Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial.

BACKGROUND: Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested. OBJECTIVE: To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. METHODS: PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. RESULTS: The study is ongoing. Results will be published when the study is completed. CONCLUSION: PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. TRIAL REGISTRATION: The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588 ). Registered 30 November 2018.

The effect of needle tip tracking on procedural time of ultrasound-guided lumbar plexus block: a randomised controlled trial.

Technology that facilitates performance of deep peripheral nerve blocks is of clinical interest. The Onvision™ is a new device for ultrasonographic needle tip tracking that incorporates an ultrasound sensor on the needle tip that is then represented by a green circle on the ultrasound screen. The primary aim of this study was to investigate the effect of needle tip tracking on procedural time in the first human volunteer study. Secondary outcome measures included: number of hand movements; hand movement path length; block success rate; block onset time; block duration; discomfort experienced by the volunteers; and the anaesthetists' confidence as to whether their block would be successful. Two anaesthetists performed ultrasound-guided lumbar plexus blocks with an out-of-plane technique, with and without the use of needle tip tracking. In total, data from 25 volunteers were studied. Mean (SD) procedural time was 163 (103) s with needle tip tracking and 216 (117) s without (p = 0.10). Hand motion analysis showed that needle tip tracking was associated with a significant decrease in the mean (SD) number of intended needling hand movements (39 (29) vs. 59 (36); p = 0.03) and path lengths (3.2 (3.1) m vs. 5.5 (4.5) m; p = 0.03). No differences were found for any other secondary outcomes. The use of Onvision needle tip tracking did not reduce procedural time for out-of-plane ultrasound-guided lumbar plexus block but did reduce the number of hand movements and path lengths. This may indicate improved needle control but further studies are needed to confirm this finding.

Quality of life from a randomized trial of laparoscopic or open liver resection for colorectal liver metastases.

BACKGROUND: Most treatments for cancer cause a decline in patients' health-related quality of life (HRQoL). Limiting this decline is a universal goal for healthcare providers. Using minimally invasive instead of open surgical techniques might be one way to achieve this. The aim of this study was to compare postoperative HRQoL after open and laparoscopic liver resection. METHODS: This was a predefined substudy of an RCT comparing open with laparoscopic liver resection. Patients with colorectal liver metastases were assigned randomly to open or laparoscopic parenchyma-sparing liver resection. HRQoL was assessed with the Short Form 36 questionnaire at baseline, and 1 and 4 months after surgery. RESULTS: A total of 280 patients were randomized, of whom 273 underwent surgery (129 laparoscopic, 144 open); 682 questionnaires (83.3 per cent) were available for analysis. One month after surgery, patients in the laparoscopic surgery group reported reduced scores in two HRQoL domains (physical functioning and role physical), whereas those in the open surgery group reported reduced scores in five domains (physical functioning, role physical, bodily pain, vitality and social functioning). Four months after surgery, HRQoL scores in the laparoscopic group had returned to preoperative levels, whereas patients in the open group reported reduced scores for two domains (role physical and general health). The between-group difference was statistically significant in favour of laparoscopy for four domains after 1 month (role physical, bodily pain, vitality and social functioning) and for one domain after 4 months (role physical). CONCLUSION: Patients assigned to laparoscopic liver surgery reported better postoperative HRQoL than those assigned to open liver surgery. For role limitations caused by physical health problems, patients in the laparoscopic group reported better scores up to 4 months after surgery. Registration number: NCT01516710 ( http://www.clinicaltrials.gov).

