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Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the protumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conserved noncoding sequence of the Csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis, thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAMs) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti-PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non-small cell lung carcinoma (NSCLC) patients and critically regulates their immunosuppressive activity. The natural compound β-glucan downregulates c-Maf expression on macrophages, leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.

Background: Previous studies suggested that the metabolism is differently reprogrammed in the major subtypes of non-small cell lung cancer (NSCLC), squamous cell carcinomas (SCC) and adenocarcinomas (AdC). However, a comprehensive analysis of this differential metabolic reprogramming is lacking., Methods: Publicly available gene expression data from human lung cancer samples and cell lines were analysed. Stable isotope resolved metabolomics were performed on SCC and ADC tumours in human patients and in freshly resected tumour slices., Results: Analysis of multiple transcriptomics data from human samples identified a SCC-distinguishing enzyme gene signature. SCC tumours from patients infused with [U- 13 C]-glucose and SCC tissue slices incubated with stable isotope tracers demonstrated differential glucose and glutamine catabolism compared to AdCs or non-cancerous lung, confirming increased activity through pathways defined by the SCC metabolic gene signature. Furthermore, the upregulation of Notch target genes was a distinguishing feature of SCCs, which correlated with the metabolic signature. Notch and MYC-driven murine lung tumours recapitulated the SCC-distinguishing metabolic reprogramming. However, the differences between SCCs and AdCs disappear in established cell lines in 2D culture., Conclusions: Our data emphasise the importance of studying lung cancer metabolism in vivo. They also highlight potential targets for therapeutic intervention in SCC patients including differentially expressed enzymes that catalyse reactions in glycolysis, glutamine catabolism, serine, nucleotide and glutathione biosynthesis.

