Robotic telestenting performance in transcontinental and regional pre-clinical models.

OBJECTIVES: This study was conducted to evaluate the association of geographic distance with robotic telestenting performance by comparing performance measures in transcontinental and regional pre-clinical models of telestenting. BACKGROUND: Robotic telestenting, in which percutaneous coronary intervention (PCI) is performed on a remotely located patient, might improve PCI access, but has not been attempted over vast distances likely required to reach many underserved regions. METHODS: Telestenting performance was compared in regional (Boston to New York [206 miles]) and transcontinental (Boston to San Francisco [3,085 miles]) ex vivo models of telestenting, wherein a physician in Boston attempted robotic PCI on endovascular simulators in New York and San Francisco, respectively. PCI was attempted over both wired and fifth generation (5G)-wireless networks. Outcome measures included procedural success, procedural time, and perceived latency. RESULTS: Procedural success was achieved in 20 consecutive target lesions in the regional model and in 16 consecutive target lesions in the transcontinental model. The transcontinental model had a greater latency than the regional model over both wired (121.5 ± 2.4 ms vs. 67.8 ± 0.9 ms; p < .001) and 5G-wireless networks (162.5 ± 1.1 ms vs. 86.6 ± 0.6 ms; p < .001), but perceived latencies were graded "imperceptible" in all cases in both models. Transcontinental and regional models did not have significantly different procedural times over wired (4.1 ± 1.9 min vs. 9.0 ± 7.1 min; p = .051) or 5G-wireless (3.0 ± 0.6 vs. 6.3 ± 1.2; p = .36) networks. CONCLUSIONS: Transcontinental robotic manipulation of coronary devices is now possible and was not associated with adverse performance compared to robotic telestenting conducted regionally.

Remote robotic percutaneous coronary intervention: An animal feasibility study.

OBJECTIVES: The purpose of this study was to explore the feasibility and safety of robotic PCI performed using an off-siteremote-control system in an animal model. BACKGROUND: Access to primary percutaneous coronary intervention (PCI) remains a challenge in acute myocardial infarction management. The combination of telemedicine and robotic PCI allow the potential delivery of primary PCI to remote locations without the delay of transfer. METHODS: This single-center prospective pilot preclinical feasibility study compared robotic PCI with remote PCI on swine across three stages (adjacent room, different floor of the same building, two different buildings). Latency up to 1,000 ms was introduced into the operating environment to simulate decreased network quality (blinded to operator). The primary outcome measures were technical success and acute safety. The secondary outcome measures included lesion wiring time, procedural time and qualitative scoring of the PCI experience by the operator. RESULTS: Across 52 experiments in 15 animals, technical success was 100%. No procedural complications occurred during the study. No significant difference in lesion treatment time was detected between stages (p = .11) and between time per target vessel when latency up to 1,000 ms was introduced (p = .58). Injected delay >250 ms had the greatest impact on procedure perceived lag. Longer procedure time was associated with lower procedure impact score, regardless of injected latency. CONCLUSIONS: Remote robotic PCI was feasible and safe in an animal model. Procedural duration was acceptable and unaffected by network latency. Future studies are needed to determine the safety and feasibility of remote PCI in humans.

Erratum to video-assisted thoracoscopic versus open thoracotomy lobectomy: a Swedish nationwide cohort study.

[This corrects the article DOI: 10.21037/jtd.2018.05.177.].

Network latency and long-distance robotic telestenting: Exploring the potential impact of network delays on telestenting performance.

