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5021 Background: A baseline prostate-specific antigen (PSA) level in midlife is strongly associated with risk of lethal prostate cancer several decades later. In most prior studies, PSA was measured in archived blood from men participating in cohort studies unrelated to prostate cancer. In clinical practice, however, men commonly obtain a PSA test because of lower urinary tract symptoms. Here, we study the association between PSA values when a first PSA test was obtained as part of clinical care – and subsequent risks of prostate cancer diagnosis and death. Methods: The NPCC database contained laboratory results from 1995-2006 of the first (“baseline”) PSA test below 4.0 ng/mL in 157,836 men aged 40-69 years without prior prostate cancer (PCa) diagnosis. PSA strata were pre-defined: < 1, 1-1.99, 2-2.99, 3-3.99 ng/ml and analyses were split in two age groups based on a prior risk: 40-54 (“younger”) and 55-69 (“older”). Predictive accuracy was assessed with Harrell’s concordance (C) index. The Kaplan-Meier method was used to visualize risk of PCa death as reported on the death certificate by PSA strata for the two age groups. Results: Among 157,836 men with a PSA below 4.0 ng/mL, 83% had < 2.0 ng/mL. Risk of prostate cancer and death from prostate cancer were strongly associated with PSA-levels and age: Harrell’s C-index 0.75 and 0.72 for diagnosis of younger and older group, respectively and 0.72 for PCa death for both age groups. In the younger age group 196 deaths among 75,446 men (0.26%) were registered, in the older 943 deaths among 82,390 men (1.14%). The risk of PCa death in lowest (< 1) and highest (3-3.99) strata were 0.23% and 3.22%, respectively (189 deaths among 81,982 vs. 274 deaths among 8517 men). Conclusions: This population-based NPCC study shows as strong predictive impact of the different strata of the initial PSA measurement in routine clinical care as prior studies based on cryopreserved blood samples. [Table: see text]

To study the association between time from diagnosis to radical prostatectomy (RP-interval) and prostate cancer-specific mortality (PCSM), histological findings in the RP-specimen and failure after RP (RP-failure). Patients diagnosed with non-metastatic prostate cancer (PCa) in 2001–2010 and prostatectomized within 180 days of biopsy were identified in the Cancer Registry of Norway and the Norwegian Prostate Cancer Registry. Patients were stratified according to risk groups and RP-intervals of 0–60, 61–90, 91–120 and 121–180 days. Aalen-Johansen and Kaplan–Meier methods estimated curves for PCSM, RP-failure and overall mortality. Multivariable Cox regressions and Chi-square tests were used to evaluate the impact of RP-interval on outcomes. In 5163 eligible patients, the median time from diagnosis to RP was 93 days (range 1–180). Risk group distribution was similar in all RP-interval groups. With almost eight years of observation, no association was found between RP-interval and PCSM in the intermediate-or high-risk groups. Increasing RP-interval did not increase the rate of adverse histological outcomes or incidence of RP-failure. Increasing RP-interval up to 180 days was not associated with adverse oncological outcomes at eight years follow-up. These findings should be considered when planning for prostatectomy.

