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MicroRNAs are post-transcriptional regulators of gene expression with tissue-specific expression profiles. Dysregulation of microRNAs has been shown to play a role in carcinogenesis. Although progress has been made in the diagnosis and treatment of many cancers, pancreatic cancer remains an intractable public health problem, causing 6.58% of cancer deaths despite making up less than 3% of cancer diagnoses in the United States. No screening, diagnostic or imaging techniques exist with the sensitivity to detect pancreatic cancer in its early, operable stages. Risk factors include numerous inherited syndromes, diabetes mellitus, and hepatitis C virus infection. Here we review the literature regarding dysregulation of microRNA expression in native pancreas, pancreatic ductal adenocarcinoma (the dominant form of pancreatic cancer), and its risk factors to illuminate the biology and progression of this disease. We explore promising evidence for the use of microRNAs as prognostic and diagnostic tools, and discuss emerging reports on microRNA therapeutics.

Lung cancer remains the leading cause of cancer-related mortality worldwide. The propensity for metastasis to the central nervous system (CNS) is a major clinical hurdle contributing to the low five-year survival rate of advanced disease. CNS metastases significantly outnumber primary brain tumors and carry a dismal prognosis in part due to the inability of therapeutic agents to cross the blood brain barrier. Standard treatment using radiation has been largely ineffective in improving mortality, suggesting the need for new agents targeting the critical metastatic drivers. The genetic and molecular events governing CNS metastasis from the lung are poorly understood at this time. This review highlights genetic events associated with CNS dissemination from the lung and molecular mechanisms associated with CNS metastasis. In vivo model systems that faithfully recapitulate escape from the lung and colonization of the CNS are described as tools for understanding the metastatic phenotype and for testing new therapeutic agents. A deeper understanding of the mechanisms of lung cancer metastasis to the CNS is needed to elucidate novel therapeutic avenues towards the improvement of the mortality associated with advanced stage lung cancer.

We describe three confirmed cases of squamous cell carcinoma (SCC) of the lung with metastasis to the gastrointestinal (GI) tract, with two having epidermal growth factor receptor (EGFR) exon 19 deletions in all available specimens. One of these patients received EGFR tyrosine kinase directed therapy for a brief period with some symptom relief. Consideration of EGFR exon 19 mutation testing in SCC of the lung, particularly for those with GI tract metastasis, may identify this potentially drug-targetable entity.

Background Non-invasive characterization of a tumor's molecular features could enhance treatment management. Quantitative computed tomography (CT) based texture analysis (QTA) has been used to derive tumor heterogeneity information, and the appearance of the tumors has been shown to relate to patient outcome in non-small cell lung cancer (NSCLC) and other cancers. In this study, we examined the potential of tumoral QTA to differentiate K-ras mutant from pan-wildtype tumors and its prognostic potential using baseline pre-treatment non-contrast CT imaging in NSCLC. Methods Tumor DNA from patients with early-stage NSCLC was analyzed on the LungCarta Panel. Cases with a K-ras mutation or pan-wildtype for 26 oncogenes and tumor suppressor genes were selected for QTA. QTA was applied to regions of interest in the primary tumor. Non-parametric Mann Whitney test assessed the ability of the QTA, clinical and patient characteristics to differentiate between K-ras mutation from pan-wildtype. A recursive decision tree was developed to determine whether the differentiation of K-ras mutant from pan-wildtype tumors could be improved by sequential application of QTA parameters. Kaplan-Meier survival analysis assessed the ability of these markers to predict survival. Results QTA was applied to 48 cases identified, 27 had a K-ras mutation and 21 cases were pan-wildtype. Positive skewness and lower kurtosis were significantly associated with the presence of a K-ras mutation. A five node decision tree had sensitivity, specificity, and accuracy values (95% CI) of 96.3% (78.1–100), 81.0% (50.5–97.4), and 89.6% (72.9–97.0); respectively. Kurtosis was a significant predictor of OS and DFS, with a lower kurtosis value linked with poorer survival. Conclusions Lower kurtosis and positive skewness are significantly associated with K-ras mutations. A QTA feature such as kurtosis is prognostic for OS and DFS. Non-invasive QTA can differentiate the presence of K-ras mutation from pan-wildtype NSCLC and is associated with patient survival.

