Transvenous phrenic nerve stimulation: setting up a clinical program.

BACKGROUND: Central sleep apnea (CSA) is a form of sleep-disordered breathing caused by a lack of the drive to breathe during sleep. Phrenic nerve stimulation (PNS) was approved in 2017 for treatment of moderate to severe CSA. However, information on setting up a successful PNS program is lacking. We describe our institution's program to provide a framework to bridge the gap between clinical research and clinical application for PNS therapy. METHODS: The PNS program was created as a joint program between cardiology and sleep medicine. The program team included cardiologists, sleep medicine specialists, advanced practice providers, clinic managers, and staff who worked together in the evaluation, implantation, and management of patients. RESULTS: Thus far, 33 patients have been implanted at our institution. We have noted resolution of central apneas with PNS and improvement in patient sleep symptoms. The multidisciplinary clinic with cardiology and sleep medicine has led to high patient satisfaction and has facilitated a cohesive relationship between implant and management teams. CONCLUSIONS: PNS therapy is an effective treatment option for CSA. While the therapy treats central apneas, it will not affect upper airway obstruction. Proper patient identification is important and cooperative management between cardiology and sleep medicine enhances patient care and experience. Challenges of establishing a multidisciplinary program include identification of providers, clinic space, and scheduling. Once established, the program provides an important service to a vulnerable patient population.

Deep learning-based dose prediction to improve the plan quality of volumetric modulated arc therapy for gynecologic cancers.

BACKGROUND: In recent years, deep-learning models have been used to predict entire three-dimensional dose distributions. However, the usability of dose predictions to improve plan quality should be further investigated. PURPOSE: To develop a deep-learning model to predict high-quality dose distributions for volumetric modulated arc therapy (VMAT) plans for patients with gynecologic cancer and to evaluate their usability in driving plan quality improvements. METHODS: A total of 79 VMAT plans for the female pelvis were used to train (47 plans), validate (16 plans), and test (16 plans) 3D dense dilated U-Net models to predict 3D dose distributions. The models received the normalized CT scan, dose prescription, and target and normal tissue contours as inputs. Three models were used to predict the dose distributions for plans in the test set. A radiation oncologist specializing in the treatment of gynecologic cancers scored the test set predictions using a 5-point scale (5, acceptable as-is; 4, prefer minor edits; 3, minor edits needed; 2, major edits needed; and 1, unacceptable). The clinical plans for which the dose predictions indicated that improvements could be made were reoptimized with constraints extracted from the predictions. RESULTS: The predicted dose distributions in the test set were of comparable quality to the clinical plans. The mean voxel-wise dose difference was -0.14 ± 0.46 Gy. The percentage dose differences in the predicted target metrics of D 1 % ${D}_{1{\mathrm{\% }}}$ and D 98 % ${D}_{98{\mathrm{\% }}}$ were -1.05% ± 0.59% and 0.21% ± 0.28%, respectively. The dose differences in the predicted organ at risk mean and maximum doses were -0.30 ± 1.66 Gy and -0.42 ± 2.07 Gy, respectively. A radiation oncologist deemed all of the predicted dose distributions clinically acceptable; 12 received a score of 5, and four received a score of 4. Replanning of flagged plans (five plans) showed that the original plans could be further optimized to give dose distributions close to the predicted dose distributions. CONCLUSIONS: Deep-learning dose prediction can be used to predict high-quality and clinically acceptable dose distributions for VMAT female pelvis plans, which can then be used to identify plans that can be improved with additional optimization.

Restless Legs Syndrome and Other Common Sleep-Related Movement Disorders.

