The role of induction chemotherapy for orbital invasion in sinonasal malignancies: A systematic review.

BACKGROUND: Sinonasal malignancies (SNMs) frequently present with orbital invasion. Orbital exenteration (OE) can lead to significant morbidity. Induction chemotherapy (IC) is a promising treatment alternative that may allow for orbit preserving (OP) treatments without compromising patient survival. This systematic review was conducted to synthesize the published data on SNM patients with orbital invasion who underwent IC, including tumor response, orbital outcomes, and survival. METHODS: The study protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Databases Embase, Cochrane, Medline, and Scopus, from inception to July 17, 2023, were searched. RESULTS: Nineteen studies were included, encompassing 305 SNM patients with orbital invasion treated with IC. Fourteen studies reported an overall IC response rate (positive response defined as complete or partial tumor volume reduction) of 77.2%. Among included studies, OE rates after IC ranged from 0 to 40%. Three studies reported a high rate of posttreatment functional orbital preservation (89.8-96.0%). Five studies specifically reported that 62.5% (60 out of 96) of patients were downgraded from planned OE to OP treatment following IC. Three studies reported a significant overall survival (OS) improvement in IC responders versus IC nonresponders. Following IC, 5-year OS ranged from 44.2 to 55.5%. Patients with olfactory neuroblastoma demonstrated the highest IC response rate and lowest OE rate (100 and 0%, respectively) versus those with sinonasal undifferentiated carcinomas (68.4 and 0%) or squamous cell carcinomas (76.7 and 16%). CONCLUSIONS: For select patients, IC may allow for OP in locally advanced SNMs with orbital involvement.

Quality of Life Outcomes for Parotid Malignancies.

BACKGROUND: This study describes patient-reported outcome measures (PROMs) and associated factors in patients who underwent surgery for malignant parotid tumors (MPT). METHODS: This is a retrospective study of all surgically treated MPT patients in a multidisciplinary head and neck cancer (HNC) survivorship clinic (2017-2023). PROMs included University of Washington Quality of Life Questionnaire (UW-QOL), Eating Assessment Tool (EAT-10), Patient Health Questionnaire (PHQ-8), Generalized Anxiety Disorder (GAD-7), Neck Disability Index (NDI), and Insomnia Severity Index. Multivariable regression analysis was used to investigate clinical predictors associated with PROMs. RESULTS: In 62 MPT patients, the prevalence of clinically relevant dysphagia symptoms (EAT-10), elevated symptoms of depression (PHQ-8), moderate/severe symptoms of anxiety (GAD-7), moderate/severe neck pain with activities of daily living (NDI), and moderate/severe symptoms of insomnia at last follow-up was 32.3%, 15.5%, 7.1%, 17.7%, and 7.2%, respectively. Nonparametric one-sided test revealed that patients treated with adjuvant CRT had significantly worse physical QOL, social-emotional QOL, and swallowing scores than patients treated with surgery alone (p = 0.01, p = 0.02, p = 0.03, respectively); that patients treated with surgery and adjuvant RT had significantly worse physical QOL and social-emotional QOL than patients treated with surgery alone (p < 0.01, p = 0.01, respectively) and that patients treated with surgery and adjuvant CRT had significantly worse swallowing and neck pain than patients treated with surgery and adjuvant RT (p = 0.03, p = 0.05, respectively). CONCLUSIONS: In patients with surgically treated MPT, adjuvant CRT and RT were associated with worse PROMs. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Immunotherapy in the Management of Sinonasal Mucosal Melanoma: A Systematic Review.

OBJECTIVE: The aim of this work is to comprehensively review and synthesize the literature related to sinonasal mucosal melanoma (SNMM) treatment with immunotherapy, including potentially targetable genetic mutations, survival outcomes, and adverse events. DATA SOURCES: Embase, Cochrane, Scopus, and Web of Science. REVIEW METHODS: The study protocol was designed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Databases were searched from inception through May 23, 2023. RESULTS: A total of 42 studies met inclusion criteria. Twenty-four of the included studies reported genetic mutations for a combined 787 patients with SNMM. 8.1% (95% confidence interval, CI: 7.6-8.6), 18.9% (95% CI: 18.1-19.8), and 8.5% (95% CI: 8.1-9.0) of reported patients were positive for BRAF, NRAS, and KIT mutations, respectively. The presence of brisk tumor-infiltrating lymphocytes was associated with improved recurrence-free survival and overall survival (OS). Six studies reported a combined 5-year OS after adjuvant immunotherapy treatment of 42.6% (95% CI: 39.4-45.8). Thirteen studies encompassing 117 patients reported adjuvant or salvage immune checkpoint inhibitor (ICI) immunotherapy response rates: 40.2% (95% CI: 36.8-43.6) had a positive response (tumor volume reduction or resolution). Eleven studies reported direct comparisons between SNMM patients treated with or without immunotherapy; the majority (7/11) reported survival benefit for their entire cohort or select subgroups of SNMM patients. With the transition to modern ICIs, there is a stronger trend toward survival improvement with adjuvant ICI. Tumors with Ki67 <40% may respond better to ICI's. CONCLUSION: ICI therapy can be an effective in select SNMM patients, especially those with advanced/metastatic disease.

