Small Cell Lung Cancer in Norway: Patterns of Care by Health Region and Survival Trends.

INTRODUCTION/BACKGROUND: There has been a marked survival improvement for patients with non-small-cell lung cancer. We describe the national trends in characteristics and survival, and geographical differences in diagnostic workup, treatment, and survival for patients with small-cell lung cancer (SCLC). MATERIALS AND METHODS: Patients registered with SCLC at the Cancer Registry of Norway in 2002 to 2022 were included. Trends in overall survival were estimated for all SCLC patients, patients with limited stage SCLC, patients undergoing surgery, and by health region. Adjusting for case-mix, a multivariable Cox regression was performed examining the association between health region and death. RESULTS: The study included 8374 patients. The stage distribution remained unchanged during the study period. The 5-year overall survival increased from 7.7% to 22.8% for patients with limited stage. The use of multidisciplinary team meetings varied from 62.5% to 85.7%, and the use of positron emission tomography-computer tomography varied from 70.4% to 86.2% between the health regions. Treatment patterns differed markedly between the health regions, with the proportion dying without any registered treatment ranging from 1.2% to 10.9%. For limited stage patients in 2018 to 2022, the median overall survival ranged from 16.5 to 25.5 months across health regions, and the 5-year overall survival ranged from 18.7% to 28.7% (P = .019). CONCLUSION: The survival for patients with SCLC remains poor. The use of diagnostic procedures, treatment modalities, and survival differed between regions, warranting investigations to further explore the reasons.

Increase in curative treatment and survival of lung cancer in Norway 2001-2016.

We have studied the alterations in the use of curative treatment and the outcome for lung cancer patients in Norway 2001-2016. The Cancer Registry of Norway has a practically complete registration of all cancer diagnoses, treatments given and deaths. For the years 2001-2016, 43,137 patients were diagnosed with lung cancer. Stereotactic radiotherapy was established nationwide from 2008 and its use has increased, and in 2016, 8.8% were given this treatment. In addition 20.6% were operated and 8.5% were treated with conventional radiotherapy. Thus 37.9% of those diagnosed were treated with intention to cure, compared to 22.9% in 2001 (p < 0.0001). Further, the median survival for the whole group diagnosed with lung cancer increased from 6.0 (95% CI 5.6-6.7) months in 2001 to 11.8 (95% CI 10.9-12.7) in 2016. The 5 year survival increased from 9.4 (95% CI 8.1-10.8)% to 19.9 (95% CI 19.2-20.6)% in the same period. In 2016 the age adjusted incidence rate was 59.5 per 100,000 (Norwegian standard) and had increased significantly in both sexes. There had also been an increase in mean age at diagnosis and the proportion diagnosed in an early stage. The increase in curative treatment has been paralleled with a doubling in both the median and 5-year survival. The present results are used for surveillance and as a benchmark, and we are looking forward to reaching a proportion of 40% of patients given curative treatment.

Pedicled Vein Grafts in Coronary Surgery: Perioperative Data From a Randomized Trial.

BACKGROUND: Less-than-optimal long-term patency of the saphenous vein is one of the main obstacles for the success of coronary artery bypass grafting (CABG). Results from the IMPROVE-CABG trial has shown that harvesting the saphenous vein with a pedicle of perivascular tissue less than 5 mm while using manual distention provides comparable occlusion rates but significantly less intimal hyperplasia at early follow-up. The impact of pedicled veins on duration of operations, leg wound infections, and postoperative bleeding is unknown. METHODS: One hundred patients undergoing first-time elective CABG were randomly assigned to conventional or pedicled vein harvesting. Perioperative and postoperative data were collected prospectively during the hospital stay and at follow-up. RESULTS: Duration of extracorporeal circulation was significantly longer in the pedicled vein group (mean: 76 min versus 65 min, p = 0.006); however, no significant difference was found in the cross-clamp time. No significant difference was found in intraoperative vein graft flow, postoperative bleeding, or leg wound infections (4% in each group). No reoperations were due to vein graft bleeding. CONCLUSIONS: Harvesting a pedicled vein provides comparable postoperative bleeding and leg wound infection rates in selected patients. The technique is associated with a slightly longer duration of extracorporeal circulation than harvesting conventional veins. Promising early results using the pedicled vein technique may contribute to a change in standard vein harvesting technique for CABG in selected patients.

Exercise training and losartan improve endothelial function in heart failure rats by different mechanisms.