OBJECTIVE: This article reviews common sleep-related movement disorders, including their clinical description, epidemiology, pathophysiology (if known), and evaluation and management strategies. This article will provide the reader with a good foundation for approaching concerns that are suggestive of sleep-related movement disorders to properly evaluate and manage these conditions. LATEST DEVELOPMENTS: α2δ Ligands, such as gabapentin enacarbil, can be used for the initial treatment of restless legs syndrome (RLS) or in those who cannot tolerate, or have developed augmentation to, dopamine agonists. Another option is the rotigotine patch, which has a 24-hour treatment window and may be beneficial for those who have developed augmentation with short-acting dopamine agonists. IV iron can improve RLS symptoms even in those whose serum ferritin level is between 75 ng/mL and 100 ng/mL. At serum ferritin levels greater than 75 ng/mL, oral iron will likely have minimal absorption or little effect on the improvement of RLS. Research has found an association between RLS and cardiovascular disease, particularly in people who have periodic limb movements of sleep. ESSENTIAL POINTS: RLS is the most common sleep-related movement disorder. Its pathophysiology is likely a combination of central iron deficiency, dopamine overproduction, and possibly cortical excitation. Treatment includes oral or IV iron. Dopaminergic medications can be very effective but often lead to augmentation, which limits their long-term use. Other sleep-related movement disorders to be aware of are sleep-related rhythmic movement disorder, nocturnal muscle cramps, sleep-related propriospinal myoclonus, sleep bruxism, and benign myoclonus of infancy.

Does race-ethnicity affect upper airway stimulation adherence and treatment outcome of obstructive sleep apnea?

STUDY OBJECTIVES: Untreated obstructive sleep apnea (OSA) is associated with excessive daytime sleepiness, decreased quality of life, and cardiovascular disease. Positive airway pressure is the first-line therapy for OSA; however, adherence is difficult. Upper airway stimulation is a Food and Drug Administration-approved treatment of OSA. The objective of this study was to evaluate for a difference in treatment efficacy and adherence of upper airway stimulation therapy for OSA between individuals who are White and non-White using data from the ADHERE registry. METHODS: ADHERE registry is a multicenter prospective study of real-world experience of upper airway stimulation for treatment of OSA in the United States and Europe. Propensity score matching was used to create a balanced dataset between the White and non-White groups. t-Tests at a significance level of 5% were used to compare numeric values between groups. RESULTS: There were 2,755 participants of the ADHERE registry: 27 were excluded due to not having a race identified, 125 participants identified as non-White, 2,603 identify as White, and 27 did not provide race information. Propensity score matching was used to select 110 participants, with 55 White and 55 non-White for the noninferiority analysis. We did not find a difference in adherence, treatment apnea-hypopnea index, changes in Epworth Sleepiness Scale score, or clinical global impression after intervention score between White and non-White individuals. CONCLUSIONS: Our study found that there was no statistically significant difference in adherence or efficacy with upper airway stimulation therapy between White and non-White individuals. However, the percent of non-White people implanted is low, which suggests a need to expand access to this therapy for non-White populations with OSA who cannot tolerate positive airway pressure therapy. CITATION: Khan M, Stone A, Soose RJ, et al. Does race-ethnicity affect upper airway stimulation adherence and treatment outcome of obstructive sleep apnea? J Clin Sleep Med. 2022;18(9):2167-2172.

The Effects of Insomnia and Sleep Loss on Cardiovascular Disease.

Sleep loss has negative impacts on quality of life, mood, cognitive function and heath. Insomnia or difficulty sleeping is also a prevalent issue, affecting up to 35% of the population at some point in their lives. Insomnia is linked to poor mood, increased use of health care resources, and decreased quality of life as well as possible links to cardiovascular risk factors and disease. Studies have shown an increase in cortisol levels, decreased immunity, and increased markers of sympathetic activity in sleep-deprived healthy subjects and those with chronic insomnia. The literature also shows that subjective complaints consistent with chronic insomnia and shortened sleep time, both independently and in combination, can be associated with the development of diabetes, hypertension, and cardiovascular disease. In this article, we will explore the relationship and strength of association between insufficient sleep and insomnia with these health conditions.

Association between anxiety, depression, and emotional distress and hypoglossal nerve stimulator adherence.

