How Effective is the Use of Molecular Testing in Preoperative Decision Making for Management of Indeterminate Thyroid Nodules?

INTRODUCTION: We performed Thyroseq v2 molecular testing on indeterminate thyroid nodules and evaluated whether they underwent a management change from the standard of thyroid lobectomy. METHODS: We conducted a retrospective analysis of all indeterminate thyroid nodules that underwent Thyroseq v2 molecular testing from 2014 to 2019 at a large academic center. Pathology was reviewed by thyroid cytopathologists. Thyroseq results were reported benign (malignancy probability less than 10%) or suspicious (malignancy probability greater than 30%). The primary endpoint was a management change from a diagnostic lobectomy. RESULTS: A total of 142 nodules were included: 113 (80%) Bethesda III and 29 (20%) Bethesda IV. Seventy-three nodules underwent surgical management and 69 did not. We noted a change in management in 64% (91/142) of nodules. Patients who underwent a change in management to no surgery had a significantly higher rate of benign Thyroseq result than those without a change (75.8% vs. 49.0%, p = 0.001). On logistic regression analysis, a benign Thyroseq result was a positive independent predictor of a change to no surgery (OR 3.87, 95% CI 1.69-8.89). Nodule size, multiple nodules, compressive symptoms, and history of hypothyroidism were not significant. Of the 91 patients who underwent a management change, 71% (65/91) did not undergo surgery. On follow-up (average 985 ± 615 days), 12% (8/65) of those nodules were growing or developed suspicious features requiring surgery. CONCLUSIONS: Molecular testing helped avoid surgery in almost half our population with indeterminate thyroid nodules, and benign results may help avoid surgery in asymptomatic patients with indeterminate thyroid nodules.

The Role of Surgeon-Performed Office and Preincision Ultrasounds in Localization of Parathyroid Adenomas in Primary Hyperparathyroidism.

OBJECTIVE: We studied the use of surgeon-performed office ultrasound (OU) and preincision ultrasound (PIU) in preoperatively localizing parathyroid adenomas in primary hyperparathyroidism (PHPT). METHODS: A retrospective chart review was performed for patients with PHPT who underwent parathyroidectomy between 2013 and 2015. The results of OU and PIU were recorded and compared with the final surgical pathology. RESULTS: Of 348 patients with PHPT, 285 (81.9%) had single-lesion disease, 49 (14.1%) had double-lesion disease, and 14 (4.0%) had multigland disease with 3 or more lesions. For single-lesion disease, the overall sensitivity and specificity of OU to correctly lateralize the lesion were 64.2% and 91.2%, while those of PIU were 89.4% and 93.6%, respectively. The sensitivity and specificity of PIU were comparable to those of 4-dimensional computed tomography (87.1% and 90.7%, respectively) and 99mTc-sestamibi scintigraphy (70.4% and 95.9%, respectively). While the majority of PIU cases were preceded by other imaging studies, the accuracy in localizing lesions was not largely affected by the presence of prior computed tomography and/or 99mTc-sestamibi scintigraphy, as opposed to ultrasounds only. For detecting the presence of multigland disease, the sensitivity and specificity of OU were 26% and 92.2%, while those of PIU were 64.3% and 94.7%, respectively. CONCLUSION: Surgeon-performed OU and PIU are valuable tools in preoperatively localizing the parathyroid adenoma in single-lesion disease, while their utility may be limited for double-lesion or multigland disease. PIU in particular yields high accuracy in detecting parathyroid lesions in combination with other imaging modalities.

Impacts of an Integrated Medicaid Managed Care Program for Adults with Behavioral Health Conditions: The Experience of Illinois.

This study assessed the impact of the Integrated Care Program (ICP), a new Medicaid managed care model in Illinois, on health services utilization and costs for adults with behavioral health conditions. Data sources included Medicaid claims, encounter records, and state payment data for 28,127 persons with a behavioral health diagnosis. Difference-in-differences models, in conjunction with propensity score weighting, were used to compare utilization and costs between ICP enrollees and a fee-for-service (FFS) comparison group. The model considered the impact of the SMART Act, which restricted access to care for the comparison group. Before the SMART Act, ICP was associated with 2.8 fewer all-cause primary care visits, 34.6 fewer behavioral health-specific outpatient visits, and 2.5 fewer all-cause inpatient admissions per 100 persons per month, and $228 lower total costs per member per month relative to the FFS group. After the SMART Act, ICP enrollees had increased outpatient and dental services utilization without significantly higher costs. The relative increase in utilization was due primarily to decreased utilization in the restricted FFS group after the SMART Act. By the end of the study period, the ICP group had 13.3 more all-cause primary care visits, 1.5 more emergency department visits, and 1.4 more dental visits per 100 persons per month relative to the FFS program. A fully-capitated, integrated managed care program has the potential to reduce overall Medicaid costs for people with behavioral health conditions without negative effects on service utilization.