Background: Survival following retransplantation with a single lung is worse than after double lung transplant. We sought to characterize survival of patients who underwent lung retransplantation based on the type of their initial transplant, single or double., Methods: The United Network for Organ Sharing database was queried for adult patients who underwent lung retransplantation from 2005 onward. Patients were excluded if they underwent more than one retransplantation. The patient population was divided into 4 groups based on first followed by second transplant type, respectively: single then single, double then single, double then double, and single then double. Descriptive analysis and Kaplan-Meier survival analysis were performed. A p value less than 0.05 was considered significant., Results: A total of 410 patients underwent retransplantation in the study time period. Overall mean survival for all patients who underwent retransplantation was 1,213 days. Kaplan-Meier survival analysis demonstrated no difference in graft survival between the 4 study groups (p = 0.146)., Conclusions: There was no significant difference in graft survival between recipients of retransplant with single or double lungs when stratified by previous transplant type. These results suggest that when retransplantation is performed, single lung retransplantation should be considered, regardless of previous transplant type, in an effort to maximize organ resources., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Quantitative analysis of specific exhaled carbonyl compounds (ECCs) has shown promise for the detection of lung cancer. The purpose of this study is to demonstrate the normalization of ECCs in patients after lung cancer resection., Methods: Patients from a single center gave consent and were enrolled in the study from 2011 onward. Breath analysis was performed on lung cancer patients before and after surgical resection of their tumors. One liter of breath from a single exhalation was collected and evacuated over a silicon microchip. Carbonyls were captured by oximation reaction and analyzed by mass spectrometry. Concentrations of four cancer-specific ECCs were measured and compared by using the Wilcoxon test. A given cancer marker was considered elevated at 1.5 or more standard deviations greater than the mean of the control population., Results: There were 34 cancer patients with paired samples and 187 control subjects. The median values after resection were significantly lower for all four ECCs and were equivalent to the control patient values for three of the four ECCs., Conclusions: The analysis of ECCs demonstrates reduction to the level of control patients after surgical resection for lung cancer. This technology has the potential to be a useful tool to detect disease after lung cancer resection. Continued follow-up will determine whether subsequent elevation of ECCs is indicative of recurrent disease., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. In this study, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole β-glucan particles (WGP; a ligand to engage and activate dectin-1, oral treatment in vivo) significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of polymorphonuclear MDSC but not monocytic MDSC (M-MDSC), and decreased polymorphonuclear MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80(+)CD11c(+) cells in vitro that served as potent APC to induce Ag-specific CD4(+) and CD8(+) T cell responses in a dectin-1-dependent manner. Additionally, Erk1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c(+) cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated s.c. with Lewis lung carcinoma cells. This effect was dependent on the dectin-1 receptor. Strikingly, patients with non-small cell lung carcinoma that had received WGP treatment for 10-14 d prior to any other treatment had a decreased frequency of CD14(-)HLA-DR(-)CD11b(+)CD33(+) MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Objective: Several volatile carbonyl compounds in exhaled breath have been identified as cancer-specific markers. The potential for these markers to serve as a screening test for lung cancer is reported., Methods: Patients with computed tomography-detected intrathoracic lesions and healthy control participants were enrolled from 2011 onward. One liter of breath was collected from a single exhalation from each participant. The contents were evacuated over a silicon microchip, captured by oximation reaction, and analyzed by mass spectrometry. Concentrations of 2-butanone, 3-hydroxy-2-butanone, 2-hydroxyacetaldehyde, and 4-hydroxyhexanal were measured. The overall population was divided into 3 groups: those with lung cancer, benign disease, and healthy controls. An elevated cancer marker was defined as ≥1.5 SDs above the mean concentration of the control population. One or more elevated cancer markers constituted a positive breath test., Results: In all, 156 subjects had lung cancer, 65 had benign disease, and 194 were healthy controls. A total of 103 (66.0%) lung cancer patients were early stage (stage 0, I, and II). For ≥1 elevated cancer marker, breath analysis showed a sensitivity of 93.6%, and a specificity of 85.6% for lung cancer patients. Additionally, 83.7% of stage I tumors ≤2 cm were detected; whereas only 14% of the control population tested positive. In a comparison of cancer to benign disease, specificity was proportional to the number of elevated cancer markers present., Conclusions: Screening using a low-dose CT scan is associated with high cost, repeated radiation exposure, and low accrual. The high sensitivity, convenience, and low cost of breath analysis for carbonyl cancer markers suggests that it has the potential to become a primary screening modality for lung cancer., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Tumor-associated macrophages (TAM) with an alternatively activated phenotype have been linked to tumor-elicited inflammation, immunosuppression, and resistance to chemotherapies in cancer, thus representing an attractive target for an effective cancer immunotherapy. In this study, we demonstrate that particulate yeast-derived β-glucan, a natural polysaccharide compound, converts polarized alternatively activated macrophages or immunosuppressive TAM into a classically activated phenotype with potent immunostimulating activity. This process is associated with macrophage metabolic reprograming with enhanced glycolysis, Krebs cycle, and glutamine utilization. In addition, particulate β-glucan converts immunosuppressive TAM via the C-type lectin receptor dectin-1-induced spleen tyrosine kinase-Card9-Erk pathway. Further in vivo studies show that oral particulate β-glucan treatment significantly delays tumor growth, which is associated with in vivo TAM phenotype conversion and enhanced effector T cell activation. Mice injected with particulate β-glucan-treated TAM mixed with tumor cells have significantly reduced tumor burden with less blood vascular vessels compared with those with TAM plus tumor cell injection. In addition, macrophage depletion significantly reduced the therapeutic efficacy of particulate β-glucan in tumor-bearing mice. These findings have established a new paradigm for macrophage polarization and immunosuppressive TAM conversion and shed light on the action mode of β-glucan treatment in cancer., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Anabolic biosynthesis requires precursors supplied by the Krebs cycle, which in turn requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the activity of pyruvate carboxylase (PC) and glutaminase 1 (GLS1), respectively. Due to their rapid proliferation, cancer cells have increased anabolic and energy demands; however, different cancer cell types exhibit differential requirements for PC- and GLS-mediated pathways for anaplerosis and cell proliferation. Here, we infused patients with early-stage non-small-cell lung cancer (NSCLC) with uniformly 13C-labeled glucose before tissue resection and determined that the cancerous tissues in these patients had enhanced PC activity. Freshly resected paired lung tissue slices cultured in 13C6-glucose or 13C5,15N2-glutamine tracers confirmed selective activation of PC over GLS in NSCLC. Compared with noncancerous tissues, PC expression was greatly enhanced in cancerous tissues, whereas GLS1 expression showed no trend. Moreover, immunohistochemical analysis of paired lung tissues showed PC overexpression in cancer cells rather than in stromal cells of tumor tissues. PC knockdown induced multinucleation, decreased cell proliferation and colony formation in human NSCLC cells, and reduced tumor growth in a mouse xenograft model. Growth inhibition was accompanied by perturbed Krebs cycle activity, inhibition of lipid and nucleotide biosynthesis, and altered glutathione homeostasis. These findings indicate that PC-mediated anaplerosis in early-stage NSCLC is required for tumor survival and proliferation.

