Clinical Radiographic Predictors of Response to Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

OBJECTIVE: To determine if clinically acquired cephalometric measurements, specifically soft palate size, can predict hypoglossal nerve stimulation outcomes. STUDY DESIGN: Combined prospective cohort study and retrospective review. SETTING: US sleep otolaryngology training program. METHODS: Adults with obstructive sleep apnea and apneahypopnea index greater than 15 events/h who underwent hypoglossal nerve stimulation. Eligible subjects had diagnostic preoperative sleep studies and full-night efficacy postoperative studies for analysis. Lateral neck x-rays were obtained as part of routine clinical care and measured for key cephalometric variables by trained head and neck radiologists. Continuous variables were compared using the Student t test, while χ2 testing was used for categorical variables. RESULTS: Fifty-one patients met all study criteria. On average, patients were white, middle aged, and overweight. Following hypoglossal nerve stimulation, the overall cohort achieved a significant apnea-hypopnea index reduction from 36.7 events/h to 20.6 events/h (P < .01) and a response rate of 47% (defined as apnea-hypopnea index reduction >50% and apnea-hypopnea index <20 events/h). On average, therapy responders had significantly thinner soft palates than nonresponders (13.4 ± 3.8 mm vs 16.0 ± 3.4 mm, P = .045). CONCLUSIONS: Patient-specific anatomic factors, specifically soft palate thickness, may help identify optimal candidates for hypoglossal nerve stimulation. A larger, prospective study including both anatomic and physiologic variables is required to validate these findings.

Transoral Versus Endoscopic Examination in Predicting Outcomes of Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

OBJECTIVES/HYPOTHESIS: To examine the correlation between transoral and awake endoscopic examination and investigate their respective ability to predict outcomes of hypoglossal nerve stimulation (HGNS). STUDY DESIGN: Retrospective cohort study at a US medical center. METHODS: Subjects were adults with apnea-hypopnea index (AHI) >15 events/hr who underwent HGNS according to standard indications. Eligible subjects had diagnostic preoperative sleep studies, full-night efficacy postoperative studies, as well as postoperative video recordings of transoral examination and awake endoscopy. Recordings were independently scored by two blinded reviewers. Cohen's κ coefficient, Student t test, and χ2 analyses were performed. RESULTS: Fifty-seven patients met all inclusion criteria. On average, patients were Caucasian, middle aged, and overweight. The mean preoperative AHI was 36.7 events/hr, which improved significantly to 18.3 events/hr following HGNS (P < .01). Overall, the response rate (defined as AHI reduction >50% and AHI < 20 events/hr) was 49%. There was slight correlation between transoral tongue protrusion and endoscopic tongue base movement (κ = 0.10). On transoral examination, patients with minimal/moderate tongue motion achieved a greater mean AHI reduction than patients with full motion (26.0 ± 18.0 vs. 12.8 ± 24.1, P = .02). In contrast, on awake endoscopy, patients with minimal/moderate tongue motion achieved a lesser mean AHI reduction than patients with full motion (8.7 ± 19.9 vs. 22.1 ± 22.7, P = .04). CONCLUSIONS: Transoral tongue protrusion bears an inverse relationship to HGNS success and correlates poorly with endoscopic tongue base movement. Endoscopic tongue base motion appears reflective of response to HGNS, with greater motion corresponding to greater AHI reduction. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:675-679, 2021.

Risk Factors for Rhinosinusitis After Endoscopic Transsphenoidal Adenomectomy.

