Randomized phase III trial comparing switch-maintenance pemetrexed with observation followed by pemetrexed at progression in advanced NSCLC.

Objectives: Two phase III trials show that maintenance pemetrexed therapy after platinum-doublet chemotherapy prolongs overall survival (OS) and progression free survival (PFS) in advanced non-squamous non-small-cell lung cancer (NSCLC). However, few patients in the control arms received pemetrexed at progression in these trials, performance status (PS) two patients were ineligible and few of the participants were elderly. Thus, we designed this study comparing immediate switch-maintenance pemetrexed therapy with pemetrexed at progression after platinum-doublet chemotherapy.Methods: Patients with stage IIIB/IV non-squamous NSCLC, ≥18 years, PS 0-2, and non-progression after four courses of carboplatin/vinorelbine were randomized to receive immediate maintenance pemetrexed therapy or observation followed by pemetrexed at progression. The primary endpoint was OS, secondary endpoints were PFS, toxicity and health related quality of life (HRQoL).Results: 105 patients were randomized between May 2014 and September 2017. Median age was 67 years, 36% were >70 years, 9% had PS 2, 91% stage IV and 47% were women. In the observation arm, 73% received pemetrexed at progression. Patients in the maintenance arm had a numerically longer OS (median 12.0 vs. 10.0 months; p = .10) and a statistically significant longer PFS (median 3.1 vs. 1.9 months; p < .01). In multivariable analyses adjusting for baseline characteristics, there was a trend toward improved OS (HR 0.65, 95% CI 0.42-1.01); p = .05), and a significantly improved PFS (HR 0.53, 95% CI 0.35-0.80; p < .01). There were no significant differences in toxicity or HRQoL between the treatment arms.Conclusion: There was a trend toward prolonged OS and significantly longer PFS from switch- maintenance pemetrexed therapy when 73% of patients in the control arm received pemetrexed at progression. ClinicalTrials.gov Identifier: NCT02004184.

Reasons for prolonged time for diagnostic workup for stage I-II lung cancer and estimated effect of applying an optimized pathway for diagnostic procedures.

BACKGROUND: Minimizing the time until start of cancer treatment is a political goal. In Norway, the target time for lung cancer is 42 days. The aim of this study was to identify reasons for delays and estimate the effect on the timelines when applying an optimal diagnostic pathway. METHODS: Retrospective review of medical records of lung cancer patients, with stage I-II at baseline CT, receiving curative treatment (n = 100) at a regional cancer center in Norway. RESULTS: Only 40% started treatment within 42 days. The most important delays were late referral to PET CT (n = 27) and exercise test (n = 16); repeated diagnostic procedures because bronchoscopy failed (n = 15); and need for further investigations after PET CT (n = 11). The time from referral to PET CT until the final report was 20.5 days in median. Applying current waiting time for PET CT (≤7 days), 48% would have started treatment within 42 days (p = 0.254). "Optimal pathway" was defined as 1) referral to PET CT and exercise test immediately after the CT scan and hospital visit, 2) tumor board discussion to decide diagnostic strategy and treatment, 3) referral to surgery or curative radiotherapy, 4) tissue sampling while waiting to start treatment. Applying the optimal pathway, current waiting time for PET CT and observed waiting times for the other procedures, 80% of patients could have started treatment within 42 days (p < 0.001), and the number of tissue sampling procedures could have been reduced from 112 to 92 (- 16%). CONCLUSION: Changing the sequence of investigations would significantly reduce the time until start of treatment in curative lung cancer patients at our hospital and reduce the resources needed.

Measurement of health-related quality of life during chemotherapy - the importance of timing.