Background: Historically, double lung transplantation survival rates are higher than those of single lung transplantation, but in critically ill patients a single lung transplant, with less associated operative morbidity, could afford a better outcome. This article evaluates how survival is affected in patients who have a high lung allocation score (LAS) and receive a single versus a double lung transplant., Methods: The UNOS Thoracic Transplant Database for lung transplants from January 2005 to June 2012 was used for analysis. Propensity matching was used to minimize differences between the high and low LAS groups and between single and double lung transplants in the high LAS group., Results: Within this database, there were 8,778 patients, of whom 8,050 had an LAS less than 75 and 728 had an LAS greater than or equal to 75. Kaplan-Meier survival curves stratified by high and low LAS, and by single versus double lung transplants, showed a marked decrease in survival (p<0.001) in those with a high LAS who received a single lung transplant when compared with those with a high LAS who received a double lung transplant. This was a much greater difference in survival than was present in the low LAS patient population., Conclusions: Despite a higher operative morbidity, patients who had a high LAS did substantially better in terms of survival if two lungs were transplanted rather than only one, with a larger difference in survival than for patients with a lower LAS., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: The analysis of exhaled breath is a promising noninvasive tool for the diagnosis of lung cancer, but its clinical relevance has yet to be established. We report the analysis of exhaled volatile carbonyl compounds for the identification of specific carbonyl cancer markers to differentiate benign pulmonary disease from early-stage lung cancer and to compare its diagnostic accuracy with positron emission tomography (PET) scans., Methods: Aminooxy-coated silicon microchips were used for the selective capture of exhaled carbonyls by an oximation reaction. Breath samples were collected then directed through the silicon chips by applying a vacuum. Carbonyl adducts were analyzed by Fourier transform mass spectrometry. Eighty-eight control subjects, 107 patients with lung cancer (64 stage 0, I, or II), 40 patients with benign pulmonary disease, and 7 patients with a solitary pulmonary metastasis participated. Analysis of cancer markers was performed blinded to the pathologic results., Results: Four carbonyls were defined as cancer markers with significantly higher concentrations in patients with lung cancer. The number of increased cancer markers distinguished benign disease from both early and stage III and IV lung cancer. For early-stage disease, defining greater than 2 increased markers as diagnostic of lung cancer resulted in 83% sensitivity and 74% specificity. PET scans for this same cohort resulted in 90% sensitivity but only 39% specificity. Markers normalized for 3 of the 4 markers after resection of the lung cancer., Conclusions: Analysis of specific exhaled carbonyls can differentiate early lung cancer from benign pulmonary disease. Breath analysis was more specific than PET for a lung cancer diagnosis. Judicious use of these data may expedite the care of patients with lung cancer., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Polymorphonuclear neutrophils (PMNs), the main effectors of the innate immune system, have rarely been considered as an anticancer therapeutic tool. However, recent investigations using animal models and preliminary clinical studies have highlighted the potential antitumor efficacy of PMNs. In the current study, we find that PMNs from some healthy donors naturally have potent cancer-killing activity against 4 different human cancer cell lines. The killing activity appears to be cancer cell-specific since PMNs did not kill primary normal epithelial cells or an immortalized breast epithelial cell line. Transfecting the immortalized mammary cells with plasmids expressing activated forms of the rat sarcoma viral oncogene homolog (Ras) and teratocarcinoma oncogene 21 (TC21) oncogenes was sufficient to provoke aggressive attack by PMNs. However, transfection with activated Ras-related C3 botulinum toxin substrate (Rac1) was ineffective, suggesting specificity in PMN-targeting of neoplastic cells. Furthermore, PMNs from lung cancer patients were also found to exhibit relatively poor cancer-killing activity compared to the cytolytic activity of the average healthy donor. Taken together, our results suggest that PMN-based treatment regimens may represent a paradigm shift in cancer immunotherapy that may be easily introduced into the clinic to benefit a subset of patients with PMN-vulnerable tumors.

The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the interconversion of pyruvate and lactate, is upregulated in human cancers, and is associated with aggressive tumor outcomes. Here we use an inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by reactivation of mitochondrial function in vitro, but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer-initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC, including cancer stem cell-dependent drug-resistant tumors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Surgical resection of bronchopulmonary carcinoid tumors can be curative and remains the primary treatment modality. There are limited data to delineate the optimal extent of resection for this disease., Methods: A retrospective review of the 3,270 patients diagnosed with typical and atypical carcinoid tumors between 2000 and 2007 in the Surveillance Epidemiology and End Results registry was performed., Results: The mean follow-up period was 46 months (range, 1-95 mo). Overall survival (OS) and disease-specific survival at 5 years was 80% and 90%, respectively. The mean OS was slightly better in the lobectomy group compared with those undergoing sublobar resection (86 vs 83 mo; P = .008). After adjusting for age, this finding was no longer present (P = .513). By using multivariate analysis, sublobar resection was noninferior to lobectomy with regard to disease-specific survival and OS (P < .05)., Conclusions: Compared with lobectomy, sublobar resection is associated with noninferior survival in patients with typical carcinoid of the lung., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Metabolomics provides a readout of the state of metabolism in cells or tissue and their responses to external perturbations. For this reason, the approach has great potential in clinical diagnostics. Clinical metabolomics using stable isotope resolved metabolomics (SIRM) for pathway tracing represents an important new approach to obtaining metabolic parameters in human cancer subjects in situ. Here we provide an overview of the technology development of labeling from cells in culture and mouse models. The high throughput analytical methods NMR and mass spectrometry, especially Fourier transform ion cyclotron resonance, for analyzing the resulting metabolite isotopomers and isotopologues are described with examples of applications in cancer biology. Special technical considerations for clinical applications of metabolomics using stable isotope tracers are described. The whole process from concept to analysis will be exemplified by our on-going study of nonsmall cell lung cancer (NSCLC) metabolomics. This powerful new approach has already provided important new insights into metabolic adaptations in lung cancer cells, including the upregulation of anaplerosis via pyruvate carboxylation in NSCLC.