OBJECTIVE: This study evaluated the impact of network latency on telestenting performance. BACKGROUND: The feasibility of long-distance robotic telestenting was recently demonstrated, yet the impact of network performance on telestenting remains unknown. METHODS: Ex vivo and in vivo telestenting models were constructed by connecting a robotic drive over a wired network to a robotic control system up to 103 miles away. During consecutive attempts to robotically wire a coronary artery, investigators randomly added signal latencies from 0 to 1,000 ms. Outcomes included wiring success, wiring time (time to advance wire to preselected target landmark), and perceived latency score (5 = imperceptible; 4 = noticeable but minor; 3 = noticeable; 2 = noticeable and major; 1 = unacceptable). RESULTS: Wiring success was achieved in 95 of 95 attempts in the ex vivo model and in 57 of 57 attempts in vivo. No significant difference in wiring time was observed across added latencies from 0 to 1,000 ms in the ex vivo (p = .64) or in vivo (p = .40) models. Compared to an added latency of 0 ms, perceived latency scores were not significantly different for added latencies of 150 and 250 ms (p = NS for both), but were significantly lower for latencies ≥400 ms (p < .001). CONCLUSIONS: Added latencies up to 250 ms were not associated with perceived latency, but latencies ≥400 ms were perceptible. Based on these findings, future telestenting studies should utilize networks with latencies ≤250 ms if perceived latency is to be avoided.

IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways.

BACKGROUND: Specific inflammatory pathways are indicated to contribute to severe asthma, but their individual involvement in the development of airway hyperresponsiveness remains unexplored. OBJECTIVE: This experimental study in human small bronchi aimed to provide insight into which of the type 2 and type 17 cytokines cause hyperresponsiveness of airway smooth muscle. METHODS: Explanted small bronchi isolated from human lung tissue and human airway smooth muscle cells were treated for 2 and 1 day(s), respectively, with 100 ng/mL of IL-4, IL-5, IL-13, or IL-17A, and contractile responses, Ca2+ mobilization, and receptor expression were assessed. RESULTS: Treatment with IL-13 increased the potency of histamine, carbachol, and leukotriene D4 as contractile agonists. IL-4, but not IL-5 or IL-17A, also increased the potency of histamine. In human airway smooth muscle cells, IL-13 and IL-4, but not IL-5 and IL-17A, enhanced the histamine-induced Ca2+ mobilization that was accompanied with increased mRNA expression of histamine H1 and cysteinyl leukotriene CysLT1 receptors. RNA sequencing of isolated bronchi confirmed the IL-13-mediated upregulation of H1 and CysLT1 receptors, without showing an alteration of muscarinic M3 receptors. Dexamethasone had no effects on IL-13-induced hyperresponsiveness in human bronchi, the increased Ca2+ mobilization, or the enhanced receptor expression. In contrast, antagonism of the common receptor for IL-13 and IL-4 by the biologic dupilumab prevented the effects of both IL-13 and IL-4 in human bronchi and human airway smooth muscle cells. CONCLUSIONS: The glucocorticoid-insensitive hyperrresponsiveness in isolated human airways induced by IL-13 and IL-4 provides further evidence that the IL-4Rα pathway should be targeted as a new strategy for the treatment of airway hyperresponsiveness in asthma.

Unique transcriptional and protein-expression signature in human lung tissue-resident NK cells.

Human lung tissue-resident NK cells (trNK cells) are likely to play an important role in host responses towards viral infections, inflammatory conditions and cancer. However, detailed insights into these cells are still largely lacking. Here we show, using RNA sequencing and flow cytometry-based analyses, that subsets of human lung CD69+CD16- NK cells display hallmarks of tissue-residency, including high expression of CD49a, CD103, and ZNF683, and reduced expression of SELL, S1PR5, and KLF2/3. CD49a+CD16- NK cells are functionally competent, and produce IFN-γ, TNF, MIP-1ß, and GM-CSF. After stimulation with IL-15, they upregulate perforin, granzyme B, and Ki67 to a similar degree as CD49a-CD16- NK cells. Comparing datasets from trNK cells in human lung and bone marrow with tissue-resident memory CD8+ T cells identifies core genes co-regulated either by tissue-residency, cell-type or location. Together, our data indicate that human lung trNK cells have distinct features, likely regulating their function in barrier immunity.

Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells.

