Adherence to Guidelines for Acute Rehabilitation in the Norwegian Trauma Plan.

OBJECTIVE: To evaluate adherence to 3 central operational recommendations for acute rehabilitation in the Norwegian trauma plan. METHODS: A prospective multi-centre study of 538 adults with moderate and severe trauma with New Injury Severity Score > 9. RESULTS: Adherence to the first recommendation, assessment by a physical medicine and rehabilitation physician within 72 h following admission to the intensive care unit (ICU) at the trauma centre, was documented for 18% of patients. Adherence to the second recommendation, early rehabilitation in the intensive care unit, was documented for 72% of those with severe trauma and ≥ 2 days ICU stay. Predictors for early rehabilitation were ICU length of stay and spinal cord injury. Adherence to the third recommendation, direct transfer of patients from acute ward to a specialized rehabilitation unit, was documented in 22% of patients, and occurred more often in those with severe trauma (26%), spinal cord injury (54%) and traumatic brain injury (39%). Being employed, having head or spinal chord injury and longer ICU stay were predictors for direct transfer to a specialized rehabilitation unit. CONCLUSION: Adherence to acute rehabilitation guidelines after trauma is poor. This applies to documented early assessment by a physical medicine and rehabilitation physician, and direct transfer from acute care to rehabilitation after head and extremity injuries. These findings indicate a need for more systematic integration of rehabilitation in the acute treatment phase after trauma.

The Barriers to Rapid Reperfusion in Acute ST-Elevation Myocardial Infarction.

INTRODUCTION: This study aimed to quantify the contribution of various obstacles to timely reperfusion therapy in acute ST-elevation myocardial infarction (STEMI) and to improve performance in a mixed remote rural/urban region. METHODS: From November 1, 2020 to April 23, 2021, patients with acute STEMI were prospectively monitored with the critical time intervals, treatment modalities, and outcomes registered. Selected clinical decision-makers in 11 hospitals were appointed as improvement agents and systematically provided with weekly updated information about absolute and relative performance. Suggestions for improvements were invited and shared. RESULTS: Only 29% of the 146 patients received reperfusion therapy within recommended time limits [prehospital thrombolysis, 2/48; in-hospital thrombolysis, 0/20; primary percutaneous coronary intervention (pPCI), 37/68, with median intervals from the first medical contact of 44, 49, and 133 min, respectively]. Efficiency varied considerably between health trusts: median time from the first medical contact to prehospital thrombolysis ranged from 29 to 54 min (hazard ratio 4.89). The predominant, remediable causes for delays were erroneous tactical choices and protracted electrocardiographic diagnostication, decision-making, and administration of fibrinolytic medication. During the trial, the time to pPCI was non-significantly reduced. CONCLUSION: We found several targets for system improvements in order to mitigate reperfusion delays along the entire chain of care, regardless of reperfusion modality chosen. More patients should receive prehospital thrombolysis. The most important measures will be training to ensure a more efficient on-site workflow, improved protocols and infrastructure facilitating the communication between first responders and in-hospital clinicians, and education emphasizing prehospital transport times. CLINICAL TRIALS IDENTIFIER: NCT04614805.

The risk factors for radial artery and saphenous vein graft occlusion are different.

Objectives. To determine risk factors for radial artery and saphenous vein graft occlusion during long-term follow-up after coronary artery bypass grafting (CABG). Methods: From a cohort of 119 patients who had received a radial artery graft, 76 - of whom 55 also had at least one saphenous vein graft - underwent a preplanned direct angiography and anthropometric, biochemical, and endothelial function assessment 7.6-12.1 (mean 8.9) years after CABG. Comorbidity, medication, and smoking habits were also recorded. The association between these parameters and conduit longevity was analyzed in univariable and multivariable logistic regression models. Results: Radial artery graft occlusions were associated with higher plasma levels of high-sensitive C-reactive protein and patency was best among patients with pharmacologically treated hypertension. The sole independent risk factor identified for saphenous vein graft occlusion was tobacco smoking 8-12 years postoperatively. Conclusion: Our data support the contention that the pathogenesis of radial artery graft failure is distinct from vein graft disease and is related to hypertension status and systemic inflammation. These risk factors are potential targets for preventive measures. Accordingly, the study supports the eventual design of personalized secondary prevention regimens.Clinical registration number: ISRCTN23118170.