Objectives: We sought to assess the effects of a localized anastomosis between the aorta and left lower lobe pulmonary artery on flows through central vessels and on the vascular reactivity of small pulmonary arteries distal or contralateral to the shunt., Methods: Flow rates in major vessels and tensions from small pulmonary arteries from the left and right lower lobes were determined 48 hours after creation of an end-to-side anastomosis of the left lower lobe pulmonary artery to the aorta., Results: Anastomoses increased flow through the left lower lobe pulmonary artery from 194±6 to 452±18 mL/min immediately after anastomosis to 756±19 mL/min by the time of harvest (n=88, P<.05). Flow rates in main pulmonary arteries from hosts with anastomoses were lower (557±26 vs 1033±244 mL/min), whereas aortic root flows were not different from control values (1370±53 vs 1120±111 mL/min; P=.07). Wet/dry weights of both lungs and aortic flow rates were proportional to shunt flow rates. Pulmonary artery rings harvested from the right (unshunted) lobes of high-flow hosts exhibited increased reactivity to the thromboxane agonist U46619 and phenylephrine relative to those of left pulmonary arteries from the same animal or those of control hosts., Conclusions: Our studies are the first to identify enhanced reactivity of pulmonary arteries in a lung contralateral to a localized high-output shunt between an aorta and pulmonary artery. These observations suggest that patients with localized systemic-to-pulmonary shunt could exhibit modified vascular tone in remote pulmonary arteries., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

A subtype of non-small cell lung cancer, bronchioalveolar adenocarcinoma (BAC), is more prevalent in Asian female non-smokers, and is more likely to respond to treatment with tyrosine kinase inhibitors such as erlotinib and gefitinib. Nuclear magnetic resonance and mass spectrometry-based metabolomic analysis of extracts from two different lung lesions and surrounding non-cancerous tissues of a BAC patient showed novel protein and phospholipid-associated metabolic differences that correlated with tumor development as well as PET and erlotinib sensitivity.

Unilateral pulmonary artery agenesis is a rare congenital anomaly often associated with other cardiovascular abnormalities. It is usually diagnosed and surgically treated in childhood. Subjects without associated cardiac anomalies (isolated unilateral pulmonary artery agenesis) may be asymptomatic or have recurrent respiratory infections. We report a case of left pulmonary artery agenesis in a 35-year-old man complicated by hemoptysis and treated by pneumonectomy. Physicians should be aware of unilateral pulmonary artery agenesis presenting later in life as a source of chronic respiratory symptomatology or hemoptysis.

Background: Morbidity and mortality remain significant for transthoracic (TT) and transhiatal (TH) esophagectomy. We report a case-specific approach employing either resection to minimize perioperative morbidity and mortality., Methods: All primary esophageal resections performed for benign and malignant esophageal disease were reviewed over a 10-year period. The operative approach was tailored to the location and extent of disease and the physiologic reserve of the patient., Results: In all, 115 patients underwent esophagectomy for benign (25) and malignant (90) disease. Fifty-six TT and 59 TH resections were performed. Four emergent TT cases did not have reconstruction. There was 1 hospital mortality. Perioperative transfusion was avoided in 65 patients. Respiratory complications occurred in 15. Three patients had a cervical anastomotic leak requiring open wound drainage. No association between resection type and complication was evident., Conclusions: The judicious use of both TT and TH esophagectomy resulted in an operative mortality of less than 1%, reduced operative blood loss, and a relatively low rate of perioperative complications.