Metastasis to the Thyroid Gland: A Critical Review.

BACKGROUND: Metastasis to the thyroid gland from nonthyroid sites is an uncommon clinical presentation in surgical practice. The aim of this review was to assess its incidence management and outcomes. METHODS: A literature review was performed to identify reports of metastases to the thyroid gland. Both clinical and autopsy series were included. RESULTS: Metastases to the gland may be discovered at the time of diagnosis of the primary tumor, after preoperative investigation of a neck mass, or on histologic examination of a thyroidectomy specimen. The most common primary tumors in autopsy studies are from the lung. In clinical series, renal cell carcinoma is most common. For patients with widespread metastases in the setting of an aggressive malignancy, surgery is rarely indicated. However, when patients present with an isolated metastasis diagnosed during follow-up of indolent disease, surgery may achieve control of the central neck and even long-term cure. Other prognosticators include features of the primary tumor, time interval between initial diagnosis and metastasis, and extrathyroid extent of disease. CONCLUSIONS: In patients with thyroid metastases, communication among clinicians treating the thyroid and the index primary tumor is essential. The setting is complex, and decisions must be made considering the features of the primary tumor, overall burden of metastases, and comorbidities. Careful balancing of these factors influences individualized approaches.

Genetic-epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity.

Graves disease (GD) is an autoimmune condition caused by interacting genetic and environmental factors. Genetic studies have mapped several single-nucleotide polymorphisms (SNPs) that are strongly associated with GD, but the mechanisms by which they trigger disease are unknown. We hypothesized that epigenetic modifications induced by microenvironmental influences of cytokines can reveal the functionality of GD-associated SNPs. We analyzed genome-wide histone H3 lysine 4 methylation and gene expression in thyroid cells induced by IFNα, a key cytokine secreted during viral infections, and overlapped them with known GD-associated SNPs. We mapped an open chromatin region overlapping two adjacent GD-associated SNPs (rs12101255 and rs12101261) in intron 1 of the thyroid stimulating hormone receptor (TSHR) gene. We then demonstrated that this region functions as a regulatory element through binding of the transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) at the rs12101261 site. Repression by PLZF depended on the rs12101261 disease susceptibility allele and was increased by IFNα. Intrathymic TSHR expression was decreased in individuals homozygous for the rs12101261 disease-associated genotype compared with carriers of the disease-protective allele. Our studies discovered a genetic-epigenetic interaction involving a noncoding SNP in the TSHR gene that regulates thymic TSHR gene expression and facilitates escape of TSHR-reactive T cells from central tolerance, triggering GD.

Mammary analog secretory carcinoma, low-grade salivary duct carcinoma, and mimickers: a comparative study.

Mammary analog secretory carcinoma (MASC) is a recently recognized low-grade salivary carcinoma characterized by a specific ETV6 rearrangement. We describe 14 new MASCs and examine their immunophenotypic and genetic profiles in the context of look-alikes, namely, low-and high-grade salivary duct carcinoma and acinic cell carcinoma. ETV6 rearrangement, and robust expression of mammaglobin and S100, were demonstrated in 11/11, 14/14, and 12/14 MASCs, respectively. All low-grade salivary duct carcinomas coexpressed S100/mammaglobin (6/6); none harbored ETV6 rearrangements (0/5). Given that S100/mammaglobin coexpression and absence of zymogen granules are features of both MASC and low-grade salivary duct carcinoma, these two are best distinguished histologically. The former is predominantly an extraductal neoplasm with bubbly pink cytoplasm, whereas the latter is a distinct intraductal micropapillary and cribriform process. Querying ETV6 gene status may be necessary for difficult cases. No acinic cell carcinoma expressed mammaglobin (0/13) or harbored an ETV6 rearrangement (0/7); only 1/13 acinic cell carcinomas weakly expressed S100. DOG1 expression was limited or absent among all tumor types, except acinic cell carcinoma which expressed DOG1 diffusely in a canalicular pattern. Therefore, histology and immunohistochemistry (mammaglobin, S100, DOG1) suffices in distinguishing acinic cell carcinoma from both MASC and low-grade salivary duct carcinoma. HER2 (ERBB2) amplification was detected in only 1/10 acinic cell carcinomas, but none of the MASCs or low-grade salivary duct carcinomas tested. High-grade salivary duct carcinomas frequently expressed mammaglobin (11/18) and harbored HER2 amplifications (13/15); none harbored ETV6 rearrangements (0/12). High-grade salivary duct carcinomas can easily be distinguished from these other entities by histology and HER2 amplification.