OBJECTIVES: To investigate the mechanisms of losartan- and exercise training-induced improvements on endothelial dysfunction in heart failure. DESIGN: Sprague-Dawley rats subjected to left coronary artery ligation inducing myocardial infarction and heart failure were randomized to losartan treatment, high-intensity exercise training, or both. RESULTS: Losartan, but not exercise training, reduced the heart failure-associated elevation in left ventricular end-diastolic pressure (26 ± 2 mmHg vs. 19 ± 1 mmHg after losartan). In contrast, both exercise training and losartan improved exercise capacity, by 40% and 20%, respectively; no additional effects were observed when exercise training and losartan were combined. Aortic segments were mounted on a force transducer to determine vasorelaxation. Heart failure impaired endothelium-dependent vasorelaxation, observed as a 1.9-fold reduced response to acetylcholine (EC50). Exercise and losartan improved acetylcholine-mediated vasorelaxation to the same extent, but by different mechanisms. Exercise training upregulated the nitric oxide pathway, whereas losartan upregulated a non-nitric oxide or -prostacyclin pathway; possibly involving the endothelium-dependent hyperpolarizing factor. CONCLUSIONS: Both losartan and exercise training reversed endothelial dysfunction in heart failure; exercise training via nitric oxide-dependent vasorelaxation, and losartan via an unknown mechanism that may involve endothelium-dependent hyperpolarizing factor. Thus, the combined treatment activated an additional nitric oxide- independent mechanism that contributed to reduce endothelial dysfunction.

Caloric restriction reverses hepatic insulin resistance and steatosis in rats with low aerobic capacity.

Rats selectively bred for low aerobic running capacity exhibit the metabolic syndrome, including hyperinsulinemia, insulin resistance, visceral obesity, and dyslipidemia. They also exhibit features of nonalcoholic steatohepatitis, including chicken-wire fibrosis, inflammation, and oxidative stress. Hyperinsulinemia in these rats is associated with impaired hepatic insulin clearance. The current studies aimed to determine whether these metabolic abnormalities could be reversed by caloric restriction (CR). CR by 30% over a period of 2-3 months improved insulin clearance in parallel to inducing the protein content and activation of the carcinoembryonic antigen-related cell adhesion molecule 1, a main player in hepatic insulin extraction. It also reduced glucose and insulin intolerance and serum and tissue (liver and muscle) triglyceride levels. Additionally, CR reversed inflammation, oxidative stress, and fibrosis in liver. The data support a significant role of CR in the normalization of insulin and lipid metabolism in liver.

Aerobic interval training vs. continuous moderate exercise in the metabolic syndrome of rats artificially selected for low aerobic capacity.

AIMS: The recent development of a rat model that closely resembles the metabolic syndrome allows to study the mechanisms of amelioration of the syndrome by exercise training. Here, we compared the effectiveness for reducing cardiovascular risk factors by exercise training programmes of different exercise intensities. METHODS AND RESULTS: Metabolic syndrome rats were subjected to either continuous moderate-intensity exercise (CME) or high-intensity aerobic interval training (AIT). AIT was more effective than CME at reducing cardiovascular disease risk factors linked to the metabolic syndrome. Thus, AIT produced a larger stimulus than CME for increasing maximal oxygen uptake (VO(2max); 45 vs. 10%, P < 0.01), reducing hypertension (20 vs. 6 mmHg, P < 0.01), HDL cholesterol (25 vs. 0%, P < 0.05), and beneficially altering metabolism in fat, liver, and skeletal muscle tissues. Moreover, AIT had a greater beneficial effect than CME on sensitivity of aorta ring segments to acetylcholine (2.7- vs. 2.0-fold, P < 0.01), partly because of intensity-dependent effects on expression levels of nitric oxide synthase and the density of caveolae, and a greater effect than CME on the skeletal muscle Ca2+ handling (50 vs. 0%, P < 0.05). The two exercise training programmes, however, were equally effective at reducing body weight and fat content. CONCLUSION: High-intensity exercise training was more beneficial than moderate-intensity exercise training for reducing cardiovascular risk in rats with the metabolic syndrome. This was linked to more superior effects on VO(2max), endothelial function, blood pressure, and metabolic parameters in several tissues. These results demonstrate that exercise training reduces the impact of the metabolic syndrome and that the magnitude of the effect depends on exercise intensity.

Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study.