We recently reported localized increased pulmonary arterial resistance, neointimal lesions, and medial thickening induced by aortopulmonary anastomosis in young pigs. This model was used to investigate changes in expression of genes potentially involved in pulmonary vascular remodeling employing a high throughput Atlas Human Cardiovascular Array carrying approximately 600 cardiovascular-related cDNA sequences. Data were confirmed by Northern analysis, Western blots, and histological examination. With the use of lower stringency conditions for hybridization, 56% of the 588 human genes on the array showed visible signal after autoradiography. Approximately 10% of the genes with visible hybridization were altered by shunt-induced high flow. Extracellular matrix and cell adhesion molecules were the most highly represented group of upregulated genes. To our knowledge, our data are the first to demonstrate flow-induced changes in gene expression using a combination of cross species cDNA arrays, homologous hybridization, immunospecific protein, and histology. Our observations expand the list of genes as putative candidates in pulmonary vascular remodeling and support the utility of cross-species microarray analysis in such applications.

Our purpose was to determine if abundance of proteins underlying nitric oxide (NO) and prostanoid production is altered in lungs of piglets with aortopulmonary shunts. We also evaluated whether shunted piglets exhibit abnormal pulmonary vascular responses to ACh, an endothelium-dependent agent that mediates dilation in part by NO and prostanoid release. At age 4-5 days, piglets underwent either a sham operation or placement of an aortopulmonary shunt. At age 5-6 wk, pulmonary arterial pressure (Ppa) and cardiac output by the thermodilution technique were measured in anesthetized piglets. Ppa responses to the endothelium-dependent agent, ACh, and to a non-endothelium-dependent agent, papaverine, were measured in perfused lungs. An immunoblot technique was applied to homogenates of whole lung tissue and two size groups of pulmonary arteries. In shunted piglets, Ppa and cardiac output were elevated, and Ppa responses to papaverine were reduced. ACh responses were not decreased when expressed relative to Ppa dilation with papaverine. Endothelial nitric oxide synthase (eNOS), cyclooxygenase-1, cyclooxygenase-2, prostacyclin synthase, and thromboxane synthase amounts were unaltered in all lung tissue homogenates. Altered abundance of eNOS and/or prostanoid enzymes does not contribute to the blunted dilation and the elevation in Ppa associated with aortopulmonary shunts in newborn piglets.

The occurrence of a flow "steal phenomenon" from a large branch of the internal mammary artery (IMA) is rare and its pathogenesis is still controversial. We describe a case of a patent large anomalous left IMA branch which produced recurrent angina 3 years post MIDCAB. Transcatheter coil obliteration of the vessel produced symptomatic relief. However, six months later, chest pains recurred in association with unwinding of the coil and recannulization of the collateral vessel. Successful ligation of the culprit branch using a VATS approach is presented.

Objectives: We characterized the morphology and vasomotor responses of a localized, high-flow model of pulmonary hypertension., Methods: An end-to-side anastomosis was created between the left lower lobe pulmonary artery and the aorta in 23 piglets. Control animals had a thoracotomy alone or did not have an operation. Eight weeks later, hemodynamic measurements were made. Then shunted and/or nonshunted lobes were removed for determination of vascular resistance and compliance by occlusion techniques under conditions of normoxia, hypoxia (FIO (2) = 0.03), and inspired nitric oxide administration. Quantitative histologic studies of vessel morphology were performed., Results: Eighty-three percent of animals having a shunt survived to final study. Aortic pressure, main pulmonary artery and wedge pressures, cardiac output, blood gases, and weight gain were not different between control pigs and those receiving a shunt. Six of 9 shunted lobes demonstrated systemic levels of pulmonary hypertension in vivo. Arterial resistance was higher (24.3 +/- 12.0 vs 1.3 +/- 0. 2 mm Hg. mL(-1). s(-1), P =.04) and arterial compliance was lower (0. 05 +/- 0.01 vs 0.16 +/- 0.03 mL/mm Hg, P =.02) in shunted compared with nonshunted lobes. Hypoxic vasoconstriction was blunted in shunted lobes compared with nonshunted lobes (31% +/- 13% vs 452% +/- 107% change in arterial resistance, during hypoxia, P <.001). Vasodilation to inspired nitric oxide was evident only in shunted lobes (34% +/- 6% vs 1.8% +/- 8.2% change in arterial resistance during administration of inspired nitric oxide, P =.008). Neointimal and medial proliferation was found in shunted lobes with approximately a 10-fold increase in wall/luminal area ratio., Conclusions: An aorta-lobar pulmonary artery shunt produces striking vasculopathy. The development of severe pulmonary hypertension within a short time frame, low mortality, and localized nature of the vasculopathy make this model highly attractive for investigation of mechanisms that underlie pulmonary hypertension.

