Role of Segmentectomy in Treatment of Early-Stage Non-Small Cell Lung Cancer.

PURPOSE AND DESIGN: Standard treatment for early-stage non-small cell lung cancer has traditionally involved lobectomy. Historical data that demonstrates suboptimal results for sublobar resection compared to lobectomy have been challenged in recent years with retrospective data for patients with T1a disease. For patients who are not candidates for lobectomy, options for sublobar resection include wedge resection or anatomic segmentectomy. Segmentectomy has long been held to be a better cancer operation than wedge resection, and its role in treating early-stage lung cancer remains controversial in patients who are candidates for lobectomy. A review of available literature involving segmentectomy and possible predictors of failure for segmentectomy was performed in an attempt to clarify the role of segmentectomy for early-stage lung cancer. RESULTS AND CONCLUSIONS: Current evidence is conflicting regarding the optimal scenario for sublobar resection with segmentectomy. Two large-scale randomized trials are currently addressing the question. In the meantime, certain preoperative and intraoperative considerations should be taken into account when considering segmentectomy for the treatment of early-stage non-small cell lung cancer.

PI3K/mTOR Dual Inhibitor, LY3023414, Demonstrates Potent Antitumor Efficacy Against Esophageal Adenocarcinoma in a Rat Model.

OBJECTIVE: The purpose of the current study is to determine the efficacy of a PI3K/mTOR dual inhibitor, LY3023414, on established EAC in an in vivo model. BACKGROUND: Esophageal adenocarcinoma (EAC) is a highly lethal cancer with limited treatment options. The PI3K/mTOR pathway is upregulated in EAC and may be a target for novel therapies. METHODS: Esophagojejunostomy was performed on Sprague-Dawley rats to induce carcinogenesis, and LY3023414 was cyclically administered intraperitoneally between 32 and 40 weeks postsurgery to treatment animals. Magnetic resonance imaging (MRI) and histology were used to determine clinical response. Immunohistochemistry, immunofluorescence, and Western blot were used to validate apoptosis by cleaved caspase-3, proliferation by Ki67, and pathway inhibition, respectively. RESULTS: Mean MRI tumor volume increased by 109.2% in controls (n = 32) and decreased by 56.8% in treatment animals (n=17) (P < 0.01). Treatment with LY3023414 demonstrated tumor volume increase in 0% (control = 46.4%) (P < 0.01), decrease in 58.8% (control = 7.1%) (P < 0.01), and stable volume in 41.2% (control = 46.4%) (P = 0.77). EAC prevalence in controls increased by 25%; whereas, prevalence in treatment animals decreased by 29.4% (P < 0.01). Approximately, 75% of treatment animals presenting with residual masses on MRI had a histological response >50%. Increased apoptosis by cleaved caspase-3 (P = 0.03) and decreased proliferation by Ki67 (P < 0.01) were demonstrated in the treatment arm, when compared with the control arm. On Western blot analysis of pathway checkpoints, p-mTOR (p=0.03) and PI3K-α (P = 0.04) were downregulated in treatment responsive residual tumors, when compared with controls. CONCLUSIONS: LY3023414 demonstrates efficacy against EAC in a preclinical model, establishing the rationale for clinical testing.

Preclinical Study of AUY922, a Novel Hsp90 Inhibitor, in the Treatment of Esophageal Adenocarcinoma.

