Effective Educational Approaches to Training Physicians About Lung Cancer Screening.

In 2013, the U.S. Preventative Services Task Force recommended low-dose computed tomography (LDCT) for lung cancer screening (LCS) after a national trial demonstrated a 20% reduction in lung cancer mortality with LDCT. Implementation of LCS employing LDCT depends heavily on physician education regarding multiple factors, including eligibility criteria, potential benefits and harms, and shared decision-making. To date, there are no studies of educational approaches for teaching physicians about LCS. This study aims to assess the feasibility and effectiveness of implementing an interactive, group-based learning (GBL) curriculum to teach physicians about LCS. A prospective study was conducted at two nearby institutions from 2017 to 2019 comparing GBL with a lecture format as measured by total knowledge about LCS, acceptability of the educational format, and ease of implementation. We surveyed participants regarding total knowledge and format acceptance. Results were compared to determine whether GBL is an effective and feasible educational strategy for LDCT and LCS education. Residents and faculty participating in GBL demonstrated greater total knowledge compared with residents and faculty participating in the lecture format. Participants in both cohorts preferred a mix of GBL and lecture formats. All participants believed that GBL facilitates implementation of LCS better than lecture-based learning. GBL is an effective and feasible approach for educating physicians about LCS, though it is more time- and resource-intensive than a lecture approach. However, healthcare providers believe GBL will facilitate implementation of LCS more than lectures.

The University of Pennsylvania Medical School Commencement of 1889: Aequanimitas and the Agnew Clinic.

Academic commencements ceremonies usually do not result in memorable occasions and once ended usually are forgotten. Not so for the University of Pennsylvania's School of Medicine commencement on May 1,1889, which was marked by an address by William Osler, the retirement of the renowned Professor of Surgery, D. Hayes Agnew, and the presentation to the University of Thomas Eakins' remarkable masterpiece, "The Agnew Clinic." Osler had been on the faculty of the University for 5 years and in his keynote address, Aequanimitas, he laid out 2 elements, imperturbability and equanimity, that he stated would "make or mar" the lives of the students he was addressing. His words and message that day have continued to resonate for medical students and many others up to the present day. Osler ended his address on a more somber note, seemingly surprising the assembled, by announcing his imminent departure from the University. He would soon be one of the 4 founders of the Johns Hopkins Hospital along with fellow Penn faculty member, Howard Kelly. Osler was not the only one on the verge of leaving as this commencement also marked the end of the career of D. Hayes Agnew. To honor him on this occasion of his retirement the 3 classes of medical students had commissioned Eakins to paint a portrait of their revered professor, which was presented on this commencement day and accepted by Trustee Dr S. Weir Mitchell on behalf of the University. The day was indeed one to be remembered.

Adherence to annual lung cancer screening with low-dose CT scan in a diverse population.

PURPOSE: Our aim was to develop a novel approach for lung cancer screening among a diverse population that integrates the Centers for Medicare and Medicaid Services (CMS) recommended components including shared decision making (SDM), low-dose CT (LDCT), reporting of results in a standardized format, smoking cessation, and arrangement of follow-up care. METHODS: Between October of 2015 and March of 2018, we enrolled patients, gathered data on demographics, delivery of SDM, reporting of LDCT results using Lung-RADS, discussion of results, and smoking cessation counseling. We measured adherence to follow-up care, cancer diagnosis, cancer treatment, and smoking cessation at 2 years after initial LDCT. RESULTS: We enrolled 505 patients who were 57% African American, 30% Caucasian, 13% Hispanic, < 1% Asian, and 61% were active smokers. All participants participated in SDM, 88.1% used a decision aid, and 96.1% proceeded with LDCT. Of 496 completing LDCT, all received a discussion about results and follow-up recommendations. Overall, 12.9% had Lung-RADS 3 or 4, and 3.2% were diagnosed with lung cancer resulting in a false-positive rate of 10.7%. All 48 patients with positive screens but no cancer diagnosis adhered to follow-up care at 1 year, but only 35.4% adhered to recommended follow-up care at 2 years. The annual follow-up for patients with negative lung cancer screening results (Lung-RADS 1 and 2) was only 23.7% after one year and 2.8% after 2 years. All active smokers received smoking cessation counseling, but only 11% quit smoking. CONCLUSION: The findings show that an integrated lung cancer screening program can be safely implemented in a diverse population, but adherence to annual screening is poor.