Background Treatment options in patients with advanced urothelial carcinoma (aUC) have improved significantly in the last decade, highlighting the need for adequate biomarkers. High tumor CGB5 mRNA, encoding Human Chorionic Gonadotrophin β (hCGβ) and elevated serum free hCGβ are related to poorly differentiated UC and correlated to poor prognosis. Hypothetically, hCG could be used as serum tumor marker in aUC patients. Patients and methods From December 2018 to November 2020, serum hCG levels were measured in 62 aUC patients referred to the oncology department, Akershus University Hospital. Median age 68 years, 42 male and 21 female. Total serum hCG (intact hCG + free hCGβ) was measured by electrochemiluminescence immunoassay “ECLIA”. In order to compensate for hypogonadism-related increases, hCG ≥ 50% above upper normal limit was considered as being elevated (hCG+), otherwise it was considered negative (hCG-). Further, hCG levels were defined as increasing (↑) or declining (↓) at treatment evaluation and follow up. Radiologically, patients had newly diagnosed disease (ND), progressive disease (PD) or non-PD (stable disease, partial or complete response) according to RECIST 1.1 at evaluation and follow up. hCG values were correlated with radiological findings at diagnosis, during and after treatment. Statistics by 2 x 2 contingency table and Chi Square (χ2) test. Results At least one hCG+ value was measured in 38 of 62 patients (61%), range 0.8 - 62,700 IU/L, and hCG was elevated in 22 of 43 patients (51%) with available hCG value at diagnosis, mean 15 IU/L (range 0.8 - 58). In total 213 hCG measurements could be correlated with concomitant CT or MR scans. At radiologic evaluation of ND & PD, hCG+/↑ and hCG -/↓ was found in 62 and 50 measurements, respectively. At non-PD, hCG -/↓ and hCG+/↑ was found in 94 and 7 measurements, respectively. For ND & PD versus non-PD, hCG showed a sensitivity and specificity of 55% and 93% respectively (95% CI 46-65% and 86-97%), positive and negative predictive value of 90% and 65% (95% CI 81-95% and 60-70%) and accuracy of 73% (95% CI 66-79%), χ2: p Conclusions Ectopic hCG production was observed in 61% of aUC patients with a strong and meaningful correlation between hCG changes and radiologic evaluation of treatment response. Intriguingly, hCG increase sometimes preceded radiologic PD, thus categorized as “false positive” until subsequent radiologic PD. hCG appears to be a promising tumor marker for biochemical treatment response evaluation in aUC patients. Citation Format: Katarina Puco, Johan Bjerner, Stig Müller, Gunder M. Lilleaasen, Haldor Husby, Mattias Røed-Undlien, Daniel Heinrich, Fredrik A. Dahl, Oluf D. Røe, Jan Oldenburg. Utility of hCG as a biomarker of treatment response in advanced urothelial cancer: A population based series at Akershus University Hospital, Norway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 481.

Purpose Since January 2015, all men referred to urologists in Norway due to elevated PSA or other suspicion of prostate cancer underwent multiparametric MRI (mpMRI) before prostate biopsy. At our hospital, patients and the initial MRI were assessed by an urologist and if deemed necessary, patients were referred to another institution for MR/US fusion biopsies. Before MR/US biopsy, patients underwent a second mpMRI. Since we noticed disagreement of these two mpMRIs before biopsy, we retrospectively assessed the level of agreement between the two mpMRIs from the two institutions. Methods During the first 6 months of 2015, 292 patients were referred to our outpatient clinic. We referred 126 patients of these to the other institution for MR/US fusion biopsy. The 2 mpMRIs were performed within 4 weeks. We analyzed MR reports and schematics for number of lesions and highest PIRADS score per side of the prostate and histological result of the biopsies. Bland–Altman’s plot was used to compare the level of agreement between the two mpMRIs of the same patient before biopsy. Results There was a poor level of agreement between the two mpMRIs and a statistically significant difference in PIRADS scores. Regression analysis showed that there was no proportional or systematic bias. Conclusion In unselected patients with elevated PSA, there seems to be a significant variation of mpMRI results across institutions. The PIRADS scoring system needs to be validated with regards to MR equipment, mpMRI protocols and inter-reader variability of radiologists.

Background— We addressed the hypothesis that the inotropic drugs dobutamine and levosimendan both induce surplus oxygen consumption (oxygen wasting) relative to their contractile effect in equipotent therapeutic doses, with levosimendan being energetically more efficient. Methods and Results— Postischemically reduced left ventricular function (stunning) was created by repetitive left coronary occlusions in 22 pigs. This contractile dysfunction was reversed by infusion of either levosimendan (24 μg/kg loading and 0.04 μg · kg −1 · min −1 infusion) or an equipotent dose of dobutamine (1.25 μg · kg −1 · min −1 ). Contractility and cardiac output were normalized by both drug regimens. The energy cost of drug-induced contractility enhancement was assessed by myocardial oxygen consumption related to the mechanical indexes tension-time index, pressure-volume area, and total mechanical energy. ANCOVA did not reveal any increased oxygen cost of contractility for either drug in these doses. However, both dobutamine and levosimendan at supratherapeutic levels (10 μg · kg −1 · min −1 and 48 μg/kg loading with 0.2 μg · kg −1 · min −1 infusion, respectively) induced a highly significant increase in oxygen consumption related to mechanical work, compatible with the established oxygen-wasting effect of inotropy ( P P =0.007 for levosimendan as assessed by pressure-volume area). Conclusion— Therapeutic levels of neither dobutamine nor levosimendan showed inotropic oxygen wasting in this in vivo pig model. Thus, relevant hemodynamic responses can be achieved with an adrenergic inotrope without surplus oxygen consumption.

