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Context.— Salivary gland neoplasms are rare lesions in the head and neck (H&N) pathology realm. There are more than 20 malignant and 15 benign salivary gland neoplasms in the 5th edition of the World Health Organization classification of H&N tumors. These neoplasms consist of heterogeneous groups of uncommon diseases that make diagnosis and treatment challenging for the clinical team. Using an algorithmic immunohistochemical approach–defined tumor origin and type has proven to be effective and advantageous. Immunohistochemistry may be used as sort of a “diagnostic looking glass,” not as a positive or negative type tool, but as an indispensable complement to a hematoxylin-eosin morphologic pattern–based approach. Furthermore, the understanding of the novel discoveries of the salivary gland gene fusions and the molecular aspects of these tumors make the process easier and improve the diagnosis as well as treatment aspects. This review reflects our experience with more recent diagnostic antibodies, which include MYB RNA, Pan-TRK, PLAG1, LEF1, and NR4A3. Each of these is linked with a specific type of neoplasm; for example, gene fusions involving the PLAG1 and HMGA2 oncogenes are specific for benign pleomorphic adenomas, MYB is associated with adenoid cystic carcinoma. Objective.— To review these more recent antibodies, which highly enhance salivary gland neoplasm diagnosis. Data Sources.— The study sources involved literature PubMed searches, including multiple review articles, case reports, selected book chapters, and Geisinger Medical Center cases. Conclusions.— Salivary gland tumors are a rare, varied group of lesions in H&N pathology. We need to have continuous readings and revisions of the molecular consequences of these fusion oncoproteins and their subsequent targets, which will eventually lead to the identification of novel driver genes in salivary gland neoplasms.

Maladaptation of the sympathetic nervous system contributes to the progression of cardiovascular disease and risk for sudden cardiac death, the leading cause of mortality worldwide. Axonal modulation therapy (AMT) directed at the paravertebral chain blocks sympathetic efferent outflow to the heart and maybe a promising strategy to mitigate excess disease-associated sympathoexcitation. The present work evaluates AMT, directed at the sympathetic chain, in blocking sympathoexcitation using a porcine model. In anesthetized porcine (n = 14), we applied AMT to the right T1-T2 paravertebral chain and performed electrical stimulation of the distal portion of the right sympathetic chain (RSS). RSS-evoked changes in heart rate, contractility, ventricular activation recovery interval (ARI), and norepinephrine release were examined with and without kilohertz frequency alternating current block (KHFAC). To evaluate efficacy of AMT in the setting of sympathectomy, evaluations were performed in the intact state and repeated after left and bilateral sympathectomy. We found strong correlations between AMT intensity and block of sympathetic stimulation-evoked changes in cardiac electrical and mechanical indices (r = 0.83–0.96, effect size d = 1.9–5.7), as well as evidence of sustainability and memory. AMT significantly reduced RSS-evoked left ventricular interstitial norepinephrine release, as well as coronary sinus norepinephrine levels. Moreover, AMT remained efficacious following removal of the left sympathetic chain, with similar mitigation of evoked cardiac changes and reduction of catecholamine release. With growth of neuromodulation, an on-demand or reactionary system for reversible AMT may have therapeutic potential for cardiovascular disease-associated sympathoexcitation. NEW & NOTEWORTHY Autonomic imbalance and excess sympathetic activity have been implicated in the pathogenesis of cardiovascular disease and are targets for existing medical therapy. Neuromodulation may allow for control of sympathetic projections to the heart in an on-demand and reversible manner. This study provides proof-of-concept evidence that axonal modulation therapy (AMT) blocks sympathoexcitation by defining scalability, sustainability, and memory properties of AMT. Moreover, AMT directly reduces release of myocardial norepinephrine, a mediator of arrhythmias and heart failure.

Rationale: Cardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Objective: Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node (SAN) as an initial discovery step. Methods and Results: We report an in-depth, multiscale structural and functional characterization of the innervation of the SAN by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies, including tissue clearing, immunohistochemical, and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiological mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular conduction, and left ventricular contractility. Using this approach, we comprehensively demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. Conclusions: This report provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.