BACKGROUND: Side effects of chemotherapy may occur at different time-points in the treatment cycle, and the exact assessment time relative to chemotherapy may affect HRQoL scores. The current study examined the variation of HRQoL during chemotherapy cycles, and whether differences in HRQoL scores varied at selected time-points between patients allocated to two different chemotherapy regimens. MATERIAL AND METHODS: Patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) were randomly assigned to receive three cycles of carboplatin plus vinorelbine (VC) or gemcitabine (GC) every 3 weeks. HRQoL was reported on the EORTC QLQ-C30 and LC13 on days 1, 4, 8, 11 and 15 of every cycle. Global health status, nausea/vomiting, fatigue and dyspnea (LC13) were defined as the HRQoL scales of primary interest. RESULTS: Fifty-two patients were enrolled. Variation of mean scores of global health status, nausea/vomiting and fatigue showed a consistent pattern during chemotherapy. Day 4 appeared to be the time-point when chemotherapy influenced HRQoL the most. The differences in mean HRQoL scores between the two treatment arms varied at the different time-points, especially for nausea/vomiting. CONCLUSION: There was a clinically relevant variation of HRQoL during chemotherapy cycles, with increased symptom burden the first week following treatment. Our results suggest that timing of HRQoL assessment can influence the chances of detecting differences between the treatment regimens.

Medical complexity and time to lung cancer treatment - a three-year retrospective chart review.

BACKGROUND: The time from a referral for suspected lung cancer is received at a hospital until treatment start has been defined as a quality indicator. Current Norwegian recommendation is that ≥70% should start surgery or radiotherapy within 42 calendar days and systemic therapy within 35 days. However, delays can occur due to medical complexity. The aim of this study was to quantify the proportion of patients who started treatment within the recommended timeframes; and to assess the proportion of non-complex patients for which there were no good reasons for delays. METHODS: We performed a retrospective chart review of all patients diagnosed with lung cancer at a university hospital during 2011-2013. We defined "non-complex" patients as those who underwent ≤1 tissue diagnostic procedure and had no delays due to comorbidity, intercurrent disease or complications to diagnostic procedures ("Medical delays") of more than three days. RESULTS: Four hundred forty-nine cases were analyzed; 142 (32%) had >1 tissue diagnostic procedures; 67 (15%) had medical delays >3 days; 262 (58%) were non-complex and 363 (81%) received treatment for lung cancer. Median number of days until surgery or radiotherapy was 48 (overall) and 41 (non-complex patients). The proportions who started surgery or radiotherapy within 42 days were 41% (overall) and 56% (non-complex). Corresponding numbers for systemic therapy were 29 days (overall) and 25 days (non-complex), and 64% (overall) and 80% (non-complex). CONCLUSION: Fewer lung cancer patients than desired started treatment within the recommended timeframes. Even among the least complex patients, too few patients received timely treatment. The reasons need to be identified and understood, and changes in the organization appear to be necessary in order to offer timely treatment to more patients.

PET/MR brain imaging: evaluation of clinical UTE-based attenuation correction.

UNLABELLED: One of the greatest challenges in PET/MR imaging is that of accurate MR-based attenuation correction (AC) of the acquired PET data, which must be solved if the PET/MR modality is to reach its full potential. The aim of this study was to investigate the performance of Siemens' most recent version (VB20P) of MR-based AC of head PET data, by comparing it to CT-based AC. METHODS: (18)F-FDG PET data from seven lymphoma and twelve lung cancer patients examined with a Biograph mMR PET/MR system were reconstructed with both CT-based and MR-based AC, avoiding sources of error arising when comparing PET data from different systems. The resulting images were compared quantitatively by measuring changes in mean SUV in ten different brain regions in both hemispheres, as well as the brainstem. In addition, the attenuation maps (µ maps) were compared regarding volume and localization of cranial bone. RESULTS: The UTE µ maps clearly overestimate the amount of bone in the neck, while slightly underestimating the amount of bone in the cranium, and the localization of bone in the cranial region also differ from the CT µ maps. In air/tissue interfaces in the sinuses and ears, the MRAC method struggles to correctly classify the different tissues. The misclassification of tissue is most likely caused by a combination of artefacts and the insufficiency of the UTE method to accurately separate bone. Quantitatively, this results in a combination of overestimation (0.5-3.6 %) and underestimation (2.7-5.2 %) of PET activity throughout the brain, depending on the proximity to the inaccurate regions. CONCLUSIONS: Our results indicate that the performance of the UTE method as implemented in VB20P is close to the theoretical maximum of such an MRAC method in the brain, while it does not perform satisfactorily in the neck or face/nasal area. Further improvement of the UTE MRAC or other available methods for more accurate segmentation of bone should be incorporated.