Aiding shared decision making in lung cancer screening: two decision tools.

BACKGROUND: Shared decision making (SDM) preceding lung cancer screening is important for populations that are underrepresented in lung cancer screening trials. Current evidence-based guidelines; however, do not address personal risk and outcomes in underrepresented populations. This study compared two SDM decision aids (Option Grids and Shouldiscreen.com) for SDM efficacy, decision regret and knowledge. METHODS: We conducted a prospective trial of lung cancer screening patients (N = 237) randomized to SDM with Option Grids or Shouldiscreen.com. To evaluate the SDM process after lung cancer screening, patients answered two questionnaires: CollaboRATE and Decision Regret. Patients also completed a questionnaire to test their knowledge of lung cancer screening. RESULTS: Patients were predominantly African American (61.6%), though multiple races, varying education levels and equal genders were represented. Patients in both Option Grids and Shouldiscreen.com groups reported favorable SDM experiences (P = 0.60) and equivalent knowledge about lung cancer screening (P = 0.43). Patients using Shouldiscreen.com had less knowledge regarding the potential complications of subsequent testing (P = 0.02). Shouldiscreen.com patients had increased regret regarding their decision to pursue screening (P = 0.02). CONCLUSIONS: Option Grids and Shouldiscreen.com both facilitated a meaningful SDM process. However, Option Grids patients experienced decreased decision regret and enhanced knowledge of the potential complications of screening.

Examining Gender Differences in Lung Cancer Screening.

It is unknown if gender influences outcome of lung cancer screening with Low Dose CT (LDCT), especially with frequent and continued underrepresentation of women in clinical trials. We examined a balanced cohort of men and women with the hypothesis that there would be no difference in participation or results between men and women undergoing lung cancer screening. In an urban, academic medical center, we prospectively collected data on patients referred for lung cancer screening from October 2015 to August 2018. We studied gender, age, ethnicity, level of education and smoking history. We measured results of LDCT using Lung-RADS reporting system. 546 patients underwent LDCT between October 2015 and August 2018. 279 (51%) were female and 267 (49%) were males. Age, education status or smoking patterns did not significantly differ between females and males There was a significant difference between males and females in the distribution of LDCT results (p = 0.05). 81 females and 105 males were diagnosed with Lung-RADS 1; 99 females and 92 males with Lung-RADS 2; 15 females and 8 males with Lung-RADS 3; 19 females and 11 males with Lung-RADS 4. Overall, 10 females (3.5%) and 3 males (1.1%) were diagnosed with lung cancer (risk difference 2.4, 95% CI-0.0006-0.05, p = 0.09). Women are often underrepresented in clinical trials. Preliminary results from our lung cancer screening program demonstrate equal participation and equal benefit from the screening program. Long term data is needed to study survival benefit.

An Enhanced Shared Decision Making Model to Address Willingness and Ability to Undergo Lung Cancer Screening and Follow-Up Treatment in Minority Underserved Populations.

