Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Assessment of hospital surge capacity using the MACSIM simulation system: a pilot study.

AIM: The aim of this study was to use a simulation model developed for the scientific evaluation of methodology in disaster medicine to test surge capacity (SC) in a major hospital responding to a simulated major incident with a scenario copied from a real incident. METHODS: The tested hospital was illustrated on a system of magnetic boards, where available resources, staff, and patients treated in the hospital at the time of the test were illustrated. Casualties were illustrated with simulation cards supplying all data required to determine procedures for diagnosis and treatment, which all were connected to real consumption of time and resources. RESULTS: The first capacity-limiting factor was the number of resuscitation teams that could work parallel in the emergency department (ED). This made it necessary to refer severely injured to other hospitals. At this time, surgery (OR) and intensive care (ICU) had considerable remaining capacity. Thus, the reception of casualties could be restarted when the ED had been cleared. The next limiting factor was lack of ventilators in the ICU, which permanently set the limit for SC. At this time, there was still residual OR capacity. With access to more ventilators, the full surgical capacity of the hospital could have been utilized. CONCLUSIONS: The tested model was evaluated as an accurate tool to determine SC. The results illustrate that SC cannot be determined by testing one single function in the hospital, since all functions interact with each other and different functions can be identified as limiting factors at different times during the response.

In vitro and in vivo evaluation of Dideco's paediatric cardiopulmonary circuit for neonates weighing less than five kilograms.

The neonate cardiopulmonary bypass (CPB) circuit, including a KIDS D100 oxygenator (The Sorin Group, Mirandola, Italy) and a D130 arterial filter (The Sorin Group), was evaluated in vitro with respect to the removal of free micro gas bubbles. No gas bubbles > 40microm were measured after the arterial filter D130 upon manual introduction of 10 ml of air into the venous line or during the use of vacuum-assisted venous drainage (VAVD). The D130 arterial filter removed 88 % of gas bubbles < 40 microm during manual introduction of air into the venous line; however, only 50 % of gas bubbles < 40 microm were removed during the use of VAVD. The same CPB circuit was evaluated in vivo to compare with another CPB circuit, including a D901 oxygenator (The Sorin Group) and arterial filter D736 (The Sorin Group), in 155 neonates weighing < or =5 kg. The D100 circuit required significantly less priming volume than the D901 circuit. Postoperative haemoglobin was significantly higher, artificial ventilation time was significantly shorter and postoperative bleeding was significantly less in the D100 group. This neonate CPB circuit effectively removed the gas bubbles and required up to 37% less priming volume and, thus, decreased the need for blood transfusion.

Genotoxic effects of nanosized and fine TiO2.

The in-vitro genotoxicity of nanosized TiO(2) rutile and anatase was assessed in comparison with fine TiO(2) rutile in human bronchial epithelial BEAS 2B cells using the single-cell gel electrophoresis (comet) assay and the cytokinesis-block micronucleus test. BEAS 2B cells were exposed to eight doses (1-100 microg/cm(2)) of titanium(IV) oxide nanosized rutile (>95%, <5% amorphous SiO(2) coating; 10 x 40 nm), nanosized anatase (99.7%; <25 nm), or fine rutile (99.9%; <5 microm) for 24, 48, and 72 h. Fine rutile reduced cell viability at lower doses than nanosized anatase, which was more cytotoxic than nanosized rutile. In the comet assay, nanosized anatase and fine rutile induced DNA damage at several doses with all treatment times. Dose-dependent effects were seen after the 48- and 72-h treatments with nanosized anatase and after the 24-, 48- (in one out of two experiments), and 72-h treatments (one experiment) with fine rutile. The lowest doses inducing DNA damage were 1 microg/cm(2) for fine rutile and 10 microg/cm( 2) for nanosized anatase. Nanosized rutile showed a significant induction in DNA damage only at 80 microg/cm(2) in the 24-h treatment and at 80 and 100 microg/ cm(2) in the 72-h treatment (with a dose-dependent effect). Only nanosized anatase could elevate the frequency of micronucleated BEAS 2B cells, producing a significant increase at 10 and 60 microg/cm( 2) after the 72-h treatment (no dose-dependency). At increasing doses of all the particles, MN analysis became difficult due to the presence of TiO(2) on the microscopic slides. In conclusion, our studies in human bronchial epithelial BEAS 2B cells showed that uncoated nanosized anatase TiO(2) and fine rutile TiO(2) are more efficient than SiO( 2)-coated nanosized rutile TiO(2) in inducing DNA damage, whereas only nanosized anatase is able to slightly induce micronuclei.