Stereotactic Radiosurgery for Patients with Spinal Metastases from Thyroid Cancer: A 20-Year Experience.

OBJECTIVE: Primary thyroid cancer metastasizing to the spine portends poor survival and low quality of life. Current management strategies continue to evolve. This single-institution retrospective study analyzes outcomes after spinal stereotactic radiosurgery for patients with spinal metastases from thyroid cancer. METHODS: Nineteen patients (median age: 64.5 years) were treated with stereotactic radiosurgery (SRS) for spinal primary thyroid metastases (40 metastases, 47 vertebral levels) between 2003 and 2023. Nineteen (47.5%) lesions had epidural involvement and 20 (50%) lesions were classified as potentially unstable or unstable via the Spinal Instability Neoplastic Score. The median tumor volume per lesion was 33 cc (range: 1.5-153). The median single fraction prescription dose was 20 Gy (range: 12-23.5). RESULTS: The median follow-up period was 15 months (range: 2-40). Five (12.8%) lesions locally progressed at a median of 9 months (range: 4-26) after SRS. The 1-, 2-, and 3-year local tumor control rates per lesion were 90.4%, 83.5%, and 75.9%, respectively. On univariate analysis, age at SRS >70 years (P = 0.05, hazard ratio: 6.86, 95% confidence interval: 1.01-46.7) was significantly correlated with lower rates of local tumor control. The median overall survival was 35 months (range: 2-141). The 1-, 2-, and 3-year overall survival rates were 73.7%, 50.4%, and 43.2%, respectively. For 33 lesions initially associated with pain, patients reported pain improvement (22 lesions, 66.7%), stability (10 lesions, 30.3%), and worsening (1 lesion, 3.0%) after SRS. One patient developed dysphagia 4 months after SRS treatment. CONCLUSIONS: SRS can be utilized as an effective and safe primary and adjuvant treatment option for primary thyroid metastases to the spine.

The role of spine stereotactic radiosurgery for patients with breast cancer metastases.

PURPOSE: Breast cancer that metastasizes to the spine is associated with low quality of life and poor survival. Radiosurgery has an increasing role in this patient population. This single-institution (2003-2023) study analyzes clinical outcomes and prognostic factors for patients who underwent spinal stereotactic radiosurgery (SSRS) for metastatic breast cancer. METHODS: Ninety patients (155 unique breast cancer spinal metastases) were treated with SSRS. The median age was 57 years (range: 35-88), and the median KPS was 80 (range: 40-100). Forty-two (27%) lesions were managed surgically prior to radiosurgery. At SSRS, 75 (48%) lesions impinged or compressed the spinal cord per the epidural spinal cord scale (ESCC). Seventy-nine (51%) lesions were categorized as potentially unstable or unstable by the Spinal Instability Neoplastic Score (SINS). RESULTS: The median follow-up was 15 months (range: 1-183). The median single-session tumor volume was 25.4 cc (range: 2-197), and the median single-fraction prescription dose was 17 Gy (range: 12-25). Seven (5%) lesions locally progressed. The 1-, 2-, and 5-year local control rates were 98%, 97%, and 92%, respectively. The median overall survival (OS) for the cohort was 32 months (range: 2-183). The 1-, 2-, and 5-year OS rates were 72%, 53%, and 30%, respectively. On univariate analysis, KPS ≥ 80 (p = 0.009, HR: 0.51, 95% CI: 0.31-0.84) was associated with improved OS. Patient-reported pain improved (68%), remained stable (29%), or worsened (3%) following radiosurgery. Fifteen (10%) radiation-induced toxicities were reported. CONCLUSIONS: Spinal radiosurgery is a safe and highly effective long-term treatment modality for metastases to the spine that originate from breast cancer.

Prediction of 30-day and 1-year postoperative complications after balloon-assisted kyphoplasty in the elderly using the Risk Analysis Index.