Background: Because of the transient nature of pharyngeal phase dysphagia, posttranshiatal esophagectomy patients provide a model for studying the correlation of dysphagic symptoms and aspiration with deglutitive biomechanics., Methods: We studied 8 transhiatal esophagectomy patients (age range, 51 to 78 years) and 8 normal age-matched controls in upright position using lateral and anteroposterior (AP) projection videofluoroscopy during three 5 mL barium swallows., Results: The maximum upper esophageal sphincter (UES) AP diameter and maximum anterior excursion of the hyoid bone in patients with transhiatal esophagectomy who experienced aspiration (6.2+/-0.6 and 9.0+/-2.0 mm, respectively) were significantly smaller than those of age-matched normal controls (9.4+/-0.7 and 17.0+/-1.0 mm, respectively). Resolution of aspiration was associated with a significant increase in AP diameter of the UES as well as anterior and superior excursion of the hyoid bone (p<0.05)., Conclusions: Dysphagic symptoms and aspiration in posttranshiatal esophagectomy patients are associated with significant abnormalities of deglutitive biomechanics. Improvement in deglutitive biomechanics is associated with resolution of dysphagic symptoms as well as postdeglutitive aspiration in these patients.

Little information is available regarding the vasoactive effects of epoxyeicosatrienoic acids (EETs) in the lung. We demonstrate that 5, 6-, 8,9-, 11,12-, and 14,15-EETs contract pressurized rabbit pulmonary arteries in a concentration-dependent manner. Constriction to 5,6-EET methyl ester or 14,15-EET is blocked by indomethacin or ibuprofen (10(-5) M), SQ-29548, endothelial denuding, or submaximal preconstriction with the thromboxane mimetic U-46619. Constriction of pulmonary artery rings to phenylephrine is blunted by treatment with the epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide. Pulmonary arteries and peripheral lung microsomes metabolize arachidonate to products that comigrate on reverse-phrase HPLC with authentic regioisomers of 5,6-, 8,9-, 11,12-, and 14,15-EETs, but no cyclooxygenase products of EETs could be demonstrated. Proteins of the CYP2B, CYP2E, CYP2J, CYP1A, and CYP2C subfamilies are present in pulmonary artery and peripheral lung microsomes. Constriction of isolated rabbit pulmonary arteries to EETs is nonregioselective and depends on intact endothelium and cyclooxygenase, consistent with the formation of a pressor prostanoid compound. These data raise the possibility that EETs may contribute to regulation of pulmonary vascular tone.

Background: A model of shunt-induced pulmonary hypertension was used to study the effects of pulmonary overcirculation on endothelial nitric oxide synthase (eNOS) and cytochrome P450-4A (cP450-4A) vasodilatory mechanisms and related hemodynamic responses., Methods: An aortopulmonary shunt was constructed in 6-week-old piglets (n = 7, sham-operated controls n = 8). Hemodynamic measurements were made 4 weeks later under serial experimental conditions: baseline (fractional concentration of oxygen, 0.4); inhaled nitric oxide, 25 ppm (INO); hypoxia (fractional concentration of oxygen, 0.14); hypoxia + INO; N(omega)-nitro-L-arginine methylester (L-NAME 30 mg/kg intravenously, competitive NOS inhibitor); and L-NAME + INO. Lung protein levels of eNOS and cP450-4A and NOS activity were compared between groups., Results: Shunted animals had a higher baseline pulmonary artery pressure (p < 0.05). L-NAME resulted in a greater increase in pulmonary vascular resistance in shunted animals (150% +/- 26% shunt versus 69% +/- 14% control; p = 0.01). The INO administered during baseline conditions decreased pulmonary vascular resistance only in control animals (p < 0.05). Protein levels of eNOS and NOS activity were similar in both groups; however, cP450-4A protein levels were decreased in the shunted group (p = 0.02)., Conclusions: The NO production was preserved in shunted animals but they demonstrated greater vasodilatory dependence on NO, evidenced by an exaggerated increase in pulmonary vascular resistance after NOS inhibition. Loss of the cP450-4A vasodilatory system may be the driving force for NO dependency in the shunted pulmonary circulation.

To determine the diagnostic efficacy of thoracoscopic fine-needle aspiration (FNA) of solitary pulmonary nodules suspicious for lung cancer, we performed intraoperative thoracoscopic FNA for diagnostic purposes in 8 consecutive patients with peripheral solitary pulmonary nodules suspicious for lung cancer. Thoracoscopic FNA yielded an accurate diagnosis in all cases. There were 5 cases of non-small cell lung carcinoma, 1 small cell lung carcinoma, 1 renal carcinoma metastasis, and 1 inflammatory nodule. Results of FNA were obtained in less than 10 minutes in 6 cases. Maximum time to diagnosis was 20 minutes. The surgical procedure was expedited in the 6 cases of lung cancer because lobectomy followed FNA rather than the performance of a diagnostic wedge resection. A minor hematoma after FNA was the single complication. Thoracoscopic FNA yielded a prompt and accurate diagnosis of peripheral solitary pulmonary nodules. Thoracoscopic FNA should be considered as an alternative to preoperative percutaneous FNA, which risks pneumothorax and patient discomfort. In cases of lung cancer, thoracoscopic FNA allows the surgeon to bypass a diagnostic wedge resection and to proceed with definitive lobectomy.