OBJECTIVE: Patients undergoing endoscopic transsphenoidal adenomectomy (eTSA) for pituitary tumors are at risk for postoperative complications, including rhinosinusitis. We aimed to determine if preoperative sinonasal disease is a risk factor for postoperative rhinosinusitis (PRS). STUDY DESIGN: Retrospective review. SETTING: Tertiary academic center in U.S. SUBJECTS AND METHODS: Patients with a diagnosis of pituitary adenoma who underwent eTSA between 2007-2016. PRS patients were matched to non-PRS patients or sex, age, tumor size, skull base reconstruction with intranasal tissue grafting, and concurrent septoplasty. Groups were statistically analyzed for potential preoperative risk factors of sinonasal disease (patient-reported, radiographic, endoscopic). RESULTS: 49 of 987 patients who underwent eTSA developed PRS (44.9% male, 71.4% Caucasian, mean age 49.3y). On analysis of individual risk factors, there was a significantly higher proportion of patients with a history of prior sinonasal surgery in the PRS group than the non-PRS group (25.5% vs. 6.5%, p = 0.01); however, this group difference became insignificant on multivariate analysis. There were no significant group differences with regard to history of sinus infections, nasal symptoms, seasonal allergies, radiographic abnormalities, or sinonasal disease on endoscopy. CONCLUSION: This is the first study to investigate preoperative sinonasal disease as a risk factor for PRS after eTSA. The risk factors considered did not demonstrate definitive risk for PRS, although a history of prior sinonasal surgery should be investigated further.

Intraoperative identification of mixed activation profiles during hypoglossal nerve stimulation.

STUDY OBJECTIVES: The effectiveness of hypoglossal nerve stimulation (HGNS) in the treatment of obstructive sleep apnea (OSA) depends on the selective stimulation of nerve fibers that innervate the tongue muscles that produce tongue protrusion (genioglossus) and stiffening (transverse/vertical) while avoiding fibers that innervate muscles that produce tongue retraction (styloglossus/hyoglossus). Postoperative treatment failures can be related to mixed activation of retractor and protrusor muscles, despite intraoperative efforts to identify and avoid nerve fibers that innervate the retractor muscles. This study describes a novel intraoperative protocol that more optimally identifies mixed activation by utilizing an expanded set of stimulation/recording parameters. METHODS: This study was a case series in a university hospital setting of patients undergoing unilateral hypoglossal nerve stimulation implantation for obstructive sleep apnea. Data included electromyographic responses in the genioglossus and styloglossus/hyoglossus to intraoperative stimulation with an implantable pulse generator using unipolar (- - -, o-o) and bipolar (+-+) settings. RESULTS: In a subset of patients (3/55), low-intensity unipolar implantable pulse generator stimulation revealed significant mixed activation of the styloglossus/hyoglossus and genioglossus muscles that was not evident under standard bipolar implantable pulse generator stimulation conditions. Additional surgical dissection and repositioning of the electrode stimulation cuff reduced mixed activation. CONCLUSIONS: A novel intraoperative neurophysiological monitoring protocol was able to detect significant mixed activation during hypoglossal nerve stimulation that was otherwise absent using standard parameters. This enabled successful electrode cuff repositioning and a dramatic reduction of mixed activation.

Bone microenvironment signaling of cancer stem cells as a therapeutic target in metastatic prostate cancer.

Prostate cancer (PCa) is one of the most prevalent cancers and the second leading cause of cancer death among US males. When diagnosed in an early disease stage, primary tumors of PCa may be treated with surgical resection or radiation, sometimes combined with androgen deprivation therapy, with favorable outcomes. Unfortunately, the treatment efficacy of each approach decreases significantly in later stages of PCa that involve metastasis to soft tissues and bone. Metastatic PCa is a heterogeneous disease containing host cells, mature cancer cells, and subpopulation of cancer stem cells (CSC). CSCs are highly tumorigenic due to their self-renewing and differentiating potential, clinically resulting in recurrence and resistance to standard therapies. Therefore, there is a large unmet clinical need to develop therapies, which target CSC activity. In this review, we summarize the main signaling pathways that are implicated in the current pre-clinical and clinical studies of recurrent metastatic PCa within the bone microenvironment targeting CSCs and discuss the trajectory of therapeutics moving forward.