Changes in skeletal muscle mass during palliative chemotherapy in patients with advanced lung cancer.

BACKGROUND: Sarcopenia is a defining feature of cancer cachexia associated with physical decline, poor quality of life and poor prognosis. Thus, maintaining muscle mass is an important aim of cachexia treatment. Many patients at risk for developing cachexia or with cachexia experience side effects of chemotherapy that might aggravate the development of cachexia. However, achieving tumor control might reverse the catabolic processes causing cachexia. There is limited knowledge about muscle mass changes during chemotherapy or whether changes in muscle mass are associated with response to chemotherapy. PATIENTS AND METHODS: In this pilot study, patients with advanced non-small cell lung cancer (NSCLC) receiving three courses of palliative chemotherapy were analyzed. Muscle mass was measured as skeletal muscle cross sectional area (SMCA) at the level of the third lumbar vertebrae using CT images taken before and after chemotherapy. RESULTS: In total 35 patients, 48% women, mean age 67 years (range 56-86), participated; 83% had stage IV disease and 71% were sarcopenic at baseline. Mean reduction in SMCA from pre- to post-chemotherapy was 4.6 cm2 (CI 95% -7.3--1.9; p<0.002), corresponding to a 1.4 kg loss of whole body muscle mass. Sixteen patients remained stable or gained SMCA. Of these, 14 (56%) responded to chemotherapy, while two progressed (p=0.071). Maintaining or gaining SMCA resulted in longer median overall survival (loss: 5.8 months, stable/gain: 10.7 months; p=0.073). Stage of disease (p=0.003), treatment regimen (p=0.023), response to chemotherapy (p=0.007) and SMCA change (p=0.040), but not sarcopenia at baseline, were significant prognostic factors in the multivariate survival analyses. CONCLUSION: Almost half of the patients had stable or increased muscle mass during chemotherapy without receiving any cachexia treatment. Nearly all of these patients responded to the chemotherapy. Increase in muscle mass, but not sarcopenia at baseline, was a significant prognostic factor.

[Occupational lung cancer in Sør-Trøndelag county]. / Arbeidsbetinget lungekreft i Sør-Trøndelag.

BACKGROUND: Lung cancer can be caused by occupational exposure. This is not always recognised or reported, and not all patients receive the benefits to which they are entitled. MATERIAL AND METHOD: We collected occupational case histories for patients from Sør-Trøndelag county with a first-time diagnosis of lung cancer. The number of reported cases of occupationally related lung cancer was collected from the Norwegian Labour Inspection Authority, and information on approval of occupational illness was collected from the Norwegian Labour and Welfare Authority (NAV). RESULTS: 105 patients with lung cancer took part in the study, 73 men and 32 women. Among the men, altogether 12 cases (16%) were assessed as likely and 16 (22%) as possibly occupationally related. Among the women, none of the cases were assessed as occupationally related. The reporting frequency from the health regions to the Norwegian Labour Inspection Authority varied from 1.7% to 5.1%. Altogether 9 out of 11 likely cases and 5 out of 12 possible cases of occupationally related lung cancer were granted injury compensation by the Norwegian Labour and Welfare Authority. INTERPRETATION: In this study, we found that approximately 20% of the cases of lung cancer in men are occupationally related, and that the underreporting of occupationally related lung cancer appears to be considerable. The obligation of doctors to report to the Norwegian Labour Inspection Authority should be made better known. Most likely, more patients would have had their lung cancer verified as an occupational illness and could have received injury compensation if they had been aware of the opportunity to apply for this.

Associations Between Time to Treatment Start and Survival in Patients With Lung Cancer.