UNLABELLED Our previous studies indicate that left ventricular end-systolic pressure-volume relations (ESPVRs) or elastance (Ees) are not reduced in studies where expected reductions of contractility should be found (i.e., heart failure, stunning, and endotoxemia). The present study was done to assess whether this phenomenon is due to a particular load sensitivity of elastance, rendering this index inappropriate as a measurement of contractility in pathologic states in vivo. METHODS AND RESULTS Analysis of previously generated data revealed an increased ESPVR in stunned hearts, in pigs made endotoxemic, and in hearts rapidly paced. After inducing acute heart failure by microembolization, the ESPVR was increased when assessed using linear relations but reduced when assessing ESPVR by a curvilinear algorithm. To further evaluate the effect of different load alterations on ESPVR, this relation was generated by (i) inferior vena caval occlusions (VCOs); (ii) gradually occluding the descending aorta (pressure interventions); and (iii) rapidly infusing blood (120 mL) into the left atrium (volume increments). The load protocol was applied in 5 pigs, before and after the left ventricle was stunned by 11 brief left main coronary artery occlusions/reperfusions (accumulated ischemia 20 min affecting 81% of the left ventricle). Correlation coefficients for left ventricular elastance ranged from 0.93 to 0.99 in all the 3 types of loading interventions. Despite significant reductions in stroke volume, stroke work, and dP/dtmax, VCO-calculated linear and curvilinear Ees increased 90 min after stunning (55% +/- 4% and 94% +/- 6%, respectively). Linear Ees during pressure interventions decreased 36% +/- 1%, whereas curvilinear Ees decreased 33% +/- 3%. During volume infusions, linear Ees decreased 27% +/- 2%. We achieved the same results after blocking the baroreceptor reflexes using hexamethonium. CONCLUSIONS The Ees is particularly load dependent and will reflect load interventions more than the inotropic state of the cardiac muscle. A VCO-generated Ees increase could be an unmasking of a pronounced preload sensitivity in failing myocardium.

Tissue Doppler-derived indices of strain (epsilon) and strain rate (SR) have been developed to assess regional cardiac function. However, the effect of left ventricular (LV) size on epsilon and SR has not been studied in depth. The aim of this study was to assess to what extent heart size influence epsilon or SR.In 21 anaesthetized pigs ranging from 12.5 to 70.0 kg, tissue Doppler-derived epsilon and SR, and haemodynamic parameters, were assessed during controlled heart rates and different loading conditions. dP/dt did not correlate to pig weight, suggesting constant contractility during growth. Longitudinal epsilon and SR were significantly higher in smaller compared with larger hearts. The hyperbolic correlation between pigs weight and epsilon and SR was r(2)=0.621 and 0.372, respectively, both P0.0001. Afterload elevation induced a reduction in longitudinal epsilon (from -24.2+/-3.2 to -12.1+/-5.5%, P=0.001) and SR (from -2.3+/-0.8 to -1.3+/-2.4 s(-1), P=0.034), whereas increasing preload increased epsilon (from -26.4+/-10.3 to -38.1+/-14.3%, P=0.006) and SR (from -2.3+/-0.9 to -4.22+/-1.8 s(-1), P=0.002).Longitudinal epsilon and SR decrease with increasing LV dimensions in spite of an unaltered contractility. These results show and confirm that heart size influences epsilon and SR, which are highly load-dependent parameters.

