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Critical airway stenosis is challenging for surgeons and anesthesiologists to secure a reliable airway for ventilation. The use of venovenous (VV)-extracorporeal membrane oxygenation (ECMO) has been described as a strategy to provide adequate gas exchange in such instances. We present a case of a young female with a complex paratracheal mass significantly compressing the trachea; a planned intraoperative VV-ECMO was instituted to allow safe orotracheal intubation of a double-lumen endotracheal tube for lung isolation and tumor resection.

BACKGROUND: We sought to evaluate trends and clinical and economic outcomes between robotic-assisted lobectomy (RL), video-assisted thoracoscopic lobectomy (VL), and open pulmonary lobectomy (OL). METHODS: Patients who underwent a lobectomy for malignancy from January 1, 2008, to September 30, 2015, were identified in the Premier Healthcare Database. Propensity score matched (PSM) comparisons were performed between RL versus VL and RL versus OL. Patient characteristics were applied to generate propensity scores. In-hospital and perioperative 30-day outcomes and costs were compared within matched cohorts. RESULTS: From 2008 to 2015, there was a marked decline for OL (71% to 43%, P25 lobectomies were performed annually, the total cost of RL was comparable to VL (P=0.09) and OL (P=0.11). CONCLUSIONS: During the study period, the utilization of RL increased substantially and was associated with improved perioperative outcomes compared with VL and OL. When annual hospital volume was >25 cases, these clinical advantages persisted and there was no significant cost difference between RL, VL, or OL. RL is an effective and cost-comparable approach for lobectomy in patients with lung malignancy.

Investigations into the human 8-oxodGTPase, MutT Homolog 1 (MTH1), have risen sharply since the first-in-class MTH1 inhibitors were reported to be highly tumoricidal. However, MTH1 as a cancer therapeutic target is currently controversial because subsequently developed inhibitors did not exhibit similar cytotoxic effects. Here, we provide the first direct evidence for MTH1-independent 8-oxodGTPase function in human cancer cells and human tumors, using a novel ATP-releasing guanine-oxidized (ARGO) chemical probe. Our studies show that this functionally redundant 8-oxodGTPase activity is not decreased by five different published MTH1-targeting small molecules or by MTH1 depletion. Significantly, while only the two first-in-class inhibitors, TH588 and TH287, reduced cancer cell viability, all five inhibitors evaluated in our studies decreased 8-oxodGTPase activity to a similar extent. Thus, the reported efficacy of the first-in-class MTH1 inhibitors does not arise from their inhibition of MTH1-specific 8-oxodGTPase activity. Comparison of DNA strand breaks, genomic 8-oxoguanine incorporation, or alterations in cellular oxidative state by TH287 versus the noncytotoxic inhibitor, IACS-4759, contradict that the cytotoxicity of the former results solely from increased levels of oxidatively damaged genomic DNA. Thus, our findings indicate that mechanisms unrelated to oxidative stress or DNA damage likely underlie the reported efficacy of the first-in-class inhibitors. Our study suggests that MTH1 functional redundancy, existing to different extents in all cancer lines and human tumors evaluated in our study, is a thus far undefined factor which is likely to be critical in understanding the importance of MTH1 and its clinical targeting in cancer.

Physicians throughout the world, across various specialties, are faced with diagnostic challenges of appropriately identifying the source of hemotosysis, which could range from a simple treatable infection, to the more ominous massive hemorrhage from the aorta requiring emergency, life saving surgery. Aortobronchopulmonary fistula, which is an abnormal communication between the thoracic aorta and the pulmonary tree, is an uncommon but often lethal condition if not promptly surgically intervened. Over the decades, the underlying cause has shifted, from primarily due to an aortic infection, such as tuberculosis, to now secondarily as a result of endovascular repair of the intrathoracic aorta. The best treatment modality, whether open surgical repair, endovascular management, or hybrid approach continues to be debated given the high operative morbidity and mortality of open repair and need to address the pulmonary communication, with optimal management still undetermined.

Melanoma as a very aggressive type of cancer is still in urgent need of improved treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and arginine deiminase (ADI-PEG20) are two of many suggested drugs for treating melanoma. Both have shown anti-tumor activities without harming normal cells. However, resistance to both drugs has also been noted. Studies on the mechanism of action of and resistance to these drugs provide multiple targets that can be utilized to increase the efficacy and overcome the resistance. As a result, combination strategies have been proposed for these drug candidates with various other agents, and achieved enhanced or synergistic anti-tumor effect. The combination of TRAIL and ADI-PEG20 as one example can greatly enhance the cytotoxicity to melanoma cells including those resistant to the single component of this combination. It is found that combination treatment generally can alter the expression of the components of cell signaling in melanoma cells to favor cell death. In this paper, the signaling of TRAIL and ADI-PEG20-induced arginine deprivation including the main mechanism of resistance to these drugs and exemplary combination strategies is discussed. Finally, factors hampering the clinical application of both drugs, current and future development to overcome these hurdles are briefly discussed.

Objective The use of segmentectomy for peripheral T ≤2 cm, N0 non-small cell lung cancer (NSCLC) has increased in the last decade. We sought to compare clinical outcomes and overall survival between robotic, video-assisted thoracoscopic surgery (VATS), and open segmentectomy. Methods The National Cancer Database was queried for patients with clinical T ≤2 cm, N0 NSCLC who underwent segmentectomy via robotic, thoracoscopic (VATS), and open approaches (2010 to 2015). Univariate and Cox regression analyses were used to compare surgical approaches and to evaluate predictors of overall survival. Statistical analyses were done using SPSS Version 21.0. Results Segmentectomy was performed in 3,888 patients during the study period with 406 robotic, 1,837 VATS, and 1,645 open patients. VATS and robotic segmentectomy were performed more often at academic or comprehensive community cancer programs as compared to community programs ( P < 0.05). Conversion to open thoracotomy was similar between robotic and VATS groups when stratified by hospital volume. Lymph node yield was significantly higher for robotic (median = 6), compared to VATS (median = 5) or open (median = 4; P < 0.001). Length of stay was decreased for robotic versus open ( P < 0.01). No differences in 30-day readmissions ( P = 0.12) were observed among the 3 modalities. Overall survival was similar among groups ( P = 0.18). Conclusions Robotic segmentectomy provides similar clinical outcomes compared to other standardized approaches for clinical T ≤2 cm, N0 NSCLC. A higher lymph node yield in robotic segmentectomy was not associated with improved survival in this study population.