BACKGROUND: Individuals with the metabolic syndrome are 3 times more likely to die of heart disease than healthy counterparts. Exercise training reduces several of the symptoms of the syndrome, but the exercise intensity that yields the maximal beneficial adaptations is in dispute. We compared moderate and high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with the metabolic syndrome. METHODS AND RESULTS: Thirty-two metabolic syndrome patients (age, 52.3+/-3.7 years; maximal oxygen uptake [o(2)max], 34 mL x kg(-1) x min(-1)) were randomized to equal volumes of either moderate continuous moderate exercise (CME; 70% of highest measured heart rate [Hfmax]) or aerobic interval training (AIT; 90% of Hfmax) 3 times a week for 16 weeks or to a control group. o(2)max increased more after AIT than CME (35% versus 16%; P<0.01) and was associated with removal of more risk factors that constitute the metabolic syndrome (number of factors: AIT, 5.9 before versus 4.0 after; P<0.01; CME, 5.7 before versus 5.0 after; group difference, P<0.05). AIT was superior to CME in enhancing endothelial function (9% versus 5%; P<0.001), insulin signaling in fat and skeletal muscle, skeletal muscle biogenesis, and excitation-contraction coupling and in reducing blood glucose and lipogenesis in adipose tissue. The 2 exercise programs were equally effective at lowering mean arterial blood pressure and reducing body weight (-2.3 and -3.6 kg in AIT and CME, respectively) and fat. CONCLUSIONS: Exercise intensity was an important factor for improving aerobic capacity and reversing the risk factors of the metabolic syndrome. These findings may have important implications for exercise training in rehabilitation programs and future studies.

Exercise training restores aerobic capacity and energy transfer systems in heart failure treated with losartan.

OBJECTIVE: Clinical and experimental studies demonstrate that exercise training improves aerobic capacity and cardiac function in heart failure, even in patients on optimal treatment with angiotensin inhibitors and beta-blockers, but the cellular mechanisms are incompletely understood. Since myocardial dysfunction is frequently associated with impaired energy status, the aim of this study was to assess the effects of exercise training and losartan on myocardial systems for energy production and transfer in heart failure. METHODS: Maximal oxygen uptake, cardiac function and energy metabolism were assessed in heart failure after a myocardial infarction induced by coronary artery ligation in female Sprague-Dawley rats. Losartan was initiated one week after infarction and exercise training after four weeks, either as single interventions or combined. Animals were sacrificed 12 weeks after surgery. RESULTS: Heart failure, confirmed by left ventricular diastolic pressure >15 mmHg and by >20 mmHg drop in peak systolic pressure, was associated with 40% lower aerobic capacity and significant reductions in enzymes involved in energy metabolism. Combined treatment yielded best improvement of aerobic capacity and ventricular pressure characteristics. Exercise training completely restored aerobic capacity and partly or fully restored creatine and adenylate kinases, whereas losartan alone further reduced these enzymes. In contrast, losartan reduced left ventricle diastolic pressure, whereas exercise training had a neutral effect. CONCLUSION: Exercise training markedly improves aerobic capacity and cardiac function after myocardial infarction, either alone or in combination with angiotensin inhibition. The two interventions appear to act by complementary mechanisms; whereas exercise training restores cardiac energy metabolism, mainly at the level of energy transfer, losartan unloads the heart by lowering filling pressure and afterload.

Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study.

BACKGROUND: Exercise training reduces the symptoms of chronic heart failure. Which exercise intensity yields maximal beneficial adaptations is controversial. Furthermore, the incidence of chronic heart failure increases with advanced age; it has been reported that 88% and 49% of patients with a first diagnosis of chronic heart failure are >65 and >80 years old, respectively. Despite this, most previous studies have excluded patients with an age >70 years. Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfarction heart failure. METHODS AND RESULTS: Twenty-seven patients with stable postinfarction heart failure who were undergoing optimal medical treatment, including beta-blockers and angiotensin-converting enzyme inhibitors (aged 75.5+/-11.1 years; left ventricular [LV] ejection fraction 29%; VO2peak 13 mL x kg(-1) x min(-1)) were randomized to either moderate continuous training (70% of highest measured heart rate, ie, peak heart rate) or aerobic interval training (95% of peak heart rate) 3 times per week for 12 weeks or to a control group that received standard advice regarding physical activity. VO2peak increased more with aerobic interval training than moderate continuous training (46% versus 14%, P<0.001) and was associated with reverse LV remodeling. LV end-diastolic and end-systolic volumes declined with aerobic interval training only, by 18% and 25%, respectively; LV ejection fraction increased 35%, and pro-brain natriuretic peptide decreased 40%. Improvement in brachial artery flow-mediated dilation (endothelial function) was greater with aerobic interval training, and mitochondrial function in lateral vastus muscle increased with aerobic interval training only. The MacNew global score for quality of life in cardiovascular disease increased in both exercise groups. No changes occurred in the control group. CONCLUSIONS: Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity, endothelial function, and quality of life in patients with postinfarction heart failure. These findings may have important implications for exercise training in rehabilitation programs and future studies.