Failure to address willingness and ability to undergo lung cancer treatment before lung cancer screening could cause patients unnecessary anxiety, cost and care. We employed an enhanced shared decision making (SDM) model to address willingness and ability to undergo lung cancer screening of low dose CT (LDCT) scanning. We hypothesized that enhanced SDM was feasible and did not discourage patients from undergoing lung cancer screening. We performed a prospective study of patients referred for lung cancer screening. We measured adherence to the LCS protocol, including consent to discuss lung cancer treatment if cancer is found and direct questions to patients about willingness and ability to undergo lung cancer treatment. We measured race, gender, adherence to the consent process and questions regarding willingness and ability to undergo lung cancer treatment and subsequent uptake of LDCT. All 190 patients have a documented SDM visit addressing the risks and benefits of lung cancer screening and consented to discuss lung cancer treatment if lung cancer is diagnosed. One hundred and seventy-nine (179) of 190 (94%) answered yes to being willing and able to undergo lung cancer treatment. One hundred and eighty-seven (187) patients underwent LDCT (98.4%). Discussion about willingness and ability to undergo lung cancer treatment should be an essential component of a SDM discussion prior to LDCT. This study demonstrated that an enhanced SDM experience is feasible in a clinical setting. Furthermore, patients proceeded with LDCT following the enhanced SDM process.

Warming barium sulfate improves esophageal leak detection in pig model.

BACKGROUND: Barium esophagograms have poor sensitivity in detecting leaks. We hypothesized that heating barium would decrease viscosity, facilitate extravasation, and enhance its sensitivity in detecting esophageal leaks. METHODS: We characterized the viscosity of barium at increasing temperatures. We measured the radiopacity of barium at 25°C and 50°C. We determined the smallest diameter defect in esophagus that barium can detect by perforating a porcine esophageal segment with angiocatheters of various diameters, injecting barium at 25°C, and observing extravasation of contrast. We repeated this with barium heated to 30°C, 40°C, 50°C, and 70°C. To determine the ability of barium to detect a staple line leak, we perforated a stapled esophageal segment by air insufflation, injected barium at different temperatures, and monitored extravasation. We used Visipaque, a water-soluble contrast agent, for comparison in all experiments. RESULTS: The viscosity of barium decreased with increasing temperature. The radiopacity of barium did not change with increasing temperature and was higher than that of Visipaque (P < 0.001). The size of the smallest detectable leak decreased from 2.1 mm with barium at 25°C to 1.3 mm at 40°C and 1.1 mm with Visipaque (P < 0.0001). The sensitivity of staple line leak detection increased from 0% for barium at 25°C to 80% (P = 0.02) with barium at 40°C. There was no significant difference in sensitivity between barium at 40°C and Visipaque. CONCLUSIONS: Barium warmed to 40°C offers the best sensitivity of esophageal leak detection without compromising radiopacity. Barium at 40°C may be the optimum choice for swallow study to detect esophageal leaks.

Changes in age, stage distribution, and survival of patients with esophageal adenocarcinoma over three decades in the United States.

BACKGROUND: Our aim was to evaluate the changes in age, stage distribution, and overall survival (OS) of patients with esophageal adenocarcinoma (EAC) over time. METHODS: Patients from the Surveillance, Epidemiology, and End Results (SEER) database aged ≥ 20 with invasive EAC, diagnosed from 1973-2003 were reviewed. Survival follow-up ended in 2006. RESULTS: There were 11,620 patients; 6580 (57%) aged ≥ 65. The stage distribution was 22%, 35%, and 43% for localized, regional, and distant metastasis for patients aged <65, and 33%, 33%, and 34% for patients aged ≥ 65. The number of patients ≥ 65 years with localized stage increased over time. Three-year OS for localized, regional, and distant disease increased from 19%, 10%, and 1% in 1973-1976, to 34%, 13%, and 2% in 1987-1991, and to 45%, 25%, and 4% in 2002-2003 (P < 0.001). A sub-analysis of 5475 patients from 1988-2002 showed better survival for patients with esophagectomy for all stages. Three-year OS for 2074 patients with esophagectomy improved every 5 years from 1988-2002 (39%, 43% to 54%, P < 0.001). Stratified by stage, year and esophagectomy status, patients aged <65 had better survival compared to patients aged ≥ 65 (P < 0.001). CONCLUSIONS: There has been a substantial improvement in overall survival among patients with invasive EAC over the last 3 decades. Patients receiving esophagectomy had longer survival. Survival with esophagectomy improved in each time period. Although younger EAC patients were diagnosed at more advanced stages over time, they had better survival.