NK cells in the human lung respond to influenza A virus- (IAV-) infected target cells. However, the detailed functional capacity of human lung and peripheral blood NK cells remains to be determined in IAV and other respiratory viral infections. Here, we investigated the effects of IAV infection on human lung and peripheral blood NK cells in vitro and ex vivo following clinical infection. IAV infection of lung- and peripheral blood-derived mononuclear cells in vitro induced NK cell hyperresponsiveness to K562 target cells, including increased degranulation and cytokine production particularly in the CD56brightCD16- subset of NK cells. Furthermore, lung CD16- NK cells showed increased IAV-mediated but target cell-independent activation compared to CD16+ lung NK cells or total NK cells in peripheral blood. IAV infection rendered peripheral blood NK cells responsive toward the normally NK cell-resistant lung epithelial cell line A549, indicating that NK cell activation during IAV infection could contribute to killing of surrounding non-infected epithelial cells. In vivo, peripheral blood CD56dimCD16+ and CD56brightCD16- NK cells were primed during acute IAV infection, and a small subset of CD16-CD49a+CXCR3+ NK cells could be identified, with CD49a and CXCR3 potentially promoting homing to and tissue-retention in the lung during acute infection. Together, we show that IAV respiratory viral infections prime otherwise hyporesponsive lung NK cells, indicating that both CD16+ and CD16- NK cells including CD16-CD49a+ tissue-resident NK cells could contribute to host immunity but possibly also tissue damage in clinical IAV infection.

Surgery for pulmonary metastases from colorectal cancer: survival and prognostic factors.

BACKGROUND: This study aimed to describe overall survival following pulmonary metastasectomy for colorectal cancer (CRC) in Sweden, and to assess the discrimination of a recently proposed risk prediction model. METHODS: Individual-level data of 756 patients who underwent resection of pulmonary metastases from CRC between 2009 and 2015 were obtained from ThoR, a Swedish national quality register for thoracic surgery. We classified patients into three risk categories according to the number of preoperative risk factors [age, disease-free interval (DFI), presence of extrathoracic lesions, number of pulmonary metastases] established in a prior study. We estimated the hazard ratios (HRs) and 95% confidence interval (CI) by Cox regression and the restricted mean survival time difference as group contrast measures. RESULTS: During a median follow-up time of 2.9 years, 35% (268/756) patients died. At 5 years, overall survival was 56% (95% CI: 51-60%). In a Cox regression model with risk category as the only independent variable, the HR for all-cause mortality was 1.94 (95% CI: 1.38-2.72, P<0.001) and 4.35 (95% CI: 2.49-7.62, P<0.001) in the moderate- (n=558) and high-risk categories (n=32), respectively, versus the low-risk category (n=166). At 5 years, the differences in restricted mean survival time were 6 months (P<0.001) and 1.5 years (P<0.001) in the moderate- and high-risk categories, respectively, versus the low-risk category. CONCLUSIONS: Five-year survival after surgery for pulmonary metastases from CRC in Sweden was similar or higher compared with contemporary reports. A prognostic model, initially developed in Japanese patients, had excellent discrimination in an external validation cohort of Swedish patients.

Video-assisted thoracoscopic versus open thoracotomy lobectomy: a Swedish nationwide cohort study.

BACKGROUND: The aim of this nationwide observational cohort study was to investigate the early postoperative complications and long-term survival following video-assisted thoracoscopic surgery (VATS) lobectomy compared to open thoracotomy lobectomy for early stage non-small cell lung cancer (NSCLC). METHODS: We used the Swedish national quality register for general thoracic surgery and included all patients who underwent lobectomy for NSCLC during 2012-2015. We compared postoperative complications and long-term survival in patients who underwent VATS lobectomy at our institution to patients who underwent open lobectomy at the other seven hospitals in Sweden. We used inverse probability of treatment weighting to limit differences in baseline characteristics between the groups and used standardized mean differences to assess balance after weighting. RESULTS: We included 1,601 patients who underwent open (n=1,316) or VATS (n=285) lobectomy for NSCLC. The mean age was 67.7 years in both groups and comorbidities were well balanced, but the open thoracotomy group had a higher proportion of patients with more advanced cancer stage. After weighting, all baseline characteristics were well balanced. Most patients (84%) did not have postoperative complications; 83% vs. 86% in the open and VATS group, respectively (P=0.41). The 30- and 90-day mortality was 0.7% vs. 0.3% (P=0.38) and 1.7% vs. 0.3% (P=0.09) in the open thoracotomy and VATS group, respectively. There were significantly more transfusions (5.0% vs. 1.4%, P=0.008) and pneumonia (5.5% vs. 0.6%, P=0.002) in the in the open thoracotomy and VATS group, respectively. The overall survival at 1 and 5 years was 92% vs. 97% and 63% vs. 78% in the open thoracotomy and VATS group, respectively; HR (95% CI): 0.47 (0.33-0.68). CONCLUSIONS: We found less postoperative complications and better long-term survival following VATS lobectomy compared to open thoracotomy lobectomy for NSCLC. The implementation of a VATS lobectomy program did not compromise patient safety or the oncological efficacy.