Therapeutic Positive Airway Pressure Level Predicts Response to Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

STUDY OBJECTIVES: To determine whether therapeutic positive airway pressure (PAP) level predicts response to hypoglossal nerve stimulation (HGNS) for obstructive sleep apnea using the coprimary outcomes of apnea-hypopnea index (AHI) and 4% oxygen desaturation index. METHODS: Combined cohort study from two US sleep otolaryngology training programs. Subjects were adults with AHI > 15 events/h who underwent HGNS. Eligible subjects had diagnostic preoperative sleep studies, full-night efficacy postoperative studies and therapeutic PAP levels available for analysis. Low and high PAP groups were compared using the t test for continuous variables and chi-square test for categorical variables. RESULTS: Fifty-six patients met all inclusion criteria. On average, patients were male, Caucasian, middle-aged, and overweight. Thirteen patients were in the low PAP group (< 8 cm H2O) and 43 patients in the high PAP group (≥ 8 cm H2O). Although both groups experienced improvement of polysomnographic measures with HGNS, the low PAP group achieved a significantly larger mean AHI reduction (36.7 ± 22.7 versus 18.4 ± 23.4, P = .02). Additionally, the low PAP group had a greater response rate (defined as AHI < 20 events/h and > 50% reduction of AHI) than the high PAP group (92% versus 44%, P < .01). CONCLUSIONS: Therapeutic PAP level may aid in the discernment of candidacy for HGNS, with a strong positive predictive value for PAP levels < 8 cm H2O. A larger prospective study is needed to confirm these findings. CITATION: Lee CH, Seay EG, Walters BK, Scalzitti NJ, Dedhia RC. Therapeutic positive airway pressure level predicts response to hypoglossal nerve stimulation for obstructive sleep apnea. J Clin Sleep Med. 2019;15(8):1165-1172.

IMAGES: Drug-Induced Sleep Endoscopy: An Investigative Tool for Mechanisms of PAP Failure.

ABSTRACT: This is a case report of a 60-year-old female with mild obstructive sleep apnea (OSA) who presented to CPAP Alternatives clinic following multiple failed attempts at positive airway pressure (PAP) therapy. She underwent drug-induced sleep endoscopy (DISE) with the concurrent application of PAP via two different mask types. Application of the oronasal mask at low pressures demonstrated soft palate collapse, while high pressures resulted in posterior tongue collapse. In contrast, application of the nasal mask eliminated palatal and tongue obstruction at low pressures, despite mask leak at higher pressures. She was recommended a trial of nasal autoPAP, which with the use of a chinstrap, resulted in both subjective and objective improvement of her OSA.

Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.

Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.

Suppression of epileptogenesis-associated changes in response to seizures in FGF22-deficient mice.

In the developing hippocampus, fibroblast growth factor (FGF) 22 promotes the formation of excitatory presynaptic terminals. Remarkably, FGF22 knockout (KO) mice show resistance to generalized seizures in adults as assessed by chemical kindling, a model that is widely used to study epileptogenesis (Terauchi et al., 2010). Repeated injections of low dose pentylenetetrazol (PTZ) induce generalized seizures ("kindled") in wild type (WT) mice. With additional PTZ injections, FGF22KO mice do show moderate seizures, but they do not kindle. Thus, analyses of how FGF22 impacts seizure susceptibility will contribute to the better understanding of the molecular and cellular mechanisms of epileptogenesis. To decipher the roles of FGF22 in the seizure phenotype, we examine four pathophysiological changes in the hippocampus associated with epileptogenesis: enhancement of dentate neurogenesis, hilar ectopic dentate granule cells (DGCs), increase in hilar cell death, and formation of mossy fiber sprouting (MFS). Dentate neurogenesis is enhanced, hilar ectopic DGCs appeared, and hilar cell death is increased in PTZ-kindled WT mice relative to PBS-injected WT mice. Even in WT mice with fewer PTZ injections, which showed only mild seizures (so were not kindled), neurogenesis, hilar ectopic DGCs, and hilar cell death are increased, suggesting that mild seizures are enough to induce these changes in WT mice. In contrast, PTZ-injected FGF22KO mice do not show these changes despite having moderate seizures: neurogenesis is rather suppressed, hilar ectopic DGCs do not appear, and hilar cell death is unchanged in PTZ-injected FGF22KO mice relative to PBS-injected FGF22KO mice. These results indicate that FGF22 plays important roles in controlling neurogenesis, ectopic migration of DGCs, and hilar cell death after seizures, which may contribute to the generalized seizure-resistant phenotype of FGF22KO mice and suggests a possibility that inhibition of FGF22 may alleviate epileptogenesis.