PURPOSE: To evaluate relationships between hypoglossal nerve stimulator (HNS) adherence and the presence of anxiety, depression, and emotional distress. METHODS: This is a cross-sectional study of subjects with moderate to severe obstructive sleep apnea (OSA), who had HNS implanted and activated at The Ohio State University Medical Center (OSUMC). Patient usage data from the previous 6 months was obtained from 33 patients. Adherence was defined as ≥28 h of use per week. Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) were administered, and the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) score was calculated for all subjects. RESULTS: Sixty-five percent were adherent with average usage of 46.5±11.7 h per week vs 7.7±7.5 h per week in the non-adherent group. The average GAD-7 were 3.90±3.98 in the adherent group vs. 8.27±6.69 in the non-adherent group (p=0.049). PHQ-9 score was 6.15±4.31 vs. 10.09±7.53 (p=0.118), and PHQ-ADS was 10.05±7.49 vs. 19.20±9.80 (p=0.035). There were no statistically significant differences in age, gender, pre-treatment AHI, and post-treatment AHI between the two groups, though there was a trend to higher age in the adherent group. CONCLUSIONS: This study demonstrated higher GAD-7 and PHQ-ADS scores in the non-adherent group compared to those who were adherent to HNS supporting that anxiety and emotional distress may contribute to HNS therapy adherence. To our knowledge, this is the first study evaluating the relationship between anxiety, depression, emotional distress, and HNS adherence. Screening patients with the GAD-7 and PHQ-9 prior to implantation may be helpful when evaluating patient adherence to therapy.

The Effects of Insomnia and Sleep Loss on Cardiovascular Disease.

Sleep loss has negative impacts on quality of life, mood, cognitive function, and heath. Insomnia is linked to poor mood, increased use of health care resources, decreased quality of life, and possibly cardiovascular risk factors and disease. Studies have shown increase in cortisol levels, decreased immunity, and increased markers of sympathetic activity in sleep-deprived healthy subjects and those with chronic insomnia. The literature shows subjective complaints consistent with chronic insomnia and shortened sleep can be associated with development of diabetes, hypertension, and cardiovascular disease. This article explores the relationship between insufficient sleep and insomnia with these health conditions.

Cost minimization using an artificial neural network sleep apnea prediction tool for sleep studies.

RATIONALE: More than a million polysomnograms (PSGs) are performed annually in the United States to diagnose obstructive sleep apnea (OSA). Third-party payers now advocate a home sleep test (HST), rather than an in-laboratory PSG, as the diagnostic study for OSA regardless of clinical probability, but the economic benefit of this approach is not known. OBJECTIVES: We determined the diagnostic performance of OSA prediction tools including the newly developed OSUNet, based on an artificial neural network, and performed a cost-minimization analysis when the prediction tools are used to identify patients who should undergo HST. METHODS: The OSUNet was trained to predict the presence of OSA in a derivation group of patients who underwent an in-laboratory PSG (n = 383). Validation group 1 consisted of in-laboratory PSG patients (n = 149). The network was trained further in 33 patients who underwent HST and then was validated in a separate group of 100 HST patients (validation group 2). Likelihood ratios (LRs) were compared with two previously published prediction tools. The total costs from the use of the three prediction tools and the third-party approach within a clinical algorithm were compared. MEASUREMENTS AND MAIN RESULTS: The OSUNet had a higher +LR in all groups compared with the STOP-BANG and the modified neck circumference (MNC) prediction tools. The +LRs for STOP-BANG, MNC, and OSUNet in validation group 1 were 1.1 (1.0-1.2), 1.3 (1.1-1.5), and 2.1 (1.4-3.1); and in validation group 2 they were 1.4 (1.1-1.7), 1.7 (1.3-2.2), and 3.4 (1.8-6.1), respectively. With an OSA prevalence less than 52%, the use of all three clinical prediction tools resulted in cost savings compared with the third-party approach. CONCLUSIONS: The routine requirement of an HST to diagnose OSA regardless of clinical probability is more costly compared with the use of OSA clinical prediction tools that identify patients who should undergo this procedure when OSA is expected to be present in less than half of the population. With OSA prevalence less than 40%, the OSUNet offers the greatest savings, which are substantial when the number of sleep studies done annually is considered.

Meta-analysis: continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes.