ANTECEDENTES: La mayoría de los tratamientos para el cáncer causan una disminución de la calidad de vida relacionada con la salud (health-related quality of life, HRQoL) de los pacientes. Limitar este declive es un objetivo universal para los proveedores de atención médica. El uso de técnicas quirúrgicas mínimamente invasivas en lugar de abiertas podría ser una forma de lograrlo. El objetivo de este estudio fue comparar la HRQoL postoperatoria después de la resección hepática abierta y laparoscópica. MÉTODOS: Se trata de un subestudio predefinido de un ensayo aleatorizado y controlado que comparó la resección hepática abierta con la laparoscópica. Los pacientes con metástasis hepáticas colorrectales se asignaron aleatoriamente al grupo de resección hepática con preservación de parénquima por vía abierta o por vía laparoscópica. La HRQoL se evaluó con el cuestionario abreviado SF-36 en el momento basal y al cabo de 1 y 4 meses después de la cirugía. RESULTADOS: Un total de 280 pacientes fueron aleatorizados, de los cuales 273 se sometieron a cirugía (129 = laparoscópica, 144 = abierta) y hubo 682 cuestionarios (83%) disponibles para el análisis. Un mes después de la cirugía, los pacientes del grupo de cirugía laparoscópica presentaron puntuaciones reducidas en dos items de HRQoL (función física y rol físico), mientras que los pacientes del grupo de cirugía abierta presentaron puntuaciones reducidas en cinco items (función física, rol físico, dolor corporal, vitalidad y función social). Cuatro meses después de la cirugía, el grupo de cirugía laparoscópica había vuelto a los niveles preoperatorios de la HRQoL, mientras que los pacientes del grupo de cirugía abierta presentaron puntuaciones reducidas para dos items (función física y salud general). La diferencia entre los grupos fue estadísticamente significativa a favor de la laparoscopia para cuatro items después de un mes de la cirugía (rol físico, dolor corporal, vitalidad y función social) y para un ítem (rol físico) después de cuatro meses. CONCLUSIÓN: Los pacientes asignados a cirugía hepática laparoscópica presentaron mejor HRQoL postoperatoria que los pacientes asignados a cirugía hepática abierta. Para las limitaciones de roles causadas por problemas físicos de salud, los pacientes de cirugía laparoscópica presentaron mejores puntuaciones a los cuatro meses tras la intervención quirúrgica.

The prevalence and severity of health problems in youth elite sports: A 6-month prospective cohort study of 320 athletes.

Little is known regarding the overall health of youth elite athletes. Our aim was to describe the prevalence and severity of health problems in a cohort of youth elite athletes representing a variety of endurance, team, and technical sports. Elite sport athletes (N = 260, 16.2 years) from different Sport Academy High Schools in Norway, and a group of their teammates (N = 60, 16.4 years) attending regular high schools, were included in the study. The Oslo Sports Trauma Research Centre (OSTRC) questionnaire on health problems was used to self-report injuries and illnesses for 26 weeks. At any given time, an average of 43% [95% CI: 37%-49%] of the elite sport athletes had some form of health problem and 25% [20%-31%] had substantial health problems. The prevalence of health problems was similar between the elite team sport athletes and their teammates, except for substantial injuries (22% [16%-30%] vs 10% [5%-20%]). Endurance sport athletes reported more illnesses (23% [15%-35%]) than technical and team sport athletes (10% [5%-20%] and 8% [4%-14%]). In contrast, technical and team sport athletes reported more injuries (36% [95% CI: 25-48] and 37% [95% CI 29-45]) compared to endurance sport athletes (15% [8%-25%]). The total impact of health problems was roughly split in thirds between overuse injuries (37%), acute injuries (34%), and illnesses (30%). This is the first prospective study to present self-reported injury and illness data in a large heterogeneous group of youth elite athletes, documenting a substantial impact of both injuries and illnesses on the health of this population.

Early interaction in autism spectrum disorder: Mothers' and children's behaviours during joint engagement.

BACKGROUND: More knowledge about the interaction between young children with autism spectrum disorder and their parents is one way to improve intervention. This study aims to investigate the behaviours of mothers and children with autism spectrum disorder during joint engagement, with a focus on pacing or rate (i.e., incidences per minute) of their behaviours when being in this state. METHOD: Video recordings of 10 min of free-play between 58 children (2-4 years) diagnosed with childhood autism and their mothers were used to examine rate of mothers' and children's behaviours (i.e., toy introduction, toy expansion, positive affect, and language) during joint engagement, the association between rate of mothers and children's behaviours, the relation between rate of mothers' behaviours and time in joint engagement, and how child factors might be associated with the latter. RESULTS: Mothers(m) and children(c) showed similar rate of positive affect (Mm  = 0.6/Mc  = 0.5) and toy expansion (Mm  = 0.7/Mc  = 0.7) per minute, whereas mothers talked almost three times more than their children (Mm  = 10.2/Mc  = 3.8). In contrast, mothers introduced fewer toys compared to the children (Mm  = 0.7/Mc  = 1.2). Rate of mothers' toy introduction, toy expansion, and positive affect was inversely related to time in joint engagement (Regression coefficient = -70.7 to -48.5, p = .006 to .024). Rates of mothers' and children's behaviours were associated (Spearman rank order coefficient = .53 to .29, p < .001 to .03), but neither rate of children's behaviours nor mental age was associated with the observed relation between rate of these maternal behaviours and time in joint engagement. CONCLUSION: Time in joint engagement was related to rate of mothers' behaviours and children's mental age but not to rate of children's behaviours in this study. Thus, intervention teaching parents of young children with autism strategies designed to increase time in joint engagement may be vital. The complex nature of the interaction between mother and child behaviours in promoting joint engagement warrants further elucidation.