Neurogenesis is enhanced and mossy fiber sprouting arises in FGF7-deficient mice during development.

One of the most common types of epilepsy in adults is temporal lobe epilepsy. Temporal lobe epilepsy is often resistant to pharmacological treatment, requiring urgent understanding of its molecular and cellular mechanisms. It is generally accepted that an imbalance between excitatory and inhibitory inputs is related to epileptogenesis. We have recently identified that fibroblast growth factor (FGF) 7 is critical for inhibitory synapse formation in the developing hippocampus. Remarkably, FGF7 knockout mice are prone to epileptic seizures induced by chemical kindling (Terauchi et al., 2010). Here we show that FGF7 knockout mice exhibit epileptogenesis-related changes in the hippocampus even without kindling induction. FGF7 knockout mice show mossy fiber sprouting and enhanced dentate neurogenesis by 2 months of age, without apparent spontaneous seizures. These results suggest that FGF7-deficiency impairs inhibitory synapse formation, which results in mossy fiber sprouting and enhanced neurogenesis during development, making FGF7 knockout mice vulnerable to epilepsy.

Erythropoietin couples hematopoiesis with bone formation.

BACKGROUND: It is well established that bleeding activates the hematopoietic system to regenerate the loss of mature blood elements. We have shown that hematopoietic stem cells (HSCs) isolated from animals challenged with an acute bleed regulate osteoblast differentiation from marrow stromal cells. This suggests that HSCs participate in bone formation where the molecular basis for this activity is the production of BMP2 and BMP6 by HSCs. Yet, what stimulates HSCs to produce BMPs is unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrate that erythropoietin (Epo) activates Jak-Stat signaling pathways in HSCs which leads to the production of BMPs. Critically, Epo also directly activates mesenchymal cells to form osteoblasts in vitro, which in vivo leads to bone formation. Importantly, Epo first activates osteoclastogenesis which is later followed by osteoblastogenesis that is induced by either Epo directly or the expression of BMPs by HSCs to form bone. CONCLUSIONS/SIGNIFICANCE: These data for the first time demonstrate that Epo regulates the formation of bone by both direct and indirect pathways, and further demonstrates the exquisite coupling between hematopoiesis and osteopoiesis in the marrow.

Expression of PGK1 by prostate cancer cells induces bone formation.

Prostate cancer (PCa) is one of the solid tumors that metastasize to the bone. Once there, the phenotype of the bone lesions is dependent upon the balance between osteoblastogenesis and osteoclastogenesis. We previously reported that overexpression of phosphoglycerate kinase 1 (PGK1) in PCa cell lines enhanced bone formation at the metastatic site in vivo. Here, the role of PGK1 in the bone formation was further explored. We show that PCa-derived PGK1 induces osteoblastic differentiation of bone marrow stromal cells. We also found that PGK1 secreted by PCa inhibits osteoclastogenesis. Finally, the expression levels of the bone-specific markers in PCa cells were higher in cells overexpressing PGK1 than controls. Together, these data suggest that PGK1 secreted by PCa regulates bone formation at the metastatic site by increasing osteoblastic activity, decreasing osteoclastic function, and expressing an osteoblastic phenotype by PCa cells.