Advances in pre-operative imaging localization (4-D CT, MIBI/SPECT, ultrasound) and rapid intra-operative PTH (ioPTH) monitoring have provided the tools necessary to optimize precision and accuracy ...in the operative approach.1–3 Surgical cure rates for primary hyperparathyroidism are greater than 95% in the hands of experienced surgeons.4 Identifying methods to further improve success while also limiting potential complications remains a challenge. Common variations include extending the time from pre-incision/pre-excision ioPTH to 15 or 20 minutes and broadening the >50% decrease in ioPTH to also require a drop into the normal reference range.5,6 Multiple studies have sought to further refine the Miami criteria in an effort to minimize missed multiglandular disease and improve operative success.5,7 Balancing a successful outcome with increased operative time and the potential for increased morbidity from a bilateral neck exploration remains the goal. Minimally invasive parathyroidectomy with ioPTH has been demonstrated to decrease the need for bilateral neck exploration, reduce hospital costs, and shorten hospital stays.1,9,10 The clinical utility of ioPTH becomes somewhat muted when attempts to increase the cure rate come at the expense of unnecessary bilateral neck explorations and increased operative time, ineffectually gilding the lily with no significant difference in operative outcome.
Endocrine surgeons focus their operations on the thyroid, parathyroid, and adrenal glands. Because of rather confined spaces in the neck, an emphasis on small incisions and minimally invasive ...techniques, and regular use of headlights and loupes, endocrine surgeons are at increased risk for MSDs. In this issue of the American Journal of Surgery, Jensen and colleagues report the results of their study, which investigates work-related MSDs in endocrine surgeons.1 The authors created a 43-question survey applying previously published MSD surveys as a framework. Ergonomists have described the working conditions of surgeons as being at least on par and often harsher than those of industrial workers.2 Multiple cross-sectional studies have reported higher prevalence estimates of work-related MSDs in surgeons as compared with the general population and even labor-intensive occupations such as mining and manufacturing.3, 4 A recent review aiming to identify the prevalence of MSDs in minimally invasive surgeons found a 74% prevalence of physical complaints among laparoscopic surgeons.5 Similar work evaluating self-reported MSDs experienced by plastic surgeons reported a prevalence of 82%.4 On a somewhat more positive note, a report evaluating MSDs in otolaryngologists in the UK, where some principles of micro-breaks and postural ergonomics have been incorporated by the National Health Services into online e-learning modules for the induction of new doctors, the responding prevalence of MSDs was just 47%.6 Though a 47% prevalence of MSDs remains excessively high, it is notable that it is significantly lower as compared to those reported by respondents from countries where ergonomics principles are not part of continuing medical education curricula.
Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression ...accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor—β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal—regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.
Autophagy is a highly conserved process for maintaining cellular homeostasis. Upregulation of autophagy promotes metastasis by promoting the cancer stem cell state while also stimulating tumor cell ...migration and invasion. We hypothesized that autophagy upregulation would be critical for cancer stem cell maintenance as well as cellular migration and invasion in thyroid cancer.
Validated papillary (MDA-T32, MDA-T68), follicular (FTC-133), and anaplastic (ATC-8505c) human thyroid cancer cell lines in culture were first assessed for autophagic capacity after bafilomycin clamping. Cancer stem cells were quantified by flow cytometry for aldehyde dehydrogenase and thyrosphere formation assay. Scratch migration and Matrigel invasion assays were performed in the presence of known autophagy inhibitors: Lys05, chloroquine, and FIP200siRNA.
Autophagy activity was observed across all cell lines. Thyrosphere formation, aldehyde dehydrogenase activity, and CD44 expression were reduced with inhibition of autophagy in MDA-T32, MDA-T68, FTC-133, and 8505c cells. Similarly, cell migration and invasion were attenuated: 42% (FIP200siRNA), 78% (Lys05), P < .001 in MDA-T32 cells; 54% (FIP200siRNA), 67% (Lys05), P < .001 in MDA-T68 cells; 73% (FIP200siRNA), 71% (Lys05), P < .001) in FTC-133 cells; and 60% (FIP200siRNA), 90% (Lys05), P < .001 in 8505c cells. Invasion assays demonstrated a 73%, 39%, 75%, and 65.1% reduction in the presence of Lys05 in T32, T68, FTC-133, and 8505c cells, respectively. We observed similar reductions in invasion with FIP200siRNA: 61%, 62%, 55%, and 81.4% in T32, T68, FTC-133, and 8505c cells.
Autophagy is upregulated across multiple thyroid cancer subtypes. In thyroid cancer cell lines, inhibition of autophagy attenuates cancer stem cell viability, cell migration, and invasion suggesting a role for autophagy in the progression of thyroid cancer. Greater understanding of autophagy regulation in thyroid cancer will aid in developing targeted therapeutics.
Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive ...signaling by the transforming growth factor-{szligbeta} (TGF-{szligbeta}) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-{szligbeta} signaling and can be prevented by TGF-{szligbeta} antagonists such as TGF-{szligbeta}-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.