Increased proteolysis, myosin depletion, and atrophic AKT-FOXO signaling in human diaphragm disuse.

RATIONALE: Patients on mechanical ventilation who exhibit diaphragm inactivity for a prolonged time (case subjects) develop decreases in diaphragm force-generating capacity accompanied by diaphragm myofiber atrophy. OBJECTIVES: Our objectives were to test the hypotheses that increased proteolysis by the ubiquitin-proteasome pathway, decreases in myosin heavy chain (MyHC) levels, and atrophic AKT-FOXO signaling play major roles in eliciting these pathological changes associated with diaphragm disuse. METHODS: Biopsy specimens were obtained from the costal diaphragms of 18 case subjects before harvest (cases) and compared with intraoperative specimens from the diaphragms of 11 patients undergoing surgery for benign lesions or localized lung cancer (control subjects). Case subjects had diaphragm inactivity and underwent mechanical ventilation for 18 to 72 hours, whereas this state in controls was limited to 2 to 4 hours. MEASUREMENTS AND MAIN RESULTS: With respect to proteolysis in cytoplasm fractions, case diaphragms exhibited greater levels of ubiquitinated-protein conjugates, increased activity of the 26S proteasome, and decreased levels of MyHCs and α-actin. With respect to atrophic signaling in nuclear fractions, case diaphragms exhibited decreases in phosphorylated AKT, phosphorylated FOXO1, increased binding to consensus DNA sequence for Atrogin-1 and MuRF-1, and increased supershift of DNA-FOXO1 complexes with specific antibodies against FOXO1, as well as increased Atrogin-1 and MuRF-1 transcripts in whole myofiber lysates. CONCLUSIONS: Our findings suggest that increased activity of the ubiquitin-proteasome pathway, marked decreases in MyHCs, and atrophic AKT-FOXO signaling play important roles in eliciting the myofiber atrophy and decreases in diaphragm force generation associated with prolonged human diaphragm disuse.

Disparities in Health Care Delivery Systems.

Racial disparities in health care systems exist in all phases of health care delivery. The Affordable Care Act has been unable to completely mitigate disparities in health care as the root cause (ie, socioeconomic inequality) remains unaddressed. Uninsured status, lack of transportation, high costs, health literacy, provider unavailability, lack of trust in the health system, and implicit bias block minority populations from obtaining deserved quality care. With the COVID-19 crisis, increased sensitivity and development of innovative approaches to provide accessibly and quality health care are necessary.

Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans.

BACKGROUND: The combination of complete diaphragm inactivity and mechanical ventilation (for more than 18 hours) elicits disuse atrophy of myofibers in animals. We hypothesized that the same may also occur in the human diaphragm. METHODS: We obtained biopsy specimens from the costal diaphragms of 14 brain-dead organ donors before organ harvest (case subjects) and compared them with intraoperative biopsy specimens from the diaphragms of 8 patients who were undergoing surgery for either benign lesions or localized lung cancer (control subjects). Case subjects had diaphragmatic inactivity and underwent mechanical ventilation for 18 to 69 hours; among control subjects diaphragmatic inactivity and mechanical ventilation were limited to 2 to 3 hours. We carried out histologic, biochemical, and gene-expression studies on these specimens. RESULTS: As compared with diaphragm-biopsy specimens from controls, specimens from case subjects showed decreased cross-sectional areas of slow-twitch and fast-twitch fibers of 57% (P=0.001) and 53% (P=0.01), respectively, decreased glutathione concentration of 23% (P=0.01), increased active caspase-3 expression of 100% (P=0.05), a 200% higher ratio of atrogin-1 messenger RNA (mRNA) transcripts to MBD4 (a housekeeping gene) (P=0.002), and a 590% higher ratio of MuRF-1 mRNA transcripts to MBD4 (P=0.001). CONCLUSIONS: The combination of 18 to 69 hours of complete diaphragmatic inactivity and mechanical ventilation results in marked atrophy of human diaphragm myofibers. These findings are consistent with increased diaphragmatic proteolysis during inactivity.

