Jeffrey L. Port

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1+ cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin α4β1), and that tumour-specific growth factors upregulate fibronectin—a VLA-4 ligand—in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: A propensity-matched analysis from the STS database

BACKGROUND Several single-institution series have demonstrated that compared with open thoracotomy, video-assisted thoracoscopic lobectomy may be associated with fewer postoperative complications. In the absence of randomized trials, we queried the Society of Thoracic Surgeons database to compare postoperative mortality and morbidity following open and video-assisted thoracoscopic lobectomy. A propensity-matched analysis using a large national database may enable a more comprehensive comparison of postoperative outcomes. METHODS All patients having lobectomy as the primary procedure via thoracoscopy or thoracotomy were identified in the Society of Thoracic Surgeons database from 2002 to 2007. After exclusions, 6323 patients were identified: 5042 having thoracotomy, 1281 having thoracoscopy. A propensity analysis was performed, incorporating preoperative variables, and the incidence of postoperative complications was compared. RESULTS Matching based on propensity scores produced 1281 patients in each group for analysis of postoperative outcomes. After video-assisted thoracoscopic lobectomy, 945 patients (73.8%) had no complications, compared with 847 patients (65.3%) who had lobectomy via thoracotomy (P < .0001). Compared with open lobectomy, video-assisted thoracoscopic lobectomy was associated with a lower incidence of arrhythmias [n = 93 (7.3%) vs 147 (11.5%); P = .0004], reintubation [n = 18 (1.4%) vs 40 (3.1%); P = .0046], and blood transfusion [n = 31 (2.4%) vs n = 60 (4.7%); P = .0028], as well as a shorter length of stay (4.0 vs 6.0 days; P < .0001) and chest tube duration (3.0 vs 4.0 days; P < .0001). There was no difference in operative mortality between the 2 groups. CONCLUSIONS Video-assisted thoracoscopic lobectomy is associated with a lower incidence of complications compared with lobectomy via thoracotomy. For appropriate candidates, video-assisted thoracoscopic lobectomy may be the preferred strategy for appropriately selected patients with lung cancer.

Celecoxib, a Selective Cyclo-Oxygenase-2 Inhibitor, Enhances the Response to Preoperative Paclitaxel and Carboplatin in Early-Stage Non–Small-Cell Lung Cancer

PURPOSE Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2). METHODS In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib. RESULTS All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone. CONCLUSION In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

Total Number of Resected Lymph Nodes Predicts Survival in Esophageal Cancer

Objective:Several population-based studies have shown that the total number of surgically removed lymph nodes is independently associated with overall and disease-free survival in a variety of gastrointestinal cancers. In this retrospective study, the impact of total nodal count on overall survival in esophageal cancer was examined using a single institution surgical database. Methods:We conducted a retrospective review of 264 patients with esophageal cancer treated by esophagectomy without neoadjuvant therapy between January 1988 and December 2006. The association between overall survival (the primary endpoint) and the total number of dissected lymph nodes was evaluated using multivariable Cox regression models. Results:When the total number of resected nodes was examined as a categorical variable based on quartiles (category 1: ≤16, category 2: 17–25, category 3: 26–40, category 4: >40) there was a reduced hazard of death with increasing number of examined nodes. Compared with those in category 1, the death hazard was reduced by 34% (P = 0.08), 48% (P = 0.001), and 49% (P = 0.001), respectively, for patients in categories 2, 3, and 4. For node negative patients a significantly reduced hazard was present only when more than 40 nodes were resected (HR = 0.23, P = 0.01). For node positive patients the death hazard was significantly reduced for those in all higher categories compared with those in category 1 (HR = 0.53, 0.39, 0.49; P = 0.03, 0.001, 0.02, respectively). Conclusion:These data support the findings from population based studies in esophageal cancer and other gastrointestinal tumors, suggesting that a higher nodal count favorably influences survival.

Myeloid Progenitor Cells in the Premetastatic Lung Promote Metastases by Inducing Mesenchymal to Epithelial Transition

Tumors systemically initiate metastatic niches in distant target metastatic organs. These niches, composed of bone marrow-derived hematopoietic cells, provide permissive conditions for future metastases. However, the mechanisms by which these cells mediate outgrowth of metastatic tumor cells are not completely known. Using mouse models of spontaneous breast cancer, we show enhanced recruitment of bone marrow-derived CD11b(+)Gr1(+) myeloid progenitor cells in the premetastatic lungs. Gene expression profiling revealed that the myeloid cells from metastatic lungs express versican, an extracellular matrix proteoglycan. Notably, versican in metastatic lungs was mainly contributed by the CD11b(+)Ly6C(high) monocytic fraction of the myeloid cells and not the tumor cells or other stromal cells. Versican knockdown in the bone marrow significantly impaired lung metastases in vivo, without impacting their recruitment to the lungs or altering the immune microenvironment. Versican stimulated mesenchymal to epithelial transition of metastatic tumor cells by attenuating phospho-Smad2 levels, which resulted in elevated cell proliferation and accelerated metastases. Analysis of clinical specimens showed elevated versican expression within the metastatic lung of patients with breast cancer. Together, our findings suggest that selectively targeting tumor-elicited myeloid cells or versican represents a potential therapeutic strategy for combating metastatic disease.