RATIONALE: Obstructive sleep apnea (OSA) is an independent risk factor for the development of insulin resistance (IR). Treatment with continuous positive airway pressure (CPAP) for OSA has shown conflicting results on IR. OBJECTIVES: To conduct a meta-analysis of randomized controlled trials (RCTs) that have evaluated the effect of CPAP on a validated index of IR, the homeostasis model assessment of insulin resistance (HOMA-IR). METHODS: PubMed and Embase were searched through August 10, 2012. Two independent reviewers screened citations to identify trials of the effect of CPAP on HOMA-IR. Data were extracted for postintervention HOMA-IR values. MEASUREMENTS AND MAIN RESULTS: A total of five studies that enrolled 244 subjects (83% male) met the inclusion criteria. None of the subjects in the included studies had diabetes. The pooled estimate of the difference in means in HOMA-IR between the CPAP and sham CPAP/control groups was -0.44 (95% confidence interval, -0.82 to -0.06; P = 0.02). The funnel plot does not suggest the presence of any publication bias. The I-squared index for the data on difference in means in HOMA-IR between the CPAP and sham CPAP/control groups was 0.00 (P = 0.61). CONCLUSIONS: The pooled estimate of RCTs shows a favorable effect of CPAP on insulin resistance as measured by HOMA-IR in patients with OSA without diabetes. The effect size on HOMA-IR is modest, but not insignificant, when compared with the effects of thiazolidinedione in nondiabetic patients with metabolic syndrome. Further research and RCTs are warranted involving a larger number of patients and longer treatment periods to determine the beneficial effects of CPAP on IR.

Proton beam craniospinal irradiation reduces acute toxicity for adults with medulloblastoma.

PURPOSE: Efficacy and acute toxicity of proton craniospinal irradiation (p-CSI) were compared with conventional photon CSI (x-CSI) for adults with medulloblastoma. METHODS AND MATERIALS: Forty adult medulloblastoma patients treated with x-CSI (n=21) or p-CSI (n=19) at the University of Texas MD Anderson Cancer Center from 2003 to 2011 were retrospectively reviewed. Median CSI and total doses were 30.6 and 54 Gy, respectively. The median follow-up was 57 months (range 4-103) for x-CSI patients and 26 months (range 11-63) for p-CSI. RESULTS: p-CSI patients lost less weight than x-CSI patients (1.2% vs 5.8%; P=.004), and less p-CSI patients had >5% weight loss compared with x-CSI (16% vs 64%; P=.004). p-CSI patients experienced less grade 2 nausea and vomiting compared with x-CSI (26% vs 71%; P=.004). Patients treated with x-CSI were more likely to have medical management of esophagitis than p-CSI patients (57% vs 5%, P<.001). p-CSI patients had a smaller reduction in peripheral white blood cells, hemoglobin, and platelets compared with x-CSI (white blood cells 46% vs 55%, P=.04; hemoglobin 88% vs 97%, P=.009; platelets 48% vs 65%, P=.05). Mean vertebral doses were significantly associated with reductions in blood counts. CONCLUSIONS: This report is the first analysis of clinical outcomes for adult medulloblastoma patients treated with p-CSI. Patients treated with p-CSI experienced less treatment-related morbidity including fewer acute gastrointestinal and hematologic toxicities.

Involved field radiation for Hodgkin's lymphoma: the actual dose to breasts in close proximity.

To decrease the risk of late toxicities in Hodgkin's lymphoma (HL) patients treated with radiation therapy (RT) (HL), involved field radiation therapy (IFRT) has largely replaced the extended fields. To determine the out-of-field dose delivered from a typical IFRT to surrounding critical structures, we measured the dose at various points in an anthropomorphic phantom. The phantom is divided into 1-inch-thick slices with the ability to insert TLDs at 3-cm intervals grid spacing. Two treatment fields were designed, and a total of 45 TLDs were placed (equally spaced) at the margin of the each of the 2 radiation fields. After performing a computed tomography simulation, 2 treatment plans targeting the mediastinum, a typical treatment field in patients with early stage HL, were generated. A total dose of 3060 cGy was delivered to the gross tumor volume for each field consecutively. The highest measured dose detected at 1 cm from the field edge in the planning target volume was 496 cGy, equivalent to 16% of the isocentric dose. The dose dropped significantly with increasing distance from the field edge. It ranged from 1.1-3.9% of the isocentric dose at a distance of 3.2-4 cm to <1.6% at a distance of >6 cm. Although the computer treatment planning system (CTPS) frequently underestimated the dose delivered, the difference in dose between measured and generated by CTPS was <2.5% in 90 positions measured. The collateral dose of radiation to breasts from IFRT is minimal. The out-of-field dose, although mildly underestimated by CTPS, becomes insignificant at >3 cm from the field edge of the radiation field.