Early invasive treatments in patients with acute heart failure (AHF) are critical components to improve outcome. We aimed to establish if such treatments were applied according to existing guidelines and also to assess the subsequent mortality in the complete AHF population. All patients with AHF admitted to the intensive care unit/coronary care unit during the years 2003-2004 (n=302) were retrospectively reviewed and classified according to the European Society of Cardiology. Invasive revascularization was applied more frequently in patients with cardiogenic shock following acute coronary syndromes (78%, n=40) than in less severe AHF (58%, n=62, P

Introduction: Arginine vasopressin (AVP) is increasingly used to restore mean arterial pressure (MAP) in low-pressure shock states unresponsive to conventional inotropes. This is potentially deleterious since AVP is also known to reduce cardiac output by increasing vascular resistance. The effects of AVP on blood flow to vital organs and cardiac performance in a circulation altered by cardiac ischemia are still not sufficiently clarified. We hypothesised that restoring MAP by low dose, therapeutic level AVP would reduce vital organ blood flow in a setting of experimental acute left ventricular dysfunction. Methods: Cardiac output (CO) and arterial blood flow to the brain, heart, kidney and liver were measured in nine pigs using transit-time flow probes. Left ventricular pressure-volume catheter and central arterial and venous catheters were used for haemodynamic recordings and blood sampling. Transient left ventricular ischemia was induced by intermittent left coronary occlusions resulting in a 17% reduction in cardiac output and a drop in MAP from 87 ± 3 to 67 ± 4 mmHg (p < 0.001). A low-dose therapeutic level of AVP (0.005 U/kg/min) was used to restore MAP to pre-ischemic values (93 ± 4 mmHg). Results: AVP further impaired systemic perfusion (CO and brain, heart and kidney blood flow reduced by 29, 18, 23 and 34%, respectively) due to a 2.0-, 2.2-, 1.9- and 2.1-fold increase in systemic, brain, heart and kidney specific vascular resistances. The hypoperfusion induced by AVP was associated with an increased systemic oxygen extraction. Oxygen saturation in blood drawn from the great cardiac vein fell from 29 ± 1 to 21 ± 3% (p = 0.01). Finally, these effects were reversed 40 min after AVP was withdrawn. Conclusion: Low dose AVP induced a pronounced reduction in vital organ blood flow in pigs after transient cardiac ischemia. This indicates a potentially deleterious effect of AVP in patients with heart failure or cardiogenic shock due to impaired coronary perfusion.

Objective: To determine whether adenosine instead of supranormal potassium in cold crystalloid cardioplegia gives satisfactory cardiac arrest and improved cardioprotection. Cold crystalloid cardioplegia with adenosine, procaine and magnesium (A) was compared with standard cold crystalloid hyperkalemic cardioplegia (K). Methods: Sixteen pigs were randomized to receive either cold K (n =8 ) or A (n = 8), where hyperkalemia was substituted with 1.2 mM adenosine. The cold (6 8C) cardioplegia was given intermittently and antegradely, with an aortic cross-clamp time of 1 h. Hemodynamic data was continuously measured and pressure—volume conductance catheters were used to determine global left ventricular systolic and diastolic function. Coronary flow and O2 content differences allowed determination of left ventricular energetics. Bloodsamples,andleft ventricularmicrodialysis were usedto measureparameters of ischemia. Measurements were doneat1 and 2 h after cross-clamp release.Results: Mean arterial pressure was reduced with 55 mmHg (standard deviation, SD: 19) in the K group versus 30 mmHg (SD:14) inthe A group2 h aftercross-clamprelease (p = 0.030).Left ventricular contractility expressedas slope ofthe preloadrecruitablestroke work index (Mw) was reduced to 53% (SD: 14) in the K group versus 78% (SD: 23) in the A group 2 h after cross-clamp release (p = 0.046). Reduction of maximum of first derivate of pressure with respect to time (dP/dtmax) was 804 mmHg/s (SD: 189) in the K group versus 538 mmHg/s (SD: 184) in the A group ( p= 0.033). The slope of the myocardial oxygen consumption—pressure volume area was at 2 h reperfusion increased from 1.37 (SD: 0.64)to2.86(SD:1.27)intheKgroup,whereasnoshiftwasdetectedintheAgroup(p = 0.019).CardiactroponinTmeasuredinthecoronarysinus 1 h after cross-clamprelease was 1.25 mg/l (SD: 0.64) inthe K group versus 0.73 mg/l(SD: 0.31) in the A group (p = 0.046).Conclusion:Adenosine instead of supranormal potassium in cold crystalloid cardioplegia gives satisfactory cardiac arrest, improves post cardioplegic left ventricular systolic function and efficiency, and attenuates myocardial cell damage. # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