Correction: Rehabilitation Needs, Service Provision, and Costs in the First Year Following Traumatic Injuries: Protocol for a Prospective Cohort Study.

[This corrects the article DOI: 10.2196/25980.].

Rehabilitation Needs, Service Provision, and Costs in the First Year Following Traumatic Injuries: Protocol for a Prospective Cohort Study.

BACKGROUND: Traumatic injuries, defined as physical injuries with sudden onset, are a major public health problem worldwide. There is a paucity of knowledge regarding rehabilitation needs and service provision for patients with moderate and major trauma, even if rehabilitation research on a spectrum of specific injuries is available. OBJECTIVE: This study aims to describe the prevalence of rehabilitation needs, the provided services, and functional outcomes across all age groups, levels of injury severity, and geographical regions in the first year after trauma. Direct and indirect costs of rehabilitation provision will also be assessed. The overarching aim is to better understand where to target future efforts. METHODS: This is a population-based prospective follow-up study. It encompasses patients of all ages with moderate and severe acute traumatic injury (New Injury Severity Score >9) admitted to the regional trauma centers in southeastern and northern Norway over a 1-year period (2020). Sociodemographic and injury data will be collected. Upon hospital discharge, rehabilitation physicians estimate rehabilitation needs. Rehabilitation needs are assessed by the Rehabilitation Complexity Scale Extended-Trauma (RCS E-Trauma; specialized inpatient rehabilitation), Needs and Provision Complexity Scale (NPCS; community-based rehabilitation and health care service delivery), and Family Needs Questionnaire-Pediatric Version (FNQ-P). Patients, family caregivers, or both will complete questionnaires at 6- and 12-month follow-ups, which are supplemented by telephone interviews. Data on functioning and disability, mental health, health-related quality of life measured by the EuroQol Questionnaire (EQ-5D), and needs and provision of rehabilitation and health care services are collected by validated outcome measures. Unmet needs are represented by the discrepancies between the estimates of the RCS E-Trauma and NPCS at the time of a patient's discharge and the rehabilitation services the patient has actually received. Formal service provision (including admission to inpatient- or outpatient-based rehabilitation), informal care, and associated costs will be collected. RESULTS: The project was funded in December 2018 and approved by the Regional Committee for Medical and Health Research Ethics in October 2019. Inclusion of patients began at Oslo University Hospital on January 1, 2020, and at the University Hospital of North Norway on February 1, 2020. As of February 2021, we have enrolled 612 patients, and for 286 patients the 6-month follow-up has been completed. Papers will be drafted for publication throughout 2021 and 2022. CONCLUSIONS: This study will improve our understanding of existing service provision, the gaps between needs and services, and the associated costs for treating patients with moderate and major trauma. This may guide the improvement of rehabilitation and health care resource planning and allocation. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25980.

Direct angiography demonstrates equal 8-12 years patency rates of radial artery and saphenous vein grafts.

Objectives: The benefits of coronary artery bypass surgery depend on lasting graft patency. To aid rational graft selection, the relative long-term merits of radial artery and saphenous vein grafts need to be determined by a gold standard method and with minimal clinically driven selection bias. Methods: The patency rates of various conduits were determined by direct angiography in 76 patients from a cohort of 119 undergoing coronary artery bypass grafting 7.6-12.1 (mean 8.9) years before. Results: 14 out of 76 radial artery and 10 out of 61 saphenous vein grafts were occluded (rates 0.18 and 0.16, respectively). Conclusion: The high long-term patency rate of saphenous vein grafts does not support a preferential use of the radial artery as a coronary artery bypass conduit. Clinical registration number: ISRCTN23118170.

