 (30%) met inclusion criteria. The average follow-up period was 2.4 years after CEIM. IM recurred in 334 (20%) and was nondysplastic or indefinite for dysplasia in 86% (287 of 334); the average length of recurrent BE was 0.6 cm. In Kaplan-Meier analysis, more advanced pretreatment histology was associated with an increased yearly recurrence rate. Compared with patients without recurrence, patients with recurrence were more likely, based on bivariate analysis, to be older, have longer BE segments, be non-Caucasian, have dysplastic BE before treatment, and require more treatment sessions. In multivariate analysis, the likelihood for recurrence was associated with increasing age and BE length, and non-Caucasian race. CONCLUSIONS: BE recurred in 20% of patients followed up for an average of 2.4 years after CEIM. Most recurrences were short segments and were nondysplastic or indefinite for dysplasia. Older age, non-Caucasian race, and increasing length of BE length were all risk factors. These risk factors should be considered when planning post-RFA surveillance intervals.

Developmental toxicity study of lersivirine in mice.

Lersivirine is a second-generation nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of HIV-1. An embryo-fetal developmental toxicity study was performed to evaluate the maternal and developmental toxicity of lersivirine in pregnant mice. Mated Crl:CD1(ICR) mice were administered 0, 150, 350, and 500 mg/kg lersivirine once daily by oral gavage on gestation days 6 to 17, followed by cesarean section on gestation day 18. The first 2 days of dosing for the high-dose group were done at 250 mg/kg to allow induction of hepatic metabolizing enzymes, after which the dose was increased to 500 mg/kg/day. This dosing paradigm allowed for maintenance of exposure in the high-dose group despite the considerable autoinduction that occurs in rodents following lersivirine treatment. Lersivirine did not cause an increase in external, visceral, or skeletal malformations. Intrauterine growth retardation, demonstrated by reduced fetal body weights and increased variations associated with delayed skeletal ossification, was noted at 350 and 500 mg/kg/day. The results of these studies indicate that lersivirine is not teratogenic in mice.

Tissue distribution of anidulafungin in neonatal rats.

Anidulafungin, an echinocandin, is currently approved for treatment of fungal infections in adults. There is a high unmet medical need for treatment of fungal infections in neonatal patients, who may be at higher risk of infections involving bone, brain, and heart tissues. This in vivo preclinical study investigated anidulafungin distribution in plasma, bone, brain, and heart tissues in neonatal rats. Postnatal day (PND) 4 and PND 8 Fischer (F344/DuCrl) rats were dosed subcutaneously once with anidulafungin (10 mg/kg) or once daily for 5 days (PND 4-8). Plasma and tissue samples were collected and anidulafungin levels were measured by liquid chromatography-tandem mass spectrometry. The mean plasma Cmax and AUC0-24 values were consistent with single-dose plasma pharmacokinetics (dose normalized) reported previously for adult rats. Observed bone concentrations were similar to plasma concentrations regardless of dosing duration, with bone-to-plasma concentration ratios of approximately 1.0. Heart concentrations were higher than plasma, with heart to plasma concentration ratios of 1.3- to 1.8-fold. Brain concentrations were low after single dose, with brain-to-plasma concentration ratio of approximately 0.23, but increased to approximately 0.71 after 5 days of dosing. Tissue concentrations were nearly identical after single-dose administration in both PND 4 and PND 8 animals, indicating that anidulafungin does not appear to differentially distribute in this period in neonatal rats. In conclusion, anidulafungin distributes to bone, brain, and heart tissues of neonatal rats; such results are supportive of further investigation of efficacy against infections involving bone, brain, and heart tissues.

Non-clinical safety assessment and toxicokinetics of voriconazole and anidulafungin in the juvenile rat: a combination study design in support of a Paediatric Investigation Plan.

Anidulafungin and voriconazole are potent antifungal agents that may provide a powerful therapeutic option over current therapies when coadministered. A non-clinical combination toxicity study was required as part of the voriconazole Paediatric Investigation Plan. Rats received anidulafungin or voriconazole alone or in combination once daily from postnatal day (PND) 21-56 with a recovery period to PND 84. Doses used were based upon the approximate adult rat no observed adverse-effect level (NOAEL). Transient and reversible reductions in bodyweight, haematology, serum chemistry, liver weight and minimal liver changes were associated with anidulafungin. Voriconazole caused an increase in gamma-glutamyltransferase in female rats only. No increased toxicity was observed with the combination. Toxicokinetics were determined using a validated dual-analyte bioanalytical method. Systemic exposure at juvenile rat NOAELs was comparable to that found with adult rats in previous studies. There were no drug-drug interactions affecting exposure of either drug. Juvenile rats were not more sensitive to each drug dosed alone compared with adult rat data on the single drugs. No novel, additive or synergistic toxicities were noted with the combination in juvenile rats. This study will support future studies of the combination of voriconazole and anidulafungin in children with invasive fungal infection.

