Mark W. Onaitis

Basal cells as stem cells of the mouse trachea and human airway epithelium

The pseudostratified epithelium of the mouse trachea and human airways contains a population of basal cells expressing Trp-63 (p63) and cytokeratins 5 (Krt5) and Krt14. Using a KRT5-CreERT2 transgenic mouse line for lineage tracing, we show that basal cells generate differentiated cells during postnatal growth and in the adult during both steady state and epithelial repair. We have fractionated mouse basal cells by FACS and identified 627 genes preferentially expressed in a basal subpopulation vs. non-BCs. Analysis reveals potential mechanisms regulating basal cells and allows comparison with other epithelial stem cells. To study basal cell behaviors, we describe a simple in vitro clonal sphere-forming assay in which mouse basal cells self-renew and generate luminal cells, including differentiated ciliated cells, in the absence of stroma. The transcriptional profile identified 2 cell-surface markers, ITGA6 and NGFR, which can be used in combination to purify human lung basal cells by FACS. Like those from the mouse trachea, human airway basal cells both self-renew and generate luminal daughters in the sphere-forming assay.

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.

Thoracoscopic Lobectomy Is a Safe and Versatile Procedure: Experience With 500 Consecutive Patients

Objective:Advantages of thoracoscopic lobectomy for early stage non-small cell lung cancer (NSCLC), as compared with lobectomy by conventional thoracotomy, include less postoperative pain and shorter length of hospitalization. The outcomes after thoracoscopic lobectomy in patients with more complex pulmonary conditions are analyzed to determine safety, efficacy, and versatility. Methods:A prospective database of 500 consecutive patients who underwent thoracoscopic lobectomy between June 1999 and January 2006 was queried. Demographic, histopathologic, perioperative, and outcome variables were assessed using standard descriptive statistics and Kaplan-Meier survival analyses. Results:Thoracoscopic lobectomy was successfully performed in 492 patients (conversion rate, 1.6%). Pathologic analysis included primary NSCLC in 416 patients (83.2%), centrally located secondary pulmonary malignancy in 37 patients (7.4%), and a variety of benign conditions in 45 patients (9%). Among the 416 patients with NSCLC, pathologic analysis demonstrated stage I in 330 patients (55.3%), stage II in 40 patients (9.6%), and stage III or greater NSCLC in 44 patients (10.6%). The operative and perioperative (30-day) mortality was 0% and 1%, respectively. The overall 2-year survival rate for the entire cohort was 80%, and the 2-year overall survival rates for stage I NSCLC, stage II or greater NSCLC, secondary pulmonary malignancy, and granulomatous disease patients were 85%, 77%, 73%, and 89%, respectively. Conclusions:Thoracoscopic lobectomy is applicable to a spectrum of malignant and benign pulmonary disease and is associated with a low perioperative morbidity and mortality rate. Survival rates are comparable to those for lobectomy with thoracotomy.

Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy

OBJECTIVES Advantages of thoracoscopic lobectomy include less postoperative pain, shorter hospitalization, and improved delivery of adjuvant chemotherapy. The incidence of postoperative complications has not been thoroughly assessed. This study analyzes morbidity after lobectomy to compare the thoracoscopic approach and thoracotomy. METHODS By using a prospective database, the outcomes of patients who underwent lobectomy from 1999-2009 were analyzed with respect to postoperative complications. Propensity-matched groups were analyzed based on preoperative variables and stage. RESULTS Of the 1079 patients in the study, 697 underwent thoracoscopic lobectomy, and 382 underwent lobectomy by means of thoracotomy. In the overall analysis thoracoscopic lobectomy was associated with a lower incidence of atrial fibrillation (P = .01), atelectasis (P = .0001), prolonged air leak (P = .0004), transfusion (P = .0001), pneumonia (P = .001), sepsis (P = .008), renal failure (P = .003), and death (P = .003). In the propensity-matched analysis based on preoperative variables, when comparing 284 patients in each group, 196 (69%) patients who underwent thoracoscopic lobectomy had no complications versus 144 (51%) patients who underwent thoracotomy (P = .0001). In addition, thoracoscopic lobectomy was associated with a lower incidence of atrial fibrillation (13% vs 21%, P = .01), less atelectasis (5% vs 12%, P = .006), fewer prolonged air leaks (13% vs 19%, P = .05), fewer transfusions (4% vs 13%, P = .002), less pneumonia (5% vs 10%, P = .05), less renal failure (1.4% vs 5%, P = .02), shorter chest tube duration (median of 3 vs 4 days, P < .0001), and shorter length of hospital stay (median of 4 vs 5 days, P < .0001). CONCLUSIONS Thoracoscopic lobectomy is associated with a lower incidence of major complications, including atrial fibrillation, compared with lobectomy by means of thoracotomy. The underlying factors responsible for this advantage should be analyzed to improve the safety and outcomes of other thoracic procedures.