Background Dispersion in ventricular repolarization is relevant for arrhythmogenesis. Objective The purpose of this study was to determine the spatiotemporal effects of sympathetic stimulation on ventricular repolarization. Methods In 5 anesthetized female open-chest pigs, ventricular repolarization was measured from the anterior, lateral, and posterior walls of the left ventricle (LV) and right ventricle using up to 40 transmural plunge needles (4 electrodes each) before and after left stellate ganglion stimulation (LSGS) and right stellate ganglion stimulation. In addition, LSGS was performed in 3 pigs (2 male, 1 female) before and after verapamil (5–10 mg/h) administration. Results LSGS yielded a biphasic response in repolarization in the lateral and posterior walls of the LV, with prolongation at ∼5 seconds (10 ± 1.5 ms) and shortening at 20–30 seconds of stimulation (–28.9 ± 4.4 ms) during a monotonic pressure increase. While the initial prolongation was abolished by verapamil, late shortening was augmented. Sequential transections of the vagal nerve and stellate ganglia augmented repolarization dispersion responses to LSGS in 2 of 5 hearts. An equal pressure increase by aortic occlusion resulted in a homogeneous shortening of repolarization in the LV, and the effects were smaller than those during LSGS. Right stellate stimulation shortened repolarization mainly in the anterior LV wall, but the effects were smaller than those of LSGS. Conclusion LSGS first prolongs (through the L-type calcium current) and then shortens repolarization. The effect of LSGS was prominent in the posterior and lateral, not the anterior, LV walls.

A 15-year-old male presented to the hospital with a 2-month history of a right parotid mass. Magnetic resonance imaging revealed an encapsulated 3.7 cm mass. Fine-needle aspiration suggested a monomorphic adenoma (prior to utilization of the Milan Classification system). Total parotidectomy was performed with dissection and preservation of the facial nerve. Surgical pathology identified the lesion as sclerosing polycystic adenosis (SPA) after examining the histopathological and immunohistochemistry findings. SPA is a rare lesion which leads to inflammatory changes in the salivary gland. The most common site impacted is the parotid gland but also can affect other major or minor salivary glands. The fibrocystic changes are morphologically like the histological developments of sclerosing adenosis of breast tissue. Those changes consist of fibrosis, apocrine metaplasia, and different degrees of proliferation of ducts, acini, and myoepithelial cells. The pathogenesis of SPA is unknown but recent studies suggest that it could be a neoplasm. Treatment with surgical excision is effective and its' recurrence is rare. This case report details the cytomorphology, histology, and immunohistochemical profile of SPA.

Introduction: Myocardial infarction (MI) induces sympathovagal imbalance, predisposing for ventricular tachyarrhythmias (VT). Thoracic epidural anesthesia reduces VT burden through sympathetic blockade. However, it is unknown if sympathetic afferent activation may cause vagal dysfunction, and if blockade of these spinal afferents can improve vagal function and reduce VT burden. Methods: Chronic MI was percutaneously created in Yorkshire pigs (n=8). In terminal experiments 6 to 8 weeks post MI, an epidural catheter was placed at the C7-T1 epidural space. After sternotomy, a 56 electrode sock was placed over the ventricles to record activation recovery intervals (ARI, surrogate of action potential duration). Effective refractory periods (ERP) were assessed via extra-stimulus pacing and left ventricular (LV) pressure monitored via a pressure catheter. Vagal function was assessed by baroreflex sensitivity (BRS) after phenylephrine (3 μg/kg, IV). ARIs, ERP, LV function, and BRS were checked before and after epidural RTX (0.6 μg/kg/ml). VT inducibility was assessed by endocardial extra-stimulus pacing from the right ventricular apex. Results: Epidural RTX led to a modest hemodynamic response peaking at 10.2 ± 4.2 min post-RTX with stabilization by 118 ± 15 min, characterized by increased LV systolic pressure (121±5.6 to 133±9.7 mmHg; p =ns) and contractility (1411±74 to 1514±163 mmHg/s; p =ns). While ARI and atrial/ventricular ERP did not change significantly, BRS was significantly augmented by 2 hrs (2.1±0.6 to 4.3±0.8 ms/mmHg, p p Conclusion: Blockade of nociceptive spinal sympathetic afferents by RTX augments reflexive vagal function without altering basal cardiac function. Blockade of nociceptive afferents and restoration of parasympathetic function alone may be sufficient to suppress VT.

This review will systematically highlight the pros and cons of cervical cancer screening with HPV (human papillomavirus) testing and cytological methods (Papanicolaou (Pap) test). When comparing the screening modalities, various facets will be addressed, such as cost effectiveness, and harms and benefits across different demographics and age groups. It is important to note that due to the expansive variance in material costs, practices, and resource availability across different geographical regions, these comparisons are far from straight forward, and ultimately make it challenging to render definitive global recommendations. Thus, the intent of this review is to highlight some of the differences in difference cervical cancer screening modalities that can help one to choose an optimal screening method in their specific situation.