We present a rare case pulmonary metastasis of an early stage endometrial cancer nearly 20 years after curative surgical resection. Our patient had a remote history of hysterectomy for endometrial cancer in 1998 and later had Stage 1B right upper lobe lung cancer treated with lobectomy and adjuvant chemotherapy in 2014. She was found to have an enlarging nodule in the left upper lobe in 2018, which was thought to be another primary lung cancer. She underwent left upper lobe segmentectomy for an intraoperative diagnosis of adenocarcinoma by diagnostic wedge resection of the lung nodule. Final pathologic examination of the resected tumor demonstrated an endometrial adenocarcinoma. It is important for thoracic surgeons to remain vigilant, keeping secondary lung cancer in the differential diagnosis for patients with complex oncologic histories.

Critical airway stenosis presents a challenge for surgeons and anesthesiologists alike in securing a reliable airway for adequate ventilation. The use of veno-venous (VV) extra-corporeal membrane oxygenation (ECMO) has been described as a strategy to provide adequate gas exchange in such instances. We present a case of a young female with a complex paratracheal mass significantly compressing the trachea in whom a planned intra-operative VV ECMO was instituted to allow safe oro-tracheal intubation of a double lumen endotracheal tube for lung isolation and tumor resection.

Mediastinal paragangliomas are very uncommon neuroendocrine neoplasms. Due to their tissue of origin (sympathetic ganglia of the great vessels), they tend to arise deep within pericardial space and, more importantly, intimately attached to great vessels, which makes surgical resection, even with cardiopulmonary bypass, very challenging. This commentary accompanies the case report describing complex surgical management of a paraganglioma located in the anterior mediastinum that was initially thought to be a thymoma.

Stereotactic body radiation therapy (SBRT) is increasingly being offered for early stage non-small cell lung cancer (NSCLC). We sought to evaluate long-term survival outcomes after lobectomy and SBRT in patients aged 80 years or more with stage I NSCLC.The National Cancer Database was queried for patients with clinical stage IA and IB (size 40 mm or smaller) NSCLC who underwent SBRT or lobectomy. Only patients with no comorbidities were selected. Number of lymph nodes (LN) examined was used to stratify lobectomy patients into 0 LN, 1 to 6 LN, and 7 or more LN. Propensity score analysis was used to adjust treatment groups. Kaplan-Meier and multivariate Cox regression analysis were used for survival analysis.A total of 8964 patients with stage I NSCLC treated with lobectomy were compared with 286 patients who received SBRT. Using propensity matched pairs, lobectomy (7 LN or more) had significantly improved survival as compared with SBRT (median 74 vs 53.2 months, P.05); however, no survival differences were observed when 0 LN were sampled (median 53.8 vs 52.3 months, P = .88). In multivariate analysis, lobectomy was associated with significantly improved survival (hazard ratio 0.726; 95% confidence interval; 0.580 to 0.910; P = .005). In addition, age, sex, high grade, and tumor size were independent predictors of survival.Among healthy octogenarians with clinical stage I NSCLC who are good surgical candidates, lobectomy offers better survival than SBRT. Adequate LN dissection allows true nodal staging and opportunity for adjuvant treatment when unsuspected nodal metastases are found.

Background: EBUS-TBNA is an integral tool in the diagnosis and staging of lung cancer and other diseases involving mediastinal lymphadenopathy. Most studies attesting to the performance of EBUS-TBNA are prospective analyses performed under strict protocols. The objective of our study was to compare the accuracy of EBUS-TBNA to surgery in diagnosing hilar and mediastinal pathologies in a tertiary hospital, staffed by pulmonologists with and without formal interventional pulmonary training. Methods: We retrospectively analyzed subjects who underwent EBUS-TBNA followed by a confirmatory surgical procedure from January 2012 to December 2018. The primary outcome was to evaluate the accuracy of EBUS-TBNA in the diagnosis of all mediastinal disease. Secondary analyses determined the accuracy of EBUS-TBNA in cancer, NSCLC, and non-malignant lesions individually. Results: One hundred and forty-three subjects had an EBUS-TBNA procedure followed by surgery. EBUS-TBNA for all pathologies had an accuracy of 81.2% (CI 95% 73.8-87.4) and sensitivity of 55.1% (CI 95% 41.5-68.3). The accuracy and sensitivity of individual groups were: cancer (81.7, 48.8%), NSCLC (84, 48.3%), and non-malignancy (78.9, 60%). The NSCLC group had 15 false negatives and 5 (33.3%) of them were due to non-sampling of EBUS accessible nodes. Missed sampling led to a change in the final staging in 8.6% of NSCLC subjects. Conclusion: The accuracy of EBUS-TBNA across all groups was comparable to those reported previously. However, the sensitivity was comparatively lower. This was primarily due to the large number of EBUS-TBNA accessible lymph nodes that were not sampled. This data highlights the need for guidelines outlining the best sampling approach and lymph node selection.