BACKGROUND: Time-to-treatment is defined as a quality indicator for cancer care but is not well documented. We investigated whether meeting Norwegian timeframes of 35/42 days from referral until start of chemotherapy or surgery/radiotherapy for lung cancer was associated with survival. PATIENTS AND METHODS: The medical records of 439 lung cancer patients at a regional cancer center were reviewed and categorized according to treatment: (i) surgery; ii) radical radiotherapy; iii) stereotactic radiotherapy; iv) palliative treatment, no cancer symptoms; v) palliative treatment with severe cancer symptoms). RESULTS: Proportions receiving timely treatment varied significantly at 39%, 48%, 10%, 44% and 89%, respectively (p<0.001). Overall, those starting treatment on time had the shortest median overall survival (10.6 vs. 22.6 months; p<0.001). This was also the case for palliative (5.3 vs. 11.4 months) (p<0.001) but not for curative treatment (not reached vs. 38.3 months) (p=0.038). CONCLUSION: Timely treatment is not necessarily associated with improved survival.

Analysis of Intra-Tumoral Macrophages and T Cells in Non-Small Cell Lung Cancer (NSCLC) Indicates a Role for Immune Checkpoint and CD200-CD200R Interactions.

Non-small cell lung carcinoma (NSCLC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths. Immunotherapy with immune checkpoint inhibitors shows beneficial responses, but only in a proportion of patients. To improve immunotherapy in NSCLC, we need to map the immune checkpoints that contribute immunosuppression in NSCLC-associated immune cells and to identify novel pathways that regulate immunosuppression. Here, we investigated the gene expression profiles of intra-tumoral immune cells isolated from NSCLC patients and compared them to the expression profiles of their counterparts in adjacent healthy tissue. Transcriptome analysis was performed on macrophages, CD4+ and CD8+ T cells. The data was subjected to Gene Ontology (GO) term enrichment and weighted correlation network analysis in order to identify mediators of immunosuppression in the tumor microenvironment in NSCLC. Immune cells from NSCLC revealed a consistent differential expression of genes involved in interactions between myeloid cells and lymphocytes. We further identified several immunosuppressive molecules and pathways that may be activated in tumor-associated macrophages in NSCLC. Importantly, we report novel data on immune cell expression of the newly described CD200/CD200R1 pathway, and the leukocyte immunoglobulin-like receptors (LILRs), which may represent novel innate immune checkpoints, dampening the anti-tumor T cell immune response in NSCLC. Our study substantiates the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy.

Ectonucleotidase CD39 and Checkpoint Signalling Receptor Programmed Death 1 are Highly Elevated in Intratumoral Immune Cells in Non-small-cell Lung Cancer.

Lung cancer is the leading cause of cancer death in both sexes worldwide and has a predicted 5-year survival rate of <20%. Immunotherapy targeting immune checkpoints such as the programmed death 1 (PD-1) signaling pathway has led to a shift of paradigm in the treatment of advanced non-small-cell lung cancer (NSCLC) but remains without effect in ∼80% of patients. Accumulating evidence suggests that several immunosuppressive mechanisms may work together in NSCLC. The contribution and cooperation between different immunosuppressive mechanisms in NSCLC remain unknown. Recently, the CD39-adenosine pathway has gained increasing attention as a crucial immunosuppressive mechanism and possible target for immunotherapy. Immune cells were extracted from lung and tumor tissue after lung resection in 12 patients by combined enzymatic and mechanical tissue disaggregation. A multiparameter flow cytometry panel was established to investigate the expression and coexpression of CD39 and PD-1 on key lymphocyte subtypes. Frequencies of CD39+, PD-1+, and CD39+/PD-1+cells were higher among both CD4+ and CD8+ T cells isolated from NSCLC tumor tissue than in T cells from normal lung tissue. Similarly, the frequency of FoxP3+ CD4+ T cells (Tregs) was highly significantly elevated in tumor tissue compared to adjacent lung tissue. The consistent upregulation of CD39 on immune cells in tumor microenvironment indicates that the CD39 signaling pathway may, in addition to the PD-1 pathway, represent another important mechanism for tumor-induced immunosuppression in NSCLC. In addition, the present study indicates that a comprehensive immune response profiling with flow cytometry may be both feasible and clinically relevant.

Release of neuroendocrine products in the pulmonary circulation during intermittent hypoxia in isolated rat lung.