Increasing accrual in cancer clinical trials with a focus on minority enrollment: The William Beaumont Hospital Community Clinical Oncology Program Experience.

BACKGROUND: The authors reviewed changes in accrual to cancer clinical trials over the last 2 decades at their institution with a focus on minority participation after the implementation of a community clinical oncology program (CCOP) and an aggressive, education-orientated minority outreach program (MOP). METHODS: Data on patient enrollment in clinical trials for the years 1988 to 2010 was obtained from the William Beaumont Hospital (WBH) Cancer Clinical Trials Office. The type and number of cancers diagnosed and treated during the same period were obtained from the WBH tumor registry data. The MOP was initiated in the fall of 2003 with a focus on culture-specific cancer education. RESULTS: With the development of the CCOP, clinical trials accrual increased significantly by 10-fold (P = .001). The primary service area for the CCOP consistently averaged an 85% to 90% Caucasian population. During the same period, the minority population for the service area remained stable between 8.8% and 10% and did not change significantly. From 1999 to 2004, the WBH tumor registry data demonstrated that minorities represented 8.6% of cancers registered, whereas the average yearly minority enrollment from 2002 to 2004 was 5.4%. After initiation of the MOP, minority accrual doubled to 11% by 2010 with stable minority demographics. CONCLUSIONS: The current findings support the importance of a CCOP in supporting the accrual of patients to national clinical trials and increasing access to state-of-the art research. These data also strongly support focusing additional energy and educational efforts on targeting minority representation in clinical trials.

Juvenile toxicity assessment of anidulafungin in rats: an example of navigating case-by-case study design through scientific and regulatory challenges.

BACKGROUND: Anidulafungin, an echinocandin antifungal marketed for adult use, is being considered for use in pediatric populations, including neonates. The evolution of the nonclinical pediatric safety strategy for anidulafungin serves as an example of case-by-case negotiation through the European Medicines Agency pediatric investigation plan process, resulting in an acceptable juvenile rat toxicity study. METHODS: Study design challenges included animal selection, route, dose, age, and duration of dosing in relation to brain maturity, and appropriate study endpoints. The definitive study consisted of subcutaneous dosing at 0, 3, 10, and 30 mg/kg/day from postnatal day 4 to 62 (preterm infant to adulthood) with a 5-week recovery period. Study endpoints evaluated the potential for increased juvenile sensitivity to liver toxicity (seen in adults) and for novel toxicities in the central nervous system. RESULTS: Anidulafungin-related effects included slightly reduced body weight, increased liver weight, and a mild decrease in red blood cell mass with increased reticulocyte count. There was no liver pathology and in the posttreatment phase there were no effects on neurological function. Following recovery, effects on body weight, hematology, and liver weight were reversing or reversed. CONCLUSIONS: Therefore, the juvenile rat no-adverse-effect-level was 30 mg/kg/day. Exposures at this dose are similar to those achieved at the adult rat no-adverse-effect-level, suggesting that the juvenile rat is no more sensitive to anidulafungin than the adult rat. In conclusion, dialog and negotiation between the sponsor and the European Medicines Agency allowed for successful execution of a nonclinical safety strategy that enabled further clinical investigation of anidulafungin in pediatric populations.

Consensus for Thoracoscopic Left Upper Lobectomy-Essential Components and Targets for Simulation.

BACKGROUND: Simulation-based training is a valuable component of cardiothoracic surgical education. Effective curriculum development requires consensus on procedural components and focused attention on specific learning objectives. Through use of a Delphi process, we established consensus on the steps of video-assisted thoracoscopic surgery (VATS) left upper lobectomy and identified targets for simulation. METHODS: Experienced thoracic surgeons were randomly selected for participation. Surgeons voted and commented on the necessity of individual steps comprising VATS left upper lobectomy. Steps with greater than 80% of participants in agreement of their necessity were determined to have established "consensus." Participants voted on the physical or cognitive complexity of each, or both, and chose steps most amenable to focused simulation. RESULTS: Thirty thoracic surgeons responded and joined in the voting process. Twenty operative steps were identified, with surgeons reaching consensus on the necessity of 19. Components deemed most difficult and amenable to simulation included those related to dissection and division of the bronchus, artery, and vein. CONCLUSIONS: Through a Delphi process, surgeons with a variety of practice patterns can achieve consensus on the operative steps of left upper lobectomy and agreement on those most appropriate for simulation. This information can be implemented in the development of targeted simulation for VATS lobectomy.

