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Pulmonary adenofibroma (PAF) is a rare neoplasm that may be related to solitary fibrous tumor (SFT). A subset of PAFs harbor the NAB2-STAT6 fusion that is typical of SFT, but a significant proportion do not. Their distinction is clinically important as SFTs can potentially have an aggressive clinical course, while there has been no report of a PAF behaving in a malignant fashion. We report a case of a 60-year-old male who developed a SFT and PAF in the same lung. The SFT harbored a NAB2-STAT6 fusion, while the PAF did not have any identifiable fusion. This case represents the first instance of a single patient with both of these tumors occurring simultaneously in the same lung.

Prostate cancer is the most common non-cutaneous malignancy diagnosed in men. When it metastasizes, it usually spreads to bone and/or lymph nodes. A handful of cases have described prostatic metastases to the lung; however, this is usually in the setting of existing bone lesions [1]. Here we describe a unique case in which a patient was found to have both metastatic prostate cancer to the lung and a primary lung cancer in the absence of any other evidence of extra-prostatic disease.

A 49-year-old woman with a medical history of essential hypertension presented to the ED with severe pain in the left superior chest and dull aching pain in the upper flank, lasting for the last 2 days.

Wire-localized excision of nonpalpable breast cancer is imprecise, resulting in positive margins 25-30% of the time.Patients underwent preoperative supine magnetic resonance imaging (MRI). A radiologist outlined the tumor edges on consecutive images, creating a three-dimensional (3D) view of its location. Using 3D printing, a bra-like plastic form (the Breast Cancer Locator [BCL]) was fabricated, with features that allowed a surgeon to (1) mark the edges of the tumor on the breast surface; (2) inject blue dye into the breast 1 cm from the tumor edges; and (3) place a wire in the tumor at the time of surgery.Nineteen patients with palpable cancers underwent partial mastectomy after placement of surgical cues using patient-specific BCLs. The cues were in place in5 min and no adverse events occurred. The BCL accurately localized 18/19 cancers. In the 18 accurately localized cases, all 68 blue-dye injections were outside of the tumor edges. Median distance from the blue-dye center to the pathologic tumor edge was 1.4 cm, while distance from the blue dye to the tumor edge was5 mm in 4% of injections, 0.5-2.0 cm in 72% of injections, and2 cm in 24% of injections. Median distance from the tumor center to the BCL-localized wire and to the clip placed at the time of diagnosis was similar (0.49 vs. 0.73 cm) on specimen mammograms.Information on breast cancer location and shape derived from a supine MRI can be transferred safely and accurately to patients in the operating room using a 3D-printed form.

Many tonsillar tumors present clinically as cervical nodal metastases and the primary tumor is often difficult to find. HPV-driven tonsillar carcinoma begins in the reticulated crypt epithelium, possibly through viral integration. The basement membrane is not complete in the reticulated crypt epithelium, which may enhance the immune function. We examined the reticulated crypt epithelium in a normal case and five neoplastic tonsils with cervical metastasis as the presenting symptom to further investigate whether tonsil carcinoma in-situ exists. Our results suggest that in-situ carcinoma may need to be excluded from the future staging for human papilloma virus associated tonsillar tumors.

The benign mediastinal vascular lesion is an area in medicine with ambiguous terminology and poor interand intra-disciplinary agreement. Lymphangiohemangioma of the mediastinum is a rare, benign entity with few previous reports in the US literature. We present a case of a 55-year-old woman with shortness of breath and chest pain who was found to have an anterior mediastinal mass on imaging. The MRI features favored a mediastinal hemangioma with a differential diagnosis that included thymoma. The multilobulated mass was surgically removed however the left phrenic nerve was sacrificed during the resection. Histologically the lesion consisted of dilated vascular spaces of varying sizes with intra-luminal, calcified phleboliths. A variety of equivocal diagnostic terms were considered for a benign, mediastinal vascular lesion. Subsequent immunohistochemistry (IHC) showed the vessel lining consisted of both vascular and lymphatic endothelium therefore the final diagnosis made was mediastinal lymphangiohemangioma.