Myocardial infarction causes pathological changes in the autonomic nervous system, which exacerbate heart failure and predispose to fatal ventricular arrhythmias and sudden death. These changes are characterized by sympathetic activation and parasympathetic dysfunction (reduced vagal tone). Reasons for the central vagal withdrawal and, specifically, whether myocardial infarction causes changes in cardiac vagal afferent neurotransmission that then affect efferent tone, remain unknown. The objective of this study was to evaluate whether myocardial infarction causes changes in vagal neuronal afferent signaling. Using in vivo neural recordings from the inferior vagal (nodose) ganglia and immunohistochemical analyses, structural and functional alterations in vagal sensory neurons were characterized in a chronic porcine infarct model and compared with normal animals. Myocardial infarction caused an increase in the number of nociceptive neurons but a paradoxical decrease in functional nociceptive signaling. No changes in mechanosensitive neurons were observed. Notably, nociceptive neurons demonstrated an increase in GABAergic expression. Given that nociceptive signaling through the vagal ganglia increases efferent vagal tone, the results of this study suggest that a decrease in functional nociception, possibly due to an increase in expression of inhibitory neurotransmitters, may contribute to vagal withdrawal after myocardial infarction.

Mapping the structure/function organization of the cardiac nervous system is foundational for implementation of targeted neuromodulation-based therapeutics for the treatment of cardiac disease.The purpose of this study was to define the spatial organization of intrathoracic parasympathetic and sympathetic efferent projections to the heart.Yucatan mini-pigs (N = 11) were anesthetized and the thoracic cavity exposed. Electrical stimulation of the cervical vagi and stellate ganglia was performed individually, and hemodynamic responses were assessed in the intact state and after progressive debranching of each thoracic vagosympathetic trunk (VST). Subsequently, residual cardiac efferent projections arising from paravertebral chain ganglia (T1-T4) were evaluated by stimulation before and after individual ganglionic debranching.Stimulation of the cervical vagi decreased heart rate and contractility while prolonging the activation-recovery interval (ARI). Stimulation of the stellate ganglia increased heart rate and contractility and decreased ARI. The majority of parasympathetic and sympathetic cardiac-evoked responses were mitigated after debranching of the right VST rostral to heart, whereas the left VST demonstrated a distribution with greater dispersion and caudal intrathoracic shift compared to the right. After complete thoracic VST debranching, stimulation of the T4 paravertebral chain ganglia demonstrated residual cardiac sympathetic efferent innervation to the heart in ∼50% of animals. That response was mitigated by transecting medial ganglionic branches.The nexus point for optimum neuromodulation engagement of parasympathetic efferent projections to the heart is the cervical vagus and the T1-T2 paravertebral chain ganglia for sympathetic control. Removal of principal sympathetic efferent projections to heart requires targeting the T1-T4 regions of the paravertebral chain.

The mechanisms underlying premature ventricular contraction (PVC)-induced cardiomyopathy (PIC) remain unknown. Transient receptor potential vanilloid-1 (TRPV1) afferent fibers are implicated in the reflex processing of cardiac stress.The purpose of this study was to determine whether cardiac TRPV1 afferent signaling promote PIC.A PIC swine model (50% PVC burden) was created via an implanted pacemaker. We selectively depleted cardiac TRPV1 afferent fibers using percutaneous epicardial application of resiniferatoxin (RTX). Animals were randomized to PVC only (n = 11), PVC+RTX (n = 11), or control (n = 6). We examined early-stage (4 weeks after implantation; n = 5) and late-stage PIC (8 weeks after implantation; n = 6). At terminal experimentation, animals underwent echocardiography, serum sampling, and physiological and autonomic reflex testing.Depletion of cardiac TRPV1 afferents by RTX treatment was confirmed by absent sensory fibers and absent functional responses to TRPV1 activators. Left ventricular ejection fraction was worse in late-stage than early-stage PIC (P.01). At 4 weeks (early stage), left ventricular ejection fraction was higher in PVC+RTX vs PVC animals (51.7% ± 1.6% vs 45.0% ± 2.1%; P = .030), whereas no significant difference between PVC and PVC+RTX was observed at 8 weeks (late stage). Histologic studies demonstrated reduced fibrosis in PVC+RTX vs PVC alone at 4 weeks (2.27% ± 0.14% vs 3.01% ± 0.21%; P = .020), suggesting that RTX mitigated profibrotic pathways induced by persistent PVCs.TRPV1 afferent depletion alleviates left ventricular dysfunction in early- but not late-stage PIC. This temporal effect suggests that multiple pathways promote PIC, of which TRPV1 afferents are a part.

Cardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node as an initial discovery step. Here, we report an in-depth, multi-scale structural and functional characterization of the innervation of the sinoatrial node (SAN) by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies including tissue clearing, immunohistochemical and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiologic mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular (AV) conduction and left ventricular (LV) contractility. For the first time, we demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. This provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.