Evidence that SOX2 overexpression is oncogenic in the lung.

Background SOX2 (Sry-box 2) is required to maintain a variety of stem cells, is overexpressed in some solid tumors, and is expressed in epithelial cells of the lung. Methodology/Principal Findings We show that SOX2 is overexpressed in human squamous cell lung tumors and some adenocarcinomas. We have generated mouse models in which Sox2 is upregulated in epithelial cells of the lung during development and in the adult. In both cases, overexpression leads to extensive hyperplasia. In the terminal bronchioles, a trachea-like pseudostratified epithelium develops with p63-positive cells underlying columnar cells. Over 12–34 weeks, about half of the mice expressing the highest levels of Sox2 develop carcinoma. These tumors resemble adenocarcinoma but express the squamous marker, Trp63 (p63). Conclusions These findings demonstrate that Sox2 overexpression both induces a proximal phenotype in the distal airways/alveoli and leads to cancer.

Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience.

ObjectiveTo examine clinical outcomes in patients receiving neoadjuvant chemoradiation for locally advanced rectal adenocarcinoma. Summary Background DataPreoperative radiation therapy, either alone or in combination with 5-fluorouracil-based chemotherapy, has proven both safe and effective in the treatment of rectal cancer. However, data are lacking regarding which subgroups of patients benefit from the therapy in terms of decreased local recurrence and increased survival rates. MethodsA retrospective chart review was performed on 141 consecutive patients who received neoadjuvant chemoradiation (5-fluorouracil ± cisplatin and 4,500–5,040 cGy) for biopsy-proven locally advanced adenocarcinoma of the rectum. Surgery was performed 4 to 8 weeks after completion of chemoradiation. Standard statistical methods were used to analyze recurrence and survival. ResultsMedian follow-up was 27 months, and mean age was 59 years (range 28–81). Mean tumor distance from the anal verge was 6 cm (range 1–15). Of those staged before surgery with endorectal ultrasound or magnetic resonance imaging, 57% of stage II patients and 82% of stage III patients were downstaged. The chemotherapeutic regimens were well tolerated, and resections were performed on 140 patients. The percentage of sphincter-sparing procedures increased from 20% before 1996 to 76% after 1996. On pathologic analysis, 24% of specimens were T0. However, postoperative pathologic T stage had no effect on either recurrence or survival. Positive lymph node status predicted increased local recurrence and decreased survival. ConclusionsNeoadjuvant chemoradiation is safe, effective, and well tolerated. Postoperative lymph node status is the only independent predictor of recurrence and survival.

Evidence for type II cells as cells of origin of K-Ras–induced distal lung adenocarcinoma

Identifying the cells of origin of lung cancer may lead to new therapeutic strategies. Previous work has focused upon the putative bronchoalveolar stem cell at the bronchioalveolar duct junction as a cancer cell of origin when a codon 12 K-Ras mutant is induced via adenoviral Cre inhalation. In the present study, we use two “knock-in” Cre-estrogen receptor alleles to inducibly express K-RasG12D in CC10+ epithelial cells and Sftpc+ type II alveolar cells of the adult mouse lung. Analysis of these mice identifies type II cells, Clara cells in the terminal bronchioles, and putative bronchoalveolar stem cells as cells of origin for K-Ras–induced lung hyperplasia. However, only type II cells appear to progress to adenocarcinoma.

Thoracoscopic lobectomy has increasing benefit in patients with poor pulmonary function: a Society of Thoracic Surgeons Database analysis.