The aim of this study was to evaluate the release of neuroendocrine (NE) products into the pulmonary circulation during intermittent hypoxia (IH) in isolated buffer-perfused and ventilated rat lungs. Isolated single-pass perfused rat lungs were repeatedly ventilated with hypoxic (2% O(2)) and normoxic (21% O(2)) gases for 5-min intervals. Perfusate collected during the study was analysed for bombesin-like-peptides (BLPs) and serotonin. In addition, immunohistochemical evaluation of the neuropeptides calcitonin gene-related peptide (CGRP) and chromogranin A (CgA) in the lung was performed. During IH, perfusate levels of BLPs decreased compared to lungs ventilated with normoxic gas only. After 15 min of IH, perfusate levels of BLPs were significantly lower than at corresponding time in normoxic lungs (2.6+/-0.7 pg ml(-1) versus 9.2+/-1.9 pg ml(-1), p=0.036). No significant difference between the study groups was observed in perfusate levels of serotonin. Immunohistochemical evaluation of the lungs revealed significantly increased number of pulmonary NE cells immunoreactive for CGRP in IH ventilated lungs compared to controls (10.1+/-1.5 neuroepithelial bodies (NEBs) (cm(2))(-1) versus 5.0+/-1.5 NEBs (cm(2))(-1), p=0.032). No change in the immunoreactivity for CgA was observed. The present study suggests that intermittent periods of hypoxia are associated with a rapid physiological modulation of the release of NE products into the pulmonary circulation in an isolated rat lung model.

Carbon monoxide levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological hypertrophy.

Cigarette smoke contains hundreds of potentially toxic compounds and is an important risk factor for cardiovascular disease. However, the key components responsible for endothelial and myocardial dysfunction have not been fully identified. The objective of the present study was to determine the cardiovascular effects of long-term inhalation of carbon monoxide (CO) administrated to give concentrations in the blood similar to those observed in heavy smokers. Female rats were exposed to either CO or air (control group) (n = 12). The CO group was exposed to 200 ppm CO (100 h/wk) for 18 mo. Rats exposed to CO had 24% lower maximal oxygen uptake, longer (145 vs. 123 microm) and wider (47 vs. 25 microm) cardiomyocytes, reduced cardiomyocyte fractional shortening (12 vs. 7%), and 26% longer time to 50% re-lengthening than controls. In addition, cardiomyocytes from CO-exposed rats had 48% lower intracellular calcium (Ca2 +) amplitude, 22% longer time to Ca2 + decay, 34% lower capacity of sarcoplasmic reticulum Ca2 +-ATPase (SERCA2a), and 37% less t-tubule area compared to controls. Phosphorylation levels of phospholamban at Ser16 and Thr17 were significantly reduced in the CO group, whereas total concentration of phospholamban and SERCA2a were unchanged. Cardiac atrial natriuretic peptide, vascular endothelial growth factor, cyclic guanosine monophosphate, calcineurin, calmodulin, pERK, and pS6 increased, whereas pAkt and pCaMKII delta remained unchanged by CO. Endothelial function and systemic blood pressure were not affected by CO exposure. Long-term CO exposure reduces aerobe capacity and contractile function and leads to pathological hypertrophy. Impaired Ca2 + handling and increased growth factor signaling seem to be responsible for these pathological changes.

Learning endobronchial ultrasound transbronchial needle aspiration - a 6-year experience at a single institution.

INTRODUCTION: Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) has become an important diagnostic tool for the pulmonologist. Learning this procedure and maintaining technical skills requires continuous practice and evaluation. OBJECTIVES: The aims of the study were a retrospective evaluation of the diagnostic quality of the EBUS-technique and the learning profile of the endoscopy team during the first years (2007-2013) of experience in an unselected population. METHODS: EBUS-TBNA procedures were analysed for clinical data, including results from surgery or clinical/radiological follow-up for at least 6 months. Rapid on-site cytological evaluation (ROSE) was introduced on regular basis the forth year. RESULTS: A total of 711 EBUS-TBNA from 635 patients were included. The percentage of representative EBUS-TBNA initially decreased the first years (minimum 60,9%), before increased to a final result of 82,4%. There was a lower proportion of representative EBUS-TBNA in the benign group (76,8%) vs the malignant group (85,8%). A significant increase in the proportion of representative EBUS-TBNA was seen after ROSE had been introduced. The major indications were diagnosing/staging of lung cancer (54%) and mediastinal lymphadenopathy of unknown cause (25,7%). The sensitivity detecting malignancy was 94,9%, negative predictive value 81,2% and diagnostic accuracy 95,8%. During the study period the percentage of re-examinations with EBUS-TBNA declined from 18,0% to 8,2%. CONCLUSION: After an initial run-in period with declining results, the overall diagnostic yield of EBUS-TBNA increased and reached acceptable levels. These results underline the importance of continuously evaluation of our own results when new methods are implemented in clinical practice.