Prevention of surgical resident attrition by a novel selection strategy.

OBJECTIVE(S): We modified the resident selection strategy in an attempt to reduce resident attrition (RA). SUMMARY BACKGROUND DATA: Despite implementation of the Accreditation Council for Graduate Medical Education work rules, lifestyle and generational priorities have fostered a persistent and relatively high attrition rate for surgical trainees. METHODS: An independent external review of residents who left the training program and a detailed analysis of the resident selection strategy were performed by an organizational management expert. Modifications implemented in 2005 (the intervention) included standardization of the screening and interview format. Applicants were required to submit a 500 words essay related to stress management, organizational skills, future aspirations, and prioritization abilities. Their responses formed the basis of an extended, personalized, and structured interview script. Candidate characteristics and RA were compared for the 5 years before and after the intervention, using Fisher exact test or chi2. RESULTS: Age, sex, birthplace, medical school ranking, step 1 score, and American Board of Surgey In-Training Examination performance were not significantly different between the selection strategy groups. Risk factors for RA included ABSITE performance and gender. Resident performance and subsequent RA were significantly affected by the resident selection strategy. CONCLUSIONS: RA was dramatically reduced following the intervention. A custom designed process to identify candidates most likely to succeed substantially improved resident retention in a demanding academic training program.

Thymic Neuroendocrine Tumors and Thymic Carcinoma: Demographics, Treatment, and Survival.

OBJECTIVE: Although rare, thymic neuroendocrine tumors (TNET) and thymic carcinoma (TC) are the most common thymic nonthymomatous malignancies; their survival outcomes have not been thoroughly compared. We analyzed the clinical, treatment, and survival characteristics of TNET and TC. METHODS: We retrospectively identified patients with a histologic diagnosis of TNET or TC in the National Cancer Database (2004 to 2015). Exclusion criteria were age <18 years and unstaged tumors. Descriptive statistics, survival analysis, and multivariable Cox regression analyses were used in elucidating associations. RESULTS: One thousand four hundred eighty-nine patients were included (TNET: 19.8%). Patients with TNET were significantly younger (57 vs 62.5 years), more likely to be male (70.5% vs 60.0%), and have localized tumors (45.4% vs 32.3%). Patients with TC more frequently underwent chemotherapy (56.1% vs 34.9%), radiation (56.9% vs 39.3%), and trimodality therapy (21.3% vs 11.5%), while resection rates were similar (55.3% vs 58.3%). The 5-year survival was 62% for TNET and 52% for TC, but comparable following multivariable adjustment. Age, stage, and Charlson-Deyo score were negative predictors of survival, while surgery and trimodality therapy were positive predictors. On subanalysis, adjuvant radiation therapy (ART) improved the survival of margin-positive tumors and was an independent predictor of survival for both tumor types (hazard ratio = 0.5). CONCLUSIONS: Our analysis of the largest series of TNET and TC showed a survival rate surpassing 50% at 5 years. These outcomes seem to be influenced by surgical resection and ART. Standardized staging and surgical protocols including lymph node sampling are still warranted to better elucidate the treatment algorithm of these tumors.

Transforming growth factor-beta receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers.