Clinical guided computer tomography decisions are advocated in potentially severely injured trauma patients: a one-year audit in a level 1 trauma Centre with long pre-hospital times.

BACKGROUND: The International Commission on Radiological Protection's (ICRP) justification principles state that an examination is justified if the potential benefit outweighs the risk for radiation harm. Computer tomography (CT) contributes 50% of the radiation dose from medical imaging, and in trauma patients, the use of standardized whole body CT (SWBCT) increases. Guidelines are lacking, and reviews conclude conflictingly regarding the benefit. We aimed to study the degree of adherence to ICRP's level three justification, the individual dose limitation principle, in our institution. METHODS: This is a retrospective clinical audit. We included all 144 patients admitted with trauma team activation to our regional Level 1 trauma centre in 2015. Injuries were categorized according to the Abbreviated Injury Scale (AIS) codes. Time variables, vital parameters and interventions were registered. We categorized patients into trauma admission SWBCT, selective CT or no CT examination strategy groups. We used descriptive statistics and regression analysis of predictors for CT examination strategy. RESULTS: The 144 patients (114 (79.2%) males) had a median age of 31 (range 0-91) years. 105 (72.9%) had at least one AIS ≥ 2 injury, 26 (18.1%) in more than two body regions. During trauma admission, at least one vital parameter was abnormal in 46 (32.4%) patients, and 73 (50.7%) underwent SWBCT, 43 (29.9%) selective CT and 28 (19.4%) no CT examination. No or only minor injuries were identified in 17 (23.3%) in the SWBCT group. Two (4.6%) in the selective group were examined with a complement CT, with no new injuries identified. A significantly (p < 0.001) lower proportion of children (61.5%) than adults (89.8%) underwent CT examination despite similar injury grades and use of interventions. In adjusted regression analysis, patients with a high-energy trauma mechanism had significantly (p = 0.028) increased odds (odds ratio = 4.390, 95% confidence interval 1.174-16.413) for undergoing a SWBCT. CONCLUSION: The high proportion of patients with no or only minor injuries detected in the SWBCT group and the significantly lower use of CT among children, indicate that use of a selective CT examination strategy in a higher proportion of our patients would have approximated the ICRP's justification level three, the individual dose limitation principle, better.

Injury coding in a national trauma registry: a one-year validation audit in a level 1 trauma centre.

BACKGROUND: Hospitals must improve patient safety and quality continuously. Clinical quality registries can drive such improvement. Trauma registries code injuries according to the Abbreviated Injury Scale (AIS) and benchmark outcomes based on the Injury Severity Score (ISS) and New ISS (NISS). The primary aim of this study was to validate the injury codes and severities registered in a national trauma registry. Secondarily, we aimed to examine causes for missing and discordant codes, to guide improvement of registry data quality. METHODS: We conducted an audit and established an expert coder group injury reference standard for patients met with trauma team activation in 2015 in a Level 1 trauma centre. Injuries were coded according to the AIS. The audit included review of all data in the electronic health records (EHR), and new interpretation of all images in the picture archiving system. Validated injury codes were compared with the codes registered in the registry. The expert coder group's interpretations of reasons for discrepancies were categorised and registered. Inter-rater agreement between registry data and the reference standard was tested with Bland-Altman analysis. RESULTS: We validated injury data from 144 patients (male sex 79.2%) with median age 31 (inter quartile range 19-49) years. The total number of registered AIS codes was 582 in the registry and 766 in the reference standard. All injuries were concordantly coded in 62 (43.1%) patients. Most non-registered codes (n = 166 in 71 (49.3%) patients) were AIS 1, and information in the EHR overlooked by registrars was the dominating cause. Discordant coding of head injuries and extremity fractures were the most common causes for 157 discordant AIS codes in 74 (51.4%) patients. Median ISS (9) and NISS (12) for the total population did not differ between the registry and the reference standard. CONCLUSIONS: Concordance between the codes registered in the trauma registry and the reference standard was moderate, influencing individual patients' injury codes validity and ISS/NISS reliability. Nevertheless, aggregated median group ISS/NISS reliability was acceptable.