Thoracic esophageal perforations: a decade of experience

BACKGROUND Perforation of the thoracic esophagus is a formidable challenge. Treatment and outcome are largely determined by the time to presentation. We reviewed our experience with esophageal perforations to determine the overall mortality and whether the time to presentation should influence management strategy. METHODS A retrospective chart review was performed on all patients treated for perforation of the thoracic esophagus from 1990 to 2001. There were 26 patients (14 men and 12 women; median age, 62 years; range, 36 to 89 years). Fourteen patients presented within 24 hours (early), and 12 patients presented after 24 hours (delayed). Nine of the 12 patients in the delayed group presented after 72 hours. The causes of the perforations were as follows: instrumentation (19 patients), Boerhaaves syndrome (2 patients), intraoperative injury (1 patient), and other (4 patients). In the early group, 3 patients were treated conservatively, 10 patients underwent primary repair, and 1 patient required esophagectomy for carcinoma. In the delayed group, 3 patients were treated conservatively, 6 underwent successful repair of the perforation, 1 had a T-tube placement through the perforation and eventually required an esophagectomy, and 2 had an esophagectomy as primary surgical treatment. RESULTS Hospital mortality was 3.8% (1 of 26) and morbidity was 38% (10 of 26). Persistent leaks occurred in 3 patients, 2 after primary repair and 1 after T-tube drainage. All patients selected for conservative management successfully healed their perforation. CONCLUSIONS Primary repair can be carried out in most cases of thoracic esophageal perforation regardless of time to presentation, with a low mortality rate. A small but carefully selected group of patients may be treated successfully without operation. Esophagectomy should be reserved for patients with carcinoma or extensive necrosis of the esophagus.

Positron emission tomography scanning poorly predicts response to preoperative chemotherapy in non-small cell lung cancer

BACKGROUND The ability to accurately predict pathologic response to preoperative chemotherapy may have a significant impact on the treatment strategy for non-small cell lung cancer (NSCLC). The purpose of this study was to examine the accuracy of positron emission tomography (PET) scanning in predicting the pathologic response to preoperative chemotherapy in the primary tumor and draining lymph nodes. METHODS A total of 25 patients were enrolled in two separate phase II trials investigating induction chemotherapy for NSCLC. All patients underwent pre-treatment and post-treatment PET scans followed by surgical resection. A significant PET scan response was defined as a reduction in the standard uptake value by 50% or more. We defined a major pathologic response as either no disease or microscopic disease only in the primary tumor. The percentage change in standard uptake value was then calculated and correlated with pathologic response in the primary tumor. In addition, the presence or absence of nodal metastases as determined by the postchemotherapy PET scan was compared with final pathologic nodal stage. RESULTS The positive and negative predictive values for PET detection of major pathologic response in the primary tumor were 43% and 100%, respectively. Positron emission tomography did not accurately predict nodal status in 52% of patients. The positive and negative predictive values of PET to detect node-positive disease were 73% and 64%, respectively. For N2 disease the positive predictive value of PET scans was less than 20%. CONCLUSIONS Positron emission tomography scanning does not reliably predict pathologic response to preoperative chemotherapy in NSCLC in either the primary tumor or the draining lymph nodes.

Outcomes after lobectomy using thoracoscopy vs thoracotomy: a comparative effectiveness analysis utilizing the Nationwide Inpatient Sample database

