Dendritic Cell-Based Immunotherapy in Patients With Resected Pancreatic Cancer.

PURPOSE: Immunotherapies have shown limited responses in patients with advanced pancreatic cancer. Recently, we reported that dendritic cell (DC)-based immunotherapy induced T-cell responses against pancreatic cancer antigens. The primary objective of this study was to determine the efficacy of DC-based immunotherapy to prevent recurrence of disease. METHODS: This was a single-center, open-label, single-arm, combined phase I/II trial. The primary end point was the 2-year recurrence-free survival (RFS) rate. A 2-year RFS rate of ≥60% was defined as a clinically meaningful improvement. We included patients with pancreatic cancer after resection and completion of standard-of-care (SOC) treatment without recurrent disease on cross-sectional imaging. Patients were treated with autologous DCs pulsed with an allogeneic mesothelioma tumor cell lysate, comprising antigens also expressed in pancreatic ductal adenocarcinoma. RESULTS: Thirty-eight patients were included in the analysis of the primary end point (47% male, 53% female). The median age was 62 years (IQR, 55-68). Twenty-eight patients (74%) received five DC vaccinations and completed the study protocol. Three patients (8%) received four vaccinations, and seven patients (16%) received three vaccinations. After a median follow-up of 25.5 months, 26 patients (68%) had not developed recurrence of disease. The estimated 2-year RFS was 64%. Vaccination led to the enrichment of circulating activated CD4+ T cells and the detection of treatment-induced immune responses in vitro. T-cell receptor-sequencing analyses of a resected solitary lung metastasis showed influx of vaccine-specific T cells. CONCLUSION: This study reached its primary end point of a 2-year RFS rate of ≥60% following pancreatectomy after SOC treatment and adjuvant DC-based immunotherapy in patients with pancreatic cancer. These results warrant a future randomized trial.

Externally validated treatment algorithm acceptably predicts nonoperative treatment success in patients with anterior cruciate ligament rupture.

PURPOSE: This study aims to develop and externally validate a treatment algorithm to predict nonoperative treatment success or failure in patients with anterior cruciate ligament (ACL) rupture. METHODS: Data were used from two completed studies of adult patients with ACL ruptures: the Conservative versus Operative Methods for Patients with ACL Rupture Evaluation study (development cohort) and the KNee osteoArthritis anterior cruciate Ligament Lesion study (validation cohort). The primary outcome variable is nonoperative treatment success or failure. Potential predictor variables were collected, entered into the univariable logistic regression model and then incorporated into the multivariable logistic regression model for constructing the treatment algorithm. Finally, predictive performance and goodness-of-fit were assessed and externally validated by discrimination and calibration measures. RESULTS: In the univariable logistic regression model, a stable knee measured with the pivot shift test and a posttrauma International Knee Documentation Committee (IKDC) score <50 were predictive of needing an ACL reconstruction. Age >30 years and a body mass index > 30 kg/m2 were predictive for not needing an ACL reconstruction. Age, pretrauma Tegner score, the outcome of the pivot shift test and the posttrauma IKDC score are entered into the treatment algorithm. The predictability of needing an ACL reconstruction after nonoperative treatment (discrimination) is acceptable in both the development and the validation cohort: area under the curve = resp. 0.69 (95% confidence interval [CI]: 0.58-0.81) and 0.68 (95% CI: 0.58-0.78). CONCLUSION: This study shows that the treatment algorithm can acceptably predict whether an ACL injury patient will have a(n) (un)successful nonoperative treatment (discrimination). Calibration of the treatment algorithm suggests a systematical underestimation of the need for ACL reconstruction. Given the limitations regarding the sample size of this study, larger data sets must be constructed to improve the treatment algorithm further. LEVEL OF EVIDENCE: Level II.

Tumor Necrosis Factor Inhibitor Use Increases Birthweight in Pregnant Women With Rheumatoid Arthritis Independently of the Soluble Fms-Like Tyrosine Kinase-1/Placental Growth Factor Ratio.