OBJECTIVE: To assess the efficacy of heat-shock protein 90 (Hsp90) inhibitor, NVP-AUY922-AG (AUY922), in the treatment of esophageal adenocarcinoma (EAC) in vitro and in vivo. BACKGROUND: EAC is a leading cause of cancer death, and current treatment options are limited. Hsp90, a chaperone protein that regulates several oncoproteins, is upregulated in EAC, and may be a novel target for therapy. METHODS: In vitro, EAC cell lines were utilized to evaluate AUY922, alone and in combination with 5-fluorouracil (5-FU) and cisplatin. BrdU ELISA and flow cytometry were used to assess proliferation and measure apoptosis, respectively. Western blot and RT-PCR were performed to quantitate Hsp90 pathway expression. In vivo, esophagojejunostomy was performed on rats and treatment animals received AUY922 32 to 40 weeks postoperatively. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, gross histological evaluation, and Hsp90 pathway expression. RESULTS: In vitro, AUY922 demonstrated antiproliferative activity in both cell lines and showed enhanced efficacy with cisplatin and 5-FU. Western Blot and RT-PCR demonstrated downregulation of CDK1 and CDK4 and upregulation of Hsp72. In vivo, AUY922 showed decrease in tumor volume in 36.4% of rats (control = 9.4%), increase in 9.1% (control = 37.5%), and stable disease in 54.5% (control = 43.7%). Necropsy confirmed the presence of EAC in 50% of treatment animals and 75% of control animals. mRNA expression, pre- and posttreatment, demonstrated significant downregulation of MIF, Hsp70, Hsp90ß, and CDK4, and upregulation of Hsp72. CONCLUSIONS: AUY922 exhibits antitumor efficacy in vitro and in vivo for EAC, suggesting the need for human clinical trials.

Associations of microbiota and toll-like receptor signaling pathway in esophageal adenocarcinoma.

BACKGROUND: Toll-like receptors (TLRs) recognize known molecules from microbes and have an established role in tumorigenesis. Using a rat model of esophageal adenocarcinoma, and human clinical samples, we investigated genes central to TLR-mediated signal transduction and characterized the esophageal microbiome across the spectrum of esophageal adenocarcinoma carcinogenesis. METHODS: We surgically induced bile/acid reflux in rats and their esophagi were harvested at 40 weeks post-surgery. Tissue samples from the model were selected for gene expression profiling. Additionally, for rat and human samples microbiome analysis was performed using PCR-ESI-MS-TOF technology with validation by fluorescence in situ hybridization. RESULTS: Gene expression results in the rat model indicated a significant upregulation of TLRs 1-3, 6, 7 and 9 in EAC compared to normal epithelium. PCR-ESI-MS-TOF analysis revealed a prevalence of Escherichia coli in Barrett's esophagus (60%) and esophageal adenocarcinoma (100%), which was validated by fluorescence in situ hybridization. In the human clinical samples, Streptococcus pneumonia was detected in high abundance in gastroesophageal reflux disease and Barrett's esophagus (50-70%) in comparison to tumor adjacent normal epithelium, dysplasia, and esophageal adenocarcinoma (20-30%). E. coli was detected in the Barrett's esophagus and esophageal adenocarcinoma groups but was absent in the tumor adjacent normal epithelium, dysplasia, and the gastroesophageal reflux disease groups. CONCLUSIONS: We demonstrated an association between the TLR signaling pathway and E. coli hinting towards possible early molecular changes being mediated by microbes in the rat model of esophageal adenocarcinoma carcinogenesis. Studies on human clinical samples also corroborate results to some extent; however, a study with larger sample size is needed to further explore this association.

A utility of peroral endoscopic myotomy (POEM) across the spectrum of esophageal motility disorders.

BACKGROUND: Peroral endoscopic myotomy (POEM) has been performed as a novel endoscopic procedure to treat achalasia with favorable outcome. The objective of this study was to assess the outcome of POEM in our initial series and to assess the safety and efficacy of POEM in a variety of esophageal motility-related clinical problems. METHODS: This is a retrospective cross-sectional study involving all patients with esophageal motility disorders defined by the Chicago classification, who had undergone consideration for POEM at our institution. Validated questionnaires such as gastroesophageal reflux disease health-related quality of life (GERD-HRQL), reflux symptom index (RSI) and achalasia disease-specific health-related quality of life were obtained pre- and postoperatively. RESULTS: From January 2013 to October 2014, a total of 35 POEMs (achalasia n = 25, non-achalasia n = 10) were performed on 33 patients (female n = 20, male n = 13, mean age 56.9 years). There was no mortality. The rate of inadvertent mucosotomy was 17.1%. The rate of complications requiring interventions was 5.7%. During a mean follow-up period of 7 months (range 0.5-17), 92% of patients with achalasia and 75% of those with non-achalasia motility disorders had a symptomatic improvement in dysphagia. Chest pain was completely resolved in all patients with achalasia (8/8) and 80% of patients with non-achalasia (4/5). The GERD-HRQL, RSI and dysphagia scores significantly improved after POEM in patients with achalasia. There was a significant improvement in GERD-HRQL and RSI scores, and a trend toward lower dysphagia score in patients with non-achalasia. CONCLUSIONS: The outcome of POEM to treat achalasia and non-achalasia motility disorders is consistent with previous studies. Potential benefit of POEM includes not only its flexibility to adjust the length and location of myotomy but also the ability to extend myotomy proximally without thoracoscopy or thoracotomy. POEM can be combined with laparoscopic procedures and used as "salvage" for localized esophageal dysmotility.