The sympathetic nervous system plays an important role in the occurrence of ventricular tachycardia (VT). Many patients, however, experience VT despite maximal doses of beta blocker therapy, possibly due to the effects of sympathetic cotransmitters such as neuropeptide Y (NPY). The purpose of this study was to determine, in a porcine model, whether propranolol at doses higher than clinically recommended could block ventricular electrophysiological effects of sympathoexcitation via stellate ganglia stimulation, and if any residual effects are mediated by NPY. Greater release of cardiac NPY was observed at higher sympathetic stimulation frequencies (10 and 20 vs. 4 Hz). Despite treatment with even higher doses of propranolol (1.0 mg/kg), electrophysiological effects of sympathetic stimulation remained, with residual shortening of activation recovery interval (ARI), a surrogate of action potential duration (APD). Adjuvant treatment with the NPY Y(1) receptor antagonist BIBO 3304, however, reduced these electrophysiological effects while augmenting inotropy. These data demonstrate that high-dose beta blocker therapy is insufficient to block electrophysiological effects of sympathoexcitation, and a portion of these electrical effects in vivo are mediated by NPY. Y(1) receptor blockade may represent a promising adjuvant therapy to beta-adrenergic receptor blockade.

INTRODUCTION Frequent premature ventricular complexes (PVCs) can lead to symptoms, such as cardiomyopathy and increased mortality. Beta-blockers are recommended as first-line therapy to reduce PVC burden; however, the response is unpredictable. The objective of this study is to determine whether PVC diurnal-variability patterns are associated with different clinical profiles and predict drug response. METHODS Consecutive patients with frequent PVCs (burden ≥ 1%), referred for Holter monitoring between 2014 and 2016, were included. Follow-up Holters, when available, were assessed after beta-blocker initiation to assess response (≥50% reduction). Patients were divided into three groups on the basis of relationship between hourly PVC count and mean HR during each of the 24 Holter hours: (1) fast-HR-dependent-PVC (F-HR-PVC) for positive correlation (Pearson, P < 0.05), (2) slow-HR-dependent-PVC (S-HR-PVC) for a negative, and (3) independent-HR-PVC (I-HR-PVC) when no correlation was found. RESULTS Of the 416 patients included, 50.2% had F-HR-PVC, 35.6% I-HR-PVC, and 14.2% S-HR-PVC with distinct clinical profiles. Beta-blocker therapy was successful in 34.0% patients overall: patients with F-HR-PVC had a decrease in PVC burden (18.8 ± 10.4% to 9.3 ± 6.6%, P < 0.0001; 62% success), I-HR-PVC had no change (18.4 ± 17.9% to 20.6 ± 17.9%, P = 0.175; 0% success), whereas S-HR-PVC had an increase in burden (14.6 ± 15.3% to 20.8 ± 13.8%, P = 0.016; 0% success). The correlation coefficient was the only predictor of beta-blocker success (AUC = 0.84, sensitivity = 100%, specificity = 67.7%; r ≥ 0.4). CONCLUSIONS A simple analysis of Holter PVC diurnal variability may provide incremental value to guide clinical PVC management. Only patients displaying a F-HR-PVC profile benefited from beta-blockers. An alternative strategy should be considered for others, as beta-blockers may have no effect or can even be harmful.

Infrequent intraprocedural premature ventricular complexes (PVCs) may impede radiofrequency catheter ablation (RFA) outcome, and pharmacologic induction is unpredictable.The purpose of this study was to determine whether PVC circadian variation could help predict drug response.Consecutive patients referred for RFA with detailed Holter monitoring and frequent monomorphic PVCs were included. Patients were divided into 3 groups based on hourly PVC count relationship to corresponding mean heart rate (HR) during each of the 24 hours on Holter: fast-HR-dependent PVC (F-HR-PVC) type for a positive correlation (Pearson, P.05), slow-HR-dependent PVC (S-HR-PVC) type for a negative correlation, and independent-HR-PVC (I-HR-PVC) when no correlation was found.Fifty-one of the 101 patients (50.5%) had F-HR-PVC, 39.6% I-HR-PVC, and 9.9% S-HR-PVC; 30.7% had infrequent intraprocedural PVC requiring drug infusion. The best predictor of infrequent PVC was number of hours with PVC count120/h on Holter (area under the curve 0.80, sensitivity 83.9%, specificity 74.3%, for ≥2 h). Only F-HR-PVC patients responded to isoproterenol. Isoproterenol washout or phenylephrine infusion was successful for the 3 S-HR-PVC patients, and no drug could increase PVC frequency in the 12 I-HR-PVC patients. Long-term RFA success rate in patients with frequent PVCs at baseline (82.9%) was similar to those with infrequent PVC who responded to a drug (77.8%; P = .732) but significantly higher than for those who did not respond to any drug (15.4%; P.0001).A simple analysis of Holter PVC circadian variability provides incremental value to guide pharmacologic induction of PVCs during RFA and predict outcome. Patients with infrequent I-HR-PVC had the least successful outcomes from RF ablation.