Obstructive sleep apnea and stroke.

Obstructive sleep apnea (OSA) is a common disorder that has been associated with many cardiovascular disease processes, including hypertension and arrhythmias. OSA has also been identified as an independent risk factor for stroke and all-cause mortality. OSA is highly prevalent in patients with transient ischemic attacks and stroke. Routinely screening patients with transient ischemic attacks or stroke for sleep apnea is becoming more common. In stroke patients with OSA, treatment with continuous positive airway pressure may prevent subsequent cardiovascular events and improve neurologic outcomes. This review explores the pathophysiology of the association between OSA and stroke, and the clinical implications of identification and treatment of OSA in patients with stroke.

Induction and concurrent taxanes enhance both the pulmonary metabolic radiation response and the radiation pneumonitis response in patients with esophagus cancer.

PURPOSE: The primary aim of this study was to assess pulmonary radiation toxicity quantitatively in patients who received thoracic radiotherapy combined with induction and/or concurrent chemotherapy with or without taxanes for esophageal cancer. METHODS AND MATERIALS: The study subjects were 139 patients treated at the University of Texas M.D. Anderson Cancer Center for esophageal cancer and who had undergone [(18)F]-fluorodeoxyglucose positron emission tomography/computed tomography between November 1, 2003 and December 15, 2007 for disease restaging after chemoradiotherapy. The patients were grouped into those who had not received taxanes (Group 1), those who had received induction or concurrent taxanes (Group 2), and those who had received both induction and concurrent taxanes (Group 3). Clinical pulmonary toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Linear regression was applied to the fluorodeoxyglucose uptake vs. radiation dose to determine the pulmonary metabolic radiation response (PMRR) for each case. The clinical toxicity scores and PMRR among the groups were evaluated for significance differences. RESULTS: The crude rate of pneumonitis symptoms was 46%, 62%, and 74% for Group 1, 2, and 3, respectively. The analysis of variance test of log(PMRR) by treatment was significant (p = .0046). Group 3 had a 61% greater PMRR compared with Group 1 (p = .002). Group 2 had a 38% greater PMRR compared with Group 1 (p = .015). Finally, Group 3 had a 17% greater PMRR compared with Group 2 (p = .31). A PMRR enhancement ratio of 1.60 (95% confidence interval, 1.19-2.14) was observed for Group 3 vs. Group 1. CONCLUSION: Patients given induction and concurrent taxane chemotherapy had a significantly greater PMRR and clinical pneumonitis symptoms compared with the patients whose chemotherapy regimen did not include taxanes.

Continuous positive airway pressure therapy reduces right ventricular volume in patients with obstructive sleep apnea: a cardiovascular magnetic resonance study.

STUDY OBJECTIVES: There are few data on the effects of continuous positive airway pressure (CPAP) therapy on the structural and functional characteristics of the right heart in patients with obstructive sleep apnea (OSA). We sought to leverage the advantages of cardiac magnetic resonance imaging (CMR) and hypothesized that CPAP treatment would improve right ventricular (RV) function in a group of patients with OSA who were free of other comorbid conditions. METHODS: Patients with severe (apnea-hypopnea index > or = 30/h) untreated OSAwere prospectively enrolled. CMR included 3-dimensional measurement of biventricular size and function, and rest/stress myocardial perfusion and was performed at baseline and after 3 months of CPAP therapy. RESULTS: Fifteen patients with mild to moderate desaturation were enrolled; 2 could not undergo CMR due to claustrophobia and obesity. There were significant decreases in the Epworth Sleepiness Scale score (p < 0.0001) and RV end-systolic and RV end-diastolic volumes (p < 0.05) with CPAP. There was a trend toward improvement in RV ejection fraction, but the improvement did not reach statistical significance. Other measures such as left ventricular volumes, left ventricular ejection fraction, myocardial perfusion reserve index, and thickness of the interventricular septum and ventricular free wall did not change significantly. CONCLUSIONS: This preliminary study found that CPAP treatment decreases RV volumes in patients with severe OSA who are otherwise healthy. CMR offers a novel technique to determine the effects of CPAP on ventricular structure and function in patients with OSA. A randomized controlled study is needed to confirm the results of our study.