Embryo-fetal developmental toxicity of figitumumab, an anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody, in cynomolgus monkeys.

BACKGROUND: Insulin-like growth factor (IGF) signaling has been linked to tumor cell survival and tumorigenesis. The anti-IGF-1 receptor monoclonal antibody, figitumumab, has been developed as an anti-cancer therapeutic. As part of the safety evaluation, an embryo-fetal developmental toxicity study was conducted in the cynomolgus monkey. METHODS: Figitumumab was administered once weekly intravenously at a dose of 5, 15, or 100 mg/kg during the period of major organogenesis (gestation days [GD] 20-48) with scheduled cesarean section around GD100. Maternal endpoints included clinical observations, food consumption, body weights, hematology, placental weights, toxicokinetics, and immunogenicity. Fetal evaluations included viability; body weights; external, visceral, and skeletal examination (and measurements); drug exposure; and immunogenicity. RESULTS: There was a dose-dependent increase in embryo-fetal loss in the presence of decreased maternal food consumption and slight reduction in body weight. Figitumumab-related embryo-fetal developmental toxicity was observed as growth retardation exhibited by reduced fetal body weights at all doses with corresponding developmental delays in morphology. Treatment-related fetal structural malformations were also observed in the mid- and high-dose groups. CONCLUSIONS: Maternal figitumumab dosing only during the period of organogenesis was associated with pregnancy loss and fetal growth deficits; both considered consistent with inhibition of IGF signaling. Fetal malformations were also observed, and were considered secondary to altered placental function and/or reduced fetal growth; however, direct inhibition of IGF signaling in the conceptus cannot be ruled out. This appears to be the first report of treatment-related fetal anomalies with a monoclonal antibody when administered only during the period of major organogenesis.

Complete anterior-posterior minimally invasive thoracoscopic robotic-assisted and posterior tubular approach for resection of thoracic dumbbell tumor.

Thoracic dumbbell tumors are relatively uncommon neoplasms that arise from the neurogenic elements. Surgical resection can be challenging as the tumor involves both the spinal canal and thoracic cavity. Historically, thoracotomy and laminectomy were utilized for the resection of these tumors. Although single-stage removal of such tumors has been described recently, there is no prior description of a total minimally invasive single-stage resection of a thoracic dumbbell ganglioneuroma. The current report describes a completely minimally invasive surgical resection for such a tumor performed using the posterior minimally invasive tubular approach to resect the intraspinal component with ligation of the T2 nerve root in conjunction with robotic-assisted thoracoscopic resection of the extraforaminal, intrathoracic component of the tumor. This report illustrates the safety and utility of a completely minimally invasive endoscopic resection of a thoracic dumbbell tumor that can potentially obviate the morbidity associated with open surgical resections for such tumors.

Understanding barriers to lung cancer screening in primary care.

BACKGROUND: Low-dose computed tomography (LDCT) scan for lung cancer screening is underutilized. Studies suggest that up to one-third of providers do not know the current lung cancer screening guidelines. Thus, identifying the barriers to utilization of LDCT scan is essential. METHODS: Primary care providers in three different healthcare settings in the United States were surveyed to assess provider knowledge of LDCT scan screening criteria, lung cancer screening practices, and barriers to the utilization of LDCT scan screening. Fisher's Exact, Chi-Squared, and Kruskal-Wallis tests were used to compare provider responses. Multivariable logistic regression was used to test the association between provider characteristics and the likelihood of utilizing LDCT scan for lung cancer screening. RESULTS: The survey was sent to 614 providers, with a 15.7% response rate. Overall, 29.2% of providers report never ordering LDCT scans for eligible patients. Providers practicing at a community or academic hospital more frequently order LDCT scans than those practicing at a safety net hospital. Academic- and community-based providers received a significantly higher mean knowledge score than safety net-based providers [academic 6.84 (SD 1.33), community 6.72 (SD 1.46), safety net 5.85 (SD 1.38); P<0.01]. Overall, only 6.2% of respondents correctly identified all six Centers for Medicare and Medicaid Services eligibility criteria when challenged with three incorrect criteria. Common barriers to utilization of LDCT scan included failure of the electronic medical record (EMR) to notify providers of eligible patients (54.7%), patient refusal (37%), perceived high false-positive rate leading to unnecessary procedures (18.9%), provider time constraints (16.8%), and lack of insurance coverage (13.7%). CONCLUSIONS: Provider knowledge of lung cancer screening guidelines varies, perhaps contributing to underutilization of LDCT scan for lung cancer screening. Improved provider education at safety net hospitals and improving EMR-based best practice alerts may improve the rate of lung cancer screening.