Extended versus limited arch replacement in acute Type A aortic dissection.

OBJECTIVES: The recommended extent of surgical resection and reconstruction of the arch in acute DeBakey Type I aortic dissection is an ongoing controversy. However, several recent reports indicate a trend towards a more extensive arch operation in several institutions. We have analysed the recent data from the International Registry of Acute Aortic Dissection to assess the choice of procedure over time and to evaluate the surgical outcome in a 'real-world' database. Our aim was to compare short- and mid-term outcomes of limited repairs versus complete arch surgery. METHODS: Of the 1241 patients included in the 'Interventional Cohort' of the International Registry of Acute Aortic Dissection from March 1996 to March 2015, 907 underwent ascending aortic or hemiarch replacement (Group A) and 334 had extended arch replacement (Group B). An extended resection was a surgeon's 'judgement call'. Logistic regression analysis, propensity-adjusted multivariable comparisons and Kaplan-Meier curves were used for analyses. RESULTS: Overall in-hospital mortality was 14.2% with no difference between groups (Group A 13.1%, Group B 17.1%). Coma/altered consciousness (odds ratio 3.16, 95% confidence interval 1.60-6.25, P = 0.001), hypotension, tamponade or shock (2.03, 1.11-3.73, P = 0.022) and any pulse deficit (1.92, 1.04-3.54, P = 0.038) were predictors of in-hospital mortality in a propensity score-adjusted multivariable analysis. Overall 5-year survival was 69.4% in the ascending group and 73.1% in the total arch group (P = 0.83 by Kaplan-Meier analysis). For survivors of the index hospitalization, the 5-year freedom from death, aortic rupture and reintervention were 71.1% in Group A and 76.4% in Group B (P = 0.54 by Kaplan-Meier analysis). CONCLUSIONS: Selective, or 'surgeon's choice', extended arch replacement had no discernible acute downside compared with less extensive surgery. Whether extended arch replacement improves the prognosis beyond 5 years remains to be settled.

The International Registry of Acute Aortic Dissections (IRAD) - experiences from the first 20 years.

An international collaboration on various aspects of acute aortic syndromes, IRAD or The International Registry of Acute Aortic Dissections, is celebrating its 20th anniversary this year (2016). In this paper, we present important lessons learned during these first 20 years.

Evaluation of a trauma team activation protocol revision: a prospective cohort study.

BACKGROUND: Correct triage based on prehospital information contributes to a better outcome for potentially seriously injured patients. In 2011 we changed the trauma team activation (TTA) criteria in our center in order to improve the high over- and undertriage properties of the protocol. Five criteria that were unable to predict severe injury were removed. In the present study, we evaluated the protocol revision by comparing over- and undertriage in the former and present set of criteria. METHODS: All severely injured patients (Injury Severity Score (ISS) > 15) and all patients admitted with TTA in the period of 01.01.2013 - 31.12.2014 were included in the study. We defined overtriage as the fraction of patients with TTA when ISS ≤15 and undertriage as the fraction of patients without TTA when ISS > 15. We also evaluated triage with the occurrence of emergency procedures immediately after admission. RESULTS: 324 patients were included, 164 patients had ISS>15, 287 were admitted with TTA. Over- and undertriage were 74 % and 28 % respectively. When we used emergency procedure as reference, the figures were 83 % and 15 % respectively. Undertriaged patients had significantly more neurosurgical injuries and were significantly more often transferred from an acute care hospital. DISCUSSION: Over- and undertriage are almost the same as before the criteria were revised, and higher thanrecommended levels. CONCLUSIONS: Revision of the TTA criteria has not improved triage, and further measures are necessary to achieveacceptable levels.

Lung cancer treatment is influenced by income, education, age and place of residence in a country with universal health coverage.