Bilateral sequential lung transplantation was complicated by pulmonary artery anastomotic stenosis and bilateral pulmonary thromboemboli. Pulmonary artery thrombus was eliminated by intrathrombotic but not by systemic administration of urokinase. The pulmonary emboli resulted in localized pulmonary infarctions, supporting the need for thrombolytic intervention to restore pulmonary perfusion in the absence of collateral bronchial blood flow after lung transplantation. Pulmonary artery stenosis was relieved by endovascular stenting, avoiding an early reoperative procedure. This case suggests that direct administration of thrombolytic agent may be superior to intravenous administration in the treatment of pulmonary thromboemboli. Pulmonary arterial anastomotic stenoses after lung transplantation can be relieved by endovascular procedures.

Objective: The goal of this study was to clarify the issue of functional oxygen requirement by regimented exercise oximetry in patients undergoing lung reduction surgery., Methods: Thirty-seven patients underwent lung reduction surgery and were followed up for at least 3 months. Patients routinely completed a 6-week program of cardiopulmonary rehabilitation. Preoperative and postoperative spirometry, dyspnea scores, 6-minute walk distances, respiratory mechanics, and exercise oximetry were recorded., Results: After the operation, patients had a 37% increase in forced vital capacity and a 59% increase in forced expiratory volume in 1 second. Six-minute walk distance increased from 913 +/- 310 feet before the lung reduction operation to 1202 +/- 274 feet 6 months after the operation (p < 0.001). Maximal inspiratory and expiratory pressures were significantly increased in 16 patients after lung reduction surgery. Perceived dyspnea was significantly improved. Exercise pulse oximetry demonstrated that 83% of patients met American Thoracic Society criteria for supplemental oxygen use before lung reduction surgery. After the operation, 70% of patients continued to meet American Thoracic Society criteria for supplemental oxygen use. Notably, 10 patients with exertional desaturation while breathing room air discontinued supplemental oxygen use because of a reduction in dyspnea., Conclusions: These findings demonstrate significant subjective and functional improvements related to lung reduction surgery. Exercise-induced hypoxia was not reversed by lung reduction surgery. Discontinuance of supplemental oxygen use owing to reduction in dyspnea and improved physical performance may not be warranted in lieu of continued exertional desaturation.

Purpose: Considerable attention has been given to ambulation and dyspnea in the population with chronic obstructive pulmonary disease; however, previous studies leave the question of what constitutes functional ambulation in this population unanswered. This article examines ambulation for functional independence in the community for patients with-end-stage emphysema based on their self-selected walking velocity (SSWV) during a 6-minute walk (6 MW) and a timed get up and go (GUG) test., Methods: Fifty-nine patients (28 women, 31 men; mean age of 65.1 +/- 7.2 years) referred for lung transplantation or lung volume reduction surgery (mean forced expiratory volume in 1 second [FEV1] of 0.60 +/- 0.20 L; mean FEV1 as percent of predicted [FEV1%] of 22.7 +/- 8.7%) each had a 6 MW and GUG test performed on the same day. Calculations for SSWV and estimated energy expenditure were determined using the horizontal walking formula by the American College of Sports Medicine., Results: No statistically significant gender differences were identified for distance walked (235.1 +/- 92.0 m), rest time taken (33.2 +/- 58.5 seconds), actual walk time (5.5 +/- 1.0 minutes), or SSWV (42.2 +/- 13.9 m/min or 1.6 +/- 0.5 miles per hour) during the 6 MW. Men tended to walk farther and faster but rested more. The SSWV during the GUG test was similar (mean 41.8 +/- 10.9 m/min or 1.6 +/- 0.4 miles per hour) to the SSWV during the 6 MW. Estimated energy expenditure was approximately 1.6 to 3.4 metabolic equivalents (METS; mean 2.3 +/- 0.5 METS)., Conclusion: The literature defines independent community ambulation as the ability to walk at least 332 m at a near-normal velocity of approximately 80 m/min. This study population was significantly impaired for both distance and the velocity required to ambulate independently in the community. Documentation of both rest time and walk time taken during a 6 MW test will enable SSWV to be calculated and interpreted as it relates to independent community ambulation.