BACKGROUND: To study whether the use of TNF (tumor necrosis factor) inhibitors (TNFi) by pregnant women with rheumatoid arthritis affects sFlt-1 (soluble Fms-like tyrosine kinase-1), PlGF (placental growth factor), or their impact on birthweight. METHODS AND RESULTS: sFlt-1 and PlGF were measured in all trimesters of pregnancy in the Preconception Counseling in Active Rheumatoid Arthritis study and were compared according to the use of TNFi. The association of sFlt-1 and PlGF with birthweight in relation to TNFi was determined. The study included 158 women, of whom 52.5% used TNFi during pregnancy. Both sFlt-1 and PlGF increased during pregnancy, whereas their ratio declined. Taking into consideration the trimester-related variation in levels of sFlt-1 and PlGF, after correction for relevant confounders, the sFlt-1/PlGF ratio was not significantly different between patients who did or did not use TNFi (sFlt-1/PlGF ratio in the second trimester compared with the first trimester: estimated change 8.17 [95% CI, 2.54-26.29], P=0.79; sFlt-1/PlGF ratio in the third trimester compared with the first trimester: estimated change 6.25 [95% CI, 1.73-22.50], P=0.25). In women who did not use TNFi, birthweight was significantly lower (3180 versus 3302 g; P=0.03), and sFlt-1 displayed a negative correlation with birthweight (r=-0.462, P<0.001) and birthweight percentile (r=-0.332, P=0.008). In TNFi users, these correlations were absent. CONCLUSIONS: TNF inhibitor use increases birthweight in pregnant women with rheumatoid arthritis independently of the sFlt-1/PlGF ratio. REGISTRATION: http://clinicaltrials.gov. Unique identifier: NCT01345071.

Are serum cobalt and chromium levels predictors for patient-reported outcome measures in the ASR hip resurfacing arthroplasty?

Aims: The aims of this study were to determine if an increasing serum cobalt (Co) and/or chromium (Cr) concentration is correlated with a decreasing Harris Hip Score (HHS) and Hip disability and Osteoarthritis Outcome Score (HOOS) in patients who received the Articular Surface Replacement (ASR) hip resurfacing arthroplasty (HRA), and to evaluate the ten-year revision rate and show if sex, inclination angle, and Co level influenced the revision rate. Methods: A total of 62 patients with an ASR-HRA were included and monitored yearly postoperatively. At follow-up, serum Co and Cr levels were measured and the HHS and the HOOS were scored. In addition, preoperative patient and implant variables and the need for revision surgery were recorded. We used a linear mixed model to relate the serum Co and Cr levels to different patient-reported outcome measures (PROMs). For the survival analyses we used the Kaplan-Meier and Cox regression model. Results: We found that an increase of one part per billion (ppb) in serum Co and Cr levels correlated significantly with worsening of the HHS in the following year. This significant correlation was also true for the HOOS-Pain and HOOS-quality of life sub scores. The overall ten-year survival rate in our cohort was 65% (95% confidence interval (CI) 52.5 to 77.6). Cox regression analysis showed a significant hazard ratio (HR) of 1.08 (95% CI 1.01 to 1.15; p = 0.028) for serum Co level. No significance was found with sex or inclination angle. Conclusion: This study shows that increasing serum Co and Cr levels measured in patients with an ASR-HRA are predictive for deterioration in HHS and HOOS subscales in the following year. Increasing serum Co and Cr should forewarn both surgeon and patient that there is a heightened risk of failure. Continued and regular review of patients with an ASR-HRA implant by measurement of serum Co/Cr levels and PROMs remains essential.

Systemic Metabolomics in a Framework of Genetics and Lifestyle in Age-Related Macular Degeneration.