Preparation of nanoparticle dispersions for in-vitro toxicity testing.

Studies on potential toxicity of engineered nanoparticle (ENP) in biological systems require a proper and accurate particle characterization to ensure the reproducibility of the results and to understand biological effects of ENP. A full characterization of ENP should include various measurements such as particle size and size distribution, shape and morphology, crystallinity, composition, surface chemistry, and surface area of ENP. It is also important to characterize the state of ENP dispersions. In this study, four different ENPs, rutile and anatase titanium dioxides and short single- and multi-walled carbon nanotubes, were characterized in two dispersion media: bronchial epithelial growth medium, used for bronchial epithelial BEAS cells, and RPMI-1640 culture media with 10% of fetal calf serum (FCS) for human mesothelial (MeT-5A) cells. The purpose of this study was to determine the characteristics of ENPs and their dispersions as well as to compare dispersion additives suitable for toxicity tests and thus establish an appropriate way to prepare dispersions that performs well with the selected ENP. Dispersion additives studied in the media were bovine serum albumin (BSA) as a protein resource, dipalmitoyl phosphatidylcholine (DPPC) as a model lung surfactant, and combination of BSA and DPPC. Dispersions were characterized using optical microscopy and transmission electron microscopy. Our results showed that protein addition, BSA or FCS, in cell culture media generated small agglomerates of primary particles with narrow size variations and improved the stability of the dispersions and thus also the relevance of the in-vitro genotoxicity tests to be done.

Metabonomics, dietary influences and cultural differences: a 1H NMR-based study of urine samples obtained from healthy British and Swedish subjects.

The aim of this study was to assess the feasibility and comparability of metabonomic data in clinical studies conducted in different countries without dietary restriction. A (1)H NMR-based metabonomic analysis was performed on urine samples obtained from two separate studies, both including male and female subjects. The first was on a group of healthy British subjects (n = 120), whilst the second was on healthy subjects from two European countries (Britain and Sweden, n = 30). The subjects were asked to provide single, early morning urine samples collected on a single occasion. The (1)H NMR spectra obtained for urine samples were visually inspected and analysed chemometrically using principal components analysis (PCA). These inspections highlighted outliers within the urine samples and displayed interesting differences, revealing characteristic dietary and cultural features between the subjects of both countries, such as high trimethylamine-N-oxide (TMAO)-excretion in the Swedish population and high taurine-excretion, due to the Atkins diet. This study suggests that the endogenous urinary profile is subject to distinct cultural and severe dietary influences and that great care needs to be taken in the interpretation of 'biomarkers of disease and response to drug therapy' for diagnostic purposes.

Unexpected medical coincidences require systematic and careful strategies: an example.

In a cohort of 14 children with identical cardiac xenografts, two boys developed acute myeloid leukaemia 11 and 16 months respectively after the operation. A dedicated working group designed a scheme intending to take care of all aspects of the situation. This article focuses on preferred strategies towards patients, relatives, government, and the media. We did not find any substantial evidence supporting the association between bovine xenografts and two cases of acute myeloid leukaemia.

Outcome of congenital heart defects--a population-based study.

