Royce F. Calhoun

Survival Comparison of Adenosquamous, Squamous Cell, and Adenocarcinoma of the Lung After Lobectomy

BACKGROUND Primary adenosquamous carcinoma (ASC) of the lung is a rare tumor that may carry a poor prognosis. We examined a national database to see if ASC exhibited distinct clinical behavior from squamous cell (SC) and adenocarcinoma (AC) of the lung. METHODS This is a retrospective study querying the Surveillance, Epidemiology, and End Results database to identify 872 surgical patients diagnosed with ASC, 7888 with SC, and 12,601 with AC of the lung from 1998 to 2002. Analysis characterized clinical variables to determine patterns of presentation and compared survival among the above three histologic groups after lobectomy for stage I and II disease. RESULTS ASC represented 4.1% of the 21,361 patients examined. ASC tended toward right side (56.9%) laterality and upper lobe (60.0%) location. Compared with AC, patients with ASC and SC were more likely to be male (p < 0.0001), and ASC patients had worse histologic grade (p< 0.0001). Survival after lobectomy for stage I and II disease was significantly reduced in ASC and SC compared with AC (p < 0.0001). ASC had a significantly increased hazard ratio of 1.35 and 1.27 relative to AC and SC, respectively. Other significant negative predictors of survival included tumor grade of III and IV, stage II, age, and black ethnicity. CONCLUSIONS This large review demonstrates that ASC is an uncommon tumor with distinct clinical behavior and worse prognosis than AC and SC. Further insight into the molecular profile of ASC is needed to determine the cause of its biologic aggressiveness.

A phase 2 cooperative group adjuvant trial using a biomarker-based decision algorithm in patients with stage i non-small cell lung cancer (SWOG-0720, NCT00792701)

This cooperative group adjuvant phase 2 trial in patients with completely resected stage I non‐small cell lung cancer with tumor diameters measuring ≥ 2 cm was designed to assess the feasibility and preliminary efficacy of assigning patients to therapy or observation using a molecularly based decision algorithm.

Adjuvant chemotherapy of stage I non-small cell lung cancer in North America.

The utility of adjuvant chemotherapy after surgical resection for early-stage non-small cell lung cancer (NSCLC) is now well established. Although a number of randomized clinical trials have demonstrated the efficacy of platinum-based chemotherapy in the overall population treated, subset analysis, excepting Japanese studies, has uniformly shown the greatest efficacy for patients with stage II and III disease and the least benefit for patient with stage I disease. We review data regarding adjuvant therapy of stage I NSCLC from clinical trials performed in North America and Europe. Pertinent trials from Japan are discussed elsewhere in this issue.

Racial disparities on the use of invasive and noninvasive staging in patients with non-small cell lung cancer.

Introduction: Racial disparities have been reported in non-small cell lung cancer (NSCLC) staging and therapeutic outcomes. We investigated whether such disparities exist in the era of modern noninvasive staging modalities, including positron emission tomography scan use. Methods: NSCLC patients from the California Cancer Registry diagnosed between January 1, 1994, and December 31, 2004, were included. The likelihood of obtaining invasive (thoracoscopy, bronchoscopy, and mediastinoscopy) and noninvasive staging procedures (computed tomography, magnetic resonance imaging, and positron emission tomography scans), along with surgical resection, were analyzed using logistic regression adjusted for known confounders. Results: Of 13,762 NSCLC patients, 12,395 with adequate staging information were included. 10,217 patients (82%) were classified as white, 2178 patients (18%) were non-white, and 738 were black patients (6%). No association was seen between race and the use of either noninvasive (odds ratio [OR] = 1.02; p = 0.76) or invasive staging procedures (OR = 0.96; p = 0.44). However, compared with white patients, black patients had a lower likelihood of undergoing surgery, regardless of noninvasive (OR = 0.6; p <0.001) or invasive staging use (OR = 0.63; p = 0.02). There was no survival difference for those who underwent surgery between white and non-white patients, regardless of noninvasive (hazard ratio = 0.95; p = 0.45) or invasive staging (hazard ratio = 1.03; p = 0.79). Conclusions: In contrast to prior published work, we found no difference in rates of both invasive and noninvasive staging between white and non-white patients. However, non-white patients—particularly blacks—were less likely to receive surgery. The reason for the apparent difference in surgical rates could not be explained by the variables we evaluated. Thus, other factors such as personal preference or access to care require further investigation.