Introduction Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) patients predicts response to EGFR tyrosine kinase inhibitors (TKIs). The Idylla™ system (Biocartis, Mechelen, Belgium) is a fully integrated, cartridge-based platform that provides automated sample processing and real-time PCR-based mutation detection in a single-use cartridge. This study evaluated the Idylla™ EGFR Mutation Assay cartridges against next-generation sequencing (NGS) using formalin fixed, paraffin embedded (FFPE) lung cancer tissue samples. Methods Thirty-four FFPE lung adenocarcinoma tissue samples were tested on the Idylla™ system. 21 had at least one mutation in EGFR and 13 had no EGFR mutation as determined by NGS analysis using the Ion AmpliSeq 50-gene Cancer Hotspot Panel v2 (Thermo Fisher Scientific). One 10 ​μm FFPE tissue section was used for each Idylla™ test and all cases met the Idylla™ minimum tumor content requirement (≥10%). Results Idylla™ results were in complete agreement with those obtained by NGS for EGFR mutations targeted by the Idylla™. NGS identified two additional EGFR mutations that are not targeted by the Idylla™ in two samples (E709V and V774M). No EGFR mutations were detected by the Idylla™ in samples determined by NGS as having wild-type EGFR. Conclusion The fully automated Idylla™ system offers rapid and reliable testing for clinically actionable mutations in EGFR directly from FFPE tissue sections. Its simplicity and ease of use compared to other available molecular techniques make it suitable for routine clinical use in a variety of settings.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040 . 1

Maine has among the highest rates of lung cancer in the United States (US). Maine serves as a geographical representation of US rural communities, and their associated health disparities. As the key risks of tobacco use decrease and radon abatement increases, previously obscured environmental exposures may measurably contribute to the attributable risk fraction of lung cancer. To generate hypotheses of novel environmental exposures associated with lung cancer, we investigated if there was non-random spatial distribution of lung cancer in Maine. Case data (n = 14,038) between 1995 and 2006 were obtained from the Maine Cancer Registry. Population data were obtained from the 2000 US Census. We assessed the spatial distribution of lung cancers among white cases by histopathology subtype [non-small cell lung carcinoma (NSCLC): adenocarcinoma (n = 3680), squamous cell (n = 2801) and large cell (n = 1195); and small cell lung carcinoma (SCLC) (n = 1994)], using spatial scan statistic, assuming a discrete Poisson distribution adjusted for age and population density. Because of time-dependent trends in lung cancer differential diagnostic criteria, we repeated our analyses, limiting it to 2002-2006. While SCLC rates were equivalent across the state, we identified discrete regions with elevated rates of adenocarcinoma among females and squamous cell carcinoma among males. Independent of gender, the most striking geospatial observation was elevated large cell lung cancer specifically in one of the poorest counties in the US. A selective spatial distribution of large cell lung cancer has not been previously reported. More research is needed to identify factors inducing large cell carcinoma pathology, and to determine if in rural communities health disparities are associated with increased risk for this diagnosis.

KRAS mutant non-small cell lung cancers (NSCLCs) vary in clinical outcome depending on which specific KRAS mutation is present. Shorter progression free survival has been associated with KRAS variants G12C and G12V. Cell lines with these variants depend to a greater extent on the RAS/RAF/MEK/ERK signaling pathway and become more susceptible to MEK inhibition. Because different KRAS mutations may lead to altered drug sensitivity, we aimed to determine specific KRAS mutation status in a NSCLC patient cohort at our institution. A total of 502 NSCLC samples were screened for somatic mutations using the 50 gene AmpliSeq™ Cancer Hotspot Panel v2 (CHPv2). However only samples positive for variants in the KRAS gene were included in this study. Variants identified in the KRAS genes were curated using publicly available databases. The overall mutation rate in the KRAS gene was 32.7% (164/502). The most common KRAS mutations were G12C (41%), G12V (19%), and G12D (14%) along with less frequent variants. After re-mining our sequencing data, we found that more than a half of our KRAS mutant NSCLC patients could potentially benefit from the addition of a MEK inhibitor such as selumetinib to standard chemotherapeutic agents. Due to mutated KRAS, these patients will likely fail traditional anti-EGFR therapies but be eligible for newer combination therapies.