Insights into the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness, point towards a complex interplay of genetic and lifestyle factors triggering various systemic pathways. This study aimed to characterize metabolomic profiles for AMD and to evaluate their position in the trias with genetics and lifestyle. This study included 5923 individuals from five European studies. Blood metabolomics were assessed using a nuclear magnetic resonance platform of 146 metabolites. Associations were studied using regression analyses. A genetic risk score (GRS) was calculated using ß-values of 49 AMD variants, a lifestyle risk score (LRS) using smoking and diet data, and a metabolite risk score (MRS) using metabolite values. We identified 61 metabolites associated with early-intermediate AMD, of which 94% were lipid-related, with higher levels of HDL-subparticles and apolipoprotein-A1, and lower levels of VLDL-subparticles, triglycerides, and fatty acids (false discovery rate (FDR) p-value < 1.4 × 10-2). Late AMD was associated with lower levels of the amino acids histidine, leucine, valine, tyrosine, and phenylalanine, and higher levels of the ketone bodies acetoacetate and 3-hydroxybutyrate (FDR p-value < 1.5 × 10-3). A favorable lifestyle characterized by a healthy diet was associated with higher levels of amino acids and lower levels of ketone bodies, while an unfavorable lifestyle, including smoking, showed opposite effects (FDR p-value < 2.7 × 10-2). The MRS mediated 5% of the effect of the GRS and 20% of that of the LRS on late AMD. Our findings show that metabolomic profiles differ between AMD stages and show that blood metabolites mostly reflect lifestyle. The severity-specific profiles spur further interest into the systemic effects related to disease conversion.

Multimarker Analysis of Serially Measured GDF-15, NT-proBNP, ST2, GAL-3, cTnI, Creatinine, and Prognosis in Acute Heart Failure.

BACKGROUND: Studies on serially measured GDF-15 (growth differentiation factor 15) in acute heart failure (HF) are limited. Moreover, several pathophysiological pathways contribute to HF. Therefore, we aimed to explore the (additional) prognostic value of serially measured GDF-15 using a multi-marker approach to more accurately predict HF risk. METHODS: TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure) is a prospective cohort of 496 patients with acute HF who were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Blood sampling was scheduled at 7 moments during 1-year follow-up. GDF-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), ST2 (suppression of tumorigenicity 2), galectin-3, troponin I, and creatinine were measured in a central laboratory. We associated repeated measurements of these biomarkers with the composite primary end point of all-cause mortality and HF rehospitalization, using multivariable joint modeling. RESULTS: Median age was 74 years, and 37% were women. Median baseline GDF-15 was 4632 pg/mL. The primary end point was reached in 188 (40%) patients. The average estimated GDF-15 level increased weeks before the primary end point was reached. The hazard ratio per 1 SD difference in log-GDF-15 was 2.14 (95% CI, 1.78-2.57) unadjusted, 1.96 (1.49-2.53) after adjustment for clinical confounders and 1.44 (1.05-1.91) when jointly modeled with all biomarkers. The adjusted HRs for NT-proBNP were 2.38 (1.78-3.33) and 1.52 (1.15-2.08), respectively. The multimarker model combining GDF-15, NT-proBNP, and troponin I provided a favorable risk discrimination (area under the curve=0.785). CONCLUSIONS: Sequentially measured GDF-15 independently and dynamically predicts risk of adverse outcomes during 1-year follow-up after index admission for acute HF. NT-proBNP remains a robust predictor among potential candidates. Multiple biomarkers should be considered for stratification in clinical practice. REGISTRATION: URL: https://www.trialregister.nl/trial/1783; Unique Identifier: NTR1893. (The trial can be found temporarily at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR1893.).

Lurbinectedin shows clinical activity and immune-modulatory functions in patients with pre-treated small cell lung cancer and malignant pleural mesothelioma.

