Long-term follow-up with MRI scans after enucleation of peripheral nerve schwannomas: results from a single center case series.

BACKGROUND: Enucleation is a surgical technique to resect peripheral nerve schwannomas. The procedure has a low risk for postoperative deficit, but a small chance for recurrence, because tumor cells may remain inside the pseudocapsule that is left after resection. MRI scans are frequently performed after surgery to investigate potential residual tumor, but currently there is little information in the literature on the value of follow-up with MRI. MATERIAL AND METHODS: All patients that underwent enucleation of a peripheral nerve schwannoma between October 2013 and June 2022 were included. Postoperative MRI scans (Gadolinium enhanced) made at different time-points after the surgery were re-examined for residual enhancement. Patients with residual enhancement were contacted to inform whether symptoms had recurred. RESULTS: A total of 75 schwannoma enucleations in 74 patients were included. The first postoperative MRI scan, performed three months after the surgery, showed no residual enhancement in 50 patients. In the remaining 24 patients, another MRI scan was made one year after the surgery, which still showed a possible remnant in 11 patients. On the third MRI scan, performed two years after enucleation, there were seven suspected cases (9%). None of these patients had clinical symptoms at a mean postoperative follow-up of five years. CONCLUSIONS: Our data shows that the value of postoperative MRI scans after enucleation of peripheral nerve schwannomas is limited, because residual enhancement in the beginning can be non-specific and the small percentage of patients, that persistently had a potential remnant, were all asymptomatic.

Incidence and temporal evolution of delayed peridevice leak after left atrial appendage closure.

BACKGROUND: Peridevice leak (PDL) after left atrial appendage closure (LAAC) portends adverse outcomes. OBJECTIVE: The purpose of this study was to assess the incidence, predictors, clinical implications, and temporal evolution of PDL after LAAC. METHODS: This single-center retrospective study included all patients who underwent LAAC with Watchman FLX and had no PDL detected at the time of implantation. The primary end point was the incidence of new PDL at initial imaging. The composite secondary end point included continued oral anticoagulation after initial imaging, device-related thrombus, stroke or transient ischemic attack, major bleeding, and need for PDL closure at longest follow-up. Temporal evolution of PDL was assessed in patients with available surveillance imaging. RESULTS: Of the 355 patients who completed imaging at 47 days (interquartile range [IQR] 6 days), 139 (39%) had new PDL with a mean leak size of 3.2 ± 1.4 mm (median 3.0 mm; IQR 2.0 mm; range 1.0-9.0 mm]. Multiple deployment attempts and larger device size were positive predictors of PDL, while increased contrast volume administration was a negative predictor of PDL. The composite secondary end point occurred in 42 (30%) and 33 (15%) patients with and without PDL, respectively (P < .001). Of the 139 patients with PDL, 43 (31%) had surveillance imaging where the leak size regressed from 3.7 ± 1.8 mm at 46 days (IQR 7 days) to 1.7 ± 2.0 mm at 189 days (IQR 127 days) (P < .001). The leak size regressed in 33 (77%), remained stable in 4 (9%), and progressed in 6 (14%) cases. CONCLUSION: Despite design improvements, LAAC with Watchman FLX demonstrates a significant incidence of PDL with meaningful clinical implications. Regardless of initial size, most leaks regressed over time.

Case reports: Could sexual dysfunction in women with migraine be a side effect of CGRP inhibition?

BACKGROUND: The development and approval of antibodies targeting calcitonin gene-related peptide or its receptor mark a revolutionary era for preventive migraine treatment. Real-world evidence sheds light on rare, stigmatized or overlooked side effects of these drugs. One of these potential side effects is sexual dysfunction. CASE REPORTS: We present two cases of one 42-year-old and one 45-year-old female patient with chronic migraine who both reported sexual dysfunction as a possible side effect of treatment with galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide. DISCUSSION: As calcitonin gene-related peptide is involved in vaginal lubrication as well as genital sensation and swelling, inhibiting the calcitonin gene-related peptide pathway may lead to sexual dysfunction as a potential side effect. CONCLUSION: Sexual dysfunction in female migraine patients might be a rare and overlooked side effect of monoclonal antibodies targeting the calcitonin gene-related peptide pathway. Considering the discomfort and stigma surrounding both migraine and sexual dysfunction, we advocate for an open attitude and awareness among clinicians toward such side effects.

Preclinical characterization of the absorption and disposition of the brain penetrant PI3K/mTOR inhibitor paxalisib and prediction of its pharmacokinetics and efficacy in human.