Flow cytometric determination of stem/progenitor content in epithelial tissues: an example from nonsmall lung cancer and normal lung.

Single cell analysis and cell sorting has enabled the study of development, growth, differentiation, repair and maintenance of "liquid" tissues and their cancers. The application of these methods to solid tissues is equally promising, but several unique technical challenges must be addressed. This report illustrates the application of multidimensional flow cytometry to the identification of candidate stem/progenitor populations in non-small cell lung cancer and paired normal lung tissue. Seventeen paired tumor/normal lung samples were collected at the time of surgical excision and processed immediately. Tissues were mechanically and enzymatically dissociated into single cell suspension and stained with a panel of antibodies used for negative gating (CD45, CD14, CD33, glycophorin A), identification of epithelial cells (intracellular cytokeratin), and detection of stem/progenitor markers (CD44, CD90, CD117, CD133). DAPI was added to measure DNA content. Formalin fixed paraffin embedded tissue samples were stained with key markers (cytokeratin, CD117, DAPI) for immunofluorescent tissue localization of populations detected by flow cytometry. Disaggregated tumor and lung preparations contained a high proportion of events that would interfere with analysis, were they not eliminated by logical gating. We demonstrate how inclusion of doublets, events with hypodiploid DNA, and cytokeratin+ events also staining for hematopoietic markers reduces the ability to quantify epithelial cells and their precursors. Using the lung cancer/normal lung data set, we present an approach to multidimensional data analysis that consists of artifact removal, identification of classes of cells to be studied further (classifiers) and the measurement of outcome variables on these cell classes. The results of bivariate analysis show a striking similarity between the expression of stem/progenitor markers on lung tumor and adjacent tumor-free lung.

Outcomes after minimally invasive esophagectomy: review of over 1000 patients.

BACKGROUND: Esophagectomy is a complex operation and is associated with significant morbidity and mortality. In an attempt to lower morbidity, we have adopted a minimally invasive approach to esophagectomy. OBJECTIVES: Our primary objective was to evaluate the outcomes of minimally invasive esophagectomy (MIE) in a large group of patients. Our secondary objective was to compare the modified McKeown minimally invasive approach (videothoracoscopic surgery, laparoscopy, neck anastomosis [MIE-neck]) with our current approach, a modified Ivor Lewis approach (laparoscopy, videothoracoscopic surgery, chest anastomosis [MIE-chest]). METHODS: We reviewed 1033 consecutive patients undergoing MIE. Elective operation was performed on 1011 patients; 22 patients with nonelective operations were excluded. Patients were stratified by surgical approach and perioperative outcomes analyzed. The primary endpoint studied was 30-day mortality. RESULTS: The MIE-neck was performed in 481 (48%) and MIE-Ivor Lewis in 530 (52%). Patients undergoing MIE-Ivor Lewis were operated in the current era. The median number of lymph nodes resected was 21. The operative mortality was 1.68%. Median length of stay (8 days) and ICU stay (2 days) were similar between the 2 approaches. Mortality rate was 0.9%, and recurrent nerve injury was less frequent in the Ivor Lewis MIE group (P < 0.001). CONCLUSIONS: MIE in our center resulted in acceptable lymph node resection, postoperative outcomes, and low mortality using either an MIE-neck or an MIE-chest approach. The MIE Ivor Lewis approach was associated with reduced recurrent laryngeal nerve injury and mortality of 0.9% and is now our preferred approach. Minimally invasive esophagectomy can be performed safely, with good results in an experienced center.