Plasma vitamin D levels and inflammation in the aortic wall of patients with coronary artery disease with and without inflammatory rheumatic disease.

OBJECTIVES: Vitamin D modulates inflammation, and this may explain the observed associations between vitamin D status and disorders driven by systemic inflammation, such as coronary artery disease (CAD) and inflammatory rheumatic diseases (IRDs). The aims of this study were to assess vitamin D status in patients with CAD alone and in patients with CAD and IRD, and to explore potential associations between vitamin D status and the presence of mononuclear cell infiltrates (MCIs) in the aortic adventitia of these patients. METHOD: Plasma levels of 25-hydroxyvitamin D3 [(25(OH)D3] were determined by radioimmunoassay and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by enzyme immunoassay in the 121 patients from the Feiring Heart Biopsy Study (FHBS) who had available histology data on adventitial MCIs; 53 of these had CAD alone and 68 had CAD and IRD. RESULTS: In the crude analysis, vitamin D levels were similar in CAD patients with and without IRD. After adjustment for potential confounders, IRD was associated with an increase of 8.8 nmol/L [95% confidence interval (CI) 1.0-16.6; p = 0.027] in 25(OH)D3 and an increase of 18.8 pmol/L (95% CI 4.3-33.3; p = 0.012) in 1,25(OH)2D3, while MCIs in the aortic adventitia were associated with lower levels of 1,25(OH)2D3 (ß = -18.8, 95% CI -33.6 to -4.0; p = 0.014). CONCLUSIONS: IRD was associated with higher levels of both 25(OH)D3 and 1,25(OH)2D3. These findings argue against the hypothesis that patients with high systemic inflammatory burden (CAD+IRD) should have lower vitamin D levels than those with less inflammation (CAD only). Of note, when controlled for potential confounders, low 1,25(OH)2D3 levels were associated with adventitial aortic inflammation.

Collectin Liver 1 and Collectin Kidney 1 of the Lectin Complement Pathway Are Associated With Mortality After Kidney Transplantation.

Kidney transplanted patients still have significantly higher mortality compared with the general population. The innate immune system may play an important role during periods, with suppression of the adaptive immune system. In the present study, two soluble pattern recognition molecules of the innate immune system were investigated, collectin liver 1 (CL-L1) and collectin kidney 1 (CL-K1). Potential associations of their pretransplant levels and long-term graft and recipient survival were examined. The levels of CL-L1 and CL-K1 were measured at the time of transplantation in 382 patients (≥17 years) transplanted in 2000-2001. The cohort was subsequently followed until December 31, 2014. Data on patient and graft survival were obtained from the Norwegian Renal Registry. Both high CL-L1 (≥376 ng/mL) and high CL-K1 (≥304 ng/mL) levels were significantly associated with overall mortality in multivariate Cox analyses with hazard ration (HR) 1.50, 95% confidence interval (CI) 1.09-2.07, p = 0.013 and HR 1.43, 95% CI 1.02-1.99, p = 0.038, respectively. Moreover, high CL-K1 levels were significantly associated with cardiovascular mortality. No association between measured biomarkers and death-censored graft loss was found. Finally, there was a significant correlation between these two collectins, r = 0.83 (95% CI 0.80-0.86). In conclusion, CL-L1 and CL-K1 were significantly associated with mortality in kidney transplant recipients.

Vitamin concentrations 5 years after gastric bypass.