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults. Available treatments have not markedly improved patient survival in the last twenty years. However, genomic investigations have showed that the PI3K pathway is frequently altered in this glioma, making it a potential therapeutic target.Paxalisib is a brain penetrant PI3K/mTOR inhibitor (mouse Kp,uu 0.31) specifically developed for the treatment of GBM. We characterised the preclinical pharmacokinetics and efficacy of paxalisib and predicted its pharmacokinetics and efficacious dose in humans.Plasma protein binding of paxalisib was low, with the fraction unbound ranging from 0.25 to 0.43 across species. The hepatic clearance of paxalisib was predicted to be low in mice, rats, dogs and humans, and high in monkeys, from hepatocytes incubations. The plasma clearance was low in mice, moderate in rats and high in dogs and monkeys. Oral bioavailability ranged from 6% in monkeys to 76% in rats.The parameters estimated from the pharmacokinetic/pharmacodynamic modelling of the efficacy in the subcutaneous U87 xenograft model combined with the human pharmacokinetics profile predicted by PBPK modelling suggested that a dose of 56 mg may be efficacious in humans. Paxalisib is currently tested in Phase III clinical trials.

EsophAguS Deviation During RadiofrequencY Ablation of Atrial Fibrillation: The EASY AF Trial.

BACKGROUND: Injury to the esophagus has been reported in a high percentage of patients undergoing ablation of atrial fibrillation (AF). OBJECTIVES: This study assessed the incidence of esophageal injury in patients undergoing ablation of AF with and without an esophageal deviating device. METHODS: This prospective, randomized, multicenter, double-blinded, controlled Food and Drug Administration investigational device exemption trial compared the incidence of ablation-related esophageal lesions, as assessed by endoscopy, in patients undergoing AF ablation assigned to a control group (luminal esophageal temperature [LET] monitoring alone) compared with patients randomized to a deviation group (esophagus deviation device + LET). This novel deviating device uses vacuum suction and mechanical deflection to deviate a segment of the esophagus, including the trailing edge. RESULTS: The data safety and monitoring board recommended stopping the study early after randomizing 120 patients due to deviating device efficacy. The primary study endpoint, ablation injury to the esophageal mucosa, was significantly less in the deviation group (5.7%) in comparison to the control group (35.4%; P < 0.0001). Control patients had a significantly higher severity and greater number of ablation lesions per patient. There was no adverse event assigned to the device. By multivariable analysis, the only feature associated with reduced esophageal lesions was randomization to deviating device (OR: 0.13; 95% CI: 0.04-0.46; P = 0.001). Among control subjects, there was no difference in esophageal lesions with high power/short duration (31.8%) vs other radiofrequency techniques (37.2%; P = 0.79). CONCLUSIONS: The use of an esophageal deviating device resulted in a significant reduction in ablation-related esophageal lesions without any adverse events.

Pro-arrhythmic Effect of the Vein of Marshall Ethanol Ablation: A Case Report of Perimitral Flutter After Vein of Marshall Ethanol Ablation.

The ligament of Marshall is an embryological remnant of the left superior vena cava that contains neural tissues shown to be an arrhythmogenic source of atrial fibrillation (AF). Vein of Marshall (VOM) ethanol ablation is an ablation technique that can potentially treat AF by targeting the ligament of Marshall. We report a case of a patient who developed a pro-arrhythmic effect related to VOM ethanol ablation, which manifested as a perimitral flutter.

Direct current cardioversion practices following percutaneous left atrial appendage closure.

INTRODUCTION: Among patients with non-valvular atrial fibrillation (AF) and percutaneous left atrial appendage closure (LAAC) undergoing direct current cardioversion (DCCV), the need for and use of LAA imaging and oral anticoagulation (OAC) is unclear. OBJECTIVE: The purpose of this study is to evaluate the real-world use of transesophageal echocardiography (TEE) or cardiac computed tomography angiography (CCTA) before DCCV and use of OAC pre- and post-DCCV in patients with AF status post percutaneous LAAC. METHODS: This retrospective single center study included all patients who underwent DCCV after percutaneous LAAC from 2016 to 2022. Key measures were completion of TEE or CCTA pre-DCCV, OAC use pre- and post-DCCV, incidence of left atrial thrombus (LAT) or device-related thrombus (DRT), incidence of peri-device leak (PDL), and DCCV-related complications (stroke, systemic embolism, device embolization, major bleeding, or death) within 30 days. RESULTS: A total of 76 patients with AF and LAAC underwent 122 cases of DCCV. LAAC consisted of 47 (62%), 28 (37%), and 1 (1%) case of Watchman 2.5, Watchman FLX, and Lariat, respectively. Among the 122 DCCV cases, 31 (25%) cases were identified as "non-guideline based" due to: (1) no OAC for 3 weeks and no LAA imaging within 48 h before DCCV in 12 (10%) cases, (2) no OAC for 4 weeks following DCCV in 16 (13%) cases, or (3) both in 3 (2%) cases. Among the 70 (57%) cases that underwent TEE or CCTA before DCCV, 16 (23%) cases had a PDL with a mean size of 3.0 ± 1.1 mm, and 4 (6%) cases had a LAT/DRT on TEE resulting in cancellation. There were no DCCV-related complications within 30 days. DISCUSSION: There is a widely varied practice pattern of TEE, CCTA, and OAC use with DCCV after LAAC, with a 6% rate of LAT/DRT. LAA imaging before DCCV appears prudent in all cases, especially within 1 year of LAAC, to assess for device position, PDL, and LAT/DRT.