OBJECTIVE: Vertebral compression fracture (VCF) is the most prevalent fragility fracture. When conservative management fails, patients may undergo balloon-assisted kyphoplasty (BAK). In BAK, an expandable balloon preforms a cavity in the fractured vertebra before injection of bone cement. The aim of this study was to compare outcomes in patients stratified by age and frailty assessed by the Risk Analysis Index (RAI). METHODS: A retrospective analysis of 334 BAK procedures (280 patients) for osteoporotic VCFs at a single institution was performed (2015-2022). Patients with at least 1 year of follow-up were eligible for inclusion. Patient demographics were recorded, including age, sex, BMI, RAI score, tobacco and steroid use, osteoporosis treatments, and bone density. Patients who underwent outpatient surgery were identified, and length of stay (LOS) was obtained for admitted patients. The rates of additional VCFs after kyphoplasty, 30-day and 1-year postoperative complications, and reoperation were identified. RESULTS: The overall rates of additional VCFs, 30-day postoperative complications, 1-year postoperative complications, and reoperation were 16.2%, 5.1%, 12.0%, and 6.3%, respectively. Patients were stratified by age: nonelderly (< 80 years; 220 patients, 263 treated vertebrae) and elderly (≥ 80 years; 60 patients, 71 treated vertebrae). There were no differences in sex (p = 0.593), tobacco use (p = 0.973), chronic steroid use (p = 0.794), treatment for osteoporosis (p = 0.537), bone density (p = 0.056), outpatient procedure (p = 0.273), and inpatient LOS (p = 0.661) between both groups. There were also no differences in the development of additional VCFs (p = 0.862) at an adjacent level (p = 0.739) or remote level (p = 0.814), 30-day and 1-year postoperative complications (p = 0.794 and p = 0.560, respectively), and reoperation rates (p = 0.420). Patients were then analyzed by RAI: nonfrail (RAI score < 30; 203 patients, 243 treated vertebrae) and frail (RAI score ≥ 31; 77 patients, 91 treated vertebrae). There were no differences in tobacco use (p = 0.959), chronic steroid use (p = 0.658), treatment for osteoporosis (p = 0.560), bone density (p = 0.339), outpatient procedure (p = 0.241), inpatient LOS (p = 0.570), and development of additional VCFs (p = 0.773) at an adjacent level (p = 0.390) or remote level (p = 0.689). However, rates of 30-day and 1-year postoperative complications in frail patients more than doubled in comparison with nonfrail patients (p = 0.031 and p = 0.007, respectively), and frail patients trended toward reoperation (p = 0.097). CONCLUSIONS: BAK is a safe treatment in the elderly, and age alone should not be used as an exclusion criterion during patient selection. Frailty, which can be assessed reliably using the RAI, may serve as a better predictor for postoperative complications and reoperation following BAK.

Efficacy and safety of supraclavicular and pectoralis nerve blocks as primary peri-procedural analgesia for cardiac electronic device implantation: A pilot study.

BACKGROUND: Cardiac implantable electronic devices (CIEDs) are routinely implanted using intravenous drugs for sedation. However, some patients are poor candidates for intravenous sedation. OBJECTIVE: We present a case series demonstrating the safety and efficacy of a novel, ultrasound-guided nerve block technique that allows for pre-pectoral CIED implantation. The targets are the supraclavicular nerve (SCN) and pectoral nerve (PECS1). METHODS: We enrolled 20 patients who were planned for new CIED implantation. Following US-localization of the SCN and PECS1, local anesthetic (LA) was instilled at least 30-60 min pre-procedure. Successful nerve block was determined if < 5 mL of intraprocedural LA was used, along with lack of sensation with skin and deep tissue pinprick. Optional sedation was offered to patients' pre-procedure if discomfort was reported. RESULTS: Seventeen patients (85%) had a successful periprocedural nerve block, with only three patients exceeding 5 mL of LA. SCN and PECS1 success occurred in 19 (95%) and 18 (90%) patients, respectively. The overall success of nerve block by fulfilling all the criteria was demonstrated in 17 out of 20 patients (85%). Patients who reported no pain (VAS score = 0) were distributed as follows: 13 patients (65%) in the immediate post-procedure interval, 18 patients (90%) at the 1 h post-implant interval, and 14 patients (70%) at the 24 h post- implant interval. The median cumulative VAS score was 0 (IQR = 0 - 1). There were no reported significant adverse effects. CONCLUSION: SCN and PECS1 nerve blocks are safe and effective for patients undergoing CIED implantation to minimize or eliminate the use of intravenous sedation.

Systematic review and meta-analysis of topical tranexamic acid in spine surgery.