Selection of lung cancer treatment should be based on tumour characteristics, physiological reserves and preferences of the patient. Our aims were to identify and quantify other factors associated with treatment received. Lung cancer patient data from 2002 to 2011 were obtained from the national population-based Cancer Registry of Norway, Statistics Norway and the Norwegian Patient Register. Multivariable logistic regression examined whether year of diagnosis, age, sex, education, income, health trust, smoking status, extent of disease, histology and comorbidities were associated with choice of treatment; surgery or radical or palliative radiotherapy, within 1 year of diagnosis. Among the 24,324 lung cancer patients identified, the resection rate remained constant while the proportion of radical radiotherapy administered increased from 8.6 to 14.1%. Older patients, those with lower household incomes and certain health trusts were less likely to receive any treatment. Lower education and the male gender were identified as negative predictors for receiving surgery. Smoking history was positively associated with both radical and palliative radiotherapy, while comorbidity and symptoms were independently associated with receiving surgery and palliative radiotherapy. Although Norway is a highly egalitarian country with a free, universal healthcare system, this study indicates that surgery and radical and palliative radiotherapy were under-used among the elderly, those with a lower socioeconomic status and those living in certain health trusts.

Lung cancer survival in Norway, 1997-2011: from nihilism to optimism.

We examine changes in survival and patient-, tumour- and treatment-related factors among resected and nonresected lung cancer patients, and identify subgroups with the largest and smallest survival improvements.National population-based data from the Cancer Registry of Norway, Statistics Norway and the Norwegian Patient Register were linked for lung cancer patients diagnosed during 1997-2011. The 1- and 5-year relative survival were estimated, and Cox proportional hazard regression, adjusted for selected patient characteristics, was used to assess prognostic factors for survival in lung cancer patients overall and stratified by resection status.We identified 34 157 patients with lung cancer. The proportion of histological diagnoses accompanied by molecular genetics testing increased from 0% to 26%, while those accompanied by immunohistochemistry increased from 8% to 26%. The 1-year relative survival among nonresected and resected patients increased from 21.7% to 34.2% and 75.4% to 91.5%, respectively. The improved survival remained significant after adjustment for age, sex, stage and histology. The largest improvements in survival occurred among resected and adenocarcinoma patients, while patients ≥80 years experienced the smallest increase.Lung cancer survival has increased considerably in Norway. The explanation is probably multifactorial, including improved attitude towards diagnostic work-up and treatment, and more accurate diagnostic testing that allows for improved selection for resection and improved treatment options.

The treatment of spleen injuries: a retrospective study.

BACKGROUND: Hemorrhage after blunt trauma is a major contributor to death after trauma. In the abdomen, an injured spleen is the most frequent cause of major bleeding. Splenectomy is historically the treatment of choice. In 2007, non-operative management (NOM) with splenic artery embolization (SAE) was introduced in our institution. The indication for SAE is hemodynamically stable patients with extravasation of contrast, or grade 3-5 spleen injury according to the Abbreviated Organ Injury Scale 2005, Update 2008. We wanted to examine if the introduction of SAE increased the rate of salvaged spleens in our trauma center. METHOD: All patients discharged with the diagnosis of splenic injury in the period 01.01.2000 - 31.12.2013 from the University Hospital of North Norway Tromsø were included in the study. Patients admitted for rehabilitation purposes or with an iatrogenic injury were excluded. RESULTS: A total of 109 patients were included in the study. In the period 2000-7, 20 of 52 patients were splenectomized. During 2007-13, there were 6 splenectomies and 24 SAE among 57 patients. The reduction in splenectomies is significant (p < 0.001). There is an increase in the rate of treated patients (splenectomy and SAE) from 38 to 53 % in the two time periods, but not significantly (p = 0.65). CONCLUSION: The rate of salvaged spleens has increased after the introduction of SAE in our center. TRIAL REGISTRATION: The study is registered at www.clinicaltrials.gov with the identification number NCT01965548.

The role of age in complicated acute type B aortic dissection.