The Bethesda System for Reporting Thyroid Cytopathology was formalized in 2007 to stratify cytologic specimens based on their risk of malignancy. Several studies have reported significant variations ...between their institutional rate of malignancy compared to the Bethesda System for Reporting Thyroid Cytopathology. The objective of this study was to determine the national rate of malignancy for Bethesda III, Bethesda IV, and Bethesda V thyroid nodules.
From 2016 to 2019, patients with preoperative thyroid cytopathology and pathology results in National Surgical Quality Improvement database were included. The rate of malignancy was compared to the median the Bethesda System for Reporting Thyroid Cytopathology 2017, and risk factors associated with malignancy were identified for Bethesda III, Bethesda IV, and Bethesda V specimens.
In total, 13,121 patients with preoperative cytopathology and postresection pathology were identified. The national rate of malignancy was significantly higher than the Bethesda System for Reporting Thyroid Cytopathology 2017 for Bethesda III (36.2% vs 12.0%, P < .01), Bethesda IV (36.7% vs 25.0%, P < .01), and Bethesda V (91.1% vs 52.5%, P < .01) specimens. Male sex was significantly associated with malignancy in Bethesda III, Bethesda IV, and Bethesda V nodules (Bethesda III, odds ratio: 1.20, 1.01–1.42; Bethesda IV, odds ratio: 1.47, 1.27–1.71; Bethesda V, odds ratio: 1.28, 1.03–1.58). Younger age was associated with malignancy in Bethesda III patients under 55 (odds ratio: 1.23, 1.06–1.42), Bethesda IV patients under 42 (odds ratio: 1.23, 1.06–1.43), and Bethesda V patients aged less than 47 (odds ratio: 1.38, 1.15–1.67).
This is the largest cohort study to describe the national rate of malignancy for Bethesda III, IV, and V specimens in the United States. These results reveal the national rate of malignancy is higher than the implied rate of malignancy reported to patients based on the Bethesda System for Reporting Thyroid Cytopathology. We recommend counseling patients regarding this increased rate of malignancy to set appropriate expectations after surgical intervention.
The risk of malignancy from nodules with atypia of undetermined significance cytology is estimated between 5% and 15%, though more recent studies suggest rates upwards of 48%. This study sought to ...characterize preoperative predictors of malignancy to aid in clinical decision-making.
We performed a single institution retrospective review of all adult patients with unilateral thyroid nodules demonstrating atypia of undetermined significance cytology between March 1, 2013 and June 1, 2019 who underwent surgical resection (n = 266). Univariate and multivariate logistical analysis was performed using clinical and demographic variables to identify potential preoperative characteristics associated with malignant disease.
Malignancy was identified on final pathology in 24.7% of patients with atypia of undetermined significance cytology. Age, sex, exposure to ionizing radiation, family history of thyroid cancer, Hashimoto’s disease, Afirma suspicious results, and smoking were not associated with malignancy on both univariate and multivariate analysis. Nodule size >4 cm was independently associated with malignancy risk on both univariate (odds ratio 2.44, 1.09–5.43, P < .03) and multivariate (odds ratio 2.96, 1.27–6.87, P < .02) analysis.
The results of this study demonstrate that nodules with atypia of undetermined significance cytology >4 cm are strongly associated with malignancy. We recommend strong consideration of surgery for all patients with thyroid nodules >4 cm and atypia of undetermined significance cytology.
INTRODUCTIONThe utilization of minimally invasive surgery (MIS) for adrenocortical carcinoma (ACC) remains controversial due to concerns regarding the quality of surgical resection and subsequent ...oncologic risks. Current guidelines recommend open resections for all cases of suspected ACC independent of size; however, there has been increased adoption of MIS for ACC over time. We sought to determine whether the rise in the utilization of MIS is associated with worse survival outcomes for ACC. METHODSThe National Cancer Database was queried for patients with ACC who underwent surgical resection between 2010 and 2017. Patient selection, oncologic outcomes, and overall survival were compared among patients who received an MIS approach (laparoscopic or robotic) versus an open approach. RESULTSA total of 1483 patients underwent ACC resection with 982 (66.2%) patients undergoing an open approach and 501 (33.8%) receiving an MIS operation. The overall utilization of MIS for ACC increased significantly after 2013 (37.7% versus 29.5%, P < 0.01). There was no difference in overall survival between MIS and open resections on univariable (log-rank P = 0.12) analysis. On multivariable analysis, survival was improved in MIS patients versus open resection (Hazard ratio: 0.83, 95% CI: 0.70-0.99). Notably, survival remained comparable among patients who underwent resection for large ACCs (6-10 cm, log-rank P = 0.66) and giant ACCs (>10 cm, log-rank P = 0.24), irrespective of operative approach. CONCLUSIONSOur findings suggest that in appropriately selected patients with ACC, MIS can be performed safely without a significant decrease in overall survival, independent of size. We recommend consideration of a minimally-invasive approach for adrenal masses despite size >6 cm.
Transforming growth factor—β (TGFβ) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical ...trials. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal—regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFβ. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase—1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGFβ signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.
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