OBJECTIVES We examined the Nationwide Inpatient Sample (NIS) database to compare short-term postoperative outcomes following open and thoracoscopic lobectomy. Thoracoscopic (video-assisted thoracic surgery) lobectomy has been demonstrated to be associated with fewer postoperative complications compared with open thoracotomy lobectomy in several large case series. However, as no randomized trial has been performed, there are many who question this. METHODS We examined the NIS database for all patients undergoing lobectomy as their principal procedure either via thoracoscopic or open thoracotomy from 2007 to 08. We compared the postoperative outcomes of these two groups of patients after propensity matching these groups based on several preoperative variables. RESULTS Over a 2-year-period, 68 350 patients underwent a lobectomy by either thoracoscopy [n = 10 554 (15%)] or thoracotomy [n = 57 796(85%)]. Thirty-two percent of thoracoscopic lobectomies (n = 3421) were performed in either rural or non-teaching urban centres. Although in propensity-matched cohorts there was no difference in operative mortality, thoracoscopic lobectomy was associated with a lower incidence of postoperative complications [n = 4146 (40.8%) vs n = 13 913 (45.1%), P < 0.001] and shorter length of stay (5.0 vs 7.0 days; P < 0.001) compared with open lobectomy. Specifically, the incidences of supraventricular arrhythmias, myocardial infarction, pulmonary embolism and empyema were lower. CONCLUSIONS This large national database study demonstrates that thoracoscopic lobectomy is associated with fewer in-hospital postoperative complications compared with open lobectomy. Thoracoscopic lobectomy appears to be applicable to the wider general thoracic surgical community.

CXCL12 and CXCR4 in adenocarcinoma of the lung: Association with metastasis and survival

OBJECTIVES Although the chemokine CXCL12 and its receptor CXCR4 have been implicated in metastasis of non-small cell lung carcinoma, the prognostic significance of these molecules is poorly defined. This study aimed to determine whether expression of these molecules is associated with clinicopathologic features and disease-free survival in non-small cell lung carcinoma. METHODS Immunohistochemical staining for CXCL12 and CXCR4 was performed on 154 primary non-small cell lung carcinomas. Staining intensity was compared with tumor histotype, TNM stage, and disease-free survival; correlation was assessed by using the Fishers exact test, and Kaplan-Meier and Cox multivariate proportional hazards regression analysis. RESULTS Intense CXCL12 immunostaining was associated with nodal metastasis, although no difference in survival was observed. The prognostic relevance of CXCR4 was dependent on its subcellular location: in univariate analysis intense nuclear staining was significantly associated with lower T classification and improved disease-free survival in patients with adenocarcinoma, whereas cytomembranous staining was associated with distant metastasis and decreased disease-free survival. On multivariate analysis, cytomembranous CXCR4 expression conferred a significantly worse disease-free survival (relative risk, 2.8; 95% confidence interval, 1.4-5.7; P = .004). CONCLUSIONS Cytomembranous expression of the chemokine receptor CXCR4 in adenocarcinoma of the lung is an independent risk factor associated with worse disease-free survival, whereas nuclear staining confers a survival benefit. These findings are consistent with a model in which CXCR4 promotes tumor cell proliferation and metastasis when present in the cytoplasm or cell membrane, whereas localization of this molecule in the nucleus prevents it from exerting these effects.

Lobectomy in Octogenarians With Non-Small Cell Lung Cancer: Ramifications of Increasing Life Expectancy and the Benefits of Minimally Invasive Surgery

BACKGROUND As the population ages, clinicians are increasingly confronted with octogenarians with resectable non-small cell lung cancer (NSCLC). We reviewed the outcomes of octogenarians who underwent lobectomy for NSCLC by video-assisted thoracic surgery (VATS) versus open thoracotomy, to determine if there was a benefit to the VATS approach in this group. METHODS We conducted a retrospective single-institution review of patients age 80 years or greater who underwent a lobectomy for NSCLC from 1998 to 2009. Outcomes including complication rates, length of stay, disposition, and long-term survival were analyzed. RESULTS One hundred twenty-one octogenarians underwent lobectomy: 40 VATS and 81 through open thoracotomy. Compared with thoracotomy, VATS patients had fewer complications (35.0% vs 63.0%, p = 0.004), shorter length of stay (5 vs 6 days, p = 0.001), and were less likely to require admission to the intensive care unit (2.5% vs 14.8%, p = 0.038) or rehabilitation after discharge (5% vs 22.5%, p = 0.015). In multivariate analysis, VATS was an independent predictor of reduced complications (odds ratio, 0.35; 95% confidence interval, 0.15 to 0.84; p = 0.019). Survival comparisons demonstrated no significant difference between the two techniques, either in univariate analysis of stage I patients (5-year VATS, 76.0%; thoracotomy, 65.3%; p = 0.111) or multivariate analysis of the entire cohort (adjusted hazard ratio, 0.59; 95% confidence interval, 0.27 to 1.28; p = 0.183). CONCLUSIONS Octogenarians with NSCLC can undergo resection with low mortality and survival among stage I patients, which is comparable with the general lung cancer population. The VATS approach to resection reduces morbidity in this age demographic, resulting in shorter, less intensive hospitalization, and less frequent need for postoperative rehabilitation.