Purpose: MicroRNA (miRNA) expression profiles improve classification, diagnosis, and prognostic information of malignancies, including lung cancer. This study uncovered unique growth-suppressive miRNAs in lung cancer. Experimental Design: miRNA arrays were done on normal lung tissues and adenocarcinomas from wild-type and proteasome degradation-resistant cyclin E transgenic mice to reveal repressed miRNAs in lung cancer. Real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays validated these findings. Lung cancer cell lines were derived from each transgenic line (designated as ED-1 and ED-2 cells, respectively). Each highlighted miRNA was independently transfected into these cells. Growth-suppressive mechanisms were explored. Expression of a computationally predicted miRNA target was examined. These miRNAs were studied in a paired normal-malignant human lung tissue bank. Results: miR-34c, miR-145, and miR-142-5p were repressed in transgenic lung cancers. Findings were confirmed by real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays. Similar miRNA profiles occurred in human normal versus malignant lung tissues. Individual overexpression of miR-34c, miR-145, and miR-142-5p in ED-1 and ED-2 cells markedly repressed cell growth. Anti-miR cotransfections antagonized this inhibition. The miR-34c target, cyclin E, was repressed by miR-34c transfection and provided a mechanism for observed growth suppression. Conclusions: miR-34c, miR-145, and miR-142-5p were repressed in murine and human lung cancers. Transfection of each miRNA significantly repressed lung cancer cell growth. Thus, these miRNAs were growth suppressive and are proposed to exert antineoplastic effects in the lung.

The distinction between sarcomatoid carcinoma (SC) and bona fide sarcoma can be difficult using conventional immunohistochemical markers. Epithelial-mesenchymal transition (EMT) has been proposed as a histogenetic mechanism for the development of SC. Expression of selected markers of EMT (Twist and Slug) was compared with other markers of epithelial differentiation in SC and spindle cell sarcoma to determine the utility of these antigens in this differential diagnosis. Twenty-seven cases of SC (excluding those of gynecologic origin) were stained by immunohistochemistry for cytokeratins (AE1/AE3, 5D3, CK5/6, and 34betaE12), p63, claudin-1, claudin-7, epithelial cadherin, placental cadherin, epithelial cell adhesion molecule/epithelial-specific antigen, 14-3-3sigma, Twist, and Slug. A comparison group of 21 spindle or pleomorphic spindle cell sarcomas was also studied. Immunohistochemical stains were scored in a semiquantitative manner and subsequent exploratory analyses were performed using logistic regression and chi2 tests. Only cytokeratin AE1/AE3 specifically labeled SC in a statistically significant manner. Other epithelial-specific markers tested did not distinguish SC from sarcoma primarily owing to low sensitivity. However, when positive, immunostains such as CK5/6, membranous epithelial cadherin, and nuclear p63 may aid in the distinction of SC from sarcoma. EMT markers were expressed in most cases of both SC and sarcoma, and were not useful in making a differential diagnosis between these neoplasms.

Purpose: The variant allele of CCND1 G870A encodes a splice variant of the cyclin D1 protein, which possesses an increased half-life. To confirm the phenotypic effect of the variant allele, we examined the immunohistochemical staining pattern of the protein in tumors from a case population of head and neck squamous cell carcinoma (HNSCC) and compared it with the genotype of these individuals. We also examined how this genotype was associated with the risk of HNSCC and if this genotype-phenotype association was related to patient outcome. Experimental Design: In a population-based case-control study of 698 cases and 777 controls, we both genotyped all participants for the CCND1 gene and did immunohistochemical staining of the cyclin D1 protein in the HNSCC tumors. Results: The variant AA genotype was significantly associated with positive immunohistochemical staining (P < 0.02), and this variant genotype was associated with a significantly elevated odds ratio of 1.5 (95% confidence interval, 1.1-2.0) for HNSCC overall, with risk greatest in oral and laryngeal sites. Positive immunohistochemical staining was inversely related to human papillomavirus 16 DNA present in the tumor (P < 0.03). The AA genotype and superpositive immunohistochemical staining for cyclin D1 also had independent and significant effects on patient survival. Conclusions: These results strongly suggest that this splice variant, when present in two copies, is a significant predictor of both the occurrence of HNSCC as well as patient survival after treatment. These data further indicate that this variant protein is an important determinant of individual response to therapy for this disease.