BACKGROUND/OBJECTIVES: Few studies have investigated the effects of bariatric surgery on vitamin status in the long term. We examined changes in vitamin status up to 5 years after Roux-en-Y gastric bypass surgery. SUBJECTS/METHODS: Using a retrospectively maintained database of patients undergoing weight loss surgery, we identified all patients operated with Roux-en-Y gastric bypass at our tertiary care hospital during July 2004-May 2008. Data on vitamin concentrations and patient-reported intake of dietary supplements were collected up to July 2012. Linear mixed models were used to estimate changes in vitamin concentrations during follow-up, adjusting for age and sex. All patients were recommended daily oral multivitamin, calcium/vitamin D and iron supplements and 3-monthly intramuscular B-12 after surgery. RESULTS: Out of the 443 patients operated with gastric bypass, we included 441 (99.5%) patients with one or more measurements of vitamin concentrations (75.1% women; mean age 41.5 years, mean body mass index 46.1 kg/m(2) at baseline). At 5 years after surgery, the patients' estimated mean vitamin concentrations were either significantly higher (vitamin B-6, folic acid, vitamin B-12, vitamin C and vitamin A) or not significantly different (thiamine, 25-hydroxyvitamin D and lipid-adjusted vitamin E) compared with before surgery. Use of multivitamin, calcium/vitamin D and vitamin B-12 supplements was reported by 1-9% of patients before surgery, 79-84% of patients at 1 year and 52-83% of patients 5 years after surgery. CONCLUSIONS: In patients who underwent gastric bypass surgery, estimated vitamin concentrations were either significantly increased or unchanged up to 5 years after surgery.

Expectations for treatment outcomes in neck/back patients regarding improvements in pain and function. A cross-sectional pilot study.

BACKGROUND: Literature has suggested that patients' pretreatment expectations may influence both prognosis and outcome. Investigation of these possible benefits requires knowledge about what is actually expected among these patients. AIM: To investigate neck/back patients' expectations for treatment outcomes (pain and functional improvement) prior to their first meetings with specialists in physical medicine and rehabilitation (PMR). DESIGN: Cross-sectional pilot study. SETTING: PMR Neck/Back Outpatient Clinic, Oslo University Hospital. POPULATION: Patients with neck/back pain and/or functional problems referred for the first time to a neck/back PMR outpatient clinic. METHODS: Questionnaires were completed prior to an appointment with a PMR specialist. The forms consisted of one earlier designed instrument (PSOE) and one self-constructed part with six 11-point numeric rating scales (11-NRS). Eligible patients were randomly selected between January and June 2012. RESULTS: Approximately 42 % expected their status to remain un-changed. A total of 17 % expected exacerbation of their status. No differences were found between expectations regarding pain and function. Full recovery was not expected. Highly educated patients, and those reporting high usage of analgesics, had higher expectations for improvement. CONCLUSION: Few of the selected patients seemed to expect improvement. These expectations are quite pessimistic, in our opinion. More elaborate studies are needed to confirm these results.

Short-term treatment with a gonadotropin-releasing hormone antagonist, cetrorelix, in rheumatoid arthritis (AGRA): a randomized, double-blind, placebo-controlled study.

OBJECTIVES: Gonadotropin-releasing hormone (GnRH) stimulates immune responses; therefore, antagonizing GnRH with cetrorelix may have anti-inflammatory effects. The aim of this study was to assess short-term cetrorelix therapy in rheumatoid arthritis (RA) patients. METHOD: In this proof-of-concept, randomized, double-blind study involving 99 patients with active, long-standing RA, 48 patients received subcutaneous cetrorelix (5 mg/day on days 1 and 2; 3 mg/day on days 3-5) and 51 received placebo. The primary end-point was the change in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) by day 5, when the greatest GnRH suppression was anticipated. Secondary end-points included the change in tumour necrosis factor (TNF)-α, and achievement of American College of Rheumatology (ACR) responses and DAS28-CRP < 2.6 by day 5. Patients were followed up on days 10 and 15. RESULTS: By day 5, DAS28-CRP was non-significantly reduced by 0.82 in the cetrorelix group compared to a 0.57 reduction in the placebo group (p = 0.091), TNF-α (log pg/mL) was significantly reduced in the cetrorelix group compared with the placebo group [0.55, 95% confidence interval (CI) 0.08-1.01, p = 0.023], and more patients on cetrorelix achieved ACR20 responses (40% vs. 18%, p = 0.015) and DAS28-CRP < 2.6 (13% vs. 0%, p = 0.009). Inflammatory markers increased towards baseline levels after withdrawal of treatment. Rates of adverse events were similar in both groups. CONCLUSIONS: Although there was no significant difference in the primary end-point between groups, antagonizing GnRH led to significant improvements in key secondary end-points. Thus, GnRH antagonists may have rapid anti-inflammatory effects in RA, already occurring within 5 days. The data suggest a novel mode of action for TNF-α inhibition in RA, and potentially in other autoimmune diseases.