Clinicopathologic analysis of microscopic extension in lung adenocarcinoma: defining clinical target volume for radiotherapy.

PURPOSE: To determine the gross tumor volume (GTV) to clinical target volume margin for non-small-cell lung cancer treatment planning. METHODS: A total of 35 patients with Stage T1N0 adenocarcinoma underwent wedge resection plus immediate lobectomy. The gross tumor size and microscopic extension distance beyond the gross tumor were measured. The nuclear grade and percentage of bronchoalveolar features were analyzed for association with microscopic extension. The gross tumor dimensions were measured on a computed tomography (CT) scan (lung and mediastinal windows) and compared with the pathologic dimensions. The potential coverage of microscopic extension for two different lung stereotactic radiotherapy regimens was evaluated. RESULTS: The mean microscopic extension distance beyond the gross tumor was 7.2 mm and varied according to grade (10.1, 7.0, and 3.5 mm for Grade 1 to 3, respectively, p < 0.01). The 90th percentile for microscopic extension was 12.0 mm (13.0, 9.7, and 4.4 mm for Grade 1 to 3, respectively). The CT lung windows correlated better with the pathologic size than did the mediastinal windows (gross pathologic size overestimated by a mean of 5.8 mm; composite size [gross plus microscopic extension] underestimated by a mean of 1.2 mm). For a GTV contoured on the CT lung windows, the margin required to cover microscopic extension for 90% of the cases would be 9 mm (9, 7, and 4 mm for Grade 1 to 3, respectively). The potential microscopic extension dosimetric coverage (55 Gy) varied substantially between the stereotactic radiotherapy schedules. CONCLUSION: For lung adenocarcinomas, the GTV should be contoured using CT lung windows. Although a GTV based on the CT lung windows would underestimate the gross tumor size plus microscopic extension by only 1.2 mm for the average case, the clinical target volume expansion required to cover the microscopic extension in 90% of cases could be as large as 9 mm, although considerably smaller for high-grade tumors. Fractionation significantly affects the dosimetric coverage of microscopic extension.

Serum Biomarkers May Prognosticate Recurrence in Node-Negative, Non-Small Cell Lung Cancers Less Than 4 Centimeters.

BACKGROUND: A significant proportion of patients who undergo lung resection for less than 4 cm non-small cell lung cancer (NSCLC) will die of disease recurrence within 5 years. The ability to identify patients at greatest risk for recurrence may help individualize treatment and surveillance regimens and improve outcomes. We hypothesized that a serum-based biomarker panel could help risk stratify patients with node-negative NSCLC less than 4 cm for recurrence after lung resection. METHODS: An institutional biorepository of more than 1,800 cases was used to identify patients with resected, node-negative NSCLC less than 4 cm in size. Clinical and radiographic data were collected. Preoperative serum specimens were evaluated in a blinded manner for 47 biomarkers that sampled biological processes associated with metastatic progression, including angiogenesis, energy metabolism, apoptosis, and inflammation. Receiver-operating characteristics curves and log rank tests were used to evaluate individual biomarkers with respect to recurrence, followed by random forest analysis to generate and cross validate a multiple-analyte panel to risk stratify patients for recurrence. RESULTS: The cohort included 123 patients with a median follow-up of 58.2 months; 23 patients had recurrences. A seven-analyte panel consisting of human epididymis protein 4, insulinlike growth factor-binding protein 1, beta-human chorionic gonadotropin, follistatin, prolactin, angiopoietin-2, and hepatocyte growth factor optimally identified patients with disease recurrence with a cross-validated specificity of 91%, sensitivity of 22%, negative predictive value of 83%, positive predictive value of 36%, and accuracy of 78%, providing an area under the receiver-operating characteristics curve of 0.70. CONCLUSIONS: Serum-based biomarkers may be useful for risk stratifying patients with node-negative NSCLC less than 4 cm for recurrence after lung resection.