Expression of neuroendocrine markers in non-small cell lung cancer.

Neuroendocrine (NE) differentiation is reported in some cases of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the expression of NE markers in NSCLC using novel sensitive methods. 20 cases of NSCLC were examined using immunohistochemical (IHC) and immunoelectron microscopy (IEM) methods. In addition, circulating levels of the NE markers chromogranin A (CgA) and neuron-specific enolase (NSE) were measured. Using conventional IHC methods, two tumours (10%) showed immunoreactivity for synaptophysin (SYN), one (5%) for Cg and four (20%) for neural cell adhesion molecule (NCAM). Adding the tyramide signal amplification (TSA) technique, the number of immunoreactive tumours for both SYN and CgA increased to five (25%). No increased immunoreactivity was achieved for NCAM. Nine tumours (45%) were immunoreactive for SYN, CgA or NCAM. Using IEM, one of five representative samples that revealed IHC reactivity for CgA showed immunogold labelling of CgA in cytoplasmic vesicles. Elevated levels of circulating CgA or NSE did not correlate with positive IHC findings. In conclusion, using sensitive IHC methods NE differentiation was seen in a greater proportion of NSCLC than previously reported. Sensitive methods may improve our understanding of the tumour biology and represent an important diagnostic tool for future therapeutic modalities.

Cancer cachexia associates with a systemic autophagy-inducing activity mimicked by cancer cell-derived IL-6 trans-signaling.

The majority of cancer patients with advanced disease experience weight loss, including loss of lean body mass. Severe weight loss is characteristic for cancer cachexia, a condition that significantly impairs functional status and survival. The underlying causes of cachexia are incompletely understood, and currently no therapeutic approach can completely reverse the condition. Autophagy coordinates lysosomal destruction of cytosolic constituents and is systemically induced by starvation. We hypothesized that starvation-mimicking signaling compounds secreted from tumor cells may cause a systemic acceleration of autophagy during cachexia. We found that IL-6 secreted by tumor cells accelerates autophagy in myotubes when complexed with soluble IL-6 receptor (trans-signaling). In lung cancer patients, were cachexia is prevalent, there was a significant correlation between elevated IL-6 expression in the tumor and poor prognosis of the patients. We found evidence for an autophagy-inducing bioactivity in serum from cancer patients and that this is clearly associated with weight loss. Importantly, the autophagy-inducing bioactivity was reduced by interference with IL-6 trans-signaling. Together, our findings suggest that IL-6 trans-signaling may be targeted in cancer cachexia.

New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss.

BACKGROUND: Cachexia affects the majority with advanced cancer. Based on current demographic and clinical factors, it is not possible to predict who will develop cachexia or not. Such variation may, in part, be due to genotype. It has recently been proposed to extend the diagnostic criteria for cachexia to include a direct measure of low skeletal muscle index (LSMI) in addition to weight loss (WL). We aimed to explore our panel of candidate single nucleotide polymorphism (SNPs) for association with WL +/- computerized tomography-defined LSMI. We also explored whether the transcription in muscle of identified genes was altered according to such cachexia phenotype METHODS: A retrospective cohort study design was used. Analysis explored associations of candidate SNPs with WL (n = 1276) and WL + LSMI (n = 943). Human muscle transcriptome (n = 134) was analysed using an Agilent platform. RESULTS: Single nucleotide polymorphisms in the following genes showed association with WL alone: GCKR, LEPR, SELP, ACVR2B, TLR4, FOXO3, IGF1, CPN1, APOE, FOXO1, and GHRL. SNPs in LEPR, ACVR2B, TNF, and ACE were associated with concurrent WL + LSMI. There was concordance between muscle-specific expression for ACVR2B, FOXO1 and 3, LEPR, GCKR, and TLR4 genes and LSMI and/or WL (P < 0.05). CONCLUSIONS: The rs1799964 in the TNF gene and rs4291 in the ACE gene are new associations when the definition of cachexia is based on a combination of WL and LSMI. These findings focus attention on pro-inflammatory cytokines and the renin-angiotensin system as biomarkers/mediators of muscle wasting in cachexia.