Author(s): Tepper, Clifford G; Dang, Julie HT; Stewart, Susan L; Fang, Dao M; Wong, Kimberly A; Liu, Stephenie Y; Davis, Ryan R; Dao, Doan Y; Gregg, Jeffrey P; Torok, Natalie J; Chen, Moon S | Abstract: BACKGROUND:An exploratory study was performed to determine the prevalence of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs78409 [G] allele among the Hmong as a risk factor for nonalcoholic fatty liver disease (NAFLD). NAFLD/nonalcoholic steatohepatitis is the world's most common chronic liver disease and is expected to replace viral hepatitis as the leading cause of cirrhosis and potential precursor to hepatocellular carcinoma (HCC). Of all populations in California, the Hmong experience the highest risk of death from HCC and the highest prevalence of metabolic syndrome risk factors among Asians that predispose them to NAFLD. Here a genetic explanation was sought for the high rates of chronic liver disease among the Hmong. The literature pointed to the PNPLA3 rs738409 [G] allele as a potential genetic culprit. METHODS:Cell-free DNA was isolated from 26 serum samples previously collected in community settings. Quantitative polymerase chain reaction-based single-nucleotide polymorphism (SNP) genotyping was performed with a validated TaqMan SNP genotyping assay, and results were analyzed with TaqMan Genotyper software. RESULTS:The PNPLA3 rs738409 [CgG] variant occurred at a frequency of 0.46 (12 of 26; 95% confidence interval, 0.27-0.67). This carrier rate would rank the Hmong as the third highest population in the 1000 Genomes Project. CONCLUSIONS:Although this small sample size limits the generalizability, the high frequency rates of this allele along with the presence of metabolic syndrome risk factors warrant further studies into the etiology of NAFLD among the Hmong. Cancer 2018;124:1583-9. © 2018 American Cancer Society.

e20507 Background: It is reported that about 20% of patients with resected NSCLC adenocarcinoma harbor an EGFR driver mutation in the United States. Up to the recent approval of osimertinib in the adjuvant setting for resected EGFR + NSCLC based on the ADAURA trial, routine molecular profiling of early-stage lung cancer had not been standard of care. We hypothesize that there is a significant proportion of patients with resected adenocarcinoma with unknown EGFR status who could benefit from treatment that are missed with our current testing practices. Methods: We performed a retrospective analysis of Stage IB-IIIA lung adenocarcinomas resected at the University of Miami from 2014 to 2019. Eligible patients were identified from the Cancer Registry and information on EGFR mutation testing and treatment was obtained from chart review. We evaluated the prevalence of EGFR mutation testing in this population and outcomes based on EGFR mutation status. Disease free survival (DFS) and clinico-pathologic characteristics were evaluated. We estimated the number of patients that would have been eligible for EGFR testing and adjuvant osimertinib therapy in the pre-ADAURA era in our patient cohort. Results: A total of 120 patients had resected stage IB-IIIA adenocarcinoma during this five-year period (Stage IB 42.5%; Stage IIA 13.3%; Stage IIB 25%; Stage IIIA 19.2%) with a median age of 66 years. Most were females (59%), NHWs (51.5%), Hispanics (46.9%), and former smokers (66.7%). Out of patients with Stage IB-IIIA NSCLC with adenocarcinoma, 42.5% completed recommended adjuvant platinum-based chemotherapy. Only 40% of patients were referred for EGFR testing during this study period. The prevalence of EGFR mutations in this population was 10.8% (13 /120), but 59% of cases had no available EGFR testing. The most prevalent mutation was L858R (53.8%) followed by exon-19 deletions (30.8%). A total of 6 patients received an EGFR TKI therapy during the follow up period (2 in the adjuvant setting). With a median follow up of 12 mos, the rate of recurrence by stage was: Stage IB (3.9%); Stage IIB (10%); Stage IIIA (13%). Median time to disease progression or death was 13 months in this subgroup. There was no difference in disease free survival for patients with EGFR testing and those without results available in this short follow up period. Conclusions: Based on this retrospective review, up to 60% of patients with early-stage NSCLC with non-squamous histology have no available EGFR testing in the pre-ADAURA era. Of the anticipated 20% of patients with expected EGFR mutations based on historical controls, we have only identified half of patients that would have been eligible for adjuvant osimertinib. This study establishes the importance of upfront EGFR mutation testing in all NSCLC patients, not only to prognosticate, but also to identify the subset of patients who could benefit from adjuvant EGFR therapy.

Rates of venous thromboembolism are increased in thoracic malignancy; however, coagulation patterns are not established. We hypothesize that patients with esophageal and lung malignancy have similar hypercoagulable pre- and postoperative profiles as defined by rotational thromboelastometry (ROTEM). Prospective study was conducted in 47 patients with esophageal and lung cancer undergoing surgical resection. ROTEM evaluated pre/postoperative coagulation status. Patients with thoracic malignancy were hypercoagulable by ROTEM, but not by conventional coagulation tests. Preoperative hypercoagulability was higher in lung versus esophageal cancer (64 vs. 16%, p = 0.001). Lung cancer patients that were hypercoagulable preoperatively demonstrated decreased maximum clot firmness (MCF) (p = 0.044) and increased clot time (p = 0.049) after surgical resection, suggesting reversal of hypercoagulability. Resection of esophageal cancer increased hypercoagulability (16 vs. 56%, p = 0.002) via elevated MCF (reflecting platelet activity). Hypercoagulability remained at follow-up clinic for both lung and esophageal cancer patients. Hypercoagulability in patients with lung malignancies reversed following complete surgical resection, whereas hypercoagulability occurred only postoperatively in those with esophageal malignancies. In both, hypercoagulability was associated with fibrin and platelet function.

Conversion to lobectomy is typically performed when positive lymph nodes are found during intentional segmentectomy. Our objective was to evaluate survival after lobectomy and segmentectomy in patients with unsuspected nodal metastases.The National Cancer Database was queried for patients with clinical T1N0, pathological N1/N2 non-small cell lung cancer (NSCLC) who underwent either lobectomy or segmentectomy. Survival differences between the 2 groups were evaluated using a propensity score model. Cox regression analysis was used to evaluate predictors of overall survival, including adjuvant treatment. Statistical analysis was done using SPSS version 21.0 (IBM Corp, Armonk, NY).Between 2004 and 2015, unsuspected pathological N1 disease for clinical T1N0M0 NSCLC was found in 2.5% (228/9118) and 6.7% (8915/132,604) of patients who underwent segmentectomy and lobectomy, respectively. The incidence of unsuspected pathological N2 disease for clinical T1N0M0 NSCLC was 2.4% (224/9118) after segmentectomy and 3.9% (5192/132,604) after lobectomy. Using propensity matched pairs (227 pairs for N1 and 215 for N2), segmentectomy showed equivalent 5-year survival compared with lobectomy for the N1 group (41.9% vs 44.3%; P = .35), and N2 group (41.6% vs 37.2%; P = .99). In a multivariable model, adjuvant chemotherapy was associated with better survival of patients with unsuspected N1 (hazard ratio, 0.613; 95% confidence interval, 0.536-0.700; P .001) and N2 (hazard ratio, 0.684; 95% confidence interval, 0.583-0.802; P .001) nodal metastases.Survival is similar between lobectomy and segmentectomy for clinical T1N0 and unsuspected pathological N1/N2 nodal metastases. The use of adjuvant chemotherapy significantly improves survival in patients with lymph node metastasis (N1/N2) independent of the type of anatomic lung resection.

Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ). In patients with CF, abnormalities initiate in several organs before birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)–responsive CFTR G551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous CFTR G551D/G551D animals showed the greatest VX-770–mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival, and to reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first 2 weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.

e19011 Background: The National Lung Screening Trial (NLST) revealed a 20% reduction in lung cancer (LC) mortality when low-dose computed tomography (LDCT) was utilized for LC screening vs chest radiography. NLST participants were predominantly Non-Hispanic Whites, with only 1.8% Hispanics. The goal of our study was to investigate the attributes of a LC screening program in a largely Hispanic urban population and compare with NLST. Methods: We performed a retrospective analysis of 421 consecutive cases who underwent LDCT screening from 2016-2019 at University of Miami (UM), with similar inclusion criteria as the NLST. Demographic characteristics, smoking status, lung RADS, LC detection and compliance were examined & compared with NLST cohort using summary statistics and χ2 tests for categorical variables. Results: Demographic and smoking characteristics of the UM cohort didn’t resemble those of NLST LDCT cohort. UM cohort had a different racial and ethnic profile, with a higher percentage of Hispanics (47.3% vs 1.8%) and African Americans (15% vs 4.5%) in the UM cohort vs NLST cohort respectively (p < 0.001). UM cohort generally had lesser smoking intensity, and significantly fewer active smokers when compared to the NSLT cohort; 38.5% vs 48.1% respectively. The proportion of positive LDCT screens (Lung-RADS Class 3 or 4) in the UM cohort (14.1%) was almost similar to the NLST cohort (13.7%) (p = 0.81). The UM cohort had a higher LC detection rate (3.3%) than the NLST cohort (1.1%) (p < 0.001). In keeping with goals of screening, both cohorts had 50% or more LC cases detected at an early curable stage. Overall patient adherence to screening guidelines was more than 90% in NLST cohort; whereas almost a quarter of referred patients in UM cohort didn’t show for their initial decision-making visit and only 45% completed two or more scans. Conclusions: Our LDCT screening program was based in a Hispanic urban location (UM) with 47.3% Hispanics. Compared to NLST LDCT arm, the UM cohort had fewer active smokers, lighter smoking history, a more diverse population, somewhat higher LC detection rate, weaker adherence to screening related visits. More data is needed to understand obstacles to compliance with screening in minority populations.

Cellular homeostasis is dependent on a balance between DNA damage and DNA repair mechanisms. Cells are constantly assaulted by both exogenous and endogenous stimuli leading to high levels of reactive oxygen species (ROS) that cause oxidation of the nucleotide dGTP to 8-oxodGTP. If this base is incorporated into DNA and goes unrepaired, it can result in G > T transversions, leading to genomic DNA damage. MutT Homolog 1 (MTH1) is a nucleoside diphosphate X (Nudix) pyrophosphatase that can remove 8-oxodGTP from the nucleotide pool before it is incorporated into DNA by hydrolyzing it into 8-oxodGMP. MTH1 expression has been shown to be elevated in many cancer cells and is thought to be a survival mechanism by which a cancer cell can stave off the effects of high ROS that can result in cell senescence or death. It has recently become a target of interest in cancer because it is thought that inhibiting MTH1 can increase genotoxic damage and cytotoxicity. Determining the role of MTH1 in normal and cancer cells is confounded by an inability to reliably and directly measure its native enzymatic activity. We have used the chimeric A TP- r eleasing g uanine- o xidized (ARGO) probe that combines 8-oxodGTP and ATP to measure MTH1 enzymatic activity in colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) along with patient-matched normal tissue. MTH1 8-oxodGTPase activity is significantly increased in tumors across all three tissue types, indicating that MTH1 is a marker of cancer. MTH1 activity measured by ARGO assay was compared to mRNA and protein expression measured by RT-qPCR and Western blot in the CRC tissue pairs, revealing a positive correlation between ARGO assay and Western blot, but little correlation with RT-qPCR in these samples. The adoption of the ARGO assay will help in establishing the level of MTH1 activity in model systems and in assessing the effects of MTH1 modulation in the treatment of cancer.

The classification of specific cancers into distinct subgroups, based on emerging genomic technologies, has ushered in a new era of targeted therapeutics and companion diagnostics. This promise, however, is inconsistent with a model in which the growth of solid tumors, and their resistance to various chemotherapeutics, is driven by a small number of tumor-propagating cells whose transcriptome is unlikely to be captured by these technologies. We isolated such tumor propagating cells from a mouse model for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma. Medulloblastoma sphere cultures were enriched for the medulloblastoma progenitor marker SOX2, resistant to SHH inhibitors, and formed tumors in vivo. Surprisingly, these cultures, and their ability to self-renew were WNT-dependent. We show that Trp53 loss in these sphere cultures activated canonical WNT signaling and a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup medulloblastoma in vivo, in an on-target manner, leading to increased survival. Our results suggest that the tumor propagating cells driving the growth of bulk SHH-dependent medulloblastoma are themselves WNT dependent. Further, these results suggest WNT pathway inhibition as a novel therapeutic strategy to treat TRP53 deficient SHH-subgroup medulloblastoma patients, for whom few therapeutic options exist.

Pulmonary interstitial emphysema (PIE) is a common problem in premature neonates with respiratory distress syndrome. This condition is often related to barotrauma caused by mechanical ventilation or continuous positive airway pressure applied to low birth weight neonates. The clinical diagnosis can be challenging. However, after proper diagnosis, several interventions are available for successful management. We describe an infant who developed severe PIE with recurrent pneumothoraces and development of a persistent bronchopleural fistula shortly after repair of a hypoplastic aortic arch and description of successful lobectomy with the assistance of extracorporeal support (ECMO).