PURPOSE: Lurbinectedin is a promising new drug being investigated in pre-treated patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM). Its clinical activity in the real-world setting has not been investigated yet. PATIENTS AND METHODS: Clinical data of patients with SCLC and MPM who were treated with lurbinectedin were prospectively collected. Comprehensive immune cell profiling by flow cytometry was performed on screening and treating peripheral blood samples. RESULTS: A total of 95 patients (43 SCLC and 52 MPM) were treated, mostly as ≥3-line of therapy. In the SCLC cohort, a median progression-free survival (mPFS) was 1.5 months (95% CI: 1.4-3.0), and median overall survival was 7.0 months (95% CI: 4.7-not reached). Objective radiological response and disease control rate after 12 weeks were 16% and 28%, respectively. In the MPM cohort, median progression-free survival was 2.8 months (95% CI: 1.4-4.2), and median overall survival was 7.2 months (95% CI: 5.9-not reached). Disease control rate after 12 weeks was 29%, whereas no partial responses were registered. No new safety signals were observed. Lurbinectedin treatment was significantly associated with the depletion of circulating classical monocytes, which correlated with a better PFS in patients with SCLC. Lurbinectedin increased the proliferation of CD4+ and CD8+ T cells (SCLC) and natural killer and natural killer T cells (SCLC and MPM) and altered co-stimulatory and co-inhibitory receptor expression on circulating lymphocytes. CONCLUSION: Lurbinectedin has a manageable safety profile and shows clinical activity in pre-treated patients with SCLC and MPM. Its immune-modulatory functions make lurbinectedin a potential platform for immunotherapy combinations.

Development and validation of a multivariable prediction model for early prediction of chronic postsurgical pain in adults: a prospective cohort study.

BACKGROUND: Early identification of patients at risk of developing chronic postsurgical pain (CPSP) is an essential step in reducing pain chronification in postsurgical patients. We aimed to develop and validate a prognostic model for the early prediction of CPSP including pain characteristics indicating altered pain processing within 2 weeks after surgery. METHODS: A prospective cohort study was conducted in adult patients undergoing orthopaedic, vascular, trauma, or general surgery between 2018 and 2019. Multivariable logistic regression models for CPSP were developed using data from the University Medical Centre (UMC) Utrecht and validated in data from the Erasmus UMC Rotterdam, The Netherlands. RESULTS: In the development (n=344) and the validation (n=150) cohorts, 28.8% and 21.3% of patients reported CPSP. The best performing model (area under the curve=0.82; 95% confidence interval [CI], 0.76-0.87) included preoperative treatment with opioids (odds ratio [OR]=4.04; 95% CI, 2.13-7.70), bone surgery (OR=2.01; 95% CI, 1.10-3.67), numerical rating scale pain score on postoperative day 14 (OR=1.57; 95% CI, 1.34-1.83), and the presence of painful cold within the painful area 2 weeks after surgery (OR=4.85; 95% CI, 1.85-12.68). Predictive performance was confirmed by external validation. CONCLUSIONS: As only four easily obtainable predictors are necessary for reliable CPSP prediction, the models are useful for the clinician to be alerted to further assess and treat individual patients at risk. Identification of the presence of painful cold within 2 weeks after surgery as a strong predictor supports altered pain processing as an important contributor to CPSP development.

Clinical and Molecular Profiling to Develop a Potential Prediction Model for the Response to Alemtuzumab Therapy for Acute Kidney Transplant Rejection.

Alemtuzumab, a monoclonal antibody that depletes CD52-bearing immune cells, is an effective drug for the treatment of severe or glucocorticoid-resistant acute kidney transplant rejection (AR). Patient-specific predictions on treatment response are, however, urgently needed, given the severe side effects of alemtuzumab. This study developed a multidimensional prediction model with the aim of generating clinically useful prognostic scores for the response to alemtuzumab. Clinical and histological characteristics were collected retrospectively from patients who were treated with alemtuzumab for AR. In addition, targeted gene expression profiling of AR biopsy tissues was performed. Least absolute shrinkage and selection operator (LASSO) logistic regression modeling was used to construct the ALEMtuzumab for Acute Rejection (ALEMAR) prognostic score. Response to alemtuzumab was defined as patient and allograft survival and at least once an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 during the first 6 months after treatment. One hundred fifteen patients were included, of which 84 (73%) had a response to alemtuzumab. The ALEMAR-score accurately predicted the chance of response. Gene expression analysis identified 13 differentially expressed genes between responders and nonresponders. The combination of the ALEMAR-score and selected genes resulted in improved predictions of treatment response. The present preliminary prediction model is potentially helpful for the development of stratified alemtuzumab treatment for acute kidney transplant rejection but requires validation.

