Sleep apnea and the impact on cardiovascular risk in patients with Marfan syndrome

Background: Marfan syndrome (MFS) is an inherited connective tissue disorder characterized by ectopia lentis, aortic root dilation and dissection and specific skeletal features. Obstructive sleep apnea (OSA) in MFS has been described earlier but the prevalence and its relation with the cardiovascular risk is still controversial. This study aimed to further investigate these aspects. Methods: In this prospective longitudinal study, we performed an attended polysomnography in 40 MFS patients (60% women, 37 +/- 12.8 years) and evaluated several cardiovascular parameters through echocardiography, resting electrocardiogram, 24 hr-Holter monitoring and serum NT-ProBNP measurements. Results: We found that OSA was present in 42.5% of the patients and that higher body mass index was the most important factor associated with the presence of OSA. We observed that overweight was present in 27.5% of the patients in the whole cohort and in 55.6% if >40 years. Furthermore, when evaluating the impact of OSA on the cardiovascular system, we observed that patients with OSA tended to have higher systolic blood pressure, larger distal aortic diameters and a higher prevalence of ventricular arrhythmia. These differences were, however, not significant after adjusting for confounders. Conclusions: Our study shows a high prevalence of OSA and a high prevalence of overweight in MFS patients. We found some trends between OSA and cardiovascular features but we could not establish a solid association. Our study, however might be underpowered, and a multicenter collaborative study could be very useful to answer some important open questions

Different patterns of cerebral and muscular tissue oxygenation 10 years after coarctation repair

The purpose of this study was to assess whether the lower exercise tolerance in children after coarctation repair is associated with alterations in peripheral tissue oxygenation during exercise. A total of 16 children after coarctation repair and 20 healthy control subjects performed an incremental ramp exercise test to exhaustion. Cerebral and locomotor muscle oxygenation were measured by means of near infrared spectroscopy. The responses of cerebral and muscle tissue oxygenation index (cTOI, mTOI), oxygenated (O(2)Hb), and deoxygenated hemoglobin (HHb) as a function of work rate were compared. Correlations between residual continuous wave Doppler gradients at rest, arm-leg blood pressure difference and local oxygenation responses were evaluated. Age, length, and weight was similar in both groups. Patients with aortic coarctation had lower peak power output (Ppeak) (72.3 +/- 20.2% vs. 106 +/- 18.7%, P < 0.001), VO(2)peak/kg (37.3 +/- 9.1 vs. 44.2 +/- 7.6 ml/kg, P = 0.019) and %VO(2)peak/kg (85.7 +/- 21.9% vs. 112.1 +/- 15.5%, P < 0.001). Cerebral O(2)Hb and HHb had a lower increase in patients vs. controls during exercise, with significant differences from 60 to 90% Ppeak (O(2)Hb) and 70% to 100% Ppeak (HHb). Muscle TOI was significantly lower in patients from 10 to 70% Ppeak and muscle HHb was significantly higher in patients vs. controls from 20 to 80% Ppeak. Muscle O(2)Hb was not different between both groups. There was a significant correlation between residual resting blood pressure gradient and Delta muscle HHb/Delta P at 10-20W and 20-30W (r = 0.40, P = 0.039 and r = 0.43, P = 0.034). Children after coarctation repair have different oxygenation responses at muscular and cerebral level. This reflects a different balance between O-2 supply to O-2 demand which might contribute to the reduced exercise tolerance in this patient population

A phase I/II trial of fixed-dose stereotactic body radiotherapy with sequential or concurrent pembrolizumab in metastatic urothelial carcinoma : evaluation of safety and clinical and immunologic response

Background: Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates. Methods: The phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon's two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment. Discussion: The progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy

Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA

Contains fulltext : 253059.pdf (Publisher’s version ) (Open Access

The pulmonary autograft after the Ross operation : results of 25 year follow-up in a pediatric cohort

Progressive autograft dilation and need for later reoperation remain major concerns of the Ross procedure. The study investigates the clinical outcome after the Ross operation, including a longitudinal analysis of autograft dimensions over 25 years. From November 1991 to April 2019, 137 patients underwent a Ross procedure at the University Hospitals of UCL (Université catholique de Louvain)-Brussels and Ghent. Inclusion criteria were less than or equal to 18 years of age and pulmonary autograft implantation by root replacement. Outcome focused on survival, reoperation rate, and autograft size evolution through linear mixed-model analysis. A Ross or Ross-Konno operation was performed in 110 (80%) and 27 (20%) patients at a median age of 10.4 (interquartile range [IQR], 4.7-14.3) years and 0.5 (IQR, 0.04-5.2) years, respectively. Overall 10-year and 20-year survival was 87% ± 3% and 85% ± 3%, respectively, but was 93% ± 3% for isolated Ross patients. Right ventricular outflow tract-conduit exchange was required in 20.3%, whereas autograft-related reoperation was performed in 14 (10.7%) patients at a median interval of 14 (IQR, 9-16) years, for aortic regurgitation (n = 2) and autograft dilation (n = 12). Autograft z-values increased significantly at the sinus and sinotubular junction (STJ) compared with the annulus (annulus = 0.05 ± 0.38/y, sinus = 0.14 ± 0.25/y, STJ = 0.17 ± 0.34/y; P = .015). The z-value slope for autograft dimensions was significantly steeper for Ross-Konno vs Ross patients (annulus: P = .029; sinus: P < .001; STJ: P = .012), and for children having aortic arch repair (annulus: P = .113, sinus: P = .038; STJ: P = .029). The Ross operation offers children requiring aortic valve replacement an excellent survival perspective, with an acceptable risk of autograft reoperation within the first 25 years. Contrary to the autograft annulus, dilation of the sinus and STJ size is of concern. Closer surveillance of autograft dimensions might be required in patients who underwent a Ross-Konno procedure or aortic arch reconstruction