We report a venous bullet embolus into the left pulmonary artery following a gunshot wound to the right chest. The diagnosis and surgical management of migrating venous bullet emboli are reviewed.

The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor- propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a naturally occurring protein molecule in humans. Previous studies established that TRAIL is capable of inducing apoptosis of cells which express its cognate surface receptors. It is also known that TRAIL toxicity is specific for cancerous cells but not for normal ones. This has led to the development of TRAIL-derived drugs such as soluble recombinant TRAIL for the purpose of cancer treatment. However, resistance to TRAIL has also been reported in various cancer types including melanoma, a malignant tumor notorious for its resistance to therapies. In our research on the arginine-deprivation treatment for melanoma, we found that TRAIL can be synergistic with arginine depletion in causing cell death through apoptosis, and further investigations revealed that the cleavage of autophagic proteins such as Beclin-1 and Atg5 played an important part in switching autophagy toward apoptosis in melanoma cells. In this chapter, a more comprehensive review on TRAIL-induced cleavage of autophagic proteins in melanoma and relevant results from other types of cancers are discussed. The purpose of this review is to shed more light on the significance of this transition from autophagy to apoptosis through autophagic protein cleavage. These findings could be applied to the treatment of melanoma and other suitable cancers which use autophagy for survival after anticancer therapies.

Background Sirolimus (SIR) has been shown to stabilize the lung function in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). However, there is no long-term data on the prophylactic use of SIR in lung transplant recipients. This retrospective study examines the effects of SIR in the prevention of BOS. Methods From 1999 to 2009, 24 lung transplant recipients whose maintenance immunosuppression regimen consisted of tacrolimus (Tac), mycophenolate mofetil (MMF) or azathioprine (AZA), and prednisone (Pred), were switched to Tac, SIR, and Pred at 1 year after transplantation. From these 24 patients, 5 developed side effects that necessitated the cessation of SIR within 1 year, while 19 patients tolerated long-term use of SIR. The clinical outcomes of these 19 patients (SIR group) were compared with 22 lung transplant recipients whose immunosupression regimen consisted of Tac, MMF or AZA, and Pred from the time of transplant (MMF group). Survival rates and freedom from BOS were calculated by the Kaplan-Meier method. Results The SIR group had a lower incidence of BOS and viral infection ( p = 0.05), and higher survival rates ( p = 0.004). The SIR group had lower levels of Tac and received less Pred. The incidences of acute rejection, carcinoma, hypertension, and diabetes were similar between both groups. Conclusions Results from this study suggest that conversion to SIR 1 year after lung transplantation improves survival and decreases the development of BOS. Randomized studies with higher number of patients are needed to determine the prophylactic efficacy of sirolimus in preventing the development of BOS.

The extent of surgical resection for peripheral clinical T1N0M0 non-small cell lung cancer (NSCLC) ≤2 cm continues to be a matter of debate. In 1995, results from ‘The lung cancer study group’ trial established lobectomy as the standard of care. Since then, an extensive body of literature mainly composed of retrospective studies supports the use of radical anatomical segmentectomy, certainly for older patients with limited cardiopulmonary function. In a select group of patients, segmentectomy has been shown to be oncologically equivalent to lobectomy and it offers better preservation of pulmonary function (1,2). Paralleled with advancements in various diagnostic modalities, the understanding of segmental anatomy of pulmonary arteries, veins and bronchi continues to improve. Moreover, the risk of developing metachronous, recurrent or second primary lung cancer after therapeutic lung cancer resection surgery remains significant. Hence, patients with preserved lung function are more likely to withstand further therapeutic lung cancer surgery.

Background Adrenocortical carcinoma (ACC) is a rare neoplasm with a high propensity for locoregional recurrences and distant metastases for which there are no effective systemic therapies. This study was undertaken to determine outcomes of patients undergoing pulmonary metastasectomy for ACC. Methods A single-institution retrospective review was performed of patients undergoing pulmonary metastasectomy for ACC from 1979 to 2010. Results Twenty-six patients underwent 60 pulmonary metastasectomies. Fifteen patients (58%) underwent unilateral thoracotomy, 6 (23%) had staged thoracotomies, and 5 (19%) underwent median sternotomy as the initial thoracic procedure. Median number and size of lesions were 6 and 2 cm, respectively. Twenty-three patients (88%) were rendered free of disease in the lung, and 14 (54%) were rendered completely free of disease. Median overall and 5-year actuarial survivals from initial pulmonary metastasectomy were 40 months and 41%, respectively, with a median potential follow-up of 120 months. Median recurrence-free survival (RFS) and 5-year RFS for ipsilateral thoracic recurrences were 6 months, and 25%, respectively. The median RFS in the contralateral thorax was 5 months. Time to first recurrence after adrenalectomy and T stage of the primary tumor, but not adjuvant or neoadjuvant chemotherapy, were associated with increased overall survival after pulmonary metastasectomy. Conclusions This study represents the most comprehensive review of outcomes of patients undergoing pulmonary metastasectomy for ACC. Given the lack of effective systemic therapies, pulmonary metastasectomy may be beneficial in properly selected patients.

Pain is a major concern of cancer patients and a significant problem for therapy. Pain can become a predominant symptom in advanced cancers. In this open-label clinical study, the authors have treated 26 cancer patients who have been declared as terminal without the option of conventional treatment. These patients suffered from high levels of pain that was poorly managed by all available interventional approaches recommended by World Health Organization (WHO) guideline. The results indicate that intravenous infusion of dimethyl sulfoxide (DMSO) and sodium bicarbonate (SB) solution can be a viable, effective, and safe treatment for refractory pain in cancer patients. These patients had pain due to the disease progression and complication of chemotherapy and radiation. Moreover, the preliminary clinical outcome of 96-day follow-up suggests that the application of DMSO and SB solution intravenously could lead to better quality of life for patients with nontreatable terminal cancers. The data of this clinical observation indicates that further research and application of the DMSO and SB combination may help the development of an effective, safe, and inexpensive therapy to manage cancer pain.