Long-term survival after surgery for pulmonary metastases from colorectal cancer: an observational cohort study.

BACKGROUND: Evidence for pulmonary metastasectomy following colorectal cancer (CRC) is scarce. The aim of the study was to investigate long-term survival and identify prognostic factors to aid patient selection. METHODS: We included all patients who underwent pulmonary resections for CRC metastases between January 01, 2004 and December 31, 2015 in a population-based cohort study. The primary outcome measure was all-cause mortality and was ascertained from Swedish national registers. The Kaplan-Meier estimator was used to calculate cumulative survival. We used Cox regression for estimation of hazard ratios (HR) and 95% confidence intervals (CI) for the association between patient characteristics and survival. RESULTS: We included 184 patients. The number of procedures per year increased from 1 in 2004 to 34 in 2015. During a median follow-up time of 3.2 years, 36% (66/184) patients died. Overall survival at 5 years was 60% (95% CI: 50-68%) and was significantly lower compared to an age- and gender-matched Swedish population. Carcinoembryonic antigen (CEA) level was identified as a prognostic factor for mortality in the age and sex-adjusted analysis (HR, 2.46; 95% CI: 1.15-5.26, P=0.020). CONCLUSIONS: We found a steady increase in the number of pulmonary metastasectomies after CRC during the study period. We identified prethoracotomy CEA level as a prognostic factor for long-term survival, which was consistent with prior reports. The 5-year overall survival rate in our study was 60%, which was high in comparison with prior reports. Although our results indicated that current patient selection criteria were reasonable, definitive evidence of efficacy is pending.

Implementation of lung cancer CT screening in the Nordic countries.

INTRODUCTION: We review the current knowledge of CT screening for lung cancer and present an expert-based, joint protocol for the proper implementation of screening in the Nordic countries. MATERIALS AND METHODS: Experts representing all the Nordic countries performed literature review and concensus for a joint protocol for lung cancer screening. RESULTS AND DISCUSSION: Areas of concern and caution are presented and discussed. We suggest to perform CT screening pilot studies in the Nordic countries in order to gain experience and develop specific and safe protocols for the implementation of such a program.

Recurrence rate after thoracoscopic surgery for primary spontaneous pneumothorax.

OBJECTIVES: There is an on-going discussion regarding the recurrence rate after surgery for primary spontaneous pneumothorax by video assisted thoracic surgery (VATS) or by thoracotomy access. This study aimed to describe the recurrence rate, and to identify a possible learning curve, following surgery for primary spontaneous pneumothorax by VATS. DESIGN: All patients who underwent surgery for primary spontaneous pneumothorax by VATS at Karolinska University Hospital 2004-2013 were reviewed. Preoperative and operative characteristics were obtained from medical records. Patients were followed-up through telephone interviews or questionnaires and by review of medical records. The primary outcome of interest was time to recurrence of pneumothorax requiring intervention. Outcomes were compared between patients operated during 2004-June 2010 and July 2010-2013. RESULTS: 219 patients who underwent 234 consecutive procedures were included. The mean follow-up times were 6.3 and 2.9 years in the early and late period, respectively. The postoperative recurrence rate in the early period was 16% (11%-25%), 18% (12%-27%), and 18% (12%-27%), at 1, 3 and 5 years, compared to 1.7% (0.4%-6.8%), 7.6% (3.7%-15%), and 9.8% (4.8%-19%) at 1, 3 and 5 years, in the late period (p = 0.016). CONCLUSIONS: We found that the recurrence rate after thoracoscopic surgery for primary spontaneous pneumothorax decreased significantly during the study period. Our results strongly suggest that thoracoscopic surgery for pneumothorax involve a substantial learning curve.