Cyclin E is a critical G 1 -S cell cycle regulator aberrantly expressed in bronchial premalignancy and lung cancer. Cyclin E expression negatively affects lung cancer prognosis. Its role in lung carcinogenesis was explored. Retroviral cyclin E transduction promoted pulmonary epithelial cell growth, and small interfering RNA targeting of cyclin E repressed this growth. Murine transgenic lines were engineered to mimic aberrant cyclin E expression in the lung. Wild-type and proteasome degradation-resistant human cyclin E transgenic lines were independently driven by the human surfactant C (SP-C) promoter. Chromosome instability (CIN), pulmonary dysplasia, sonic hedgehog (Shh) pathway activation, adenocarcinomas, and metastases occurred. Notably, high expression of degradation-resistant cyclin E frequently caused dysplasia and multiple lung adenocarcinomas. Thus, recapitulation of aberrant cyclin E expression as seen in human premalignant and malignant lung lesions reproduces in the mouse frequent features of lung carcinogenesis, including CIN, Shh pathway activation, dysplasia, single or multiple lung cancers, or presence of metastases. This article reports unique mouse lung cancer models that replicate many carcinogenic changes found in patients. These models provide insights into the carcinogenesis process and implicate cyclin E as a therapeutic target in the lung.

BACKGROUND. Negative resection margins are likely the most important prognostic factor for a patient with a head and neck squamous cell carcinoma. Frozen-section evaluation allows a positive margin to be corrected before surgical closure and reconstruction. A final pathology report is later issued after examination of all resected tissues. The accuracy of the final pathology report relies on accuracy in the preceding steps. The current process of margin reporting in head and neck cancer resections was studied to reveal possible waste and error in the system. METHODS. Two hundred pathologists were surveyed about their center's current process of frozen-section margin evaluation. The authors of the current study used the membership log of the North American Society of Head and Neck Pathology and the list of the top 50 US cancer centers according to US News and World Report. The authors analyzed the process of frozen-section procedure using Toyota industry principles of quality improvement. RESULTS. The majority of surgeons send small fragments of tissue from the surgical defect cavity. Many pathologists receive small unoriented tissue fragments. Many resample all or most of the margins for the final pathology report without anatomic orientation from the surgeon. Other pathologists do not sample any margins. CONCLUSIONS. Final margin reporting redundancy and waste is due mainly to lack of anatomic correlation at interdisciplinary hand-offs. Oversampling and undersampling of margins may be occurring, and the accuracy of the final pathology report may be compromised. There is currently no consensus on how to best submit tissue for frozen-section evaluation of head and neck resection margins. Cancer 2006. © 2006 American Cancer Society.

Amyloidosis is a disease entity defined by the presence of extracellular deposits of proteinacious material. These deposits have a characteristic apple-green birefringence with polarized light after staining with Congo red. Amyloid involvement of the tongue is almost universally secondary to systemic disease. The mean survival of patients with a systemic form of amyloidosis is between 5 to 15 months, whereas those with the localized form have an excellent prognosis. This article presents a case of the more unusual localized form. A thorough evaluation, including abdominal fat or rectal biopsy, is essential in every patient to identify any systemic involvement. The absence of systemic amyloidosis offers a much more favorable prognosis and may be treated with simple surgical excision.

Regulatory T lymphocytes (Tregs) are known to have host-immune dampening effects in many tumors and to be associated with increased tumor recurrence. Pharmacologic therapies have been developed to target these cells and hence strengthen the host’s immune system. The FoxP3 gene is a marker of Tregs and can be visualized with immunohistochemistry (IHC). We investigated the presence and pattern of Tregs in non-small-cell lung tumors to determine possible therapeutic targets in lung cancer. We selected archival samples of primary lung carcinoma and benign inflamed lung from 32 surgical resections. We created a tissue array containing duplicate cores from the N1 and N2 nodal stations from 16 of the cases along with paired benign lung and tumor. We used whole-slide analysis for the other 16 cases. We used FoxP3 IHC to visualize Tregs in all lymphoid tissue present and to assess the quantity and pattern within the tissues. All lymphoid tissue contains Tregs, but adenocarcinoma had significantly higher levels than both inflammatory lung controls and squamous carcinomas (p ≤ 0.008). Benign N1 lymph nodes (from patients with lung cancer) showed higher numbers of Tregs for adenocarcinoma versus squamous carcinoma. These findings reveal that Tregs are present in all lung tissues examined, but with significant enrichment in adenocarcinoma. This may lead to a more permissive microenvironment for adenocarcinoma and may explain aggressive patterns of tumor spread for this histology. Lung cancer patients with adenocarcinoma histology may benefit most from Treg-targeted therapy.