Fractionated stereotactic radiotherapy for uveal melanoma: Long-term outcome and control rates.

PURPOSE: The aim of our study is to evaluate local tumour control rates, radiation side-effects, visual preservation and disease-free survival (DFS) of uveal melanoma (UM) patients treated with fractionated stereotactic radiotherapy (fSRT). METHODS: A retrospective study of UM patients, who were treated with fSRT (N = 189), was performed by the Rotterdam Ocular Melanoma Study group (ROMS), the Netherlands, between 1999 and 2014 with a follow-up of at least 5 years. RESULTS: The 1-, 3-, 5-, 10- and 15-year local tumour control rates were as follows: 99.4%, 92.8%, 92.2%, 89.3% and 89.3%, respectively. Cataract (67.8%) was the most common side-effect of fSRT followed by retinopathy (35.1%), maculopathy (23.8%), vitreous haemorrhage (20.1%), neovascular glaucoma (NVG) (20.0%) and optic neuropathy (12.4%). Patients with anterior located UMs developed cataract more frequently (p = 0.047, multivariable analysis). By multivariable analysis, significant factors for secondary enucleation were tumour recurrence (p < 0.001) and NVG (p < 0.001). In multivariable analysis, risk factors for a worse DFS were larger UM (p = 0.024) and tumours with subretinal fluid (SRF) at baseline (p = 0.038). The 5-year DFS was 77.0% and the best corrected visual acuity decreased significantly after treatment. After 5 years, 22.0% of patients and after 10 years 17.6% of patients had a visual acuity of ≤0.3 logMAR. CONCLUSION: Fractionated stereotactic radiotherapy is a good treatment option for small-, medium- and large-sized tumours with 5-year local tumour control of 92.2%. After 5 years, 22.0% of the patients had a good vision. Independently of tumour location, the visual acuity decreased significantly after treatment. Overall, the 5-year DFS was 77.0%.

Postoperative Pain and Age: A Retrospective Cohort Association Study.

BACKGROUND: As the population ages, the number of elderly people undergoing surgery increases. Literature on the incidence and intensity of postoperative pain in the elderly is conflicting. This study examines associations between age and pain-related patient reported outcomes and perioperative pain management in a dataset of surgical patients undergoing four common surgeries: spinal surgery, hip or knee replacement, or laparoscopic cholecystectomy. Based on the authors' clinical experience, they hypothesize that pain scores are lower in older patients. METHODS: In this retrospective cohort, study data were collected between 2010 and 2018 as part of the international PAIN OUT program. Patients filled out the International Pain Outcomes Questionnaire on postoperative day 1. RESULTS: A total of 11,510 patients from 26 countries, 59% female, with a mean age of 62 yr, underwent one of the aforementioned types of surgery. Large variation was detected within each age group for worst pain, yet for each surgical procedure, mean scores decreased significantly with age (mean Numeric Rating Scale range, 6.3 to 7.3; ß = -0.2 per decade; P ≤ 0.001), representing a decrease of 1.3 Numeric Rating Scale points across a lifespan. The interference of pain with activities in bed, sleep, breathing deeply or coughing, nausea, drowsiness, anxiety, helplessness, opioid administration on the ward, and wish for more pain treatment also decreases with age for two or more of the procedures. Across the procedures, patients reported being in severe pain on postoperative day one 26 to 38% of the time, and pain interfered moderately to severely with movement. CONCLUSIONS: The authors' findings indicate that postoperative pain decreases with increasing age. The change is, however, small and of questionable clinical significance. Additionally, there are still too many patients, at any age, undergoing common surgeries who suffer from moderate to severe pain, which interferes with function, supporting the need for tailoring care to the individual patient.