Follow-up after curative surgery for pancreatic ductal adenocarcinoma: asymptomatic recurrence is associated with improved survival.

AIM: There is no consensus on the optimal follow-up schedule of patients after surgery for pancreatic cancer. In this retrospective study, recurrence and survival were investigated for patients presenting with either symptomatic or asymptomatic recurrence. Patient, tumor and treatment characteristics that predicted the length of postrecurrence survival were identified. METHODS: Clinical records of 164 patients who underwent a pancreatic resection (R0/R1) for pancreatic ductal adenocarcinoma from January 2000 to December 2010 were retrieved. Patients underwent a systematic follow-up program. Patient, tumor and treatment characteristics were compared between patients with asymptomatic and symptomatic recurrence. RESULTS: Of 164 consecutive patients, 144 patients (88%) had recurrence (29 asymptomatic, 115 symptomatic). The most frequent reported symptoms were abdominal pain, fatigue/weakness, back pain, weight loss, nausea/loss of appetite and jaundice. Median time to recurrence was 12.0 months for asymptomatic and 7.0 months for symptomatic patients (P = 0.036). Median postrecurrence survival was 10.0 months for asymptomatic and 4.0 months for symptomatic patients (P < 0.0001). Median overall survival was 24.5 months for asymptomatic and 11.0 months for symptomatic patients (P < 0.0001). Symptomatic recurrence, disease free survival <12 months, and no adjuvant chemotherapy were the only independent predictors of poor postrecurrence survival. 72% of asymptomatic and 37% of symptomatic patients received oncological treatment. CONCLUSIONS: Patients with asymptomatic pancreatic cancer recurrence have improved recurrence-free, postrecurrence and overall survival. Symptoms when recurrence is diagnosed are a good surrogate marker of biological aggressiveness. Detection of asymptomatic recurrence may facilitate patient eligibility for investigational studies or other forms of treatment.

High-volume local infiltration analgesia combined with intravenous or local ketorolac+morphine compared with epidural analgesia after total knee arthroplasty.

BACKGROUND: Recently, high-volume local infiltration analgesia (LIA) in total knee arthroplasty (TKA) has been introduced, but dosage, timing, and effects of adjuvants are still debated. METHODS: We randomized 102 patients undergoing TKA to receive either epidural analgesia (EDA group) or LIA (ropivacaine 150 mg and epinephrine 0.5 mg) combined with ketorolac 30 mg and morphine 5 mg given either locally (LIA group) or i.v. (LIAiv group). Epidural analgesia was maintained for 48 h. Intra-articular re-injection via a catheter with ropivacaine 142.5 mg and either intra-articular or i.v. ketorolac 30 mg was given 24 h after surgery. Pain scores, morphine consumption, side-effects, and readiness for hospital discharge were studied. RESULTS: At discharge from the postoperative anaesthetic care unit, verbal pain scores were lower in the EDA group (P=0.004), but discharge was delayed [difference 101 min, 95% CI: (23, 178), P=0.007]. Group LIA reported lower pain scores at rest beyond 24 h after surgery [mean VAS (sd) at 24/48/72 h: LIA group 16/12/10 (14)/(13)/(11); LIAiv group 22/18/15 (17)/(15)/(12); EDA group 27/30/21 (21)/(29)/(19)]. Both the LIA and the LIAiv groups were mobilized faster and were earlier ready for hospital discharge [3.5 days (LIA group) vs 4 days (LIAiv group) vs 5.5 days (EDA group); P<0.001]. Cumulated morphine consumption (72 h) was lowest for the LIA group [80 vs 101 mg (EDA group) vs 118 mg (LIAiv group), P=0.007]. CONCLUSIONS: LIA with local adjuvants compared with epidural analgesia results in reduced opioid consumption, faster mobilization, and earlier readiness for hospital discharge. Ketorolac and morphine are more efficient when given locally than systemically. The study has been registered at clinicaltrials.gov (NCT00562627) before onset of participant enrolment: http://clinicaltrials.gov/ct2/show/NCT00562627?term=spreng&rank=2 (April 21, 2010).