The time constant of mechanical restitution (T((MRC))), proposed to reflect changes in calcium release and uptake, has been shown to increase in left ventricular (LV) failure, and might have a potential as an index of contractile function. However, in vivo studies of the effect on T((MRC)) of changing loading conditions in the normal and failing heart have not been reported. Consequently, in this study, we tested the hypothesis that the increase in T((MRC)) in vivo is independent of preload and afterload.Left ventricular pressure-volume loops were assessed at baseline in eight open chest pigs using the combined pressure-volume conductance catheter technique during right atrial pacing at 120b/min. Mechanical restitution curves (MRC) were constructed during four different loading conditions in all eight animals: uninfluenced load, reduced preload (balloon catheter in v. cava inferior), increased afterload (balloon catheter in descending aorta), and increased preload combined with reduced afterload (aortocaval shunting). Acute LV failure was then induced by microembolization through the left main coronary artery, and the experimental protocol was repeated. Contractile response was defined as the maximal first derivative of pressure (dP/dt(max)), and T((MRC)) was calculated using a least square approximation algorithm.Hemodynamic data 30min after microembolization showed decreased mean arterial pressure (98+/-14-67+/-10mmHg, (mean+/-SD) P0.0001) and dP/dt(max) (1482+/-193-1001+/-125mmHg/s, P=0.001). Stroke volume decreased from 30+/-5 to 20+/-5ml (P0.0001) compared to baseline, and preload recruitable stroke work decreased from 52+/-7 to 31+/-10mmHg (P=0.002). T((MRC)) increased in all eight animals after induction of LV failure at all loading conditions. There was no difference between the different loading conditions at baseline, nor at LV heart failure, but T((MRC)) increased significantly after the induction of heart failure (ANOVA, two ways).We have shown that the left ventricular T((MRC)) increases after developed heart failure. The increase in T((MRC)) was independent on loading conditions and thus have a potential for a contractility index.

Left ventricular unloading has a potentially deleterious effect in right ventricular failure as a result of altered septal interplay. However, a positive effect of an intraaortic balloon pump during right ventricular failure has been suggested. We investigated the impact of intraaortic balloon pumping on hemodynamics and both left and right ventricular function in an experimental model of isolated right ventricular failure.Sixteen anesthetized pigs (25 to 34 kg) were used in an in vivo model. Pressure-conductance catheters assessed right and left ventricular pressure-volume relationships. Acute right ventricular failure was induced by right coronary microembolization, and led to severely impaired right ventricular function, reduced cardiac output and arterial pressure, and an increased pulmonary vascular resistance and pulmonary arterial elastance. Animals were then randomized to balloon pump or control groups and evaluated with respect to hemodynamics and ventricular function after 1 hour.Intraaortic balloon pumping did not alter right or left ventricular contractility. However, balloon pump-treated animals had significantly improved cardiac output (+18% +/- 18% versus -6% +/- 7%; p = 0.003) and mean arterial pressure (+36% +/- 30% versus -7% +/- 14%; p = 0.004) compared with controls. Animals in the balloon pump group had lower pulmonary vascular resistance (795 +/- 63 versus 912 +/- 259 dynes . sec . cm(-5); p0.01) and pulmonary arterial elastance (1.14 +/- 0.20 versus 1.69 +/- 0.65 mm Hg/mL; p0.01), and increased stroke volume (22.3 +/- 4.7 versus 17.9 +/- 4.7 mL; p = 0.016). Right ventricular efficiency was also improved in the balloon pump group (stroke work per pressure-volume area = 0.60 +/- 0.14 versus 0.41 +/- 0.12; p0.01).Intraaortic balloon pump support does not alter right or left ventricular function in acute right ventricular failure. However, arterial pressure, cardiac output, and right ventricular efficiency are improved, possibly because of a balloon pump-induced reduction in pulmonary arterial resistance.