Density of tumor-infiltrating lymphocytes correlates with disease recurrence and survival in patients with large non-small-cell lung cancer tumors.

BACKGROUND: The density of tumor-infiltrating lymphocytes (TIL) in lung cancer is variable and may have an impact on disease course. We reviewed the histology of lobectomy specimens from patients with pathologic stage IA-IB non-small-cell lung cancer to determine the impact of TILs on recurrence and survival. MATERIALS AND METHODS: Two hundred nineteen lobectomies performed between 2002 and 2005 for stage IA-IB non-small-cell lung cancer were reviewed. Patients were stratified according to tumor size. Infiltrating patterns were graded as follows: group 1 (none to mild infiltrate) or group 2 (moderate to severe infiltrate). Recurrence rates and disease-free survival were compared between groups in each tumor size cohort. RESULTS: A higher density of TILs was associated with lower disease recurrence (60%, group 1 versus 21%, group 2, P=0.02) and improved 5-y disease-free survival (35.9%, group 1 versus 75.6%, group 2, P=0.04) in patients with tumors 5 cm or greater in diameter. There were no correlations in patients with smaller tumors. CONCLUSIONS: A higher degree of TILs within large node-negative non-small-cell lung cancer correlates with decreased risk of disease recurrence and improved disease-free survival. This subset of patients with tumor infiltration needs to be examined more closely with regards to outcomes of adjuvant chemotherapy.

Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in stage 1A non-small-cell lung cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have been found to increase survival in many forms of cancer, including, endometrial, bile ductal, colonic, esophageal, and urothelial cancers, as well as melanoma and follicular lymphoma. The relevance of TILs in the prognosis of non-small-cell lung cancer (NSCLC), however, still remains controversial. We compared the outcomes of stage 1A NSCLC with and without tumor infiltrating lymphocytes to evaluate the effects of TILs on recurrence and survival patterns. MATERIALS AND METHODS: From 2000 to 2009, 273 anatomic segmentectomies and lobectomies were performed on stage 1A NSCLC. Patients were stratified into TIL- and TIL+ cohorts based on pathologic evaluation. Further investigation was conducted on the effects of TILs in patients with and without angiolymphatic invasion. Variables analyzed include overall survival, recurrence-free survival, and type of recurrence. RESULTS: Overall 5-y survival was not affected by TIL status (65% versus 60%, P = 0.469). Five-year recurrence-free survival (RFS) was significantly increased in the TIL+ group versus the TIL- group (87% versus 73%, P = 0.011), most significantly in women (P = 0.016). The presence of angiolymphatic invasion (ALI) was associated with decreased 5-y RFS versus patients without ALI (61% versus 85%, P < 0.001). Interestingly, in the ALI negative group, TIL+ patients experienced a significantly increased 5-y recurrence-free survival versus TIL- patients (93% versus 80%, P = 0.036). CONCLUSIONS: High levels of intratumoral TILs are associated with improved recurrence-free survival in stage 1A NSCLC patients as well as a reduced likelihood of systemic recurrence. When angiolymphatic invasion is not present, the beneficial effects of TILs become even more profound.

Experimental model of laparoscopic gastric ischemic preconditioning prior to transhiatal esophagectomy.

BACKGROUND: Cervical esophagogastric anastomotic disruption following transhiatal esophagectomy (THE) is a significant problem. Gastric tip ischemia is a primary cause of anastomotic failure. We examined gastric tip blood flow when laparoscopic "ischemic preconditioning" was attempted by selectively ligating the short gastric (SG) vessels or both the left and short gastric (LG/SG) vessels prior to THE. METHODS: Seventeen (25 kg) mongrel dogs underwent laparoscopy followed 3 weeks later by THE. Three groups were studied: control group = laparoscopy only, no preconditioning (n = 6); SG group = laparoscopic ligation of SG vessels only (n = 5); and LG/SG group = laparoscopic ligation of LG and SG vessels (n = 6). Tissue blood flow was assessed using the fluorescent microsphere method. The initial microsphere injections occurred prior to pneumoperitoneum and upon completion of the laparoscopy. At the second operation, transhiatal esophagectomy was performed and microsphere blood flow assessment occurred after induction of anesthesia, after mobilization of the stomach, and after completion of the cervical esophagogastric anastomosis. The animals were euthanized and regional gastric tissue was analyzed for microsphere estimates of blood flow. Differences in blood flow were evaluated using Student's t test. RESULTS: The mean baseline gastric blood flow was 0.58 ml/min/g. After THE, the proximal gastric blood flow fell to 16% of baseline in control and 22% in SG, but was reduced to only 60% of baseline in LG/SG. This relative preservation of blood flow among the LG/SG group approached significance compared with the laparoscopy-only (control) group (P = 0.07). Ligation of SG vessels alone provided no preservation of proximal gastric blood flow following THE. CONCLUSION: Preoperative "ischemic preconditioning" through ligation of both the short and left gastric vessels may achieve preservation of blood flow to the gastric tip. Preconditioning during laparoscopic staging of esophageal carcinoma may be considered to reduce anastomotic complications following esophagectomy.