BACKGROUND: Complicated acute type B aortic dissection (cABAD) generally requires urgent intervention. Advanced age is a risk factor for mortality after thoracic aortic intervention, including surgery for aortic dissection. The purpose of this study was to investigate the exact impact of increasing age on the management and outcomes of cABAD. METHODS: We analyzed the outcomes of 583 patients with cABAD enrolled in the International Registry of Acute Aortic Dissection (IRAD) between 1996 and 2012. All patients with cABAD were categorized according to age by decade and management type (medical, surgical, or endovascular treatment), and outcomes were subsequently investigated in the different age groups. RESULTS: The mean age of the cohort was 63.4 ± 14.2 years, 36% of patients (n = 209) were greater than 70 years of age and 64% (n = 374) were less than 70 years. The utilization of surgery and endovascular techniques progressively decreased with patient age, while the rate of medical management significantly increased with age (p < 0.001). The in-hospital mortality rates for complicated patients younger than 70 years versus 70 years or more were 10.1% versus 30.0% for endovascular treatment (p = 0.001), 17.2% versus 34.2% for surgical treatment (p = 0.027), and 14.2% versus 32.2% for medical treatment (p = 0.001). Age 70 years or greater was a predictor of in-hospital mortality in multivariate analysis (odds ratio 2.37, 95% confidence interval: 1.23 to 4.54, p = 0.010). CONCLUSIONS: Advanced age has a dramatic impact on the management and outcomes of patients with cABAD. A nonsignificant trend toward lower mortality after endovascular management was observed, both for younger patients and for elderly patients.

Arterial grafts do not counteract target vessel occlusion.

OBJECTIVES: Grafted, non-occluded coronary arteries might contribute substantially to the myocardial blood supply and serve as a basis for vascular collateralization which preserves the myocardium in the event of graft occlusion. Early studies indicated that grafting with saphenous vein, but not internal mammary arteries, accelerates coronary atherosclerosis. This has not been extensively studied for the radial artery, which like the internal mammary artery (IMA) is largely resistant to atherosclerosis. A differential effect of various grafts might facilitate identification of disease-modifying principles. Our surgical cohort represented an opportunity to analyse new native coronary occlusions by comparison with preoperative angiograms. METHODS: One hundred and two patients underwent angiography 1.3-3.9 years after coronary artery bypass surgery, primarily in order to compare the patency of radial artery, IMA and saphenous vein grafts. RESULTS: Out of 290 stenotic, grafted vessels, 67 (23%) occluded during follow-up. Native occlusion occurred in 47% of the patients and correlated with serum-cholesterol. In a per target analysis, independent predictors of postoperative native occlusion were the right coronary artery territory, patent corresponding graft, the corresponding graft being an IMA and end-to-side anastomosis. CONCLUSIONS: Target vessel occlusion is similar with radial artery and saphenous vein grafts and proceeds rapidly even in the current era of secondary prophylaxis against atherosclerosis. Competitive graft flow appears to promote occlusion. Contrary to previous studies, we do not find vein grafts to be inferior to IMA grafts with respect to preservation of native vessel patency.

Extent of preoperative false lumen thrombosis does not influence long-term survival in patients with acute type A aortic dissection.

BACKGROUND: Partial thrombosis of the false lumen has been related to aortic growth, reoperations, and death in the chronic phase of type B and repaired type A aortic dissections. The impact of preoperative false lumen thrombosis has not been studied previously. We used data from a contemporary, multinational database on aortic dissections to evaluate whether different degrees of preoperative false lumen thrombosis influenced long-term prognosis. METHODS AND RESULTS: We examined the records of 522 patients with surgically treated acute type A aortic dissections who survived to discharge between 1996 and 2011. At the preoperative imaging, 414 (79.3%) patients had patent false lumens, 84 (16.1%) had partial thrombosis of the false lumen, and 24 (4.6%) had complete thrombosis of the false lumen. The annual median (interquartile range) aortic growth rates were 0.5 (-0.3 to 2.0) mm in the aortic arch, 2.0 (0.2 to 4.0) mm in the descending thoracic aorta, and similar regardless of the degree of false lumen thrombosis. The overall 5-year survival rate was 84.7%, and it was not influenced by false lumen thrombosis (P=0.86 by the log-rank test). Independent predictors of long-term mortality were age >70 years (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.20 to 4.56, P=0.012) and postoperative cerebrovascular accident, coma, and/or renal failure (HR, 2.62; 95% CI, 1.40 to 4.92, P=0.003). CONCLUSIONS: Patients with acute type A aortic dissection who survive to discharge have a favorable prognosis. Preoperative false lumen thrombosis does not influence long-term mortality, reintervention rates, or aortic growth.