Current treatment for advanced, metastatic melanoma is not very effective, and new modalities are needed. ADI-PEG20 is a drug that specifically targets ASS-negative malignant melanomas while sparing the ASS-expressing normal cells. Although laboratory research and clinical trials showed promising results, there are some ASS-negative cell lines and patients that can develop resistance to this drug. In this report, we combined ADI-PEG20 with another antitumor drug TRAIL to increase the killing of malignant melanoma cells. This combination can greatly inhibit cell growth (to over 80%) and also enhanced cell death (to over 60%) in four melanoma cell lines tested compared with control. We found that ADI-PEG20 could increase the cell surface receptors DR4/5 for TRAIL and that caspase activity correlated with the increased cell death. These two drugs could also increase the level of Noxa while decrease that of survivin. We propose that these two drugs can complement each other by activating the intrinsic and extrinsic apoptosis pathways, thus enhance the killing of melanoma cells.

The classification of specific cancers into distinct subgroups, based on emerging genomic technologies, has ushered in a new era of targeted therapeutics and companion diagnostics. This promise, however, is inconsistent with a model in which the growth of solid tumors, and their resistance to various chemotherapeutics, is driven by a small number of tumor-propagating cells whose transcriptome is unlikely to be captured by these technologies. We isolated such tumor propagating cells from a mouse model for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma. Medulloblastoma sphere cultures were enriched for the medulloblastoma progenitor marker SOX2, resistant to SHH inhibitors, and formed tumors in vivo. Surprisingly, these cultures, and their ability to self-renew were WNT-dependent. We show that Trp53 loss in these sphere cultures activated canonical WNT signaling and a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup medulloblastoma in vivo, in an on-target manner, leading to increased survival. Our results suggest that the tumor propagating cells driving the growth of bulk SHH-dependent medulloblastoma are themselves WNT dependent. Further, these results suggest WNT pathway inhibition as a novel therapeutic strategy to treat TRP53 deficient SHH-subgroup medulloblastoma patients, for whom few therapeutic options exist.

Analysis of biopsies from a recent clinical trial suggested that Depsipeptide FK228 (DP) inhibits Aurora kinase expression in lung cancer cells. The present study was undertaken to confirm and extend these observations.Aurora A and B mRNA levels in lung cancer cells were considerably higher than levels in normal pulmonary epithelia. DP, TSA and SAHA inhibited Aurora A, Aurora B and survivin expression with kinetics that were remarkably similar within individual cell lines, and appeared to coincide with p53 expression status. These effects were not observed following treatment with geldanamycins. Inhibition of Aurora B transcription coincided with decreased H3K9Ac and H3K4Me2 activation marks, and accumulation of H3K9Me3, as well as MBD1, MBD2 and MBD3 repression marks within the minimal Aurora B promoter. Knockdown of MBD1, -2 or -3 did not reproducibly abrogate inhibition of Aurora or survivin expression by DP or TSA. DP and TSA decreased expression and altered localization of Aurora kinases and survivin, resulting in mitotic catastrophe in lung cancer cells.Aurora A, and Aurora B levels in lung cancer cells and normal respiratory epithelia were assessed using quantitative RT-PCR techniques. These methods, as well as as Western blots were used to examine expression of Auroras A/B, and several related genes/proteins in lung cancer cells exposed to DP, TSA, SAHA and geldanamycins. Transient transfection promoter-reporter assays, and chromatin immunoprecipitation (ChIP) techniques were used to examine DP-mediated changes in activity and chromatin structure of the Aurora B promoter. Confocal imaging techniques were used to examine the effects of DP and TSA on mitotic progression in lung cancer cells.Novel transcriptional regulatory mechanisms involving Aurora kinase and survivin appear to contribute to cytotoxicity mediated by HDAC inhibitors in lung cancer cells.

Purpose Our published preclinical experiments have indicated that romidepsin mediates growth arrest and apoptosis in lung cancer cells (but not cultured normal bronchial epithelia) via chromatin remodeling mechanisms. Also, romidepsin has direct effects on survival and stress signal pathways. A phase II trial was performed to examine clinical and molecular responses mediated by this histone deacetylase (HDAC) inhibitor in patients with lung cancer. Patients and Methods Nineteen patients with neoplasms refractory to standard therapy received 4-hour romidepsin infusions (17.8 mg/m2) on days 1 and 7 of a 21-day cycle. Each full course of therapy consisted of 2 identical 21-day cycles. Plasma romidepsin levels were evaluated by liquid chromatography/mass spectrometry techniques. A variety of molecular endpoints were assessed in tumor biopsies via immunohistochemistry techniques. Long-oligo arrays were used to examine gene expression profiles in laser-captured tumor cells before and after romidepsin exposure, relative to lung cancer cells and adjacent normal bronchial epithelia from patients undergoing pulmonary resections. Results Nineteen patients were evaluable for toxicity assessment; 18 were evaluable for treatment response. Myelosuppression was dose limiting in 1 individual. No significant cardiac toxicities were observed. Maximum steady-state plasma romidepsin concentrations ranged from 384-1114 ng/mL. No objective responses were observed. Transient stabilization of disease was noted in 9 patients. Romidepsin enhanced acetylation of histone H3 (H3K9) as well as H4K16 and increased p21 expression in lung cancer cells. No obvious changes in phosho-extracellular signal–regulated kinase, ki67, or cleaved caspase-3 levels were noted. Although romidepsin appeared to induce a relatively small number of genes, this HDAC inhibitor diminished expression of > 1000 genes in laser-captured tumor cells. Interestingly, these genes, which appeared to be induced or repressed by romidepsin, were repressed or induced, respectively, in primary lung cancers relative to adjacent histologically normal bronchial epithelia, suggesting that romidepsin can reverse lung cancer gene expression in vivo. Conclusion Although exhibiting minimal clinical efficacy at this dose and schedule, romidepsin mediates biologic effects that might warrant further evaluation of this HDAC inhibitor in combination with novel agents targeting chromatin remodeling complexes, survival pathways, or death receptors in patients with lung cancer.