Expression of transcription factors that mediate epithelial-mesenchymal transition (EMT), such as Twist and Slug, is correlated with poor prognosis in many tumor types. Selected EMT markers were studied in a series of pancreatic ductal adenocarcinomas (PDAs) and benign pancreatic tissues to determine whether expression levels correlated with diagnosis, histologic grade, or patient outcome.Immunohistochemical stains for Twist, Slug, and N-cadherin were performed using a tissue microarray containing 68 PDAs and 38 samples of normal pancreas or chronic pancreatitis tissues.Twist and Slug were identified in both the nucleus and cytoplasm of benign pancreatic ductal epithelium, chronic pancreatitis, and PDA. Compared with normal ductal epithelium, nuclear levels of Twist are decreased in PDA. None of the other EMT markers showed significant differences in staining indices among the diagnostic groups. There were no correlations between EMT marker expression and histologic grade. Epithelial-mesenchymal transition marker expression was not associated with N-cadherin expression, patient outcome, or duration of survival.Decreased expression of nuclear Twist is observed in malignant pancreatic epithelium. However, use of Twist as a diagnostic marker is precluded because decreased expression is also seen in chronic pancreatitis. None of the markers studied were predictive of patient outcome.

Female A/J mice injected with the carcinogen vinyl carbamate develop atypical adenomatous hyperplasias in lungs 4 weeks after injection with the carcinogen. The number and severity of tumors then increase over time, making these mice a useful model for evaluating potential chemopreventive agents. The rexinoid LG100268 (LG268), a selective ligand for the retinoid X receptor, and the methyl amide of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) both significantly reduced the number, size, and severity of the histopathology of lung tumors in female A/J mice when fed in diet for 14 to 20 weeks. The total tumor burden was 85% to 87% lower in mice fed LG268 and CDDO-MA than in controls, and the percentage of high-grade tumors decreased from 59% in the controls to 25% or 30% with CDDO-MA and LG268. Erlotinib, which is used to treat lung cancer patients and is an inhibitor of the epidermal growth factor receptor, was less effective in this model. Immunohistochemical staining of geminin, a marker of cell cycle progression, was higher in lung sections from control mice than in mice treated with LG268. Because rexinoids and triterpenoids signal through different biological pathways, they should be tested in combination for the prevention of lung cancer. [Mol Cancer Ther 2008;7(5):1251–7]

Purpose: Bexarotene is a rexinoid (selective retinoid X receptor agonist) that affects proliferation, differentiation, and apoptosis in preclinical studies. The relationship between bexarotene levels and biomarker changes in tumor tissues has not been previously studied. Experimental Design: BEAS-2B human bronchial epithelial (HBE) cells, retinoid-resistant BEAS-2B-R1 cells, A427, H226, and H358 lung cancer cells were treated with bexarotene. Proliferation and biomarker expression were assessed. In a proof-of-principle clinical trial, bexarotene tumor tissue levels and intratumoral pharmacodynamic effects were assessed in patients with stages I to II non–small cell lung cancer. Bexarotene (300 mg/m2/day) was administered p.o. for 7 to 9 days before resection. Results: Bexarotene-induced dosage-dependent repression of growth, cyclin D1, cyclin D3, total epidermal growth factor receptor (EGFR), and phospho-EGFR expression in BEAS-2B, BEAS-2B-R1, A427, and H358, but not H226 cells. Twelve patients were enrolled, and 10 were evaluable. Bexarotene treatment was well tolerated. There was nonlinear correlation between plasma and tumor bexarotene concentrations (r2 = 0.77). Biomarker changes in tumors were observed: repression of cyclin D1, total EGFR and proliferation in one case; repression of cyclin D3, total and phospho-EGFR in another. The cases with multiple biomarker changes had high tumor bexarotene (107-159 ng/g). A single biomarker change was detected in one case with low tumor bexarotene. Conclusion: Bexarotene represses proliferation and biomarker expression in responsive, but not resistant HBE and lung cancer cells. Similar biomarker changes occur in lung tumors when therapeutic intratumoral bexarotene levels are achieved. This proof-of-principle trial approach is useful to uncover pharmacodynamic mechanisms in vivo and relate these to intratumoral pharmacokinetic effects.