Synchronous pulmonary renal cell carcinoma metastases and primary non-small cell lung cancer.

CASE 1 Case 1 is a 79-year-old woman with a significant smoking history, who underwent a nephrectomy for renal cell carcinoma (RCC) 14 years before presentation. A chest computed tomography (CT) scan demonstrated a left upper lobe 14 12 mm spiculated peripheral nodule, and an 8-mm central lobar nodule (Figure 1). A positron emission tomography scan demonstrated activity in the peripheral dominant lesion. The patient underwent a video-assisted thoracic surgery (VATS) wedge resection of the peripheral lesion. Frozen section histology demonstrated adenocarcinoma. A complete VATS lobectomy was performed with mediastinal lymph node sampling. On final pathology, the peripheral lesion was metastatic RCC, and the central lesion was a pulmonary adenocarcinoma confirmed by Thyroid Transcription Factor 1 positivity; all lymph nodes were normal.

Video assisted thoracic surgery sublobar resection of intralobar pulmonary sequestration after preoperative embolization of systemic blood supply

Intralobar pulmonary sequestration is abnormal lung tissue of embryonic origin that receives arterial blood supply from the systemic arterial circulation from the abdominal aorta. The arterial blood supply traverses the diaphragm and courses through the inferior pulmonary ligament. Intralobar pulmonary sequestrations are usually treated by anatomic lobar or sublobar resections via an open thoracotomy. Recent reports suggest the utility of a video assisted thoracic surgery (VATS) pulmonary resection. However, the presence of the feeding systemic artery often makes VATS resection difficult or impossible, due to the risk of injury to the feeding vessel, and subsequent retraction below the diaphragm. We present procedural video recordings describing a multidisciplinary procedure, where precedent coil embolization of the feeding systemic vessel allows for relative risk-free VATS sublobar resection of the intralobar pulmonary sequestration.

Repair of nonmalignant postlaryngectomy pharyngotracheal fistula

The repair of nonmalignant postlaryngectomy pharyngotracheal fistulae is not commonly encountered in medical literature. This rare complication can occur years after laryngectomy for cancer and reconstruction of a neopharynx, and is often associated with adjuvant radiation to the area, making the choice of method for surgical repair critical for success. Optimally, a pedicled myofascial flap from the pectoralis major muscle, from outside the field of radiation, is used to reinforce the repair of the fistula. We present 2 rare cases.

Disseminated primary coccidioidomycosis of the chest wall.

FIGURE 1. High-powered micrograph of Coccidioides species spherule in skeletal muscle tissue (circle). Pulmonary coccidioidomycosis, or valley fever, is a diagnosis with increasing incidence in the western United States. Although coccidioidomycosis is an infectious disease classically described to be endemic to the southwestern United States, the first cases were indentified in central California. One defined population that has been especially subject to this disease is residents of the greater Sacramento counties in California, with 0.1 to 5.0 cases per 100,000 population from 2001 to 2008. Coccidioidomycosis spreads through inhalation of aerosolized mold or arthroconidia. Although pulmonary (acute pneumonia, chronic progressive pneumonia, and pulmonary nodules) and certain extrapulmonary (nonmeningeal and meningitis) manifestations of coccidioidomycosis infection are well described, treatment of disseminated coccidioidomycosis presenting as chest wall disease is not. In this report we present 2 cases that illustrate the clinical presentation and treatment strategy of disseminated coccidioidomycosis infection of the chest wall.