Self-Reported Physical Quality of Life Before Thoracic Operations Is Associated With Long-Term Survival.

BACKGROUND: The aim was to analyze the association between baseline self-reported health-related quality of life and long-term survival after thoracic operations. METHODS: In a prospective population-based cohort study, we included patients scheduled for thoracic operations and obtained information about preoperative health-related quality of life using the validated quality-of-life instrument Short Form-36. Patients were categorized according to higher or lower physical and mental component scores, compared with an age- and sex-matched reference population. The primary outcome measure was all-cause mortality and was ascertained from Swedish national registers. We used Cox regression for estimation of hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between preoperative physical/mental quality of life and long-term survival while adjusting for differences in baseline characteristics, cancer stage, histopathologic process, and other factors. RESULTS: We included 249 patients between 2006 and 2008. During a median follow-up time of 8.0 years, 119 patients (48%) died. Having a physical component summary score less than reference was significantly associated with mortality (multivariable adjusted HR 2.02, 95% CI: 1.34 to 3.06, p = 0.001). A mental component summary score less than reference was not associated with mortality (adjusted HR 1.32, 95% CI: 0.84 to 3.06, p = 0.233). CONCLUSIONS: In patients who underwent thoracic operations, a self-reported physical quality of life lower than reference value was associated with significantly worse survival independent of histopathologic process, cancer stage, extent of operations, and other patient-related factors. The preoperative mental component of quality of life was not associated with long-term survival.

Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69-CD56dim cells.

BACKGROUND: In contrast to the extensive knowledge about human natural killer (NK) cells in peripheral blood, relatively little is known about NK cells in the human lung. Knowledge about the composition, differentiation, and function of human lung NK cells is critical to better understand their role in diseases affecting the lung, including asthma, chronic obstructive pulmonary disease, infections, and cancer. OBJECTIVE: We sought to analyze and compare the phenotypic and functional characteristics of NK cells in the human lung and peripheral blood at the single-cell level. METHODS: NK cells in human lung tissue and matched peripheral blood from 132 subjects were analyzed by using 16-color flow cytometry and confocal microscopy. RESULTS: CD56dimCD16+ NK cells made up the vast majority of NK cells in human lungs, had a more differentiated phenotype, and more frequently expressed educating killer cell immunoglobulin-like receptors compared with NK cells in peripheral blood. Despite this, human lung NK cells were hyporesponsive toward target cell stimulation, even after priming with IFN-α. Furthermore, we detected a small subset of NK cells expressing CD69, a marker of tissue residency. These CD69+ NK cells in the lung consisted predominantly of immature CD56brightCD16- NK cells and less differentiated CD56dimCD16+ NK cells. CONCLUSION: Here, we characterize the major NK cell populations in the human lung. Our data suggest a model in which the majority of NK cells in the human lung dynamically move between blood and the lung rather than residing in the lung as bona fide tissue-resident CD69+ NK cells.

Ephrin B3 interacts with multiple EphA receptors and drives migration and invasion in non-small cell lung cancer.