Radiation pneumonitis: correlation of toxicity with pulmonary metabolic radiation response.

PURPOSE: To characterize the relationship between radiation pneumonitis (RP) clinical symptoms and pulmonary metabolic activity on post-treatment [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET). PATIENTS AND METHODS: We retrospectively studied 101 esophageal cancer patients who underwent restaging FDG-PET/computed tomography imaging 3-12 weeks after completing thoracic radiotherapy. The National Institutes of Health Common Toxicity Criteria, version 3, was used to score the RP clinical symptoms. Linear regression was applied to the FDG-PET/computed tomography images to determine the normalized FDG uptake vs. radiation dose. The pulmonary metabolic radiation response (PMRR) was quantified as this slope. Modeling was performed to determine the interaction of PMRR, mean lung dose (MLD), and the percentage of lung receiving >20 Gy with RP outcomes. RESULTS: Of the 101 patients, 25 had Grade 0, 10 had Grade 1, 60 had Grade 2, 5 had Grade 3, and 1 had Grade 5 RP symptoms. Logistic regression analysis demonstrated that increased values of both MLD and PMRR were associated with a greater probability of RP clinical symptoms (p = 0.032 and p = 0.033, respectively). Spearman's rank correlation found no association between the PMRR and the dosimetric parameters (planning target volume, MLD, percentage of lung receiving >5-30 Gy). Twofold cross-validation demonstrated that the combination of MLD and PMRR was superior to either alone for assessing the development of clinical RP symptoms. The combined MLD (or percentage of lung receiving >20 Gy) and PMRR had a greater sensitivity and accuracy (53.3% and 62.5%, respectively) than either alone. CONCLUSION: The results of this study have demonstrated a significant correlation between RP clinical symptoms and the PMRR measured by FDG-PET/computed tomography after thoracic radiotherapy.

Radiation pneumonitis: local dose versus [18F]-fluorodeoxyglucose uptake response in irradiated lung.

PURPOSE: To quantify the relationship between the local radiation dose received and the posttreatment positron emission tomography/computed tomography (PET/CT) [(18)F]2-fluoro-2-deoxyglucose (FDG) uptake in the lung. METHODS AND MATERIALS: The data from 36 patients treated for esophageal cancer with thoracic radiotherapy who underwent restaging PET/CT imaging between 4 and 12 weeks after radiotherapy completion were evaluated. Their treatment planning CT was registered with the restaging PET/CT. Using histogram analysis, the voxel average FDG-PET uptake vs. radiation dose was obtained for each case. Hierarchical linear regression models for each patient were applied to study the variation in the linear trends between cases. Deviation of the dose-response curve from a linear model was tested. RESULTS: The median time between radiotherapy completion and FDG-PET imaging was 40 days (range, 26-70 days). The median of the mean standard uptake value in the lung that received 0-5 Gy was 0.63 (range, 0.36-1.27), 5-10 Gy was 0.77 (range, 0.40-1.35), 10-20 Gy was 0.80 (range, 0.40-1.72), and >20 Gy was 1.08 (range, 0.44-2.63). A hierarchical linear regression model of the radiation dose and normalized FDG uptake per case found an adequate fit with the linear model, and the addition of quadratic and logarithmic functions did not improve the fit. The 36 cases had a posterior mean of slopes range of 0.0048-0.069. CONCLUSION: The regional dose vs. radiation pneumonitis response was evaluated with FDG-PET/CT imaging. Statistical modeling found a linear relationship. The slope of this relationship varied over an order of magnitude, reflecting the range of the underlying biological response to radiation among the study population.