Migraine and cardiovascular disease: what cardiologists should know.

Migraine is a chronic neurovascular disease with a complex, not fully understood pathophysiology with multiple causes. People with migraine suffer from recurrent moderate to severe headache attacks varying from 4 to 72 h. The prevalence of migraine is two to three times higher in women compared with men. Importantly, it is the most disabling disease in women <50 years of age due to a high number of years lived with disability, resulting in a very high global socioeconomic burden. Robust evidence exists on the association between migraine with aura and increased incidence of cardiovascular disease (CVD), in particular ischaemic stroke. People with migraine with aura have an increased risk of atrial fibrillation, myocardial infarction, and cardiovascular death compared with those without migraine. Ongoing studies investigate the relation between migraine and angina with non-obstructive coronary arteries and migraine patients with patent foramen ovale. Medication for the treatment of migraine can be preventative medication, such as beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antiepileptics, antidepressants, some of the long-acting calcitonin gene-related peptide receptor antagonists, or monoclonal antibodies against calcitonin gene-related peptide or its receptor, or acute medication, such as triptans and calcitonin gene-related peptide receptor antagonists. However, these medications might raise concerns when migraine patients also have CVD due to possible (coronary) side effects. Specifically, knowledge gaps remain for the contraindication to newer treatments for migraine. All cardiologists will encounter patients with CVD and migraine. This state-of-the-art review will outline the basic pathophysiology of migraine and the associations between migraine and CVD, discuss current therapies, and propose future directions for research.

Cardiac magnetic resonance imaging for left atrial appendage closure planning.

BACKGROUND: Transesophageal echocardiography (TEE) and cardiac computed tomography angiography (CCTA) are currently utilized for left atrial appendage closure (LAAC) planning. During the recent global iodine contrast media shortage in 2022, cardiac magnetic resonance imaging (CMR) was utilized for the first time for LAAC planning. This study sought to assess the utility of CMR versus TEE for LAAC planning. METHODS: This single center retrospective study consisted of all patients who underwent preoperative CMR for LAAC with Watchman FLX or Amplatzer Amulet. Key measures were accuracy of LAA thrombus exclusion, ostial diameter, depth, lobe count, morphology, accuracy of predicted device size, and devices deployed per case. Bland-Altman Analysis was used to compare CMR versus TEE measurements of LAA ostial diameter and depth. RESULTS: 25 patients underwent preoperative CMR for LAAC planning. A total of 24 (96%) cases were successfully completed with 1.2 ± 0.5 devices deployed per case. Among the 18 patients who underwent intraoperative TEE, there was no significant difference between CMR versus TEE in LAA thrombus exclusion (CMR 83% vs. TEE 100% cases, p = .229), lobe count (CMR 1.7 ± 0.8 vs. TEE 1.4 ± 0.6, p = .177), morphology (p = .422), and accuracy of predicted device size (CMR 67% vs. TEE 72% cases, p = 1.000). When comparing the difference between CMR and TEE measurements, Bland-Altman analysis demonstrated no significant difference in LAA ostial diameter (CMR-TEE bias 0.7 mm, 95% CI [-1.1, 2.4], p = .420), but LAA depth was significantly larger with CMR versus TEE (CMR-TEE bias 7.4 mm, 95% CI [1.6, 13.2], p = .015). CONCLUSIONS: CMR is a promising alternative for LAAC planning in cases where TEE or CCTA are contraindicated or unavailable.

Long-term Survival in Breast Cancer Patients Is Associated with Contralateral Parenchymal Enhancement at MRI: Outcomes of the SELECT Study.