Outcomes with segmentectomy versus lobectomy in patients with clinical T1cN0M0 non-small cell lung cancer.

OBJECTIVE: We hypothesize that segmentectomy is associated with similar recurrence-free and overall survival when compared with lobectomy in the setting of patients with clinical T1cN0M0 non-small cell lung cancer (NSCLC; >2-3 cm), as defined by the American Joint Committee on Cancer 8th edition staging system. METHODS: We performed a single-institution retrospective study identifying patients undergoing segmentectomy (90) versus lobectomy (279) for T1c NSCLC from January 1, 2003, to December 31, 2016. Univariate, multivariable, and propensity score-weighted analyses were performed to analyze the following endpoints: freedom from recurrence, overall survival, and time to recurrence. RESULTS: Patients undergoing segmentectomy were older than patients undergoing lobectomy (71.5 vs 68.8, respectively, P = .02). There were no differences in incidence of major complications (12.4% vs 11.7%, P = .85), hospital length of stay (6.2 vs 7 days, P = .19), and mortality at 30 (1.1% vs 1.7%, P = 1) and 90 days (2.2% vs 2.3%, P = 1). In addition, there were no statistical differences in locoregional (12.2% vs 8.6%, P = .408), distant (11.1% vs 13.9%, P = .716), or overall recurrence (23.3% vs 22.5%, P = 1), as well as 5-year freedom from recurrence (68.6% vs 75.8%, P = .5) or 5-year survival (57.8% vs 61.0%, P = .9). Propensity score-matched analysis found no differences in overall survival (hazard ratio [HR], 1.034; P = .764), recurrence-free survival (HR, 1.168; P = .1391), or time to recurrence (HR, 1.053; P = .7462). CONCLUSIONS: In the setting of clinical T1cN0M0 NSCLC, anatomic segmentectomy was not associated with significant differences in recurrence-free or overall survival at 5 years. Further prospective randomized trials are needed to corroborate the expansion of the role of anatomic segmentectomy to all American Joint Committee on Cancer 8th Edition Stage 1A NSCLC.

Anterior minithoracotomy: a direct approach to the difficult hilum for upper lobectomy, pneumonectomy, and sleeve lobectomy.

BACKGROUND: Central lung cancers with pulmonary hilar involvement can pose a technical challenge when a lateral thoracotomy is used. Proximal vascular control and pulmonary vascular dissection from this approach can be challenging and potentially dangerous. We describe the use of a Chamberlain anterior minithoracotomy as an alternative approach for safe and reliable access to the pulmonary hilum. METHODS: One hundred two consecutive patients undergoing the Chamberlain approach were identified through retrospective chart review from 2002 to 2009. The supine position was used, thus reducing the likelihood of down-lung syndrome. An 8-cm anterior thoracotomy was performed over the second interspace along the line of the pectoral fibers, with preservation of the mammary artery medially and the thoracoacromial neurovascular bundle laterally. Primary outcome variables included hospital course, complications, and mortality rate. RESULTS: The mean age was 64.8 years (range, 20-89 years). Sex ratio (female:male) was 44:58. Neoadjuvant therapy was used in 43 patients (42.2%). Proposed resections were successful in 101 (99%) of 102 patients. Conversion to hemiclamshell was required in 1 patient for vascular control. Three perioperative deaths (2.9%; two pneumonectomies, one lobectomy) occurred. CONCLUSIONS: The Chamberlain mini anterior thoracotomy provides direct access to the pulmonary hilum, facilitating dissection and vascular control for large and central tumors. Reduced perioperative pain and down-lung syndrome compared to lateral approaches can be achieved. Muscle function is preserved, and intrapericardial/hilar access is expeditious. This approach enhances hilar access and avoids the vascular control and hilar exposure challenges inherent with lateral thoracotomy.

