Matthew D. Taylor

Tumor recurrence after complete resection for non-small cell lung cancer.

BACKGROUND Long-term survival after R0 resection for non-small cell lung cancer (NSCLC) is less than 50%. The majority of mortality after resection is related to tumor recurrence. The purpose of this study was to identify independent perioperative and pathologic variables that are associated with NSCLC recurrence after complete surgical resection. METHODS A retrospective examination was performed of a prospectively maintained database of patients who underwent resection for NSCLC from July 1999 to August 2008 at a single institution. Clinicopathologic variables were evaluated for their influence on time to recurrence. Coxs proportional regression hazard model examined the association of recurrence in NSCLC. RESULTS A total of 1,143 patients met inclusion criteria and had complete follow-up information. Of these patients, 378 (33.1%) had recurrence of the primary cancer. Median follow-up was 24 months (range, 3-134 months). Preoperative tumor maximum standardized uptake value (SUVmax) greater than 5 was associated with increased risk of recurrence (hazard ratio [HR], 1.81; p=0.01). Preoperative radiation was independently associated with recurrence (HR, 1.98; p=0.05) as well as the presence of pathologic stage II and stage III disease (stage II: HR, 2.53; p=0.05; stage III: HR, 6.49; p=0.006). Subgroup analysis found that sublobar resection was also associated with locoregional recurrence after resection (HR, 4.17; p=0.02) and lymphovascular invasion of distant recurrence (HR, 4.21; p=0.002). CONCLUSIONS In the largest series reported to date on postresectional recurrence of NSCLC, SUVmax greater than 5, increasing pathologic stage, and the administration of preoperative radiation were independently associated with NSCLC recurrence after resection. Sublobar resection was independently associated with locoregional recurrence, and lymphovascular invasion was associated with distant recurrence.

Fluorodeoxyglucose positron emission tomography and tumor marker expression in non–small cell lung cancer

OBJECTIVE The best current noninvasive surrogate for tumor biology is fluorodeoxyglucose positron emission tomography (FDG-PET). Both FDG-PET maximal standardized uptake values and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in non-small cell lung cancer (NSCLC). However, there are limited data correlating FDG-PET with tumor markers. The purpose of this study was to determine the correlation of tumor marker expression with FDG-PET maximal standardized uptake values in NSCLC. METHODS FDG-PET maximal standardized uptake values were calculated in patients with NSCLC (n = 149). No patient had induction chemoradiotherapy. Intraoperative NSCLC tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known NSCLC tumor markers (glucose transporter 1, p53, cyclin D1, epidermal growth factor receptor, and vascular endothelial growth factor). Each tumor marker was assessed independently by two pathologists using common grading criteria. Subgroup analysis based on histologic characteristics and regional nodal status was performed. RESULTS FDG-PET correlated with T classification (P < .0001), N stage (P = .002), and greatest tumor dimension (P < .0001). In addition, increasing maximal standardized uptake values correlated with increased expression of glucose transporter 1 (P < .0001) and p53 (P = .04) in adenocarcinoma. Epidermal growth factor receptor expression correlated with maximal standardized uptake values without predilection for histologic subtype (P = .004). CONCLUSION FDG-PET maximal standardized uptake values correlate with an increased expression of glucose transporter 1 and p53 in lung adenocarcinoma, but not squamous cell cancer. Future studies attempting to correlate FDG-PET with tumor biology will need to consider the effect of different tumor histologic types.

Phase I Trial of Intrapleural Docetaxel Administered Through an Implantable Catheter in Subjects with a Malignant Pleural Effusion

Introduction: Malignant pleural effusion (MPE) is a common complication in patients with advanced malignancy. This dose escalation phase I study was designed to determine the maximum tolerated dose of intrapleural docetaxel administered through an implantable catheter in subjects with MPE. Methods: Subjects with MPE (n = 15) with median age of 64.6 years and an Eastern Cooperative Oncology Group performance status of 0 to 2 at baseline were enrolled into four single dose levels of docetaxel administered intrapleurally after drainage of the pleural effusion and insertion of an intrapleural catheter. The study determined the pharmacokinetic properties, clinical response, and toxicity profile of intrapleural docetaxel. Results: All patients tolerated the therapy well and there were no significant toxicities. The majority of patients had a complete radiographic response. All patients receiving dose 100 mg/m2 or higher had a complete radiographic response. One dose-limiting toxicity was encountered in the dose 50 mg/m2. Pharmacokinetic data demonstrated peak plasma concentration of docetaxel between 30 minutes and 6 hours after infusion. Pleural exposure to docetaxel was 1000 times higher than systemic exposure. Conclusions: Single-dose intrapleural administration of doxetaxel is well tolerated in patients with MPE with minimal toxicity. The excellent clinical responses in this study after treatment with intrapleural doxetaxel suggest that further investigation is warranted.

