Faculty Bibliography

Conventional treatments are not adequate for the majority of lung cancer patients. Conditionally replicating adenoviruses (CRAds) represent a promising new modality for the treatment of neoplastic diseases, including non-small cell lung cancer. Specifically, following cellular infection, the virus replicates selectively in the infected tumor cells and kills the cells by cytolysis. Next, the progeny virions infect a new population of surrounding target cells, replicate again and eradicate the infected tumor cells while leaving normal cells unaffected. However, to date, there have been two main limitations to successful clinical application of these CRAd agents; i.e. poor infectivity and poor tumor specificity. Here we report the construction of a CRAd agent, CRAd-CXCR4.RGD, in which the adenovirus E1 gene is driven by a tumor-specific CXCR4 promoter and the viral infectivity is enhanced by a capsid modification, RGD4C. This agent CRAd-CXCR4.RGD, as expected, improved both of the viral infectivity and tumor specificity as evaluated in an established lung tumor cell line and in primary tumor tissue from multiple patients. As an added benefit, the activity of the CXCR4 promoter was low in human liver as compared to three other promoters regularly used for targeting tumors. In addition, this agent has the potential of targeting multiple other tumor cell types. From these data, the CRAd-CXCR4.RGD appears to be a promising novel CRAd agent for lung cancer targeting with low host toxicity.

The stage of non-small cell lung cancer (NSCLC) determines that the treatment strategy and proper staging lead to improved survival. Integrated positron emission tomography/computerized tomography (CT) scan provides more accurate staging and better targets for biopsy than traditional methods such as CT scans of the chest and upper abdomen, bone scans, and magnetic resonance imaging scans. Integrated positron emission tomography/CT is the best initial test for an indeterminate pulmonary nodule that is 8 mm or greater; for the noninvasive staging of patients with NSCLC, it is the only test that produces a quantitative assessment of an NSCLC's virulence or biologic aggressiveness in a particular patient and is the best tool for restaging patients after radiation and and/or chemotherapy. Finally, its use as a tool for postoperative surveillance is under study.

BACKGROUND: The ideal time to repeat a 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) scan to accurately restage a patient after neoadjuvant chemoradiotherapy for non-small cell lung cancer (NSCLC) is unknown. METHODS: This retrospective cohort study used a prospective database of patients who underwent neoadjuvant chemoradiotherapy, an initial and repeat FDG-PET/CT scan, and pathologic staging. The accuracy of the clinical stage suggested by repeat FDG-PET/CT was compared with the actual pathologic stage. Receiver operating characteristic (ROC) curves were used to determine when it was most accurate to repeat the FDG-PET/CT after the completion of the last dose of chest radiation. RESULTS: The study comprised 109 patients, 93 of whom patients received 60 Gy (or higher) of radiotherapy. The median time to restaging was 24 days (range, 2 to 88 days). ROC analysis showed the optimal time to restage patients was 26 days for overall staging (area under the curve [AUC], 0.88) and 29 days for N2 restaging (AUC, 0.82). The accuracy for overall stage was 3 (38%) of 8 for patients for less than 10 days, 28 (72%) of 39 for patients between 11 and 20 days, 42 (88%) of 49 between 21 and 30 days, and 8 (62%) of 13 for 31 days or more. The accuracy for these time intervals for the restaging of the N2 lymph node was 50% (1/2) 40% (2/5), 88% (7/8), and 100% (3/3), respectively. CONCLUSIONS: The optimal time to perform a repeat FDG-PET/CT scan after the completion of neoadjuvant chemotherapy and high-dose radiotherapy to maximize its accuracy for restaging patients with NSCLC is about 1 month after the last dose of radiation.

BACKGROUND: The purpose of this study was to assess the efficacy of the different techniques of lymph node biopsies in patients with suspected metastatic non-small cell lung cancer (NSCLC) in the subaortic (station #5) and paraaortic (station #6) lymph nodes. METHODS: This was a retrospective cohort study conducted of a prospective database of patients between January 2003 and June 2006 with suspected N2 disease only in the #5 or #6 lymph nodes, or both. All patients had integrated 2-deoxy-2-fluoro-D-glucose positron emission tomography/computed tomography, and nodal biopsy or thoracotomy, or both, with complete thoracic lymphadenectomy. RESULTS: There were 112 patients with clinically suspected N2 disease in lymph node stations #5 or #6, or both. The primary tumor was in the left upper lobe in 98 (88%) and in the left lower lobe in 14 (13%), and 58 had pathologic N2 disease in #5 or #6 lymph node stations only. Mediastinoscopy, used in all patients found, unsuspected N3 disease in 4 patients (3.6%) and N2 (#4L) disease in 12 (11%). Endoscopic ultrasound with fine needle aspiration (EUS-FNA), implemented in 62 patients (56%), correctly identified 41 patients (66%). Left single-incision video-assisted thoracic surgery (VATS) was used in 39 patients and was correct in 100%. Of the 58 patients, 53 (91%) completed neoadjuvant chemoradiotherapy, followed by resection, and their 5-year survival was 64%. CONCLUSIONS: EUS-FNA is less accurate for the #5 and #6 lymph node stations than left VATS. We prefer left VATS over the Chamberlain procedure for patients with suspected nodal metastases isolated only to #5 or #6 stations, and if positive, we prefer neoadjuvant therapy. The advantage of neoadjuvant therapy followed by resection compared with resection followed by adjuvant therapy remains controversial; and hence, the role for biopsy of these nodes is also controversial.