UNLABELLED: In a population-based study including 35,218 infants born alive during the 15-y period 1982-96, 360 (1%) were diagnosed as having a congenital heart defect (CHD). At a follow-up 3-18 y after birth (median 9.5 y) 154 patients (42.8%) were spontaneously cured; of these, 142 (92.2%) had ventricular septal defects (VSDs). Forty-two patients (11.7%) died, 22 of these (52.4%) during the neonatal period (0-28 d after birth). A total of 119 patients (33.1%) underwent therapeutic procedures (surgery, catheter interventions), 24 (20.2%) of whom died. Of the 95 children surviving therapeutic procedures, 54 (56.8%) had their defects completely repaired, while 41 (43.2%) had residual defects or cardiac sequelae, often of minor importance. In 69 children (19.2%) with persistent non-operated defects, 43 (62.3%) had VSDs. A chromosomal disorder, syndrome or associated extracardiac malformation occurred in 72 children (20%). CONCLUSIONS: The study underlines the broad variety in severity of CHDs, with a high neonatal mortality rate as well as a high rate of spontaneous cure. It is estimated that 25% of infants born with a CHD will grow into adult age with persistent non-operated defects, residual defects or cardiac sequelae after therapeutic procedures.

Differential recruitment of alpha 1- and beta-adrenoceptors in inotropic control of atrial child myocardium by endogenous noradrenaline.

Noradrenaline release, graded by frequency variation of field stimulation (0.1-2 Hz), in atrial myocardial specimens (n=45) from children (n=21) with congenital heart defects, was used to examine the inotropic responses of graded, receptor-selective, endogenous stimulation. Muscle trabeculae subjected to autonomic blockage by timolol, prazosin and atropine showed a slight positive force-frequency relationship (staircase phenomenon). Blockage by atropine/prazosin (i.e. beta-adrenoceptor stimulation) or atropine/timolol (i.e. alpha1-adrenoceptor stimulation) both resulted in positive inotropic effects. A group of specimens opposed by atropine and primarily subjected to frequency variation, secondly was returned to 1 Hz. Stabilization was followed by sequential reversal by beta-blocker (timolol), alpha 1-adrenoceptor stimulation by exogenous noradrenaline, reversal by alpha 1-blocker (prazosin), and finally supramaximal beta-adrenoceptor stimulation (isoprenaline). The maximal levels of inotropic responses mediated by exogenous alpha 1- and beta-adrenoceptor stimulation was estimated. Analysis of the contraction-relaxation cycles revealed that alpha1- and beta-adrenoceptors were recruited differentially. The alpha1-adrenoceptor mediated, endogenous inotropic effect at 1 Hz was close to the level obtained by exogenous noradrenaline stimulation. In contrast, less than 70% of the beta-adrenoceptor mediated, exogenous inotropic effect was expressed by endogenous noradrenaline at the same stimulating frequency, thus indicating that the alpha1-adrenoceptors may be located closer to the adrenergic nerve terminals than the beta-adrenoceptors. There may be a heterogeneous relationship within the same heart as to the relative distance between the nerve terminals and the adrenoceptors. Spatial localization of adrenergic receptors relative to adrenergic nerve terminals adds another aspect to adrenergic regulation. The alpha1-adrenoceptor pathway may play an important role, especially in low-intensity sympathetic inotropic myocardial control, whereas the beta-adrenoceptor pathway adds important effects to the high-intensity sympathetic regulation. Sympathetic activity may thus tonically stimulate the alpha1-adrenoceptor pathway, without necessarily stimulating the beta-adrenoceptor pathway to the same extent.

Assessment of primary hip osteoarthritis: comparison of radiographic methods using colon radiographs.