OBJECTIVE: Tranexamic acid (TXA) is an antifibrinolytic drug associated with reduced blood loss in a range of surgical specialties, including neurosurgery, orthopedic surgery, and cardiac surgery. Concerns about venous thromboembolism and seizures from intravenous (IV) TXA have led to increased use of topical TXA. Given the relative scarcity of the literature on topical TXA compared with that on IV TXA within neurosurgery, the authors aimed to conduct a systematic review and meta-analysis on the safety, efficacy, and optimal administration of topical TXA in a wide range of spinal procedures and pathologies. METHODS: The PRISMA guidelines, Cochrane risk of bias tool, and Newcastle-Ottawa Scale were used to extract randomized controlled trials and high-quality case-control and cross-sectional/cohort studies (adult studies only) from PubMed, Web of Science, Cochrane Library, and Embase published between 2016 and 2023. Studies were analyzed by two independent reviewers for variables including dosage, TXA administration route, type of spine procedure, blood loss, adverse events including thromboembolism and infection, postoperative hemoglobin level, and hospitalization length. Pooled analysis comparing intraoperative and postoperative blood loss, postoperative hemoglobin levels, and hospitalization length of stay on the basis of route of TXA administration was conducted. RESULTS: Four cohort studies, 1 cross-sectional study, 1 case-control study, and 12 randomized controlled trials, together involving 2045 patients, were included. The most common route of topical TXA administration was via TXA in saline solution. Other routes of topical TXA included retrograde injection and TXA-soaked Gelfoam. In pooled analysis, topical TXA significantly reduced visible blood loss (standardized mean difference [SMD] -0.22, 95% CI -0.45 to -0.00001), postoperative blood loss (SMD -1.63, 95% CI -2.03 to -1.22), and length of hospital stay (SMD -1.02, 95% CI -1.42 to -0.61), as well as higher postoperative hemoglobin (SMD 0.59, 95% CI 0.34-0.83), compared with non-TXA controls. No significant differences in outcomes were found between topical and IV TXA or between combined (topical and IV) and IV TXA. Thromboembolism and infection rates did not significantly differ between any TXA administration group and non-TXA controls. CONCLUSIONS: In pooled analyses, topical TXA was associated with decreased perioperative blood loss in a wide range of scenarios, including cervical spine surgery and thoracolumbar trauma, as well as in patients with a thromboembolic history.

Monitoring risk and preventing ischemic stroke in the very old.

INTRODUCTION: Stroke is a significant cause of death, and the leading cause of severe long-term disability for individuals over 80 (the very old), yet few studies of such risk factors for ischemic stroke, or the known mitigation techniques, in this population, and the evidence base regarding risk modification strategies in this susceptible population can be inconsistent and incomplete. This article examines current guidelines and evidence regarding medical management, lifestyle changes, and psychosocial interactions that can contribute to the primary and secondary prevention of ischemic stroke in the very old. AREAS COVERED: The authors conducted a literature search for ischemic stroke prevention and risk assessment in the elderly via PubMed. Furthermore, they describe current strategies for monitoring risk and preventing ischemic stroke in the elderly population. EXPERT OPINION: Ischemic stroke poses a significant health risk to the elderly, with prevention relying on managing modifiable risk factors such as hypertension, atrial fibrillation, diabetes, and high cholesterol, as well as promoting healthy lifestyle choices like quitting smoking, regular physical activity and a heart-healthy diet. Healthcare providers must adopt a multifaceted approach, addressing individual and population-level factors while remaining vigilant in monitoring and managing risk factors to reduce the incidence and impact of stroke in older adults.

Which supervised machine learning algorithm can best predict achievement of minimum clinically important difference in neck pain after surgery in patients with cervical myelopathy? A QOD study.