Ephrin receptors (Ephs) are reported to control metastatic signaling of non-small cell lung cancer (NSCLC) and other tumors. Here we show for the first time that blocking expression of the Eph ligand Ephrin B3 inhibits NSCLC cell migration and invasion. We demonstrate that Ephrin B3 directly binds the EphAs EphA2, EphA3, EphA4, and EphA5. EphA2 Ser897 was previously shown to drive migration propensity of tumor cells and our study reveals that EphA2 stays phosphorylated on Ser897 in the Ephrin B3/EphA2 complex in NSCLC cells of different histology. Moreover, we report that within such Ephrin B3/EphA2 complex both Akt Ser 129 and p38MAPK are found indicating a potential to drive migration/proliferation. We also found the EMT marker E-cadherin expression to be maintained or increased upon Ephrin B3 blockade in NSCLC cells. Expression of Ephrin B3 was furthermore analyzed in a cohort of NSCLC stage IA-IB cases (n=200) alongside EphA2 and Ephrin A1. We found that Ephrin B3 was concomitantly expressed with EphA2 and Ephrin A1 with higher Ephrin B3 levels found in non-squamous than in squamous tumors, whereas EphA2 was higher expressed in well-differentiated than in low-differentiated tumors. In the entire NSCLC cohort, Ephrin B3 expression was not linked to patient survival, whereas a high EphA2 expression was associated with improved survival (p=0.03). In conclusion, we show that blocking Ephrin B3 expression inhibits NSCLC proliferation-, migration- and invasion capacity which calls for further studies on interference with Ephrin B3 as a possible therapeutic avenue in this tumor malignancy.

Prostaglandin E2 inhibits mast cell-dependent bronchoconstriction in human small airways through the E prostanoid subtype 2 receptor.

BACKGROUND: Inhaled prostaglandin (PG) E2 might inhibit asthmatic responses, but the mechanisms involved remain undefined. OBJECTIVE: We sought to characterize the direct and indirect effects of PGE2 on human small airways with particular reference to the receptors mediating the responses. METHODS: Contraction and relaxation were studied in isolated human bronchi with an inner diameter of 1 mm or less. RESULTS: Low concentrations of PGE2 (0.01-1 µmol/L) relaxed the bronchi precontracted by histamine. The bronchodilator response was inhibited by the E prostanoid (EP) subtype 4 receptor antagonist ONO-AE3-208 but unaffected by the EP2 receptor antagonist PF-04418948. Higher concentrations of PGE2 (10-100 µmol/L) contracted the small airways. However, the TP receptor agonists U-46,619, PGF2α, and PGD2 were more potent than PGE2. Moreover, the bronchoconstrictor responses to PGE2 and all other tested prostanoids, including the EP1/EP3 receptor agonist 17-phenyl trinor PGE2 and the partial FP receptor agonist AL-8810, were uniformly abolished by the TP receptor antagonist SQ-29,548. In the presence of TP and EP4 antagonists, PGE2 inhibited the mast cell-mediated bronchoconstriction resulting from anti-IgE challenge. Measurement of the release of histamine and cysteinyl leukotrienes documented that this bronchoprotective action of PGE2 was mediated by the EP2 receptor, unrelated to bronchodilation, and increased with time of exposure. CONCLUSION: The pharmacology of PGE2 in isolated human small airways was different from its profile in animal models. This first demonstration of powerful EP2 receptor-mediated inhibition of IgE-dependent contractions in human airways introduces a new selective target for the treatment of asthma. This EP2 control of mast cell-mediated bronchoconstriction is presumably exaggerated in patients with aspirin-exacerbated respiratory disease.

Characterizing the chemical pathways for water formation--a deep search for hydrogen peroxide.

In 2011, hydrogen peroxide (HOOH) was observed for the first time outside the solar system (Bergman et al., Astron. Astrophys., 2011, 531, L8). This detection appeared a posteriori to be quite natural, as HOOH is an intermediate product in the formation of water on the surface of dust grains. Following up on this detection, we present a search for HOOH in a diverse sample of sources in different environments, including low-mass protostars and regions with very high column densities, such as Infrared Dark Clouds (IRDCs). We do not detect the molecule in any other source than Oph A, and derive 3sigma upper limits for the abundance of HOOH relative to H2 lower than that in Oph A for most sources. This result sheds a different light on our understanding of the detection of HOOH in Oph A, and shifts the question of why this source seems to be special. Therefore we rediscuss the detection of HOOH in Oph A, as well as the implications of the low abundance of HOOH, and its similarity with the case of O2. Our chemical models show that the production of HOOH is extremely sensitive to temperature, and is favored only in the range 20-30 K. The relatively high abundance of HOOH observed in Oph A suggests that the bulk of the material lies at a temperature in the range 20-30 K.

Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle.

Taste-sensing type 2 receptors (TAS2Rs) have been implicated in extraoral functions. Airway smooth muscle expresses TAS2Rs and is strongly relaxed by TAS2R agonists. We hypothesised that TAS2R agonists might affect vascular smooth muscle as well. Moreover, the general pharmacological profile of TAS2R agonists, which are used to investigate the functions of TAS2R׳s, are undefined. The aim of this study was to pharmacologically characterise the effects of five prototype TAS2R agonists in vascular smooth muscle. Responses to the TAS2R agonists were investigated in guinea-pig aorta and taenia coli, mouse aorta (wild-type and caveolin-1-/- mice) and human pulmonary arteries. Chloroquine, denatonium, dextromethorphan, noscapine and quinine, agonists for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, induced strong endothelium-independent relaxations (responses between 82-96% of maximal relaxations) in phenylephrine pre-contracted guinea-pig aorta that persisted in the presence of L-type Ca2+ and KCa1.1-channel blockers. Experiments in guinea-pig taenia coli revealed that denatonium and quinine also inhibited relaxations to phenylephrine, indicating antagonism of α-adrenoceptors. Only chloroquine and noscapine mediated relaxations when the guinea pig aorta was pre-contracted by U-46619 or PGF2α. Relaxations to chloroquine and noscapine after U-46619 pre-contractions were however markedly impaired in aortae from caveolin-1-/- mice. Chloroquine and noscapine mediated relaxations of human pulmonary arteries that expressed also mRNA for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, at levels similar to that of the α1A adrenoceptor. Notwithstanding whether TAS2Rs are involved or not, TAS2R agonists have profound effects on vascular smooth muscle. Chloroquine and noscapine are of special interest as their effects cannot be accounted for by conventional pathways.

Validation of the 7th TNM classification for non-small cell lung cancer: a retrospective analysis on prognostic implications for operated node-negative cases.

BACKGROUND: The 7th TNM staging system for non-small cell lung cancer (NSCLC) developed by the International Association for the study of Lung Cancer (IASLC) has been applied in Sweden since the beginning of the year 2010. The aim of this retrospective study was to evaluate the prognostic role of the 7th TNM staging system in a surgical Swedish patient cohort with node-negative NSCLC. MATERIAL AND METHODS: We collected data from stage I patients (pT1-2 pN0, 6th TNM system) who underwent surgery for NSCLC at Karolinska University Hospital from 1987 to 2002. Tumors were restaged according to the 7th TNM version. Cox multivariate survival analysis was implemented in order to determine the prognostic impact of pathological stage when classified according to either the 6th or the 7th TNM systems. RESULTS: The patient population consisted of 452 subjects. Tumor size was ≤ 3 cm in 51% of cases. The predominant histology was adenocarcinoma (53%) and lobectomy was the most common surgical procedure (82% of patients). The five-year survival rate in patients with stage IA vs. IB (6th TNM) was 62% vs. 51%, respectively (log-rank p = 0.036). Corresponding figures for the 7th TNM system were 70% in stage IA-T1a, 51% in stage IA-T1b, 54% in stage IB, 51% in stage IIA and 35% in stage IIB (log-rank p = 0.002). On multivariate analysis, adjusted by age, gender, histology, kind of surgery, grade of differentiation and smoking status, pathological stage was an independent prognostic factor if classified according to the 7th TNM version (p = 0.001), but not if scored according to the 6th TNM edition (p = 0.090). CONCLUSION: The 7th TNM classification system is a more accurate predictor of prognosis in stage I operated patients than the old classification. The new system should be implemented even on retrospective cohorts especially when investigating the prognostic implication of the expression of molecular biomarkers.