The use of esophageal transit and gastric emptying studies in the evaluation of patients undergoing laparoscopic fundoplication.

BACKGROUND: Preservation of esophageal and gastric function is a hallmark principle in ensuring optimal surgical outcomes after gastric fundoplication. In this study, we evaluated the impact of fundoplication on esophageal transit and gastric emptying using scintigraphy studies and related these functional findings to symptomatic outcomes. METHODS: A total of 106 consecutive patients (37 women, 69 men) with both preoperative and 6-month postoperative nuclear scintigraphy studies undergoing partial (Toupet) fundoplication at a single institution were analyzed. Primary variables included alterations in esophageal transit and gastric emptying times after fundoplication (1 = rapid; 2 = normal; 3 = mild delay; 4 = severe delay). Symptomatic variables included heartburn, regurgitation, dysphagia, pulmonary symptoms, and bloating. RESULTS: Mean age was 57.2 years. Symptomatic improvement was achieved in 91.5% of patients. Significant reduction of all symptoms (heartburn, regurgitation, pulmonary symptoms, and dysphagia) was noted after fundoplication, except gas bloating (4.7 vs. 20.8%). There were no significant differences in preoperative and postoperative esophageal transit (2.53 vs. 2.52) and gastric emptying (2.13 vs. 2.06) scores after fundoplication. Interestingly, 17% of esophageal transit times and 18% of gastric emptying times improved after fundoplication. However, worsening scores were seen in 16 and 12%, respectively. There was no significant postoperative dysphagia, even in patients with impaired transit times. CONCLUSIONS: Nuclear scintigraphic assessment of esophageal transit and gastric emptying are valuable, user-friendly tools to identify and avoid functional motility problems in the setting of fundoplication. These studies seem to be a reasonable alternative to manometry in assessing esophageal function before surgery in this setting. Postoperative symptoms may be related to objective changes in esophageal transit or gastric emptying. The causes may be iatrogenic in nature or related to vagal denervation with associated changes in esophagogastric compliance. Awareness of these physiologic changes may prompt further technical precautions at the time of surgery to avoid vagal injury and also may facilitate postoperative medical management.

Whole genome exon arrays identify differential expression of alternatively spliced, cancer-related genes in lung cancer.

Alternative processing of pre-mRNA transcripts is a major source of protein diversity in eukaryotes and has been implicated in several disease processes including cancer. In this study we have performed a genome wide analysis of alternative splicing events in lung adenocarcinoma. We found that 2369 of the 17 800 core Refseq genes appear to have alternative transcripts that are differentially expressed in lung adenocarcinoma versus normal. According to their known functions the largest subset of these genes (30.8%) is believed to be cancer related. Detailed analysis was performed for several genes using PCR, quantitative RT-PCR and DNA sequencing. We found overexpression of ERG variant 2 but not variant 1 in lung tumors and overexpression of CEACAM1 variant 1 but not variant 2 in lung tumors but not in breast or colon tumors. We also identified a novel, overexpressed variant of CDH3 and verified the existence and overexpression of a novel variant of P16 transcribed from the CDKN2A locus. These findings demonstrate how analysis of alternative pre-mRNA processing can shed additional light on differences between tumors and normal tissues as well as between different tumor types. Such studies may lead to the development of additional tools for tumor diagnosis, prognosis and therapy.

Survival among patients with platinum resistant, locally advanced non-small cell lung cancer treated with platinum-based systemic therapy.