Joint Modeling of Longitudinal Markers and Time-to-Event Outcomes: An Application and Tutorial in Patients After Surgical Repair of Transposition of the Great Arteries.

BACKGROUND: Most patients with congenital heart disease survive into adulthood; however, residual abnormalities remain and management of the patients is life-long and personalized. Patients with surgical repair of transposition of the great arteries, for example, face the risk to develop neoaortic valve regurgitation. Cardiologists update the prognosis of the patient intuitively with updated information of the cardiovascular status of the patient, for instance from echocardiographic imaging. METHODS: Usually a time-dependent version of the Cox model is used to analyze repeated measurements with a time-to-event outcome. New statistical methods have been developed with multiple advantages, of which the most prominent one being the joint model for longitudinal and time-to-event outcome. In this tutorial, the joint modeling framework is introduced and applied to patients with transposition of the great arteries after surgery with a long-term follow-up, where repeated echocardiographic values of the neoaortic root are evaluated against the risk of neoaortic valve regurgitation. RESULTS: The data are analyzed with the time-dependent Cox model as benchmark method, and the results are compared with a joint model, leading to different conclusions. The flexibility of the joint model is shown by adding the growth rate of the neoaortic root to the model and adding repeated values of body surface area to obtain a multimarker model. Lastly, it is demonstrated how the joint model can be used to obtain personalized dynamic predictions of the event. CONCLUSIONS: The joint model for longitudinal and time-to-event data is an attractive method to analyze data in follow-up studies with repeated measurements. Benefits of the method include using the estimated natural trajectory of the longitudinal outcome, great flexibility through multiple extensions, and dynamic individualized predictions.

Ki67 (MIB-1) as a Prognostic Marker for Clinical Decision Making Before Extended Pleurectomy Decortication in Malignant Pleural Mesothelioma.

INTRODUCTION: The role of surgery for early stage malignant pleural mesothelioma (MPM) remains controversial. Current expert opinion is only to treat patients surgically as part of multimodality therapy. It is still challenging to identify patients who will not benefit from surgery. We specifically evaluated tumor-related parameters in combination with clinical parameters to identify prognostic markers for survival. METHODS: Clinical data of 27 consecutive patients with MPM treated with extended pleurectomy and decortication within a multimodality approach were collected and analyzed. Several tumor (immuno-)histopathologic characteristics were determined on resected tumor material, among which MTAP and Ki67 (MIB-1). Univariable and multivariable analyses served to correlate clinical and tumor-related parameters to overall survival (OS) and progression-free survival (PFS). RESULTS: The median PFS (mPFS) was 15.3, and the median OS (mOS) was 26.5 months. Patients with a Ki67 score greater than 10% had a significantly shorter PFS (mPFS = 8.81 versus 25.35 mo, p = 0.001) and OS (mOS 19.7 versus 44.5 mo, p = 0.002) than those with a Ki67 score less than or equal to 10. Receiver operating characteristic curve analysis for Ki67 revealed an area under the curve of 0.756 with a sensitivity of 90% and specificity of 71% for a cutoff of 10% for Ki67. Patients with loss of MTAP had a significantly shorter mPFS (9 versus 21.1 mo, p = 0.014) and mOS (19.7 versus 42.6 mo, p = 0.047) than those without MTAP loss. CONCLUSIONS: In our study, Ki67 was prognostic for OS and PFS in patients with MPM treated with extended pleurectomy/decortication in a multimodality approach. Determination of Ki67 before surgery combined with specific clinical parameters could assist in clinical decision making by identifying patients, with high Ki67, who are unlikely to benefit from surgery.