PURPOSE: Adoptive cellular immunotherapy is a promising approach to eradicate established tumors. However, a significant hurdle in the success of cellular immunotherapy involves recently identified mechanisms of immune suppression on cytotoxic T cells at the effector phase. Transforming growth factor-beta (TGF-beta) is one of the most important of these immunosuppressive factors because it affects both T-cell and macrophage functions. We thus hypothesized that systemic blockade of TGF-beta signaling combined with adoptive T-cell transfer would enhance the effectiveness of the therapy. EXPERIMENTAL DESIGN: Flank tumors were generated in mice using the chicken ovalbumin-expressing thymoma cell line, EG7. Splenocytes from transgenic OT-1 mice (whose CD8 T cells recognize an immunodominant peptide in chicken ovalbumin) were activated in vitro and adoptively transferred into mice bearing large tumors in the presence or absence of an orally available TGF-beta receptor-I kinase blocker (SM16). RESULTS: We observed markedly smaller tumors in the group receiving the combination of SM16 chow and adoptive transfer. Additional investigation revealed that TGF-beta receptor blockade increased the persistence of adoptively transferred T cells in the spleen and lymph nodes, increased numbers of adoptively transferred T cells within tumors, increased activation of these infiltrating T cells, and altered the tumor microenvironment with a significant increase in tumor necrosis factor-alpha and decrease in arginase mRNA expression. CONCLUSIONS: We found that systemic blockade of TGF-beta receptor activity augmented the antitumor activity of adoptively transferred T cells and may thus be a useful adjunct in future clinical trials.

Tumor suppressor functions of ARLTS1 in lung cancers.

ARLTS1 is a newly characterized tumor suppressor gene located at chromosome 13q14.3 and involved in the pathogenesis of various types of tumors: two single-nucleotide polymorphisms, one of them responsible for protein truncation, were found statistically associated with familial malignancies, whereas DNA hypermethylation and genomic deletions have been identified as a mechanism of ARLTS1 down-regulation in sporadic cancers. We found that in a large portion of lung carcinomas (37%) and in all analyzed lung cancer cell lines, ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After its restoration by adenoviral transduction, ARLTS1-negative A549 and H1299 cells underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the ability of A549 and H1299 to form tumors in nude mice. Finally, we identified approximately 650 transcripts differentially expressed after restoration of ARLTS1 expression in A549 cells, suggesting that various pathways involved in cell survival, proliferation, signaling, and development mediate the effects of wild-type ARLTS1 in a lung cancer system.

Postoperative mortality after esophagectomy for cancer: development of a preoperative risk prediction model.

BACKGROUND: Surgical resection for the treatment of esophageal cancer remains a high-risk procedure. To develop a model to predict risk of postoperative death, we sought to identify factors associated with postoperative mortality for Medicare patients undergoing esophagectomy for cancer. METHODS: We evaluated patients in the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare database who underwent esophagectomy for esophageal cancer from 1997 to 2003. Variables evaluated were patient age, race, marital status, sex, tumor stage, Charlson score, and hospital volume. Hospital volume was evaluated in tertiles of even volume groups (low, < .67 cases a year; medium, .68 to 2.33 cases a year; high, > 2.33 cases a year). The primary outcome measure was postoperative mortality, defined as death within 30 days of esophagectomy or death during the hospitalization in which the primary surgical procedure was performed. In-hospital deaths more than 30 days after esophagectomy were included in the outcomes to more accurately estimate the true mortality of this procedure. Multivariable logistic regression analyses were performed to evaluate the relationship between patient and provider characteristics and postoperative mortality. Finally, characteristics identified by the regression analysis were used to generate a simplified, clinically applicable model predicting risk of postoperative mortality in the Medicare population. RESULTS: A total of 1172 patients underwent esophageal cancer surgery during this study period. Overall postoperative mortality was 14%. Multivariable logistic regression demonstrated that age, Charlson score, and hospital volume were statistically significant predictors of postoperative mortality. The other variables such as race, martial status, sex, and disease stage were not found to be significant. The odds of postoperative mortality at low-volume hospitals were almost twice those at a high-volume hospital. Age greater than 80 increased odds of mortality almost twofold. Similarly, Charlson scores of > or = 2 resulted in more than a 1.5-fold risk of postoperative mortality. Our prediction model using these variables accurately stratified postoperative mortality for this population. CONCLUSIONS: Postoperative mortality (30-day and in-hospital) remains high after esophagectomy. Age, Charlson score, and hospital volume were identified as independent predictors of postoperative mortality. A simple risk prediction model that uses preoperative clinical data accurately predicted patient postoperative mortality for this SEER-Medicare population.