OBJECTIVE: The purpose of this study was to evaluate the performance of different supervised machine learning algorithms to predict achievement of minimum clinically important difference (MCID) in neck pain after surgery in patients with cervical spondylotic myelopathy (CSM). METHODS: This was a retrospective analysis of the prospective Quality Outcomes Database CSM cohort. The data set was divided into an 80% training and a 20% test set. Various supervised learning algorithms (including logistic regression, support vector machine, decision tree, random forest, extra trees, gaussian naïve Bayes, k-nearest neighbors, multilayer perceptron, and extreme gradient boosted trees) were evaluated on their performance to predict achievement of MCID in neck pain at 3 and 24 months after surgery, given a set of predicting baseline features. Model performance was assessed with accuracy, F1 score, area under the receiver operating characteristic curve, precision, recall/sensitivity, and specificity. RESULTS: In total, 535 patients (46.9%) achieved MCID for neck pain at 3 months and 569 patients (49.9%) achieved it at 24 months. In each follow-up cohort, 501 patients (93.6%) were satisfied at 3 months after surgery and 569 patients (100%) were satisfied at 24 months after surgery. Of the supervised machine learning algorithms tested, logistic regression demonstrated the best accuracy (3 months: 0.76 ± 0.031, 24 months: 0.773 ± 0.044), followed by F1 score (3 months: 0.759 ± 0.019, 24 months: 0.777 ± 0.039) and area under the receiver operating characteristic curve (3 months: 0.762 ± 0.027, 24 months: 0.773 ± 0.043) at predicting achievement of MCID for neck pain at both follow-up time points, with fair performance. The best precision was also demonstrated by logistic regression at 3 (0.724 ± 0.058) and 24 (0.780 ± 0.097) months. The best recall/sensitivity was demonstrated by multilayer perceptron at 3 months (0.841 ± 0.094) and by extra trees at 24 months (0.817 ± 0.115). Highest specificity was shown by support vector machine at 3 months (0.952 ± 0.013) and by logistic regression at 24 months (0.747 ± 0.18). CONCLUSIONS: Appropriate selection of models for studies should be based on the strengths of each model and the aims of the studies. For maximally predicting true achievement of MCID in neck pain, of all the predictions in this balanced data set the appropriate metric for the authors' study was precision. For both short- and long-term follow-ups, logistic regression demonstrated the highest precision of all models tested. Logistic regression performed consistently the best of all models tested and remains a powerful model for clinical classification tasks.

Safety and Accuracy of Freehand Pedicle Screw Placement and the Role of Intraoperative O-Arm: A Single-Institution Experience.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The aim was to investigate the accuracy of pedicle screw placement by freehand technique and to compare revision surgery rates among three different imaging verification pathways. SUMMARY OF BACKGROUND DATA: Studies comparing different imaging modalities in freehand screw placement surgery are limited. MATERIALS AND METHODS: A single-institution retrospective chart review identified adult patients who underwent freehand pedicle screw placement in the thoracic, lumbar or sacral levels. Patients were stratified into three cohorts based on the intraoperative imaging modality used to assess the accuracy of screw position: intraoperative X-rays (cohort 1); intraoperative O-arm (cohort 2); or intraoperative computed tomography (CT)-scan (cohort 3). Postoperative CT scans were performed on all patients in cohorts 1 and 2. Postoperative CT scan was not required in cohort 3. Screw accuracy was assessed using the Gertzbein-Robbins grading system. RESULTS: A total of 9179 pedicle screws were placed in the thoracic or lumbosacral spine in 1311 patients. 210 (2.3%) screws were identified as Gertzbein-Robbins grades C-E on intraoperative/postoperative CT scan, 137 thoracic screws, and 73 lumbar screws ( P <0.001). Four hundred and nine patients underwent placement of 2754 screws followed by intraoperative X-ray (cohort 1); 793 patients underwent placement of 5587 screws followed by intraoperative O-arm (cohort 2); and 109 patients underwent placement of 838 screws followed by intraoperative CT scan (cohort 3). Postoperative CT scans identified 65 (2.4%) and 127 (2.3%) malpositioned screws in cohorts 1 and 2, respectively. Eleven screws (0.12%) were significantly malpositioned and required a second operation for screw revision. Nine patients (0.69%) required revision operations: eight of these patients were from cohort 1 and one patient was from cohort 2. CONCLUSION: When compared to intraoperative X-ray, intraoperative O-arm verification decreased the revision surgery rate for malpositioned screws from 0.37% to 0.02%. In addition, our analysis suggests that the use of intraoperative O-arm can obviate the need for postoperative CT scans.

Randomized trial of conventional versus radiofrequency needle transseptal puncture for cryoballoon ablation: the CRYO-LATS trial.

