The Pulmonary Neuroendocrine System : Physiological, pathological and tumourigenic aspects

Nevroendokrine (NE) celler er en benevnelse på spesialiserte celler som finnes diffust utbredt i flere organ i kroppen og som har evnen til å produsere og skille ut hormon-liknende substanser. I lungene oppfattes ansamlinger av disse cellene som sanseorgan som monitorerer oksygen-nivået, og de spiller sannsynligvis en viktig rolle for lungenes utvikling, regulering av lungesirkulasjon og luftstrøm, samt immunrespons. Hovedmålet med avhandlingen har vært å se på ulike sider ved lungenes NE system ved fysiologiske og patologiske tilstander, med fire delarbeider som hver for seg belyser ulike aspekt ved dette. I det første arbeidet ble den generelle NE markøren kromogranin A (CgA) målt i blodprøver fra personer som deltok i Helseundersøkelsen i Nord-Trøndelag (HUNT 1995-97). Resultatene viste at mannlige deltakere med dårlig lungefunksjon hadde høyere nivå av CgA enn deltakere med normal lungefunksjon, som et uttrykk for NE aktivering. Det andre arbeidet omhandler et 72 ukers eksponerings-forsøk med inhalasjon av karbon monoksid (CO) hos rotter gitt i konsentrasjoner som tilsvarer blod-verdier hos stor-røykere. Bortsett fra forstørret hjerte, ble det ikke funnet andre røyke-relaterte skader på hjerte/kar-systemet eller lungene. CO hadde ingen effekt på svulstforekomst eller forandringer i antall NE celler. I det tredje arbeidet ble ulike NE markører undersøkt med immunhistokjemiske, immunelektronmikroskopiske og biokjemiske metoder hos pasienter med ikke-småcellet lungecancer. Hovedfunnet her var et større antall svulster positive for NE markører enn tidligere beskrevet når signalforsterkende teknikker ble brukt ved immunhistokjemi. Dette kan ha betydning for forståelsen av svulstenes biologi, og kan være uttrykk for at lungenes NE celler er opphavsceller for flere slike svulster enn tidligere antatt. Det siste delarbeidet belyser sekresjon av substanser fra lungenes NE system ved hypoksi i en isolert, ventilert og sirkulert rottelunge-modell. Ved lave oksygennivå falt konsentrasjonen av proteinet bombesin i buffer sirkulert gjennom lungekretsløpet. I tillegg ble det funnet øket antall immunmerkede celler med calcitonin gene-related peptide, noe som tyder på redusert cellulær utskillelse ved eksponering for hypoksi. Resultatene viser at hypoksi er assosiert med raske forandringer i lungenes NE system for å opprettholde en balansert ventilasjon og sirkulasjon. Samlet gir arbeidene økt kunnskap om det nevroendokrine system ved ulike sykdoms-prosesser som luftveisobstruksjon, inhalasjon av gasser som CO, i svulstutvikling og ved fysiologiske prosesser som hypoksi.Paper II is reprinted with kind permission of Elsevier, sciencedirect.co

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 forlung cancer is 42 days. The aim of this study was to identify reasons for delays and estimate the effect on thetimelines when applying an optimal diagnostic pathway.Methods:Retrospective review of medical records of lung cancer patients, with stage I-II at baseline CT, receivingcurative 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 furtherinvestigations 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 hospitalvisit, 2) tumor board discussion to decide diagnostic strategy and treatment, 3) referral to surgery or curativeradiotherapy, 4) tissue sampling while waiting to start treatment. Applying the optimal pathway, current waiting timefor PET CT and observed waiting times for the other procedures, 80% of patients could have started treatment within42 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 incurative lung cancer patients at our hospital and reduce the resources needed

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

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

Additional file 2: of Medical complexity and time to lung cancer treatment – a three-year retrospective chart review

Medical complexity and time to lung cancer treatment. (DO 25 kb

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

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

Lung cancer is the leading cause of cancer-related death worldwide, accounting for nearly one-fifth of all cancer-related deaths. Immunotherapy with immune checkpoint inhibitors has become one of the most promising approaches in the treatment of advanced lung cancer, although beneficial responses are seen only in a proportion of patients. To improve immunotherapy treatment responses in lung cancer, we need to identify which immunosuppression mechanisms are activated in the tumor microenvironment. In this study, we investigated gene expression profiles in intra-tumoral immune cells in lung cancer, focusing on tumor-associated macrophages, and interactions with CD4+ and CD8+ T cells. Our data highlight two newly described immunosuppressive pathways, which may represent novel innate immune checkpoints dampening the anti-tumor T cell immune response in lung cancer. Our results substantiate the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy

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

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