Although well established as a marker of mesothelial cells, calretinin is also expressed in several other tissue types, including adipose tissue. Accordingly, immunohistochemical staining for calretinin has been described in an increasing number of neoplasms other than mesothelioma. A detailed analysis of calretinin expression in lipogenic tumors has not yet been reported, however. Given the known expression patterns of calretinin in normal tissues, we predicted that calretinin immunoreactivity would be detected in lipoma and the various histologic subtypes of liposarcoma, and that this marker might be of use in the differential diagnosis of selected fatty tumors. A variety of pleomorphic and small round cell sarcomas were studied for comparison. Calretinin immunoreactivity was detected, at least focally, in all 10 samples of normal adipose tissue and in 22 of 23 lipomas or lipoma variants. Staining for calretinin was also positive within the lipogenic component of 28 of 29 liposarcoma variants. Of the 7 dedifferentiated liposarcomas, 3 were focally positive for calretinin. Pleomorphic variants of other sarcomas, including undifferentiated high-grade pleomorphic sarcoma, rhabdomyosarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor also exhibited focal calretinin immunoreactivity in a minority of cases, as did some small round cell sarcomas. These results suggest that calretinin immunoreactivity in normal and neoplastic adipose tissue is more ubiquitous than previously reported and may be a useful, albeit nonspecific marker of lipogenic differentiation. However, its utility in the differential diagnosis of fatty tumors appears limited.

Agammaglobulinemia is the most common primary immunodeficiency, with an incidence of approximately 1 in 250 000 males in the United States. These patients are at risk for frequent recurrent infections, which may become fatal if untreated. Patients have increased susceptibility to encapsulated pyogenic bacteria. Haemophilus influenzae is second only to Streptococcus pneumoniae as the bacteria most frequently implicated in infections in these patients. We present a case involving an adolescent boy with X-linked agammaglobulinemia and H influenzae cervical adenopathy, confirmed twice by culture. We correlate the clinical, microbiologic, and histologic findings. Owing to the severity of infections in this population, surgical intervention is more common than in the immunocompetent population. This description may help the pathologist in considering a differential diagnosis when examining a diagnostic lymph node biopsy in these patients.

Lung cancer is a major cause of death among cancers in the U.S. Environmental exposures to tobacco or radon are considered the two highest risks for lung cancer. Maine is one of the top 15 states with the highest rates of lung cancer in the U.S., with smoking rates that vary from 20–30% across counties. We recently reported on spatial variations in radon exposure. In this study, we investigated if there were spatial regions of excessive lung cancer by gender in Maine, and if these might overlay the high radon exposure regions. Age-adjusted lung cancer incidence rates in Maine were compared to those of the US overall, using NCI SEER and CDC databases. Data for all lung cancer cases in Maine reported during 1995–2006 were obtained from the Maine Cancer Registry. Population data used Base U.S. Census 2000 data. Lung cancer incidence was adjusted for age and population density. We assessed the spatial distribution of lung cancer by subtype, using spatial scan statistic, assuming a discrete Poisson distribution. We did not adjust for race as Maine is 95% white. We also examined spatial variations by pathology sub-types classified as adenocarcinoma, small cell carcinoma, large cell carcinoma. Within Maine, Washington County, which also has the highest smoking rate, reported the highest lung cancer incidence rates [men: 131.7 (110.5,156.2); women: 73 (58.5, 90.5), compared to Maine overall (men: 97.2 (93.9,100.5); women: 66.6 (64.2, 69.1) or the US (men: 84.3 (84.1, 84.5); women: 55.8 (55.6, 55.9)]. Maine is a rural, mostly nonagrarian state, with significant health disparities due to poverty, access to healthcare and geographic isolation. In considering other disadvantaged populations, lung cancer incidence rates for Maine men and women were higher than those reported for U.S. blacks, Hispanics and American Indians. Our results showed small “hotspots” for lung cancer overall with RR greater than 1 for females (RR 1.8, p 0.03) in eastern Washington County, and for males (RR 1.7, p 0.03) in northern Washington County and in the Pittsfield Region, Somerset County. No significant differences were detected in spatial distribution for adenocarcinoma or small cell carcinoma. The most striking geospatial regions with RR greater than 1 were detected for large cell lung cancer in Washington County, one of the poorest counties in the U.S. Women exhibited very high rates (RR 5.3, p 0.002) along the southern coastal region of Washington County while men exhibited very high rates (RR 3.7, p 0.04) within a smaller region in northern coastal Washington county where we have mapped use of pesticide sprays. Published literature linking large cell carcinoma with smoking is ambivalent. Washington County and the Pittsfield Region have air and water radon exposures below 4 pCi. There are no heavy industry or highways that could implicate particulate matter. In conclusion, we found statistically significant spatial regions (p

