Summary The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGFβ superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a new therapeutic opportunity for cardiac aging.

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IMPORTANCE More than half of all new melanoma diagnoses present as clinically localized T1 melanoma, yet sentinel lymph node biopsy (SLNB) is controversial in this population given the overall low yield. Guidelines for SLNB have focused on pathologic factors, but patient factors, such as age, are not routinely considered.OBJECTIVES To identify indicators of lymph node (LN) metastasis in thin melanoma in a large, generalizable data set and to evaluate the association between patient age and LN positivity. DESIGN, SETTING, AND PARTICIPANTSA retrospective cohort study using the National Cancer Database, an oncology database representing patients from more than 1500 hospitals throughout the United States, was performed (2010)(2011)(2012)(2013). Data analysis was conducted from October 1, 2016, to January 15, 2017. A total of 8772 patients with clinical stage I 0.50 to 1.0 mm thin melanoma undergoing wide excision and surgical evaluation of regional LNs were included for study. MAIN OUTCOME AND MEASURESThe primary outcome of interest was presence of melanoma in a biopsied regional LN. Clinicopathologic factors associated with LN positivity were characterized, using logistic regression. Age was categorized as younger than 40 years, 40 to 64 years, and 65 years or older for multivariable analysis. Classification tree analysis was performed to identify high-risk groups for LN positivity.RESULTS Among the study cohort (n = 8772), 333 patients had nodal metastases, for an overall positivity rate of 3.8% (95% CI, 3.4%-4.2%). A total of 4087 (54.0%) patients were women. Median age was 56 years (interquartile range [IQR], 46-67) in patients with negative LNs and 52 years (IQR, 41-61) in those with positive LNs (P < .001). In multivariable analysis, younger age, female sex, thickness of 0.76 mm or larger, increasing Clark level, mitoses, ulceration, and lymphovascular invasion were independently associated with LN positivity. In decision tree analysis, patient age was identified as an important risk stratifier for LN metastases, after mitoses and thickness. Patients younger than 40 years with category T1b tumors 0.50 to 0.75 mm, who would generally not be recommended for SLNB, had an LN positivity rate of 5.6% (95% CI, 3.3%-8.6%); conversely, patients 65 years or older with T1b tumors 0.76 mm or larger, who would generally be recommended for SLNB, had an LN positivity rate of only 3.9% (95% CI, 2.7%-5.3%). CONCLUSIONS AND RELEVANCEPatient age is an important factor in estimating lymph node positivity in thin melanoma independent of traditional pathologic factors. Age therefore should be taken into consideration when selecting patients for nodal biopsy.

Background: Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). Methods: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidencebased review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. Results: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. Conclusion:This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

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Objectives Evaluate clinicopathologic factors contributing to regional lymph node (LN) metastases in cutaneous head and neck melanoma (HNM). Study Design Retrospective review of a national cancer database. Setting National Cancer Database (2004-2012). Methods National Cancer Database (NCDB) cases diagnosed between 2004 and 2012 were reviewed. Inclusion criteria were head and neck cutaneous site codes, melanoma histology codes, and clinically node-negative status. Independent, clinicopathologic factors associated with pathologic positive LN status were identified by multivariable logistic regression. Subset analysis was performed on thin melanoma cases of 0.75 to 1 mm tumor depth to determine factors predictive of LN involvement and survival. Results Of 66,495 cases meeting inclusion criteria, 18,882 had nodes examined pathologically with 9.7% presenting with occult positive LN involvement. Mean (SD) age was 62.9 (16.13) years, and primary sites were scalp and neck (42.2%), face (40.2%), and external ear, lip, or eyelid (7.6%). Multivariable analysis found younger age; primary site of cutaneous scalp, neck, or face; increasing thickness; mitoses; ulceration; and vertical growth phase presence were independently associated with LN positivity ( P < .001). Only 2% of 0.75- to 1.0-mm Breslow thickness cases had regional LN involvement, and age >70 was negatively associated with LN involvement ( P = .002) in this subset. Conclusion This is the largest study examining factors predictive of occult LN involvement in patients with clinical node-negative cutaneous HNM who may benefit from sentinel LN biopsy. Primary sites of external ear, lip, or eyelid are less likely to present with occult nodal involvement, and older patients with T1a melanoma ≥0.76 mm are unlikely to present with regional node metastasis and may not require sentinel node guided management.

Objective Characterize long‐term cranial nerve (CN) outcomes following sentinel lymph node biopsy (SLNB) based management for head and neck cutaneous melanoma (HNCM). Methods Longitudinal review of HNCM patients undergoing SLNB from 1997–2007. Results Three hundred fifty‐six patients were identified, with mean age 53.5 ± 19.0 years, mean Breslow depth 2.52 ± 1.87 mm, and 4.9 years median follow‐up. One hundred five (29.4%) patients had SLNB mapping to the parotid basin. Eighteen patients had positive parotid SLNs and underwent immediate parotidectomy / immediate completion lymph node dissection (iCLND), with six possessing positive parotid non‐sentinel lymph nodes (NSLNs). Fifty‐two of 356 (14.6%) patients developed delayed regional recurrences, including 20 total intraparotid recurrences: five following false negative (FN) parotid SLNB, three following prior immediate superficial parotidectomy, two following iCLND without parotidectomy, and the remaining 12 parotid recurrences had negative extraparotid SLNBs. Parotid recurrences were multiple (4.9 mean recurrent nodes) and advanced (n = 4 extracapsular extension), and all required salvage dissection including parotidectomy. Immediate parotidectomy/iCLND led to no permanent CN injuries. Delayed regional HNCM macrometastasis precipitated 16 total permanent CN injuries in 13 patients: 10 CN VII, five CN XI, and one CN XII deficits. Fifty percent (n = 10) of parotid recurrences caused ≥1 permanent CN deficits. Conclusions Regional HNCM macrometastases and salvage dissection confer marked CN injury risk, whereas early surgical intervention via SLNB ± iCLND ± immediate parotidectomy yielded no CN injuries. Further, superficial parotidectomy performed in parotid‐mapping HNCM does not obviate delayed intraparotid recurrences, which increase risk of CN VII injury. Despite lack of a published disease‐specific survival advantage in melanoma, early disease control in cervical and parotid basins is paramount to minimize CN complications. Level of Evidence 4 (retrospective case series) Laryngoscope, 130:1707–1714, 2020