OBJECTIVE: To compare the reliability of quantitative measurement of minimum hip joint space with a qualitative global assessment of radiological features for estimating the prevalence of primary osteoarthritis (OA) of the hip in colon radiographs. METHODS: All colon radiographs from patients aged 35 or older, taken at three different radiographic departments in Iceland during the years 1990-96, were examined. A total of 3002 hips in 638 men and 863 women were analysed. Intraobserver and interobserver reliability was assessed by measuring 147 randomly selected radiographs (294 hips) twice by the same observer, and 87 and 98 randomly selected radiographs (174 and 196 hips) by two additional independent observers. Minimum hip joint space was measured with a millimetre ruler, and global assessment of radiological features by a published atlas. RESULTS: With a minimum joint space of 2.5 mm or less as definition for OA, 212 hips were defined as having OA. When the global Kellgren and Lawrence assessment with grade 2 (definite narrowing in the presence of definite osteophytes) or higher as definition for OA was used, 202 hips showed OA. However, only 166 hips were diagnosed as OA with both systems. With 2.0 or 3.0 mm minimum joint space as cut off point, the difference between the two methods increased. Both intrarater and interrater reliability was significantly higher with joint space measurement than with global assessment. CONCLUSIONS: Overall prevalence of radiological OA was similar with the two methods. However, the quantitative measurement of minimum hip joint space had a better within-observer and between-observer reliability than qualitative global assessment of radiographic features of hip OA. It is thus suggested that minimum joint space measurement is a preferable method in epidemiological studies of radiological hip OA.

[Long-term follow-up of patients with congenital heart defects]. / Langsiktig oppfølging av pasienter med medfødte hjertefeil.

There are about 500 new cases of congenital heart disease per year in Norway. Modern diagnostic skills, surgical techniques and follow-up programs have contributed to higher survival rates among patients. Based on international experience, 85-90 per cent of these children will survive into adulthood. Half will suffer from conditions which should be followed up by cardiologists. This article is based upon recommendations on long-term follow-up of patients with congenital heart disease.

[Heart transplantation in Norway]. / Hjertetransplantasjon i Norge.

The first heart transplantation in the Nordic countries was performed at Rikshospitalet, Oslo in 1983. In this paper, we present our experience with this treatment up to 1999. 317 heart transplantations have been performed, an average of 23 transplantations per year. 82% of the recipients were males; 50% had heart failure due to coronary heart disease. Mean age of the recipients was 47 years (range 1-64). Our indications and contraindications are similar to most other transplantation centres. Triple immunosuppression with ciclosporin, prednisolone and azathioprine have been used as standard treatment. The survival rate after one and ten years are 85% and 53% respectively, with a significantly higher survival rate among recipients younger than 50 at transplantation, especially if the graft was from a donor younger than 35 years. The most common early postoperative complications were acute cellular rejections and infections. Transplant accelerated coronary heart disease and cancer were the main causes of late death. We believe that close co-operation between Riskshospitalet and local centres will provide the best treatment for patients needing a heart transplant.

[Measurements of N-terminal proatrial natriuretic factor in children]. / Måling av N-terminal proatrial natriuretisk faktor hos barn.

Measurement of plasma levels of natriuretic peptides are now in clinical use in adult patients with heart failure. Experiences in adult medicine cannot be extended to paediatric cardiology due to important physiological differences between adults and children. The haemodynamic background of heart failure in children with congenital heart disease is diverse, and there is no relevant functional or echocardiographic grading system. The authors present results from published studies and summarizes the results of a research project concerning the clinical potential of N-terminal proatrial natriuretic peptide (Nt-proANP) in paediatric cardiology. Peptide levels in newborn children with or without disease are not fully clarified. In children above three months of age, an elevated Nt-proANP value strongly indicates haemodynamic imbalance. This may be important in the follow-up of children with congenital heart disease. A normal value does not exclude the presence of heart disease. A case report illustrates the clinical use of Nt-proANP, and peptide levels in different haemodynamic situations are discussed.

Elevation of atrial natriuretic peptide prohormone. Hemodynamic background of the elevation of N-terminal natriuretic peptide prohormone in children with congenital heart disease.