BACKGROUND: Transseptal puncture to achieve left atrial access is necessary for many cardiac procedures, including atrial fibrillation ablation. More recently, there has been an increasing need for left atrial access using large caliber sheaths, which increases risk of perforation associated with the initial advancement into the left atrium. We compared the effectiveness of a radiofrequency needle-based transseptal system versus conventional needle for transseptal access. METHODS: This prospective controlled trial randomized 161 patients with symptomatic paroxysmal atrial fibrillation undergoing cryoballoon pulmonary vein isolation to transseptal access with a commercially available transseptal system (radiofrequency needle plus stiff pigtail wire; RF + Pigtail group) versus conventional transseptal access (standard group). The primary outcome was time required for left atrial access. Secondary outcomes included failure of the assigned transseptal system, radiation exposure, and complications. RESULTS: The median transseptal puncture time was significantly shorter using the radiofrequency needle plus stiff pigtail wire transseptal system compared with conventional transseptal (840 ± 323 vs. 956 ± 407 s, P = 0.0489). Compared to conventional transseptal puncture, fewer transseptal attempts were required (1.0 ± 0.5 RF applications vs. 1.3 ± 0.8 mechanical punctures, P = 0.0123) and the fluoroscopy time was significantly shorter (72.0 [IQR 48.0, 129.0] vs. 93.0 [IQR 60.0, 171.0] s, P = 0.0490) with the radiofrequency needle plus stiff pigtail wire transseptal system. Failure to achieve transseptal LA access with the assigned system was rarely observed (1.3% vs. 5.7%, P = 0.2192). There were no procedural complications observed with either system. CONCLUSIONS: The use of a radiofrequency needle plus stiff pigtail wire resulted in shorter time to left atrial access and reduced fluoroscopy time compared to left atrial access using conventional transseptal equipment. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03199703.

Isthmic spondylolisthesis in adults A review of the current literature.

Isthmic spondylolisthesis can be defined as the anterior translation of a vertebral body relative to the one subjacent to it and secondary to an abnormality of the pars interarticularis. Isthmic spondylolisthesis is usually asymptomatic and discovered as an incidental radiographic finding. However, it can be symptomatic due to its biomechanical effects on the adjacent neural structures and patients may present with low back and/or radicular leg pain. Standing plain radiographs can be obtained to confirm the presence or assess the degree of isthmic spondylolisthesis. Computed tomography (CT) clearly shows the pars defect and provides a better assessment of the pathology. Magnetic resonance imaging (MRI) is indicated in patients with neurologic manifestations and can be used to assess the degree of foraminal or central stenosis. Conservative management including oral anti-inflammatory medication, physical therapy, and/or transforaminal epidural corticosteroid injections can be utilized initially. Surgery can be considered in the setting of persistent symptoms unrelieved with conservative management or significant neurologic compromise. Several surgical methods and techniques are available in the management of isthmic spondylolisthesis. There has been a significant national increase in the use of interbody fusion posteriorly for the management of isthmic spondylolisthesis. Reports have suggested that interbody fusion can be a cost-effective technique in selected patients with isthmic spondylolisthesis. Future studies are encouraged to further characterize the specific indications of various surgical modalities in patients with isthmic spondylolisthesis.

The role of brain natriuretic peptide in atrial fibrillation: a substudy of the Substrate Modification with Aggressive Blood Pressure Control for Atrial Fibrillation (SMAC-AF) trial.

BACKGROUND: Catheter ablation is an established therapy for atrial fibrillation but is limited by recurrence; efforts have been made to identify biomarkers that predict recurrence. We investigated the effect of baseline NT-proBNP on AF recurrence following catheter ablation in patients randomized to aggressive (< 120/80 mmHg) or standard blood pressure management (< 140/90 mmHg) in the Substrate Modification with Aggressive Blood Pressure Control trial (SMAC-AF). METHODS: The SMAC-AF study included 173 patients resistant or intolerant to at least one class I or III antiarrhythmic drug. We studied the effect of baseline NT-proBNP on the primary outcome of AF recurrence > 3 months post-ablation. RESULTS: Of the 173 patients, 88 were randomized to the aggressive cohort, and 85 into the standard group. The primary outcome occurred in 61.4% of those in the aggressive arm, versus 61.2% in the standard arm. In the aggressive group, logNT-proBNP predicted recurrence (HR 1.28, p = 0.04, adjusted HR 1.43, p = 0.03), while in the standard cohort, it did not (HR 0.94, p = 0.62, adjusted HR 0.83, p = 0.22). NT-proBNP ≥ 280 pg/mL also predicted occurrence in the aggressive (HR 1.98, p = 0.02) but not the standard cohort (HR 1.00, p = 1.00). CONCLUSION: We conclude that pre-ablation NT-proBNP may be useful in predicting recurrence in hypertensive patients and identifying patients who benefit from aggressive blood control and upstream therapies. TRIAL REGISTRATION: NCT00438113, registered February 21, 2007.

Midodrine for the Prevention of Vasovagal Syncope : A Randomized Clinical Trial.