Chronic inhalation of carbon monoxide: effects on the respiratory and cardiovascular system at doses corresponding to tobacco smoking.

Carbon monoxide (CO) is a dangerous poison in high concentrations, but the long-term effects of low doses of CO, as in the gaseous component of tobacco smoke, are not well known. The aims of our study were to evaluate the long-term effects of inhaled CO on the respiratory and cardiovascular system at doses corresponding to tobacco smoking and its effect on tumourigenesis and pulmonary neuroendocrine (NE) cells. Female Wistar rats were exposed to either CO (200 ppm) for 20 h/day (n=51) or air (n=26) for 72 weeks. Carboxyhaemoglobin was 14.7+/-0.3% in CO exposed animals and 0.3+/-0.1% in controls. In the lungs, no signs of pathology similar to that associated with cigarette smoking were observed, and no differences in number of pulmonary NE cells were observed between the groups. Chronic CO inhalation induced a 20% weight increase of the right ventricle (p=0.001) and a 14% weight increase of the left ventricle and interventricular septum (p<0.001). Histological examination of the myocardium did not reveal any signs of scarring. In the aorta and femoral artery, no signs of atherosclerosis were observed in CO exposed rats. No exposure related carcinogenic effects were observed. Spontaneous tumours were identified in 29% of CO exposed animals and in 28% of the controls. Our results suggest that low dose CO exposure is probably not responsible for the respiratory pathology associated with tobacco smoking. The effects on the cardiovascular system seem to involve myocardial hypertrophy, but not atherogenesis.

A new removable airway stent.

BACKGROUND: Malignant airway obstruction is a feared complication and will most probably occur more frequently in the future because of increasing cancer incidence and increased life expectancy in cancer patients. Minimal invasive treatment using airway stents represents a meaningful and life-saving palliation. We present a new removable airway stent for improved individualised treatment. METHODS: To our knowledge, the new airway stent is the world's first knitted and uncovered self-expanding metal stent, which can unravel and be completely removed. In an in vivo model using two anaesthetised and spontaneously breathing pigs, we deployed and subsequently removed the stents by unravelling the device. The procedures were executed by flexible bronchoscopy in an acute and a chronic setting - a 'proof-of-principle' study. RESULTS: The new stent was easily and accurately deployed in the central airways, and it remained fixed in its original position. It was easy to unravel and completely remove from the airways without clinically significant complications. During the presence of the stent in the chronic study, granulation tissue was induced. This tissue disappeared spontaneously with the removal. CONCLUSIONS: The new removable stent functioned according to its purpose and unravelled easily, and it was completely removed without significant technical or medical complications. Induced granulation tissue disappeared spontaneously. Further studies on animals and humans are needed to define its optimal indications and future use.

Octreotide treatment for paraneoplastic intestinal pseudo-obstruction complicating SCLC.

Small cell lung cancer (SCLC) is often associated with paraneoplastic neurological syndromes like intestinal pseudo-obstruction. This syndrome is characterized by dysmotility of the bowel without mechanical obstruction. The pathogenesis of the syndrome is thought to involve autoimmune mechanisms with production of antineuronal antibodies and enteric neuronal degeneration. We report a patient with severe constipation as a clinical presentation of a paraneoplastic intestinal pseudo-obstruction complicating SCLC, who was successfully treated with the somatostatin analogue octreotide. This may be explained by effects of hormone-like substances from the tumor directly inhibiting the gut motility, rather than by autoimmune mechanisms.