Abstract 336: Genomic annotation of non-small cell lung cancer patient-derived xenograft models for personalized cancer therapy.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Recent studies have characterized non-small cell lung cancer (NSCLC) as one of the most genomically deranged of all cancers, necessitating that both new drug development and patient therapy account for intra- and inter-patient tumor heterogeneity. Clinically annotated NSCLC patient-derived xenograft (PDX) models represent a novel approach to integrate this genomic complexity into a clinically relevant pre-clinical platform. We here describe molecular characterization to profile all currently “druggable” oncogenes for NSCLC in paired PDXs and original patient NSCLC tumor (PT). Method: Genomic DNA from archival formalin-fixed, paraffin-embedded (FFPE) PT and fresh first human-to-mouse (P0) NSCLC PDX tumors were isolated and subjected to oncogene mutational profiling using Sequenoms OncoCarta Panel v1. This panel detects 238 mutations in 19 genes commonly altered in cancer. RT-PCR-based molecular analyses of EGFR and KRAS mutations, EML4-ALK fusion transcripts, and RNA expression levels of ERCC1, RRM1 and TS genes were performed by Response Genetics, Inc. Genomic DNA from 3 serially passaged NSCLC PDX tumors (2 KRAS and 1 EGFR mutation models) up to 5 passages were also analyzed. Results: In the first 7 of 9 patient-PDX NSCLC models tested, oncogene mutational fidelity was preserved between PDX and PT with a good correlation of molecular biomarker expression (p<0.01). Two paired models had discrepancies in genotyping: from harboring 2 or 3 oncomutations at a frequency of 5-17% in PT to no mutation detected in P0 tumors), likely due to intra-patient tumor heterogeneity from clonal evolution. Of 3 models that have serial passaged tumors, the frequencies of oncomutation in each model were similar among the same passage (P0) or serial passage (P0 to P5) tumors. In several models tested for in vivo drug efficacy based on the molecular biomarker expression, results matched treatment outcome of the original patients., Conclusion: Our results validate the overall genomic fidelity of PDX tumors compared to original PT. Molecular characterization of individual tumor results in a clinically and genomically annotated PDX model with potential utility for selecting and validating clinically relevant drug target(s) for personalized cancer therapy. Acknowledgement: Supported by UC Davis Comprehensive Cancer Center Developmental Award (NIH/NCI P30CA093373), UL1 RR024146 from the National Center for Research Resources, the Jackson Laboratory, Response Genetics Inc., and the Addario Foundation. Citation Format: Sonal J. Desai, Neal Goodwin, Regina Gandour-Edwards, Royce F. Calhoun, David T. Cooke, Laurel A. Beckett, Martin K.H. Maus, Stephanie H. Astrow, Philip C. Mack, Ralph deVere White, David R. Gandara, Tianhong Li. Genomic annotation of non-small cell lung cancer patient-derived xenograft models for personalized cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 336. doi:10.1158/1538-7445.AM2013-336

Integrated research platform (iGXT) for enhancing drug development and personalizing cancer therapy: Pilot study results.

3053 Background: New approaches to drug development in both the laboratory and clinic will be required to achieve the goal of personalized and molecular-based cancer therapy. Here we describe an integrated research platform (iGXT) engaging unique resources at The Jackson Laboratory (JAX-WEST), the NCI Center for Advanced Preclinical Research (CAPR) and the UC Davis Cancer Center. Non-small cell lung cancer (NSCLC) was selected for pilot studies employing this strategy due to molecular targets of interest, such as epidermal growth factor receptor (EGFR), heterogeneity in NSCLC tumor biology and the complexity of cancer signaling pathways. METHODS In pilot studies, EGFR-directed drugs of interest (example AKT inhibitor MK2206) are studied at NCI CAPR in genetically engineered mice (GEMs) bearing tumors with defined EGFR-related characteristics while NSCLC patients (pts) and JAX Nod Scid Gamma (NSG) mice with patient-derived xenografts (PDXs) from those pts are concurrently treated in a co-clinical trial paradigm, taking advantage of superior properties of the NSG mouse for propagating PDXs. Results in NSG models and pt trials are assessed by genome-wide technologies, integrated with data from CAPR, and extrapolated back to individual pts. RESULTS Tumor specimens from over 180 cancer pts have been xenotransplanted into NSG mice (~50 from NSCLC). Pilot studies at CAPR in GEMs with EGFR mutant (Tet-op-EGFR L858R +/- T790M) tumors demonstrate efficacy of MK2206 +/- erlotinib, and with the pan-EGFR inhibitor BIBW2992. Complementary in vitro studies at UCD confirm the ability of MK2206 to overcome c-MET-related resistance to erlotinib. An erlotinib-MK2206 clinical trial is ongoing. Demographics of host pts, histopatholgic features and molecular profiles will be presented. CONCLUSIONS This pilot project supports the feasibility of systematically integrating data derived from iGXT models in order to optimize drug development and treatment strategies. Findings from this platform are likely to advance understanding of differences in intra-patient tumor biology and hasten the transition to personalized cancer therapy.