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Introduction: Xenograft models of epithelial malignancies potentially have greater correlation with clinical end points. We implanted 153 primary non–small cell lung carcinomas into non-obese diabetic-severe combined immunodeficient mice to develop primary lung cancer xenografts. Sixty-three xenografts formed. However, in 19 implantations, tumors consisted of a lymphocyte proliferation without a carcinoma component. We further characterized these lymphomas to determine clinicopathological features associated with their formation. Methods: Lymphomas were investigated morphologically and by silver in situ hybridization to determine their species of origin. Characterization both of the xenograft lymphomas and the primary NSCLCs from which they were derived included immunohistochemistry for lymphoma markers and Epstein Barr virus Early RNA (EBER) by in situ hybridization. DNA was profiled using the MassARRAY platform; EML4-ALK translocations and lymphocyte infiltration were assessed in the primary tumor. Lymphoma formation was correlated with patient and primary tumor characteristics and survival. Results: The lymphocytic tumors were EBER positive, human diffuse large B-cell lymphomas (DLBCLs). Significantly more DLBCLs that formed in mice arose in primary lung adenocarcinomas and in epithelial growth factor receptor mutant never smokers. DLBCL formation was not associated with the degree of tumor-infiltrating lymphocytes or EBER-positive lymphocytes in the primary NSCLCs. Patients whose tumors developed DLBCL had longer disease-free survival compared with patients whose tumors formed epithelial xenografts (hazard ratio: 0.44; 95% confidence interval: 0.18 -1.06, Wald p = 0.07), regardless of genotype. Conclusion: We hypothesize that mechanisms involved in the active suppression of viral antigens may also be involved in the suppression of tumor antigens, and may have resulted in the observed favorable clinical outcome.

Background: Dermatofibrosarcoma protuberans (DFSP) is a relatively uncommon spindle cell tumor of the skin. It is locally aggressive and can be a therapeutic challenge. There are case reports of partial response of DFSP to the tyrosine kinase inhibitor STI571 (Imatinib), despite the reported negativity of the tumor cells for CD117. At least one publication reported focal CD117 positivity of DFSP cells, and we would like to clarify the issue. Cellular dermatofibroma (CDF) can mimic DFSP, but typical cases are easily differentiated from DFSP by their staining pattern for CD34 and factor 13a. We also report our experience with CD117 staining of typical CDFs. Methods: Thirty-seven cases of clear-cut DFSP and 13 cases of clear-cut CDF were retrieved from the archives of Sunnybrook Health Sciences Center between 2000 and 2005. Results: All DFSPs were CD34 (+), factor 13a (−) and CD117 (−). All CDFs were factor 13a (+), CD34 (−) and CD117 (−). Conclusions: Our study on a relatively large number of cases confirms the negativity of DFSP and CDF for CD117. Therefore, if adjuvant therapy is attempted with drugs such as STI571 (Imatinib), the eligibility of patients should not be based on immunohistochemical assessment of CD117 expression.

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers., National Institutes of Health (U.S.) (Grant U24 CA126561), National Institutes of Health (U.S.) (Grant U24 CA126551), National Institutes of Health (U.S.) (Grant U24 CA126554), National Institutes of Health (U.S.) (Grant U24 CA126543), National Institutes of Health (U.S.) (Grant U24 CA126546), National Institutes of Health (U.S.) (Grant U24 CA126563), National Institutes of Health (U.S.) (Grant U24 CA126544), National Institutes of Health (U.S.) (Grant U24 CA143845), National Institutes of Health (U.S.) (Grant U24 CA143858), National Institutes of Health (U.S.) (Grant U24 CA144025), National Institutes of Health (U.S.) (Grant U24 CA143882), National Institutes of Health (U.S.) (Grant U24 CA143866), National Institutes of Health (U.S.) (Grant U24 CA143867), National Institutes of Health (U.S.) (Grant U24 CA143848), National Institutes of Health (U.S.) (Grant U24 CA143840), National Institutes of Health (U.S.) (Grant U24 CA143835), National Institutes of Health (U.S.) (Grant U24 CA143799), National Institutes of Health (U.S.) (Grant U24 CA143883), National Institutes of Health (U.S.) (Grant U24 CA143843), National Institutes of Health (U.S.) (Grant U54 HG003067), National Institutes of Health (U.S.) (Grant U54 HG003079), National Institutes of Health (U.S.) (Grant U54 HG003273)

The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic and pharmacodynamic markers with clinical outcome. In addition, a novel pharmacodynamic marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. Epidermal growth factor receptor (EGFR) expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pretreatment, prior to erlotinib dosing, and during the administration of both drugs. In addition, positron emission tomography–computed tomography scans and pharmacokinetic assessments were done. Eleven patients received a total of 57 cycles (median, 5; range, 1–10). Only four patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of ≥4 cycles. Pharmacokinetic analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in seven patients. Other pharmacodynamic markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib. Mol Cancer Ther; 9(3); 751–60

Fluorescence emission and diffuse reflectance spectra of freshly excised cervical tissue were studied with two specially designed contact probes. The objective of the study was to reach a better understanding of the relationship between spectroscopic measurements and cervical tissue morphology. Tissue samples from loop electro-surgical excision and hysterectomy specimens were measured within 20 to 90 minutes of excision. Emission spectra with 337 nm excitation, and reflectance spectra were collected at wavelengths between 370 and 720 nm from different tissue sites. Hematoxylin-eosin stained slides of the measured zones were obtained and compared to the spectra. In one experiment, a contact probe with a central illumination fiber and two concentric rings of detection fibers (radii 0.1 and 1 mm), was placed in contact with the epithelium and used to measure spectra from ectocervix and endocervix. The influence of 5% acetic acid on fluorescence and reflectance spectra was also investigated. In another experiment, a single 100-micron fiber probe was placed perpendicular to a cut edge of tissue and scanned to measure spectra in depth. Depth scans were made over various areas of the cervix