Long-Term Follow-Up of Mesothelioma Patients Treated with Dendritic Cell Therapy in Three Phase I/II Trials.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a fatal neoplasm with, if untreated, poor survival of approximately nine months from diagnosis. Until recently, phase II-III immunotherapy trials did not show any significant benefit. The lack of immunotherapy efficacy can be explained by the fact that mesothelioma is a tumor with an "immune desert" phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of DCs, which were ex-vivo cultured, exposed to (tumor-associated) antigens, and subsequently activated, this "immune desert" phenotype might be turned into an "inflamed" phenotype. Three phase I/II studies have been performed and published using activated DCs, which support this concept. We here report on the long-term survival of patients treated with DCs in three phase I/II studies. METHODS: Survival data of the phase I/II trials using DC therapy in MPM patients were obtained and subsequently analyzed. In the first two trials, DCs were loaded with autologous tumor lysate. In the third trial, DCs were loaded with allogeneic mesothelioma tumor cell line lysate. RESULTS: In the three studies combined, 29 patients with MPM were treated with DC vaccination between 2006 and 2015. At data cut-off, the median OS was 27 months (95% CI: 21-47 months). OS at 2 years was 55.2% (95% CI: 39.7-76.6%), and OS at 5 years was 20.7% (95% CI: 10.1-42.2%). CONCLUSIONS: The long-term survival of DC therapy in MPM in these three trials is promising, which is the basis for the randomized phase II/III DENIM study. This DENIM study is currently enrolling, and the results of which have to be awaited for definite conclusions.

Serially Measured Cytokines and Cytokine Receptors in Relation to Clinical Outcome in Patients With Stable Heart Failure.

In this prospective cohort study of 250 stable heart failure patients with trimonthly blood sampling, we investigated associations of 17 repeatedly measured cytokines and cytokine receptors with clinical outcome during a median follow-up of 2.2 (25th-75th percentile, 1.4-2.5) years. Sixty-six patients reached the primary end point (composite of cardiovascular mortality, heart failure hospitalization, heart transplantation, left ventricular assist device implantation). Repeatedly measured levels of 8 biomarkers correlated with clinical outcomes independent of clinical characteristics. Rates of change over time (slopes of biomarker evolutions) remained independently associated with outcome for 15 biomarkers. Thus, temporal patterns of cytokines and cytokine receptors, in particular tumour necrosis factor ligand superfamily member 13B and interleukin-1 receptor type 1, might contribute to personalized risk assessment.

The unnatural history of pulmonary stenosis up to 40†years after surgical repair.

OBJECTIVE: To provide prospective information on long-term outcome after surgical correction of valvular pulmonary stenosis (PS). METHODS: Fifty-three consecutive patients operated for PS during childhood between 1968 and 1980 in one centre are followed longitudinally for 37±3.4 years, including extensive in-hospital examination every 10 years. RESULTS: Survival information was available in 100% of the original 53 patients. Cumulative survival was 94% at 20 years and 91% at 40 years. Excluding perioperative mortality (<30 days), survival was 94% at 40 years. Of 46 eligible survivors, 29 participated in the in-hospital examination and 15 gave permission to use their hospital records (96% participation). Cumulative event-free survival was 68% after 40 years: 25% needed a reintervention, 12% underwent pacemaker implantation and 9% had supraventricular arrhythmias. Early reinterventions were mainly for residual PS, late reinterventions for pulmonary regurgitation. Subjective health status was good. Exercise capacity was normal in 74% (median 96 (82-107)% of expected workload). Right ventricular and left ventricular (LV) dysfunction was found in 13% and 41%, respectively. The use of a transannular patch and younger age at surgery were predictive for late events (HR 3.02 (95% CI 1.09 to 8.37) and HR 0.81/year (95% CI 0.66 to 0.98), respectively). Use of inflow occlusion compared with cardiopulmonary bypass showed a trend towards more reinterventions (HR 3.19 (95% CI 0.97 to 10.47)). CONCLUSIONS: Survival up to 40 years after successful PS repair is nearly normal. Subjective health status is good and there is a low incidence of arrhythmias. Reinterventions, however, are necessary in one-quarter and 40 years postoperatively several patients show LV dysfunction.