Background: We sought to determine whether low diffusion capacity of the lung to carbon monoxide (DLCO) is a predictor of high postoperative mortality and morbidity after major pulmonary resection and whether major pulmonary resection in patients with low DLCO results in substantial long-term morbidity., Methods: Sixty-two major pulmonary resections were performed in 61 patients with low DLCO (DLCO < or = 60% predicted for pneumonectomy or bilobectomy; < or = 50% predicted for lobectomy). Contemporaneously, 262 other patients underwent 263 major pulmonary resections (group II). Long-term morbidity was assessed in subsets of patients with low (n = 24) and high (n = 22; DLCO > 60% predicted) DLCO., Results: The hospital mortality rates were equivalent (4.8% low DLCO versus 4.9% group II), whereas respiratory complications were more frequent in patients with low DLCO (18% versus 9.5%; p = 0.05). In the subgroup analyses, patients with low DLCO had more hospitalizations for respiratory compromise and worse median dyspnea scores. Analysis of patients with substantial dyspnea revealed an association with extended pulmonary resection and postoperative radiation therapy in patients with low DLCO., Conclusions: Patients with low DLCO underwent major pulmonary resection with a low mortality rate and an acceptable, but increased, respiratory complication rate. Long-term respiratory morbidity was increased in patients with low DLCO; however, the extent of pulmonary resection and the use of postoperative radiation therapy may have contributed to the development of dyspnea in these patients.

Study Objective: To assess the relative benefit of thoracoscopy vs open thoracotomy in the removal of benign neurogenic, mediastinal tumors (BNMTs)., Design: Retrospective comparative study of thoracoscopy and open thoracotomy., Setting: Patients underwent surgery at the thoracic surgical services of two institutions from 1988 to 1994. Patients who underwent thoracoscopy were operated on more recently, 1992 to 1994. Patients who had thoracotomies underwent resection from 1988 to 1992., Patients: All adult patients undergoing isolated removal of BNMTs at both institutions were included. Eleven patients underwent removal by posterolateral thoracotomy while six patients underwent thoracoscopic removal., Interventions: BNMTs were removed by standard posterolateral thoracotomy or by three-hole thoracoscopic techniques with extension of incisions and conversion to an open procedure as necessary., Measurements and Results: Larger tumors were more difficult to remove thoracoscopically. Two cases of transient postoperative ptosis were noted among the patients who underwent thoracoscopy. Operative time was longer in the thoracoscopy group (171 vs 112 min; p<0.05). Postoperative stay was significantly shorter (2.6 vs 4.5 days; p<0.02) and return to work tended to be more rapid (4.3 vs 7.7 weeks; p=0.13) among patients who underwent thoracoscopy., Conclusions: Thoracoscopic resection of BNMTs can be achieved safely and effectively with more rapid postoperative recovery when compared with an open thoracotomy approach to these mediastinal tumors.

A wire stent was used successfully to treat life-threatening tracheomalacia in a 5-year-old girl. Wire stents placed bronchoscopically are nonobstructing and have the potential for balloon expansion to accommodate growth.

Background: Traumatic disruption of the thoracic aorta frequently results in death before operative repair. The determinants of mortality after repair, however, are uncertain. In addition, intraoperative strategies for reducing the incidence of spinal cord injury remain controversial., Methods: The records of 45 consecutive patients undergoing repair of traumatic disruption of the thoracic aorta at a single institution during a 9-year period were reviewed in a retrospective fashion. Patient age ranged from 15 to 81 years (mean age, 33.9 years). Twenty-two patients (49%) had multiple associated injuries, and 8 (18%) had isolated aortic injuries. Nine patients (20%) experienced preoperative hypotension (systolic blood pressure of less than 90 mm Hg). Repair was performed with partial bypass in 22 patients, a heparinized shunt in 2, and no distal perfusion (clamp and sew technique) in 21., Results: Nine patient (20%) died after operation. Multivariate logistic regression analysis of preoperative and intraoperative variables identified advancing age and preoperative hypotension as independent predictors of operative death. The presence of associated injuries was not an independent predictor of operative death. All 4 patients with injuries proximal to the aortic isthmus died. Ten patients were excluded from analysis of spinal cord injury either because of preoperative neurologic deficit or because of death before postoperative evaluation. Six (17%) of the remaining 35 patients had development of paraplegia: 5 of the 15 patients having the clamp and sew technique, 1 of the 2 with a shunt, and 0 of the 18 patients with bypass (p < 0.05, clamp and sew versus bypass). In the clamp and sew group, patients in whom paraplegia developed had significantly longer aortic clamp times than those without neurologic injury (40.6 +/- 4.4 minutes versus 28.7 +/- 2.9 minutes, respectively; p < 0.05)., Conclusions: Advancing age, preoperative hypotension, and perhaps injury location are important determinants of death after repair of traumatic disruption of the thoracic aorta. Adjunctive perfusion with partial bypass should be used during repair to reduce the incidence of spinal cord injury.