Objective:Using a national database, we asked whether video-assisted thoracoscopic surgery (VATS) lobectomy is beneficial in high-risk pulmonary patients. Background:Single-institution series demonstrated benefit of VATS lobectomy over lobectomy via thoracotomy in poor pulmonary function patients [FEV1 (forced expiratory volume in 1 second) or DLCO (diffusion capacity of the lung to carbon monoxide) <60% predicted]. Methods:The STS General Thoracic Database was queried for patients having undergone lobectomy by either thoracotomy or VATS between 2000 and 2010. Postoperative pulmonary complications included those defined by the STS database. Results:In the STS database, 12,970 patients underwent lobectomy (thoracotomy, n = 8439; VATS, n = 4531) and met inclusion criteria. The overall rate of pulmonary complications was 21.7% (1832/8439) and 17.8% (806/4531) in patients undergoing lobectomy with thoracotomy and VATS, respectively (P < 0.0001). In a multivariable model of pulmonary complications, thoracotomy approach (OR = 1.25, P < 0.001), decreasing FEV1% predicted (OR = 1.01 per unit, P < 0.001) and DLCO% predicted (OR = 1.01 per unit, P < 0.001), and increasing age (1.02 per year, P < 0.001) independently predicted pulmonary complications. When examining pulmonary complications in patients with FEV1 less than 60% predicted, thoracotomy patients have markedly increased pulmonary complications when compared with VATS patients (P = 0.023). No significant difference is noted with FEV1 more than 60% predicted. Conclusions:Poor pulmonary function predicts respiratory complications regardless of approach. Respiratory complications increase at a significantly greater rate in lobectomy patients with poor pulmonary function after thoracotomy compared with VATS. Planned surgical approach should be considered while determining whether a high-risk patient is an appropriate resection candidate.

Prognostic Factors for Recurrence After Pulmonary Resection of Colorectal Cancer Metastases

BACKGROUND This study was undertaken to review a large series of resections of colorectal pulmonary metastases in the era of modern chemotherapy. METHODS A retrospective chart review of prospectively maintained thoracic surgery databases identified 378 patients who underwent pulmonary resection for colorectal cancer metastases with curative intent from 1998 to 2007. RESULTS The primary site of disease was rectum (52%), left colon (26%), right colon (16%), and unknown (6%). Before thoracic recurrence, 166 patients (44%) had previously undergone resection of extrathoracic metastases. Median disease-free interval (DFI) was 24 months from the time of the primary operation. The number of metastatic deposits resected was one in 60%, two in 20%, three in 10%, and four or more in 10%. Chemotherapy was administered to 87 patients (23%) before resection and to 169 patients (45%) after resection. Three-year recurrence-free survival was 28%, and 3-year overall survival was 78%. Multivariable analysis revealed age younger than 65 years, female sex, DFI less than 1 year, and number of metastases greater than three as independent predictors of recurrence. Of 44 patients with three or more lesions and less than 1 year DFI, none was cured by operation. By contrast, recurrence-free survival was 49% at 3 years for those with one lesion and DFI greater than 1 year. CONCLUSIONS Age younger than 65 years, female sex, DFI less than 1 year, and number of metastases greater than three predict recurrence. Medical management alone should be considered standard for patients who have both three or more pulmonary metastases and less than 1 year DFI.

Complete response to neoadjuvant chemoradiation for rectal cancer does not influence survival

Background: Up to 30% of patients with locally advanced rectal cancer have a complete clinical or pathologic response to neoadjuvant chemoradiation. This study analyzes complete clinical and pathologic responders among a large group of rectal cancer patients treated with neoadjuvant chemoradiation.Methods: From 1987 to 2000, 141 consecutive patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative 5-fluorouracil-based chemotherapy and radiation. Clinical restaging after treatment consisted of proctoscopic examination and often computed tomography scan. One hundred forty patients then underwent operative resection, with results tracked in a database. Standard statistical methods were used to examine the outcomes of those patients with complete clinical or pathologic responses.Results: No demographic differences were detected between either clinical complete and clinical partial responders or pathologic complete and pathologic partial responders. The positive predictive value of clinical restaging was 60%, and accuracy was 82%. By use of the Kaplan-Meier life table analysis, clinical complete responders had no advantage in local recurrence, disease-free survival, or overall survival rates when compared with clinical partial responders. Pathologic complete responders also had no recurrence or survival advantage when compared with pathologic partial responders. Of the 34 pathologic T0 tumors, 4 (13%) had lymph node metastases.Conclusions: Clinical assessment of complete response to neoadjuvant chemoradiation is unreliable. Micrometastatic disease persists in a proportion of patients despite pathologic complete response. Observation or local excision for patients thought to be complete responders should be undertaken with caution.