Introduction: Non-invasive methods that can characterize a tumor's molecular features could enhance treatment management. Recently, researchers have investigated tumor heterogeneity on imaging to assess how grainy or coarse a tumor seems to be in the search for oncologic prognostic markers and mechanisms. Quantitative computed tomography (CT) based texture analysis (qCTTA) has been used to derive tumor heterogeneity information, and the appearance of the tumors has been shown to relate to patient outcome in esophageal, colorectal, lung and head and neck cancer and treatment response in metastatic renal cell cancer. Furthermore histological assessment has demonstrated an association between qCTTA and hypoxia and angiogenesis in lung cancer and very recently qCTTA in combination with CT blood-flow and PET glucose-uptake identified an imaging signature for K-ras mutation status in colorectal cancer. In this study, we examined the predictive potential of tumoral qCTTA to differentiate K-ras mutant and K-ras wildtype tumors and its prognostic potential using non-contrast CT imaging in non-small cell lung cancer (NSCLC). Methods: Formalin-fixed, paraffin-embedded (FFPE) lung tumor tissues from patients with stage I and II NSCLC, diagnosed between 2001 and 2007 and undergoing definitive surgical resection were obtained. Tumor DNA was extracted and analyzed on the LungCarta Panel that interrogates 213 somatic mutations in 26 oncogenes and/or tumor suppressor genes. Cases with a K-ras mutation or pan-wildtype for all 26 oncogenes and tumor suppressor genes were selected for imaging analysis. Baseline pre-treatment non-contrast CT images that were performed as part of standard of care were retrieved for qCTTA. qCTTA was applied to regions of interest in the primary tumor and comprised an image filtration-histogram technique; where the filtration technique enhanced features of different sizes based on the spatial scale filter (SSF) value varying from fine (2mm in radius), medium (3-5mm in radius) and coarse (6mm in radius) followed by quantification of the histogram parameters – kurtosis (a measure of peakedness and tailedness) and skewness (a measure of asymmetry of the histogram). Non-parametric Mann Whitney test assessed the ability of the qCTTA, clinical and patient characteristics to differentiate between K-ras mutation from pan-wildtype whereas Kaplan-Meier survival analysis assessed the ability of these markers including K-ras mutation to predict survival. Results: 48 cases were identified and qCTTA was applied to pre-treatment non-contrast CT. The median age was 70.4 years (range 45.1-85.1), 29 were men, and 46 had a smoking history. There were 33 adenocarcinomas, 10 squamous cell carcinomas, and 5 other NSCLC. Stages IA, IB, IIA, and IIB were 16, 21, 6, and 5; respectively. At least 33 patients did not receive adjuvant chemotherapy. There were 27 cases with K-ras mutation and 21 cases that were pan-wildtype. As of the last follow-up, 18 had confirmed disease relapse, including 5 with brain metastasis, and 22 were deceased. The median disease-free survival (DFS) was 39.7 months and median overall survival (OS) was 45.0 months. Positive skewness (p=0.031) and lower kurtosis (p=0.009) were significantly associated with the presence of a K-ras mutation (n=27 vs. 21 pan-wildtype). Kurtosis was a significant predictor of OS (p=0.009) and DFS (p=0.04) with a lower kurtosis value linked with poorer survival. As expected, patients with disease relapse and older age had significantly inferior OS and DFS, whereas adenocarcinomas (n=30) had inferior DFS vs. non-adenocarcinomas (n=14)(p=0.031). In line with other published data in early-stage NSCLC, K-ras was not associated with OS or DFS. Conclusions: The outcomes in this dataset are in sync with published poor clinical prognostic features in early-stage NSCLC. Lower kurtosis (which may reflect increased number of highlighted features and intensity variation in highlighted features) and positive skewness (which may reflect bright highlighted features surrounded by darker background or lower density areas) are significantly associated with K-ras mutations. These features may suggest more tumoral necrosis and these may be due to the hostile microenvironment within a K-ras driven tumor. A qCTTA feature such as lower kurtosis is prognostic for poorer OS and DFS. Non-invasive qCTTA can differentiate the presence of K-ras mutation from pan-wildtype NSCLC and is associated with patient survival. Citation Format: Glen J. Weiss, Balaji Ganeshan, Kenneth A. Miles, David A. Campbell, Philip Y. Cheung, Samuel Frank, Ronald L. Korn. Noninvasive image texture analysis differentiates K-ras mutation from pan-wildtype NSCLC and is prognostic. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A34.