Rationale: Birt-Hogg-Dubesyndrome (BHDS) is an autosomal, dominantly inherited genodermatosis that predisposes to fibro- folliculomas, kidney neoplasms, lung cysts, and spontaneous pneumothorax. Objectives: We evaluated 198 patients from 89 families with BHDS to characterize the risk factors for pneumothorax and genotype- pulmonary associations. Methods: Helical computed tomography scans of the chest were used to screen for pulmonary abnormalities. BHD mutation data were used for genotype-pulmonary associations. We examined the relationship of pneumothorax with categorical parameters (sex, smoking history, and lung cysts) and continuous parameters (num- ber of cysts, lung cyst volume, and largest cyst diameter and vol- ume). Logistic regression analyses were used to identify the risk factors associated with pneumothorax. Measurements and Main Results: Twenty-four percent (48/198) of patients with BHDS had a history of pneumothorax. The presence of lung cysts was significantly associated with pneumothorax (p 0.006). Total lung cyst volume, largest cyst diameter and volume, and every parameter related to the number of lung cysts were significantly associated (p 0.0001) with pneumothorax. A logistic regression analysis showed that only the total number of cysts in the right parenchymal lower lobe and the total number of cysts located on the pleural surface in the right middle lobe were needed to classify a patient as to whether or not he or she was likely to have a pneumothorax. Exon location of the BHD mutation was associated with the numbers of cysts (p 0.0002). Conclusions: This study indicates that patients with BHDS have a significant association between lung cysts and spontaneous pneumothorax.

Optimal cytotoxic anticancer therapy, at the cellular level, requires effective and selective induction of cell death to achieve a net reduction of biomass of malignant tissues. Standard cytotoxic chemotherapeutics have been developed based on the observations that mitotically active cancer cells are more susceptible than quiescent normal cells to chromosomal, microtubular or metabolic poisons. More recent development of molecularly targeted drugs for cancer focuses on exploiting biological differentials between normal and transformed cells for selective eradication of cancers. The common thread of "standard" and "novel" cytotoxic drugs is their ability to activate the apoptosis-inducing machinery mediated by mitochondria, also known as the intrinsic death signaling cascade. The aim of this article is to provide an overview of the role of the mitochondria, an energy-generating organelle essential for life, in mediating death when properly activated by cytotoxic stresses.

Lung cancer is a disease with enormous global medical and economic impact that remains refractory to conventional treatment modalities. Recent insights regarding mechanisms pertaining to epigenetic regulation of gene expression during malignant transformation, together with the identification of agents that modulate chromatin structure provide new opportunities for the treatment and prevention of this lethal disease.

Purpose: The DNA methylation paradox, manifested as derepression of cancer-testis antigens, and silencing of tumor suppressors during malignant transformation, provides the rationale for the utilization of chromatin remodeling agents for cancer therapy. A phase I trial was done to examine pharmacokinetics, toxicities, and gene expression mediated by 5-aza-2′-deoxycytidine (DAC) in patients with thoracic malignancies. Experimental Design: Thirty-five patients with cancers refractory to standard therapy received continuous 72-hour DAC infusions using a phase I dose-escalation schema. Each full course of therapy consisted of two identical 35-day cycles. Plasma DAC levels were evaluated by liquid chromatography-mass spectrometry techniques. Quantitative reverse transcription-PCR, methylation-specific PCR, and immunohistochemical techniques were used to evaluate NY-ESO-1, MAGE-3, and p16 expression in tumor biopsies. Long oligonucleotide arrays were used to evaluate gene expression profiles in laser-captured tumor cells before and after DAC exposure. Results: Thirty-five patients were evaluable for toxicities; 25 were evaluable for treatment response. Myelosuppression constituted dose-limiting toxicity. The maximum tolerated dose of DAC was 60 to 75 mg/m2 depending on the number of prior cytotoxic chemotherapy regimens. No objective responses were observed. Plasma DAC concentrations approximated thresholds for gene induction in cultured cancer cells. Target gene induction was observed in 36% of patients. Posttreatment antibodies to NY-ESO-1 were detected in three patients exhibiting NY-ESO-1 induction in their tumor tissues. Complex, heterogeneous gene expression profiles were observed in pretreatment and posttreatment tissues. Conclusion: Prolonged DAC infusions can modulate gene expression in primary thoracic malignancies. These findings support further evaluation of DNA-demethylating agents alone or in combination with other regimens targeting induced gene products for the treatment of these neoplasms.

Background:Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia in the United States. Approximately 10–15% of meningococcal patients died despite antimicrobial therapies.Methods:We used vital records to assess meningococcal disease mortality in the United States during 19

Objective Malignant pleural mesothelioma is notoriously refractory to aggressive multimodality therapy. Epidermal growth factor receptor expression has been observed on malignant pleural mesothelioma cells. Epidermal growth factor receptor-mediated signaling promotes tumorigenesis and metastasis of cancer cells. The purpose of this study is to evaluate the ability of the epidermal growth factor receptor tyrosine kinase inhibitor PD153035 to abrogate the expression of prometastasis phenotypes in malignant pleural mesothelioma cells in vitro. Methods Epidermal growth factor receptor expression of malignant pleural mesothelioma cells and primary normal cells was quantitated by means of flow cytometry. PD153035-mediated growth inhibition was determined by means of 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan and clonogenic assays. Cell motility and invasion of extracellular matrix was evaluated with in vitro wound-healing and Matrigel invasion assays, respectively. Vascular epidermal growth factor levels in conditioned media were measured by using enzyme-linked immunosorbent assay. Results Epidermal growth factor receptor expression was detected on all 6 cultured malignant pleural mesothelioma cells, with 4 of 6 having normal receptor expression and 2 of 6 overexpressing the receptor. PD153035 suppressed cell motility and cell invasion through a Matrigel membrane, regardless of the baseline epidermal growth factor receptor expression. Decreased vascular epidermal growth factor production and significant inhibition of growth only occurred in malignant pleural mesothelioma cells that overexpress epidermal growth factor receptor. Conclusions Epidermal growth factor receptor tyrosine kinase inhibitor PD153035 significantly inhibited motility and invasion in malignant pleural mesothelioma cells in vitro, regardless of their epidermal growth factor receptor expression levels. Inhibition of epidermal growth factor receptor-dependent signaling might be a useful strategy to diminish malignant pleural mesothelioma recurrence after aggressive cytoreductive surgery.