Time-course of endothelial adaptation following acute and regular exercise.

BACKGROUND: Regular exercise training has emerged as a powerful tool to improve endothelium-dependent vasorelaxation. However, little is known about the magnitude of change and the permanence of exercise-induced adaptations in endothelial function. DESIGN: Rats were randomized to either 6 weeks of regular exercise or one bout of exercise. Rats were then sacrificed 0, 6, 12, 24, 48, 96 or 192 h post-exercise, and vascular responsiveness to acetylcholine was determined. METHODS: Endothelium-dependent dilation was assessed by exposure to accumulating doses of acetylcholine in ring segments of the abdominal aorta from female Sprague-Dawley rats that either exercised regularly for 6 weeks or performed a single bout of exercise. RESULTS: A single exercise session improved endothelium-dependent vasodilatation for about 48 h. Six weeks of regular exercise induced a significantly larger improvement that lasted for about 192 h. Sensitivity to acetylcholine was twofold higher in chronically trained animals than in those exposed to a single bout of exercise. The decay after a single bout of exercise was about eightfold faster than that after 6 weeks of training. CONCLUSION: The present data extend our concept of exercise-induced adaptation of endothelium-dependent vasodilatation in two regards: (1) a single bout of exercise improves endothelium-dependent dilation for about 2 days, with peak effect after 12-24 h; (2) regular exercise further improves adaptation and increases the sensitivity to acetylcholine approximately fourfold, which slowly returns to sedentary levels within a week of detraining.

Cardiovascular risk factors emerge after artificial selection for low aerobic capacity.

In humans, the strong statistical association between fitness and survival suggests a link between impaired oxygen metabolism and disease. We hypothesized that artificial selection of rats based on low and high intrinsic exercise capacity would yield models that also contrast for disease risk. After 11 generations, rats with low aerobic capacity scored high on cardiovascular risk factors that constitute the metabolic syndrome. The decrease in aerobic capacity was associated with decreases in the amounts of transcription factors required for mitochondrial biogenesis and in the amounts of oxidative enzymes in skeletal muscle. Impairment of mitochondrial function may link reduced fitness to cardiovascular and metabolic disease.

Aerobic fitness is associated with cardiomyocyte contractile capacity and endothelial function in exercise training and detraining.

BACKGROUND: Physical fitness and level of regular exercise are closely related to cardiovascular health. A regimen of regular intensity-controlled treadmill exercise was implemented and withdrawn to identify cellular mechanisms associated with exercise capacity and maximal oxygen uptake (VO2max). METHODS AND RESULTS: Time-dependent associations between cardiomyocyte dimensions, contractile capacity, and VO2max were assessed in adult rats after high-level intensity-controlled treadmill running for 2, 4, 8, and 13 weeks and detraining for 2 and 4 weeks. With training, cardiomyocyte length, relaxation, shortening, Ca2+ decay, and estimated cell volume correlated with increased VO2max (r=0.92, -0.92, 0.88, -0.84, 0.73; P<0.01). Multiple regression analysis identified cell length, relaxation, and Ca2+ decay as the main explanatory variables for VO2max (R2=0.87, P<0.02). When training stopped, exercise-gained VO2max decreased 50% within 2 weeks and stabilized at 5% above sedentary controls after 4 weeks. Cardiomyocyte size regressed in parallel with VO2max and remained (9%) above sedentary after 4 weeks, whereas cardiomyocyte shortening, contraction/relaxation- and Ca2+-transient time courses, and endothelium-dependent vasorelaxation regressed completely within 2 to 4 weeks of detraining. Cardiomyocyte length, estimated cell volume, width, shortening, and Ca2+ decay and endothelium-dependent arterial relaxation all correlated with VO2max (r=0.85, 0.84, 0.75, 0.63, -0.54, -0.37; P<0.01). Multiple regression identified cardiomyocyte length and vasorelaxation as the main determinants for regressed VO2max during detraining (R2=0.76, P=0.02). CONCLUSIONS: Cardiovascular adaptation to regular exercise is highly dynamic. On detraining, most of the exercise-gained aerobic fitness acquired over 2 to 3 months is lost within 2 to 4 weeks. The close association between cardiomyocyte dimensions, contractile capacity, arterial relaxation, and aerobic fitness suggests cellular mechanisms underlying these changes.