Marginal pulmonary function should not preclude lobectomy in selected patients with non-small cell lung cancer.

OBJECTIVE Current clinical trials are investigating the role of stereotactic body radiation therapy (SBRT) versus sublobar resection for patients with non-small cell lung carcinoma (NSCLC) and marginal pulmonary function tests (M-PFTs). We compared the outcomes of patients undergoing lobectomy with M-PFTs characterized by 2 accepted M-PFT criteria. METHODS A total of 1,259 consecutive patients underwent lobectomy for NSCLC between 1999 and 2011. Patients were stratified into 2 classifications of M-PFT: American College of Surgeons Oncology Group (ACOSOG) Z4099/Radiation Therapy Oncology Group (RTOG) 1021 trial or American College of Chest Physicians (ACCP) criteria. There were 206 patients classified as having M-PFT according to ACOSOG Z4099/RTOG 1021 criteria and 131 patients classified as having M-PFT by ACCP criteria. The primary endpoints of the study were post-operative complications and survival. RESULTS Median follow-up was 3.8 years. Cox-proportional survival analysis found that pathologic stage (P < .001), age (P < .001), and higher Zubrod functional status (P < .001) were independent predictors of mortality. Using multivariable analysis for major morbidity, M-PFT status was not associated with the development of a major complication following lobectomy (P = .68). M-PFT classification was not an independent predictor of mortality when controlling for other variables (ACOSOG Z4099/RTOG 1021 [P = .34]; ACCP criteria [P = .83]). A composite major morbidity analysis for major morbidity following lobectomy showed no association between clinicopathologic variables or M-PFTs and the occurrence of a major postoperative morbidity. CONCLUSIONS In carefully selected patients with M-PFTs, lobectomy for NSCLC can be performed with acceptable morbidity and mortality. These results need to be considered when deciding if a patient should undergo lobectomy or other therapies for resectable NSCLC.

Correlations between selected tumor markers and fluorodeoxyglucose maximal standardized uptake values in esophageal cancer

OBJECTIVE Esophageal cancer tumor biology is best assessed clinically by 2-[18F]fluoro-2-deoxy-d-glucose (FDG)-PET. Both FDG-PET maximal positron emission tomography (PET) standardized uptake values (SUVmax) and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in esophageal cancer. Interestingly, there is limited data examining the relationship between FDG-PET SUVmax and expression of these tumor markers in esophageal cancer. The purpose of this study was to determine the correlation of tumor markers with FDG-PET SUVmax in esophageal cancer. METHODS FDG-PET SUVmax was calculated in 67 patients with esophageal cancer of which 59 (88%) had adenocarcinoma. Neoadjuvant radiotherapy and/or chemotherapy were administered to 42% (28/67) of patients. Esophageal tumor tissue and surrounding normal tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for five known esophageal cancer tumor markers (GLUT-1, p53, cyclin D1, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF)). Assessment of each tumor marker was made by two independent, blinded pathologists using common grading criteria of intensity and percentage of cells stained. A p value <0.05 was considered significant. RESULTS There were 55 men (82%) and 12 women (18%) with a median age of 63 years (range 40-83). Pathologic staging included stage I (n=29, 43%), stage II (n=19, 28%), stage III disease (n=18, 27%), and stage IV disease (n=1, 2%). PET SUVmax correlated with T stage (p=0.001). In patients undergoing surgery without induction therapy, increasing SUVmax values correlated with increased expression of GLUT-1 transporter (p=0.01). There was no correlation between SUVmax and EGFR, cyclin D1, VEGF, or p53 expression in primary tumor. CONCLUSIONS FDG-PET SUVmax correlates with an increased expression of GLUT-1 transporter in esophageal cancer specimens not subjected to induction therapy. No significant difference in tumor marker expression was noted between patients undergoing induction therapy or surgery alone except p53 expression decreased in primary tumors following induction therapy. Failure of SUVmax values to correlate with known prognostic esophageal cancer tumor markers suggests that FDG-PET may have limited clinical utility in assessing response to therapies targeting these markers.

Combined proteasome and histone deacetylase inhibition attenuates epithelial–mesenchymal transition through E-cadherin in esophageal cancer cells