BACKGROUND: Recent adjuvant chemotherapy trials after resection of stage II and III non-small cell lung cancer (NSCLC) have identified important survival differences among patients with immunohistochemical evidence suggesting platinum resistance. No clinical information exists regarding the impact upon survival of patients treated with platinum agents who exhibit cellular evidence of their tumors' resistance to platinum. We evaluated the utility of the extreme drug resistance (EDR) assay to predict mortality among a consecutive group of stage II through IV NSCLC patients receiving adjuvant or definitive platinum-based chemotherapy after resection or surgical biopsy. METHODS: The Extreme Drug Resistance (EDR) Assay is a clinically validated cellular proliferation assay used to test tumors for chemotherapy drug resistance. Based on response in the EDR assay, tumor specimens from stage II through IV NSCLC patients were segregated into three groups: extreme drug resistant (EDR), intermediate drug resistant (IDR), and low drug resistant (LDR). Patient survival was evaluated after platinum-based chemotherapy. RESULTS: Platinum IDR/EDR was statistically significant in predicting shorter overall survival (29.8 months vs. 15.6 months) among platinum IDR/EDR-resistant patients compared with LDR patients (P = 0.047). Median survival was 16.6 months for patients with IDR/EDR to platinum and any other second agent of doublet therapy compared with patients with LDR to any platinum-based doublet where median survival was not achieved (P = 0.0268). CONCLUSIONS: This is the first study to demonstrate the utility of the EDR assay to predict poor clinical outcome when platinum-based therapy is used to treat patients with biological evidence of tumor resistance to platinum. These data corroborate the finding of recent studies evaluating possible molecular correlates to poor response to specific chemotherapeutic agents.

Efficacy of signal pathway inhibitors alone and in combination with Cisplatin varies between human non-small cell lung cancer lines.

BACKGROUND: Signal pathway inhibitors (SPI) are designed to act synergistically with conventional cytotoxic drugs to control cancer progression. The objective of this study was to evaluate the effect of various SPI, both alone and in combination with cisplatin, on three different non-small cell lung cancer (NSCLC) cell lines. MATERIALS AND METHODS: Cell lines (A549, 201T, 273T) representing NSCLC were treated for 72 h in the presence or absence of inhibitors to PI3K (LY-294002; Tocris Bioscience, Ellisville, MO), BCL-2 (Gossypol; Sigma-Aldrich, St. Louis, MO), Cox-2 (NS-398 [Sigma-Aldrich] or Celecoxib [Pfizer]), MAPK (U0126 [Sigma-Aldrich]), and EGFR (Iressa; AstraZeneca, Macclesfield, United Kingdom) both alone and in combination with 10 or 30 mum cisplatin (Sigma-Aldrich) (18 possible regimens for each cell line). MTT assay (Trevigen, Gaithersburg, MD) was used to measure cytotoxicity. Controls were represented by cells with either a pure culture medium (monotherapy regimen control) or culture medium with the corresponding dose of cisplatin (combination regimen control). Unpaired t-test was used to classify response to therapy as highly sensitive (P < 0.01), sensitive (0.01 < or = P < 0.05), or resistant (P > or = 0.05). Concordance was defined as a similar response category between cell lines. RESULTS: The concordance rate was 50% between each of the three cell lines when SPI were used as monotherapy. In combination regimens, the concordance rates were 33% (A549 and 273T), 17% (A549 and 201T), and 75% (273T and 201T). The 273T cells were most susceptible to therapy, having 11 (61%) highly sensitive responses, whereas A549 cells were least susceptible with 14 (78%) resistant responses. CONCLUSIONS: There is a substantial degree of variability between NSCLC cell lines in response to SPI, both alone and in combination with cisplatin.

Radiofrequency and microwave ablation of lung tumors.

Lung cancer is the most common cause of cancer-related mortality in the United States. Surgical resection remains the standard treatment for early stage, non-small cell lung cancer, and limited pulmonary metastases. However, many patients with resectable disease have significant co-morbidities which preclude surgical resection. Radiofrequency and microwave ablation are emerging modalities of treatment for these high-risk patients. Here, we review the principles, common devices in use, and treatment results of ablative therapy for lung tumors.

The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan.