BACKGROUND: Recurrent vasovagal syncope is common, responds poorly to treatment, and causes physical trauma and poor quality of life. Midodrine prevents hypotension and syncope during tilt tests in patients with vasovagal syncope. OBJECTIVE: To determine whether midodrine can prevent vasovagal syncope in usual clinical conditions. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT01456481). SETTING: 25 university hospitals in Canada, the United States, Mexico, and the United Kingdom. PATIENTS: Patients with recurrent vasovagal syncope and no serious comorbid conditions. INTERVENTION: Patients were randomly assigned 1:1 to placebo or midodrine and followed for 12 months. MEASUREMENTS: The primary outcome measure was the proportion of patients with at least 1 syncope episode during follow-up. RESULTS: The study included 133 patients who had had a median of 6 syncope episodes in the prior year (median age, 32 years; 73% female). Compared with patients receiving placebo, fewer patients receiving midodrine had at least 1 syncope episode (28 of 66 [42%] vs. 41 of 67 [61%]). The relative risk was 0.69 (95% CI, 0.49 to 0.97; P = 0.035). The absolute risk reduction was 19 percentage points (CI, 2 to 36 percentage points), and the number needed to treat to prevent 1 patient from having syncope was 5.3 (CI, 2.8 to 47.6). The time to first syncope was longer with midodrine (hazard ratio, 0.59 [CI, 0.37 to 0.96]; P = 0.035; log-rank P = 0.031). Adverse effects were similar in both groups. LIMITATION: Small study size, young and healthy patients, relatively short observation period, and high proportion of patients from 1 center. CONCLUSION: Midodrine can reduce the recurrence of syncope in healthy, younger patients with a high syncope burden. PRIMARY FUNDING SOURCE: The Canadian Institutes of Health Research.

Quality of Life and Health Care Utilization in the CIRCA-DOSE Study.

OBJECTIVES: This study evaluated the impact of contact force-guided radiofrequency ablation versus cryoballoon ablation on quality of life and health care utilization. BACKGROUND: Traditional outcome parameters, such as arrhythmia-free survival, are insufficient to evaluate the clinical impact of atrial fibrillation (AF), as it fails to the capture patient- and health system-level differences in treatment approaches. METHODS: The CIRCA-DOSE (Cryoballoon Vs. Contact-Force Atrial Fibrillation Ablation) study randomly assigned 346 patients with drug-refractory paroxysmal AF to contact force-guided radiofrequency or cryoballoon ablation. Health-related quality-of-life (HRQOL) was assessed at baseline, and at 6 and 12 months post-ablation using a disease-specific and generic HRQOL instruments. Health care utilization (hospitalization, emergency department visits, and cardioversion) and antiarrhythmic drug use for the 12 months preceding ablation was compared with the 12 months following ablation. RESULTS: Disease-specific and generic HRQOL was moderately to severely impaired at baseline and improved significantly at 6 and 12 months of follow-up (median improvement in AFEQT [Atrial Fibrillation Effect on QualiTy of Life] score 32.4 [interquartile range: 17.7 to 48.9]). When compared with the 12 months pre-ablation, the proportion and absolute number of cardioversions decreased significantly (41.1% vs. 10.1% of patients, 137 vs. 35 events; p < 0.0001). Similar significant reductions in emergency department visits (66.7% vs. 25.1% of patients, 224 vs. 87 events; p < 0.0001), and hospitalizations (25.5% vs. 14.5% of patients, 86 vs. 50 events; p < 0.001) were observed. There were no significant differences between randomized groups. CONCLUSIONS: In this multicenter randomized trial, catheter ablation with advanced-generation technologies resulted in a significant improvement in HRQOL and a significant reduction in health care utilization in the year following AF ablation. (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation [CIRCA-DOSE]; NCT01913522).

Immunomodulatory function of the cystic fibrosis modifier gene BPIFA1.

BACKGROUND: Cystic fibrosis (CF) is characterized by a progressive decline in lung function due to airway obstruction, infection, and inflammation. CF patients are particularly susceptible to respiratory infection by a variety of pathogens, and the inflammatory response in CF is dysregulated and prolonged. BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are proteins expressed in the upper airways that may have innate immune activity. We previously identified polymorphisms in the BPIFA1/BPIFB1 region associated with CF lung disease severity. METHODS: We evaluated whether the BPIFA1/BPIFB1 associations with lung disease severity replicated in individuals with CF participating in the International CF Gene Modifier Consortium (n = 6,365). Furthermore, we investigated mechanisms by which the BPIFA1 and BPIFB1 proteins may modify lung disease in CF. RESULTS: The association of the G allele of rs1078761 with reduced lung function was replicated in an independent cohort of CF patients (p = 0.001, n = 2,921) and in a meta-analysis of the full consortium (p = 2.39x10-5, n = 6,365). Furthermore, we found that rs1078761G which is associated with reduced lung function was also associated with reduced BPIFA1, but not BPIFB1, protein levels in saliva from CF patients. Functional assays indicated that BPIFA1 and BPIFB1 do not have an anti-bacterial role against P. aeruginosa but may have an immunomodulatory function in CF airway epithelial cells. Gene expression profiling using RNAseq identified Rho GTPase signaling pathways to be altered in CF airway epithelial cells in response to treatment with recombinant BPIFA1 and BPIFB1 proteins. CONCLUSIONS: BPIFA1 and BPIFB1 have immunomodulatory activity and genetic variation associated with low levels of these proteins may increase CF lung disease severity.