OBJECTIVE Metastasis is thought to be governed partially by induction of epithelial-mesenchymal transition. Combination of proteasome and histone deacetylase inhibitors has shown significant promise, but no studies have investigated this in esophageal cancer. This study investigated effects of vorinostat (histone deacetylase inhibitor) and bortezomib (proteasome inhibitor) on esophageal cancer epithelial-mesenchymal transition. METHODS Three-dimensional tumor spheroids mimicking tumor architecture were created with esophageal squamous and adenocarcinoma cancer cells. Cells were treated with tumor necrosis factor alpha (to simulate proinflammatory tumor milieu) and transforming growth factor beta (cytokine critical for induction of epithelial-mesenchymal transition). Tumor models were then treated with vorinostat, bortezomib, or both. Cytotoxic assays assessed cell death. Messenger RNA and protein expressions of metastasis suppressor genes were assessed. After treatment, Boyden chamber invasion assays were performed. RESULTS Combined therapy resulted in 3.7-fold decrease in adenocarcinoma cell invasion (P = .002) and 2.8-fold decrease in squamous cell invasion (P = .003). Three-dimensional invasion assays demonstrated significant decrease in epithelial-mesenchymal transition after combined therapy. Quantitative reverse transcriptase polymerase chain reaction and Western blot analyses revealed robust rescue of E-cadherin transcription and protein expression after combined therapy. Importantly, inhibition of the E-cadherin gene resulted in abolition of the salutary benefits of combined therapy, highlighting the importance of this metastasis suppressor gene in the epithelial-mesenchymal transition process. CONCLUSIONS Combined vorinostat and bortezomib therapy significantly decreased esophageal cancer epithelial-mesenchymal transition. This combined therapeutic effect on esophageal cancer epithelial-mesenchymal transition was associated with upregulation of E-cadherin protein expression.

Induction Chemoradiotherapy and Surgery for Esophageal Cancer: Survival Benefit With Downstaging

BACKGROUND The impact of induction chemoradiation therapy on esophageal cancer remains controversial. The purpose of this study was to evaluate the comparative effectiveness of induction chemoradiation therapy on perioperative and postoperative outcomes as well as the effect of downstaging in patients with esophageal cancer. METHODS A retrospective study of a prospectively collected database uncovered 455 consecutive patients undergoing esophagectomies for esophageal cancer between 1999 and 2011 at a high-volume institution. Comparison cohorts were patients treated with induction chemoradiation followed by surgery (n = 180) or surgery only patients (n = 189). Median follow-up was 918 days and was complete in 97%. Propensity score analysis controlled for potential allocation-to-treatment bias and created matched groups. RESULTS Clinical stage of patients in the study was as follows: stages 0 and I, 29%; stage II, 37%; stage III, 34%. Of the 369 patients, 180 (49%) patients received induction therapy and 53 (29%) achieved pathologic complete response. Induction therapy was associated with an increased need for postoperative transfusion, higher wound infection rate, and need for longer chest tube drainage. Overall, 55% of patients undergoing induction therapy were downstaged. In clinical stage III disease, patients who were downstaged were found to have a 3- and 5-year survival benefit compared with surgery alone (3-year, 51% versus 33%, p = 0.01; and 5-year, 44% versus 33%, p = 0.04). CONCLUSIONS Induction chemoradiation therapy for esophageal cancer is associated with minimal perioperative and postoperative morbidity. Downstaging of clinical stage III patients undergoing induction therapy was associated with a 3- and 5-year survival benefit compared with clinical stage III patients undergoing surgery alone.

The impact of ozone on a salt marsh cordgrass (Spartina alterniflora)

Spartina alterniflora plants were collected from salt marshes within New Jersey, South Carolina, and Georgia USA and shipped to The Pennsylvania State University. New plants were grown from rhizomes in six open-top field chambers. Three chambers received charcoal-filtered air, and three received charcoal-filtered air plus 80 ppb ozone, 8 h/day for 65 days. Flower, leaf, and shoot number per plant were recorded weekly. Photosynthetic rates were measured in week 5, and foliar injury was assessed during week 9. Final dry weight of roots, shoots, and rhizomes were determined. While ozone-treated plants from all states expressed symptoms of ozone injury, plants from South Carolina exhibited no effect of ozone on any other measured variable. Plants from the Georgia site showed ozone-induced reductions in all measured variables except leaf dry weight. Ozone-treated plants from New Jersey showed reductions in photosynthetic rate, leaf and shoot number, and root dry weights. Only plants from New Jersey produced flowers, with ozone treatment causing delay in flowering and reduction in the number of flower spikes produced.

Surgical Spectrum in the Management of Empyemas

Empyema remains a major source of morbidity and health care expenditure in the thoracic surgery community. Early intervention in pleural space infections is key to prevention of chronic empyemas and the need for surgical intervention. The advent of video-assisted thoracoscopic surgery has made it possible to treat stage I and stage II empyemas with significantly less morbidity. Although management of chronic empyema remains a significant challenge, surgical intervention is usually successful in cleaning up the pleural space.

Genetic Markers of Mediastinal Tumors

Determination of the genetic markers by the application of new genomic methodologies has provided important insight into the pathogenesis of mediastinal disease. These new techniques have enabled scientists to uncover differential gene expression patterns between subtypes of thymomas, correlate tumor marker expression with germ cell tumors, and determine a link between the NF-kappaB and JAK/STAT pathways with Hodgkins and non-Hodgkins lymphoma. Despite the progress made in the understanding of genetic markers of select mediastinal tumors, significantly more investigation is required to elucidate the molecular pathways involved in the pathogenesis of these tumors.