A phase II trial of stereotactic body radiotherapy with concurrent anti-PD1 treatment in metastatic melanoma : evaluation of clinical and immunologic response

Background: Antibodies blocking programmed cell death 1 (PD-1) have encouraging responses in patients with metastatic melanoma. Response to anti-PD-1 treatment requires pre-existing CD8+ T cells that are negatively regulated by PD-1-mediated adaptive immune resistance. Unfortunately, less than half of melanoma tumours have these characteristics. Combining anti-PD-1 treatment with other immunomodulating treatments to activate CD8+ T cells is therefore of vital importance to increase response rates and long-term survival benefit in melanoma patients. Both preclinical and retrospective clinical data support the hypothesis that radiotherapy increases the response rates to anti-PD-1 treatment by stimulating the accumulation and activation of CD8+ T cells in the tumour microenvironment. Combining radiotherapy with a PD-1 blocking antibody might therefore increase response rates and even induce long-term survival. The current phase II study will be testing these hypotheses and aims to improve local and distant tumour responses by exploiting the pro-immunogenic effects of radiotherapy in addition to anti-PD-1 treatment. Methods: The trial will be conducted in patients with metastatic melanoma. Nivolumab or pembrolizumab, both antibodies that target PD-1, will be administrated according to the recommended dosing schedule. Prior to the 2nd cycle, radiotherapy will be delivered in three fractions of 8 Gy to the largest FDG-avid metastatic lesion. The primary endpoint is the proportion of patients with a partial or complete response in non-irradiated metastases according to RECIST v1.1. Secondary endpoints include response rate according to immune related response criteria, metabolic response, local control and survival. To identify peripheral blood biomarkers, peripheral blood mononuclear cells and serum samples will be collected prospectively before, during and after treatment and subjected to flow cytometry and cytokine measurement. Discussion: The current phase II trial aims at exploring the suggested benefits of combining anti-PD-1 treatment and radiotherapy. The translational focus on immunologic markers might be suitable for predicting efficacy and monitoring the effect so to improve patient selection for future clinical applications

Analysis of the recovery phase after maximal exercise in children with repaired tetralogy of Fallot and the relationship with ventricular function

Background Few studies demonstrate delayed recovery after exercise in children and adults with heart disease. We assess the recovery patterns of gas exchange parameters and heart rate (HR) in children with repaired Tetralogy of Fallot (rToF) compared to healthy peers and investigate the correlation with ventricular function and QRS duration. Methods 45 children after rToF and 45 controls performed a maximal incremental cardiopulmonary exercise test. In the subsequent recovery period, patterns of VO2, VCO2 and HR were analysed. Half-life time (T-1/2) of the exponential decay and drop per minute (Rec(min)) were compared between groups. In the rToF group, correlations were examined between the recovery parameters and QRS-duration and ventricular function, described by fractional shortening (FS) and tricuspid annular plane systolic excursion (TAPSE) measured at baseline prior to exercise. Results Recovery of VO2 and VCO2 was delayed in rToF patients, half-life time values were higher compared to controls (T1/2VO2 52.51 11.29 s vs. 44.31 +/- 10.47 s; p = 0.001 and T1/2VCO2 68.28 +/- 13.84 s vs. 59.41 +/- 12.06 s; p = 0.002) and percentage drop from maximal value was slower at each minute of recovery (p<0.05). Correlations were found with FS (T1/2VO2: r = -0.517; p<0.001; Rec(1min)VO(2): r = -0.636, p<0.001; Rec(1min)VCO(2): r = -0.373, p = 0.012) and TAPSE (T1/2VO2: r = -0.505; p<0.001; Rec(1min)VO(2): r = -0.566, p<0.001; T1/2VCO2: r = -0.466; p = 0.001; Rec(1min)VCO(2): r = -0.507, p<0.001), not with QRS-duration. No difference was found in HR recovery between patients and controls. Conclusions Children after rToF show a delayed gas exchange recovery after exercise. This delay correlates to ventricular function, demonstrating its importance in recovery after physical activity