RATIONALE: The role of computed tomography (CT) screening for lung cancer is controversial, currently under study, and not yet fully elucidated. OBJECTIVES: To report findings from initial and 1-year repeat screening low-radiation-dose CT of the chest and 3-year outcomes for 50- to 79-year-old current and ex-smokers in the Pittsburgh Lung Screening Study (PLuSS). METHODS: Notified of findings on screening CT, subjects received diagnostic advice from both study and personal physicians. Tracking subjects for up to three years since initial screening, we obtained medical records to document diagnostic procedures, lung cancer diagnoses, and deaths. MEASUREMENTS AND MAIN RESULTS: 3,642 and 3,423 subjects had initial and repeat screening. A total of 1,477 (40.6% of 3,624) were told about noncalcified lung nodules on the initial screening and, before repeat screening, 821 (55.6% of 1,477, 22.5% of 3,642) obtained one or more subsequent diagnostic imaging studies (CT, positron emission tomography [PET], or PET-CT). Tracking identified 80 subjects with lung cancer, including 53 subjects with tumor seen at initial screening. In all, 36 subjects (1.0% of the 3,642 screened), referred for abnormalities on either the initial or repeat screening, had a major thoracic surgical procedure (thoracotomy, video-assisted thoracoscopic surgery [VATS], median sternotomy, or mediastinoscopy) leading to a noncancer final diagnosis. Out of 82 subjects with thoracotomy or VATS to exclude malignancy in a lung nodule, 28 (34.1%) received a noncancer final diagnosis. Forty of 69 (58%) subjects with non-small cell lung cancer had stage I disease at diagnosis. CONCLUSIONS: Though leading to the discovery of early stage lung cancer, CT screening also led to many diagnostic follow-up procedures, including major thoracic surgical procedures with noncancer outcomes.

Clinical significance of radiologic characterizations in COPD.

COPD is a heterogeneous disorder with clinical assessment becoming increasingly multidimensional. We hypothesized HRCT phenotype would strongly influence clinical outcomes including health status, exacerbation frequency, and BODE. COPD subjects were characterized via the SF-12, SGRQ, MMRC, physiologic testing, and standardized volumetric chest HRCT. Visual semi-quantitative estimation of bronchial wall thickness (VBT) and automated quantification of emphysema percent and bronchial wall thickness were generated. Multivariate modeling compared emphysema severity and airway abnormality with clinical outcome measures. Poisson models were used to analyze exacerbation frequency. SGRQ and SF-12 physical component scores were influenced by FEV(1)% predicted, emphysema percent, and VBT. VBT scores > 2 (scale 0-48) were associated with increased exacerbation frequency (p = 0.009) in the preceding year adjusting for age, gender, emphysema percent, smoking history and FEV(1)% predicted, although this effect was attenuated by age. Emphysema percent correlated with total BODE score in unadjusted (r = 0.73; p < 0.0001) and adjusted (p < 0.0001) analyses and with BODE individual components. HRCT provides unique COPD phenotyping information. Radiographic quantification of emphysema and bronchial thickness are independently associated with SGRQ and physical component score of the SF-12. Bronchial thickness but not emphysema is associated with exacerbation frequency, whereas emphysema is a stronger predictor of BODE and its systemic components MMRC, 6MWT, and BMI. Future research should clarify whether CT parameters complement BODE score in influencing survival.

Surgical management of epiphrenic diverticula in the minimally invasive era.

BACKGROUND: Epiphrenic diverticula are rare outpouchings of the distal esophagus that infrequently require surgical intervention for the treatment of symptoms. In cases where surgical therapy is indicated, the traditional approach is through a thoracotomy. Advances in minimally invasive techniques have led to thoracoscopic and more recently laparoscopic management of epiphrenic diverticula. The purpose of this article is to review the literature on minimally invasive surgery for epiphrenic diverticula with particular attention to the operative approach and technique, surgical mortality and morbidity, and symptomatic outcomes. METHODS: A review of the literature limited to studies in the English language and performed on humans was conducted on PubMed using the following key words: "esophageal diverticula" and "epiphrenic". Articles retrieved by the PubMed search were reviewed. CONCLUSIONS: A minimally invasive approach to epiphrenic diverticula offers reduced operative mortality, decreased length of stay, and similar symptom relief compared with open surgery in the hands of experienced laparoscopic surgeons.