Background Several single-center studies found that high contralateral parenchymal enhancement (CPE) at breast MRI was associated with improved long-term survival in patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Due to varying sample sizes, population characteristics, and follow-up times, consensus of the association is currently lacking. Purpose To confirm whether CPE is associated with long-term survival in a large multicenter retrospective cohort, and to investigate if CPE is associated with endocrine therapy effectiveness. Materials and Methods This multicenter observational cohort included women with unilateral ER-positive HER2-negative breast cancer (tumor size ≤50 mm and ≤three positive lymph nodes) who underwent MRI from January 2005 to December 2010. Overall survival (OS), recurrence-free survival (RFS), and distant RFS (DRFS) were assessed. Kaplan-Meier analysis was performed to investigate differences in absolute risk after 10 years, stratified according to CPE tertile. Multivariable Cox proportional hazards regression analysis was performed to investigate whether CPE was associated with prognosis and endocrine therapy effectiveness. Results Overall, 1432 women (median age, 54 years [IQR, 47-63 years]) were included from 10 centers. Differences in absolute OS after 10 years were stratified according to CPE tertile as follows: 88.5% (95% CI: 88.1, 89.1) in tertile 1, 85.8% (95% CI: 85.2, 86.3) in tertile 2, and 85.9% (95% CI: 85.4, 86.4) in tertile 3. CPE was independently associated with OS, with a hazard ratio (HR) of 1.17 (95% CI: 1.0, 1.36; P = .047), but was not associated with RFS (HR, 1.11; P = .16) or DRFS (HR, 1.11; P = .19). The effect of endocrine therapy on survival could not be accurately assessed; therefore, the association between endocrine therapy efficacy and CPE could not reliably be estimated. Conclusion High contralateral parenchymal enhancement was associated with a marginally decreased overall survival in patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer, but was not associated with recurrence-free survival (RFS) or distant RFS. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Honda and Iima in this issue.

Translation and natural selection of micropeptides from long non-canonical RNAs.

Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but lacking canonical coding sequences. Apparently unable to produce peptides, lncRNA function seems to rely only on RNA expression, sequence and structure. Here, we exhaustively detect in-vivo translation of small open reading frames (small ORFs) within lncRNAs using Ribosomal profiling during Drosophila melanogaster embryogenesis. We show that around 30% of lncRNAs contain small ORFs engaged by ribosomes, leading to regulated translation of 100 to 300 micropeptides. We identify lncRNA features that favour translation, such as cistronicity, Kozak sequences, and conservation. For the latter, we develop a bioinformatics pipeline to detect small ORF homologues, and reveal evidence of natural selection favouring the conservation of micropeptide sequence and function across evolution. Our results expand the repertoire of lncRNA biochemical functions, and suggest that lncRNAs give rise to novel coding genes throughout evolution. Since most lncRNAs contain small ORFs with as yet unknown translation potential, we propose to rename them "long non-canonical RNAs".

Feasibility of Assessing Cryoballoon Pulmonary Vein Occlusion With Saline Injection and a Novel Mapping System.

Thirty-eight patients had assessment of pulmonary vein occlusion with the dielectric mapping system and injection of saline as an alternative to contrast. Contrast injection was required to ascertain pulmonary vein occlusion in 31.6% (12 of 38) of subjects and 17.4% (27 of 155) of veins. No contrast was required in the last 13 subjects. In this single center study, a novel mapping-guided cryoablation approach appeared to minimize the use of contrast in pulmonary vein isolation for the treatment of atrial fibrillation.

Factors associated with enrolment in clinical trials among women with early-stage breast cancer.

BACKGROUND: Clinical trials allow development of innovative treatments and ameliorate the quality of clinical care in oncology. Data show that only a minority of patients are enrolled in clinical trials. We assessed enrolment in clinical trials and its correlates among women with early breast cancer. METHODS: We included 9516 patients with stage I-III breast cancer from the multicenter, prospective CANTO study (NCT01993498), followed-up until year 4 (Y4) post-diagnosis. We assessed factors associated with enrolment using multivariable logistic regression. In exploratory, propensity score matched analyses, we used multiple linear regression to evaluate the relationship of enrolment in clinical trials with the European Organisation for Research and Treatment of Cancer Quality Of Life (QoL) questionnaire (EORTC QLQ-C30) Summary Score and described clinical outcomes (distant disease event, invasive disease event, and death by any cause) according to enrolment. RESULTS: Overall, 1716 patients (18%) were enrolled in a clinical trial until Y4 post-diagnosis of breast cancer. Socioeconomic factors were not associated with enrolment. Centres of intermediate volume were most likely to enrol patients in clinical trials [versus low volume, odds ratio 1.45 (95% confidence interval (CI) 1.08-1.95), P = 0.0124]. Among 2118 propensity score matched patients, enrolment was associated with better QoL at Y4 (adjusted mean difference versus not enrolled 1.37, 95% CI 0.03-2.71, P = 0.0458), and clinical outcomes (enrolled versus not enrolled, distant disease event 7.3% versus 10.1%, P = 0.0206; invasive disease event 8.2% versus 10.5%, P = 0.0732; death by any cause 2.8% versus 3.7%, P = 0.2707). CONCLUSIONS: In this large study, one in five patients enrolled on a clinical trial until Y4 after diagnosis of early breast cancer. Geographical and centre-related factors were significantly associated with enrolment in clinical trials. Inclusion in clinical trials seemed associated with improved QoL and clinical outcomes. Access to innovation for early-stage breast cancer patients should be encouraged and facilitated by overcoming organizational and geographical barriers to recruitment.