cDNA arrays were used to examine gene induction in CALU-6 and H460 lung cancer cells mediated by sequential 5-aza 2'-deoxycytidine (DAC)/depsipeptide FK228 (DP) exposure in order to identify translational end points for clinical trials evaluating these agents. In both cell lines, sequential DAC/DP treatment induced expression of tissue factor pathway inhibitor-2 (TFPI-2), an inhibitor of Factor VII: tissue factor signal transduction known to diminish the malignant phenotype of cancer cells. TFPI-2 expression was diminished or absent in 16 of 32 cell lines established from thoracic malignancies. Sequential DAC/DP treatment induced TFPI-2 in cancer cells deficient for TFPI-2 expression in the basal state. Promoter methylation coincided with loss of TFPI-2 expression in a number of cancer lines. TFPI-2 promoter methylation was observed in one of five pulmonary adenocarcinomas, and seven of seven esophageal adenocarcinomas, but not corresponding normal tissues. DP enhanced acetylation of TFPI-2-associated histones in CALU-6 cells. DP or PDBU, alone, induced TFPI-2 expression in cancer cells deficient for TFPI-2 expression in the absence of promoter methylation. In these cells, DP-mediated TFPI-2 induction was abrogated by calphostin. Induction of TFPI-2 by distinct, yet cooperative mechanisms involving chromatin remodeling and PKC signaling strengthens the preclinical rationale for sequential administration of DNA demethylating agents and HDAC inhibitors in cancer patients. Furthermore, induction of TFPI-2 may be a useful surrogate marker of treatment response in individuals receiving sequential DAC/DP infusions.

Dysregulated signal transduction of growth factor receptors contributes to the process of malignant transformation by promoting cell proliferation, motility, and invasion through extracellular matrix as well as angiogenesis. Epidermal growth factor receptors (EGFR), and to a lesser extent HER2/neu, is overexpressed in the majority of nonsmall cell lung cancer (NSCLC) compared with normal tissue, making them ideal targets for the development of novel therapeutics for this disease. Multiple clinical trials have demonstrated that antireceptor strategies employing antagonistic monoclonal antibodies or low molecular weight tyrosine kinase inhibitors against EGFR are well tolerated and occasionally result in objective clinical responses in patients with advanced NSCLC. This report provides an overview of the molecular basis and the preclinical evidence supporting clinical development of anti-EGFR therapy as well as results of phase I-III clinical trials of these compounds in treating patients with solid tumors including NSCLC.

Objective: Virtual bronchoscopy is a novel technique making use of 3-dimensional reconstruction of 2-dimensional helical computed tomographic images for noninvasive evaluation of the tracheobronchial tree. This study was undertaken to evaluate the diagnostic potential of virtual bronchoscopy by comparing virtual bronchoscopic images with fiberoptic bronchoscopic findings in patients with thoracic malignant disease. Methods: Thirty-two consecutive patients with thoracic malignant tumors underwent virtual bronchoscopy for evaluation of suspected tracheobronchial lesions. For each virtual bronchoscopic examination, 200 to 300 contiguous 1.25-mm images of the thorax were obtained in only one or two 17-second breath holds by using a multislice computed tomographic scanner. Virtual bronchoscopy images were reconstructed and interpreted blind to the actual endoscopic findings. Results of virtual bronchoscopy were compared with fiberoptic bronchoscopic findings in 20 patients. Results: Anatomic computer simulation of the bronchial tree was successfully created in all patients. In 7 (35%) of 20 patients, results of fiberoptic bronchoscopy were found to be within normal limits. In all patients with normal anatomy, virtual bronchoscopy accurately correlated with the fiberoptic findings. Thirteen (65%) patients had a total of 22 abnormal findings on fiberoptic bronchoscopy. Virtual bronchoscopy detected 18 of 22 abnormal fiberoptic bronchoscopic findings: 13 of 13 obstructive lesions, 5 of 6 endoluminal lesions, and 0 of 3 mucosal lesions. The sensitivity of virtual bronchoscopy was 100% for obstructive lesions, 83% for endoluminal lesions, 0% for mucosal lesions, and 82% for all abnormalities; the specificity of virtual bronchoscopy was 100%. Conclusions: Preliminary evaluation indicates that virtual bronchoscopy may be a promising and noninvasive modality for identifying bronchial obstructions and endoluminal lesions, as well as for assessing the tracheobronchial tree beyond stenoses. However, at present, virtual bronchoscopy does not enable the detection of subtle mucosal lesions, and as such, this modality may not be appropriate for identifying premalignant lesions in the respiratory tract. Although fiberoptic bronchoscopy remains the standard modality for evaluating airway patency and mucosal lesions, virtual bronchoscopy may provide additional information that may be useful in the management of pulmonary malignant tumors. J Thorac Cardiovasc Surg 2002;123:967-72

Objective: Although well characterized in several solid tumors, the effects of Fas/Fas ligand interactions in malignant pleural mesothelioma cells have not been defined. The present study was undertaken to examine the functional status of the Fas/Fas ligand pathway in malignant pleural mesothelioma cells and to determine the feasibility of targeting this death-signal pathway for molecular intervention in patients with mesotheliomas. Methods: Fas expression in primary normal human bronchial epithelial cells and 6 malignant pleural mesothelioma cell lines was quantified by means of flow cytometry. The caspase components of the Fas-mediated apoptotic pathway were evaluated by means of Western blot techniques. Soluble Fas ligand–mediated cytotoxicity and apoptosis were evaluated by means of MTS and TUNEL assays, respectively. Cisplatin (3 μg/mL) and lymphokine-activated killer cells were used to enhance mesothelioma sensitivity to soluble Fas ligand. An H2373 nude mouse xenograft model of malignant pleural mesothelioma was established to assess the in vivo effects of soluble Fas ligand. Results: Four of 6 malignant pleural mesothelioma lines exhibited high levels of Fas expression, and 2 of 4 were inherently susceptible to soluble Fas ligand–mediated cytotoxicity (soluble Fas ligand 50% inhibitory concentration