Cryoballoon or Radiofrequency Ablation for Atrial Fibrillation Assessed by Continuous Monitoring: A Randomized Clinical Trial.

BACKGROUND: Advanced generation ablation technologies have been developed to achieve more effective pulmonary vein isolation (PVI) and minimize arrhythmia recurrence after atrial fibrillation (AF) ablation. METHODS: We randomly assigned 346 patients with drug-refractory paroxysmal AF to contact force-guided radiofrequency ablation (CF-RF; n=115), 4-minute cryoballoon ablation (Cryo-4; n=115), or 2-minute cryoballoon ablation (Cryo-2; n=116). Follow-up was 12 months. The primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) between days 91 and 365 after ablation or a repeat ablation procedure at any time. Secondary end points included freedom from symptomatic arrhythmia and AF burden. All patients received an implantable loop recorder. RESULTS: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring was 53.9%, 52.2%, and 51.7% with CF-RF, Cryo-4, and Cryo-2, respectively (P=0.87). One-year freedom from symptomatic atrial tachyarrhythmia defined by continuous rhythm monitoring was 79.1%, 78.2%, and 73.3% with CF-RF, Cryo-4, and Cryo-2, respectively (P=0.26). Compared with the monitoring period before ablation, AF burden was reduced by a median of 99.3% (interquartile range, 67.8%-100.0%) with CF-RF, 99.9% (interquartile range, 65.3%-100.0%) with Cryo-4, and 98.4% (interquartile range, 56.2%-100.0%) with Cryo-2 (P=0.36). Serious adverse events occurred in 3 patients (2.6%) in the CF-RF group, 6 patients (5.3%) in the Cryo-4 group, and 7 patients (6.0%) in the Cryo-2 group, with no significant difference between groups (P=0.24). The CF-RF group had a significantly longer procedure duration but significantly shorter fluoroscopy exposure (P<0.001 vs cryoballoon groups). CONCLUSIONS: In this multicenter, randomized, single-blinded trial, CF-RF and 2 different regimens of cryoballoon ablation resulted in no difference in 1-year efficacy, which was 53% by time to first recurrence but >98% burden reduction as assessed by continuous cardiac rhythm monitoring. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01913522.

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal ß-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and ß-catenin. A pharmacological activator of the WNT/ß-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and ß-catenin, and evidence for targeted activation of the WNT/ß-catenin pathway as a potential treatment for this disease.

Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1ß production.

Proteasome inhibitors have emerged as an effective therapy for the treatment of haematological malignancies; however, their efficacy can be limited by the development of tumour resistance mechanisms. Novel combination strategies including the addition of TLR adjuvants to increase cell death and augment immune responses may help enhance their effectiveness. Although generally thought to inhibit inflammatory responses and NF-κB activation, we found that under specific conditions proteasome inhibitors can promote inflammatory responses by mediating IL-1ß maturation and secretion after TLR stimulation. This was dependent on the timing of proteasome inhibition relative to TLR stimulation where reversal of treatment order could alternatively increase or inhibit IL-1ß secretion (P < 0.001). TLR stimulation combined with proteasome inhibition enhanced cell death in vitro and delayed tumour development in vivo in NOD SCID mice (P < 0.01). However, unlike IL-1ß secretion, cell death occurred similarly regardless of treatment order and was only partially caspase dependent, possessing characteristics of both apoptosis and necrosis as indicated by activation of caspase-1, 3, 8 and RIP3 phosphorylation. Although stimulation of various TLRs was capable of driving IL-1ß production, TLR4 stimulation was the most effective at increasing cell death in THP-1 and U937 cells. TLR4 stimulation and proteasome inhibition independently activated the RIP3 necroptotic pathway and ultimately reduced the effectiveness of caspase/necroptosis inhibitors in mitigating overall levels of cell death. This strategy of combining TLR stimulation with proteasome inhibition may improve the ability of proteasome inhibitors to generate immunogenic cell death and increase anti-tumour activity.