Accelerated Partial Breast Irradiation Using External Beam or Intraoperative Electron Radiation Therapy: 5-Year Oncological Outcomes of a Prospective Cohort Study.

PURPOSE: To evaluate the ipsilateral breast tumor recurrence (IBTR) after 2 accelerated partial breast irradiation (APBI) techniques (intraoperative electron radiation therapy [IOERT] and external beam APBI [EB-APBI]) in patients with early-stage breast cancer. METHODS AND MATERIALS: Between 2011 and 2016, women ≥60 years of age with breast carcinoma or Ductal Carcinoma In Situ (DCIS) of ≤30 mm and cN0 undergoing breast-conserving therapy were included in a 2-armed prospective multicenter cohort study. IOERT (1 × 23.3 Gy prescribed at the 100% isodose line) was applied in 1 hospital and EB-APBI (10 × 3.85 Gy daily) in 2 other hospitals. The primary endpoint was IBTR (all recurrences in the ipsilateral breast irrespective of localization) at 5 years after lumpectomy. A competing risk model was used to estimate the cumulative incidences of IBTR, which were compared using Fine and Gray's test. Secondary endpoints were locoregional recurrence rate, distant recurrence, disease-specific survival and overall survival. Univariate Cox regression models were estimated to identify risk factors for IBTR. Analyses were performed of the intention to treat (ITT) population (IOERT n = 305; EB-APBI n = 295), and sensitivity analyses were done of the per-protocol population (IOERT n = 270; EB-APBI n = 207). RESULTS: The median follow-up was 5.2 years (IOERT) and 5 years (EB-APBI). Cumulative incidence of IBTR in the ITT population at 5 years after lumpectomy was 10.6% (95% confidence interval, 7.0%-14.2%) after IOERT and 3.7% (95% confidence interval, 1.2%-5.9%) after EB-APBI (P = .002). The locoregional recurrence rate was significantly higher after IOERT than EB-APBI (12.1% vs 4.5%, P = .001). There were no differences between groups in other endpoints. Sensitivity analysis showed similar results. For both groups, no significant risk factors for IBTR were identified in the ITT population. In the per-protocol population, surgical margin status of the DCIS was the only significant risk factor for developing IBTR in both treatment groups. CONCLUSIONS: Ipsilateral breast tumor recurrences and locoregional recurrence rates were unexpectedly high in patients treated with IOERT, and acceptable in patients treated with EB-APBI.

Sleep macro- and microstructure in breast cancer survivors.

Complaints of sleep disturbance are prevalent among breast cancer (BC) patients and are predictors of quality of life. Still, electrophysiological measures of sleep are missing in patients, which prevents from understanding the pathophysiological consequences of cancer and its past treatments. Using polysomnography, sleep can be investigated in terms of macro- (e.g. awakenings, sleep stages) and micro- (i.e. cortical activity) structure. We aimed to characterize sleep complaints, and macro- and microstructure in 33 BC survivors untreated by chemotherapy and that had finished radiotherapy since at least 6 months (i.e. out of the acute effects of radiotherapy) compared to 21 healthy controls (HC). Compared to HC, BC patients had a larger number of awakenings (p = 0.008); and lower Delta power (p < 0.001), related to sleep deepening and homeostasis; greater both Alpha (p = 0.002) and Beta power (p < 0.001), related to arousal during deep sleep; and lower Theta power (p = 0.004), related to emotion regulation during dream sleep. Here we show that patients have increased cortical activity related to arousal and lower activity related to sleep homeostasis compared to controls. These results give additional insights in sleep pathophysiology of BC survivors and suggest sleep homeostasis disruption in non-advanced stages of BC.