Extended transcervical thymectomy in the treatment of myasthenia gravis.

The ideal operative technique for thymectomy in myasthenia gravis remains controversial. Most surgeons perform thymectomy via median sternotomy, some supplementing this with an even more extensive mediastinal and cervical dissection designed to remove all areas of possible ectopic thymic tissue. We and others have advocated a transcervical approach that is less morbid and costly than sternotomy approaches. The transcervical approach allows a complete extracapsular thymic resection, but it does not address all areas of potential ectopic thymic tissue. We have published our experience with 151 extended transcervical thymectomies (TCT). At mean follow-up of 53 months (complete follow-up in 97%), Kaplan-Meier estimates of complete stable remission were 33% and 35% at 3 and 6 years. If one includes patients who became asymptomatic but remained on low dose, single-drug immunosuppression as complete remissions (CRs), then the CR rates were 43% and 45% at 3 and 6 years. Longer term (mean 83 months) follow-up of the earliest 84 patients in the series showed preserved CR rates. On multivariate analysis, only preoperative Osserman Class (group mean 2.3) was significantly associated with improved CR rate. These results were obtained with a major operative complication rate of 0.7% and minor complication rate of 6.6%, and nearly every operation was performed without the need for overnight hospital admission. We believe that these response rates following TCT are sufficiently similar to those following transsternal techniques of thymectomy to allow us to recommend this less morbid and less costly operation as an eminently reasonable choice in the surgical treatment of myasthenia gravis.

Surgical treatment of thymic epithelial neoplasms.

Resection continues to be the mainstay of treatment for epithelial lesions of the thymus. This has never been in doubt for encapsulated stage I and II lesions, but we recently have come to a greater appreciation of the role of preoperative therapy for locally advanced lesions, particularly stage III disease. For any lesion that presents in the anterior mediastinum and on CT scan does not appear to be eminently resectable, a biopsy should be performed to rule out lymphoma after serum germ cell markers have been obtained to rule out the rare primary mediastinal or metastatic germ cell tumor.

A 10-gene classifier for distinguishing head and neck squamous cell carcinoma and lung squamous cell carcinoma.

PURPOSE: The risk of developing metastatic squamous cell carcinoma for patients with head and neck squamous cell carcinoma (HNSCC) is very high. Because these patients are often heavy tobacco users, they are also at risk for developing a second primary cancer, with squamous cell carcinoma of the lung (LSCC) being the most common. The distinction between a lung metastasis and a primary LSCC is currently based on certain clinical and histologic criteria, although the accuracy of this approach remains in question. EXPERIMENTAL DESIGN: Gene expression patterns derived from 28 patients with HNSCC or LSCC from a single center were analyzed using penalized discriminant analysis. Validation was done on previously published data for 134 total subjects from four independent Affymetrix data sets. RESULTS: We identified a panel of 10 genes (CXCL13, COL6A2, SFTPB, KRT14, TSPYL5, TMP3, KLK10, MMP1, GAS1, and MYH2) that accurately distinguished these two tumor types. This 10-gene classifier was validated on 122 subjects derived from four independent data sets and an average accuracy of 96% was shown. Gene expression values were validated by quantitative reverse transcription-PCR derived on 12 independent samples (seven HNSCC and five LSCC). The 10-gene classifier was also used to determine the site of origin of 12 lung lesions from patients with prior HNSCC. CONCLUSIONS: The results suggest that penalized discriminant analysis using these 10 genes will be highly accurate in determining the origin of squamous cell carcinomas in the lungs of patients with previous head and neck malignancies.