Changes in the Secretory Profile of NSCLC-Associated Fibroblasts after Ablative Radiotherapy: Potential Impact on Angiogenesis and Tumor Growth.

In the context of radiotherapy, collateral effects of ablative doses of ionizing radiation (AIR) on stromal components of tumors remains understudied. In this work, cancer-associated fibroblasts (CAFs) isolated from freshly resected human lung tumors were exposed to AIR (1x 18 Gy) and analyzed for their release of paracrine factors. Inflammatory mediators and regulators of angiogenesis and tumor growth were analyzed by multiplex protein assays in conditioned medium (CM) from irradiated and non-irradiated CAFs. Additionally, the profile of secreted proteins was examined by proteomics. In functional assays, effects of CAF-CM on proliferative and migratory capacity of lung tumor cells (H-520/H-522) and human umbilical vein endothelial cells (HUVECs) and their tube-forming capacity were assessed. Our data show that exposure of CAFs to AIR results in 1) downregulated release of angiogenic molecules such as stromal cell-derived factor-1, angiopoietin, and thrombospondin-2 (TSP-2); 2) upregulated release of basic fibroblast growth factor from most donors; and 3) unaffected expression levels of hepatocyte growth factor, interleukin-6 (IL-6), IL-8, IL-1ß, and tumor necrosis factor-α. CM from irradiated and control CAFs did not affect differently the proliferative or migratory capacity of tumor cells (H-520/H-522), whereas migratory capacity of HUVECs was partially reduced in the presence of irradiated CAF-CM. Overall, we conclude that AIR mediates a transformation on the secretory profile of CAFs that could influence the behavior of other cells in the tumor tissue and hence guide therapeutic outcomes. Downstream consequences of the changes observed in this study merits further investigations.

Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced.

BACKGROUND: Cancer-Associated Fibroblasts (CAFs) are significant components of solid malignancies and play central roles in cancer sustainability, invasion and metastasis. In this study we have investigated the invasive capacity and matrix remodelling properties of human lung CAFs after exposure to ablative doses of ionizing radiation (AIR), equivalent to single fractions delivered by stereotactic ablative radiotherapy (SART) for medically inoperable stage-I/II non-small-cell lung cancers. METHODS: CAFs were isolated from lung tumour specimens from 16 donors. Initially, intrinsic radiosensitivity was evaluated by checking viability and extent of DNA-damage response (DDR) at different radiation doses. The migrative and invasive capacities of CAFs were thereafter determined after a sub-lethal single radiation dose of 18 Gy. To ascertain the mechanisms behind the altered invasive capacity of cells, expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) were measured in the conditioned media several days post-irradiation, along with expression of cell surface integrins and dynamics of focal contacts by vinculin-staining. RESULTS: Exposing CAFs to 1 × 18 Gy resulted in a potent induction of multiple nuclear DDR foci (> 9/cell) with little resolution after 120 h, induced premature cellular senescence and inhibition of the proliferative, migrative and invasive capacity. AIR promoted MMP-3 and inhibited MMP-1 appearance to some extent, but did not affect expression of other major MMPs. Furthermore, surface expression of integrins α2, ß1 and α5 was consistently enhanced, and a dramatic augmentation and redistribution of focal contacts was observed. CONCLUSIONS: Our data indicate that ablative doses of radiation exert advantageous inhibitory effects on the proliferative, migratory and invasive capacity of lung CAFs. The reduced motility of irradiated CAFs might be a consequence of stabilized focal contacts via integrins.