We postulated previously that variables related to pulmonary flow are independent predictors of levels of atrial natriuretic peptide in children with congenital heart disease. The aim of this study was to test this hypothesis in relation to other hemodynamic and clinical variables. During catheterization we measured the levels of plasma N-terminal atrial natriuretic peptide prohormone in the plasma of 68 children with congenital heart disease. All had undergone complete clinical, echocardiographic and invasive hemodynamic investigations. The influence on the prohormone was analyzed for 10 different variables in a multiple linear regression model. The variability could be explained in large parts (adjusted R2 =77.2%) by variations in atrial pressures or sizes, together with the degree of excessive pulmonary blood flow and signs of heart failure. A value for atrial natriuretic peptide prohormone above 800 pmol/l predicted hemodynamic imbalance (defined as elevated pressures in left or right atrium or the pulmonary arteries, and/or Qp/Qs > 1.5) with a specificity of 94%, a sensitivity of 73%, a positive likelihood ratio of 12.2, and a negative likelihood ratio of 0.29. In conclusion, variables related to pulmonary blood flow are influential determinants of the levels of atrial natriureic peptide in children with congenital heart disease. Atrial pressures, and symptoms of heart failure are also of major importance.

Monocusp valve in right ventricular outflow tract.

Sixty patients aged 5 days-10.3 years (mean 2.9 years) received monocusp valve implants in the right ventricular outflow tract in corrective surgery for congenital heart disease. The free edge of the monocusp valve was attached to the posterior wall of the new pulmonary tract to cover the entire root of the pulmonary tract when the monocusp valve closed. Follow-up was 3.8 (0-11.5) years. Early mortality was 8.3% (5/60) and late mortality 3.6% (2/55). Monocusp valve regurgitation developed in all patients. Moderate or severe valve failure was found in 30 patients at median 1.4, mean 2.2 (0.2-6.8) years postoperatively. Repeat surgery was performed in seven cases because of monocusp failure. It is emphasized that monocusps potentially give short-term reduction of pulmonary regurgitation when used for right ventricular outflow tract reconstruction. Only long-term follow-up can disclose whether all patients with a monocusp valve will require repeat surgery.

Endogenous muscarinic activity attenuates adrenergic inotropic effects in field stimulated atrial myocardium from children with congenital heart defects.

To analyse the possible influence of endogenous muscarinic activity on the inotropic effects of endogenously released noradrenaline in field stimulated myocardial preparations from atria of children with congenital heart defects, we studied the maximal effect of the muscarinic antagonist atropine (1.5 micromol L(-1)). Maximal force of contraction increased by 12.8 +/- 2.0% (SEM), while the maximal rate of development of the force increased by 16.7 +/- 2.7% (SEM). Time to half maximal developed force was 57 +/- 5 s (SEM). Time to peak force, time to relax to the 20% level and relaxation time all decreased significantly after atropine. Compared with endogenous adrenoceptor stimulation alone, the combined effects of partial muscarinic and adrenergic receptor stimulation thus were moderate reductions of the maximal force of contraction and maximal rate of development of the force and increased time to peak force, time to relax to the 20% level and relaxation time. The main effect of the endogenous muscarinic activity probably was to attenuate the effect of the beta-adrenoceptor stimulation. The endogenous muscarinic activity in field stimulated atrial preparations from children is significant, and has to be taken into account in experimental set-ups.

Thyroid function during and after cardiopulmonary bypass in children.

BACKGROUND: The aim of the study was to elucidate the changes in thyroid function during and after cardiopulmonary bypass (CPB) in children. METHODS: Triiodothronine (T3), thyroxine (T4), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were determined preoperatively, at specific times throughout CPB, and serially up to 48 h postoperatively, in 10 children (median age 35, range 23-68 months) undergoing elective surgery for congenital heart disease. RESULTS: T3 decreased from 2.01 +/- 0.08 preoperatively to 0.94 +/- 0.10 nmol/l 24 h postoperatively (P < 0.05). T4 levels followed a pattern similar to changes in T3. FT4 increased from 17.4 +/- 0.7 preoperatively to 30.0 +/- 0.4 pmol/l after 30 min of CPB (P < 0.05). TSH decreased from 2.44 +/- 0.43 preoperatively to 0.93 +/- 0.21 24 h postoperatively (P < 0.05). CONCLUSION: T3, T4 and TSH are significantly depressed after open heart surgery in children.