A135 MicroRNAs (miRNAs) are noncoding small RNAs that regulate gene expression. Expression profiles of miRNAs are useful to improve classification, diagnosis, and prognostic information of specific human malignancies, including lung cancer. We sought to uncover miRNAs preferentially repressed or over-expressed in pre-malignant and malignant lung lesions in recently described transgenic cyclin E mice. These transgenic mice expressed in the lung under control of the human surfactant C promoter wild-type or proteasome degradation-resistant cyclin E species. These mice developed pulmonary dysplasia and adenocarcinoma, recapitulating pre-malignant and malignant lung lesions frequently found in lung cancer patients. Comprehensive miRNA microarray analyses were conducted using independently harvested normal and malignant lung tissues from these transgenic mice. A cluster of miRNAs was preferentially repressed in transgenic lung cancers versus normal lung tissues including: miR-34c, miR-145, miR142-5p, and other miRNAs previously associated with lung carcinogenesis. Expression profiles were independently validated by semi-quantitative and real-time polymerase chain reaction assays. In transgenic mice, single cell expression profiles were studied in pre-malignant and malignant lung lesions by in situ hybridization assays. Concordant results were obtained after analyses of paired normal-malignant human lung tissues representing each histopathologic subtype of non-small cell lung cancer. To address functional roles of repressed miRNAs, novel lung cancer cell lines were derived from murine transgenic wild-type (ED-1 cells) or proteasome-degradation resistant (ED-2 cells) cyclin E expressing lung cancers. ED-1 and ED-2 cells each caused lung adenocarcinomas to form after tail-vein injections into syngeneic FVB mice. Engineered over-expression of each basally repressed miRNA in ED-1 as well as in ED-2 cells markedly (P < 0.001) repressed cell growth. Anti-miR co-transfections antagonized these effects. A mechanism for this growth suppression was found by showing cyclin E, a predicted miR-34c bioinformatic target, was significantly repressed in miR-34c transfectants. Other miRNAs were selected for knock-down in ED-1 and ED-2 cells by virtue of their high basal expression in these cells as well as in murine transgenic lung cancers and human lung cancers versus normal lung tissues. Knock-down of candidate oncogenic miRNAs repressed lung cancer cell growth, which was antagonized by over-expression of the same miRNA. Experiments are underway in miRNA transfected ED-1 cells to assess in vivo tumorigenicity in FVB mice. Taken together, these studies uncovered candidate tumor suppressive and oncogenic miRNAs. We propose these miRNAs are molecular pharmacologic targets for lung cancer therapy and chemoprevention. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A135.

7136 Background: Bexarotene (Targretin) is a selective retinoid X receptor (RXR) agonist that appears to prolong survival in pts with NSCLC. To determine mechanisms of action, preclinical studies and a short-term, proof-of-principle clinical trial were performed. Methods: BEAS-2B immortalized human bronchial epithelial cells were treated with bexarotene and effects on EGFR and cell cycle regulatory proteins were determined by Western analyses. To evaluate bexarotene tissue pharmacokinetic (PK) and pharmacodynamic effects, 12 pts with pathologically confirmed stage I and II NSCLC were enrolled. Subjects were given 300 mg/m2/day of bexarotene orally for 7 to 9 days prior to surgical resection. Resected tumor tissue was evaluated for biomarker expression and tumor tissue bexarotene concentrations. Plasma bexarotene concentrations were measured at the time of resection. Biomarker changes were assessed immunohistochemically comparing pre- and post-treatment tissues by pathologists blinded to the tissue origin ...