The Mount Sinai clinical pathway for the management of pheochromocytoma.

OBJECTIVE: Pheochromocytomas are complex tumors that require a comprehensive and systematic management plan orchestrated by a multidisciplinary team. METHODS: To achieve these ends, The Mount Sinai Adrenal Center hosted an interdisciplinary retreat where experts in adrenal disorders assembled with the aim of developing a clinical pathway for the management of pheochromocytomas. RESULTS: The result was a consensus for the diagnosis, perioperative management, and postoperative management of pheochromocytomas, with specific recommendations from our team of adrenal experts, as well as a review of the current literature. CONCLUSION: Our clinical pathway can be applied by other institutions directly or may serve as a guide for institution-specific management.

Generating a multimodal artificial intelligence model to differentiate benign and malignant follicular neoplasms of the thyroid: A proof-of-concept study.

BACKGROUND: Machine learning has been increasingly used to develop algorithms that can improve medical diagnostics and prognostication and has shown promise in improving the classification of thyroid ultrasound images. This proof-of-concept study aims to develop a multimodal machine-learning model to classify follicular carcinoma from adenoma. METHODS: This is a retrospective study of patients with follicular adenoma or carcinoma at a single institution between 2010 and 2022. Demographics, imaging, and perioperative variables were collected. The region of interest was annotated on ultrasound and used to perform radiomics analysis. Imaging features and clinical variables were then used to create a random forest classifier to predict malignancy. Leave-one-out cross-validation was conducted to evaluate classifier performance using the area under the receiver operating characteristic curve. RESULTS: Patients with follicular adenomas (n = 7) and carcinomas (n = 11) with complete imaging and perioperative data were included. A total of 910 features were extracted from each image. The t-distributed stochastic neighbor embedding method reduced the dimension to 2 primary represented components. The random forest classifier achieved an area under the receiver operating characteristic curve of 0.76 (clinical only), 0.29 (image only), and 0.79 (multimodal data). CONCLUSION: Our multimodal machine learning model demonstrates promising results in classifying follicular carcinoma from adenoma. This approach can potentially be applied in future studies to generate models for preoperative differentiation of follicular thyroid neoplasms.

The COVID-19 Tracheostomy Experience at a Large Academic Medical Center in New York during the First Year.

Background: New York City was the epicenter of the initial surge of the COVID-19 pandemic in the United States. Tracheostomy is a critical procedure in the care of patients with COVID-19. We hypothesized that early tracheostomy would decrease the length of time on sedation, time on mechanical ventilation, intensive care unit length of stay, and mortality. Methods: A retrospective analysis of outcomes for all patients with COVID-19 who underwent tracheostomy during the first year of the COVID-19 pandemic at the Mount Sinai Hospital in New York City, New York. All adult intensive care units at the Mount Sinai Hospital, New York. Patients/subjects: 888 patients admitted to intensive care with COVID-19. Results: All patients admitted to the intensive care unit with COVID-19 (888) from 1 March 2020 to 1 March 2021 were analyzed and separated further into those intubated (544) and those requiring tracheostomy (177). Of those receiving tracheostomy, outcomes were analyzed for early (≤12 days) or late (>12 days) tracheostomy. Demographics, medical history, laboratory values, type of oxygen and ventilatory support, and clinical outcomes were recorded and analyzed. Conclusions: Early tracheostomy resulted in reduced duration of mechanical ventilation, reduced hospital length of stay, and reduced intensive care unit length of stay in patients admitted to the intensive care unit with COVID-19. There was no effect on overall mortality.

Neuromonitoring in thyroidectomy: a meta-analysis of effectiveness from randomized controlled trials.

Neuromonitoring in thyroid surgery has been employed to make nerve identification easier and decrease the rates of laryngeal nerve injuries. Several individual randomized controlled trials (RCTs) have been published, which did not identify statistical differences in the rates of recurrent laryngeal nerve (RLN) or external branch of the superior laryngeal nerve (EBSLN) injuries. The objective of this report is to perform meta-analysis of the combined results of individual studies to measure the frequency of RLN and EBSLN injuries in patients who underwent thyroidectomy with routine neuromonitoring in comparison with common practice of search and identification. RCTs comparing routine neuromonitoring versus no use in patients who underwent elective partial or total thyroidectomy were evaluated. Outcomes measured were temporary and definitive palsy of the RLN and EBSLN. A systematic review and meta-analysis was done using random effects model. GRADE was used to classify quality of evidence. Six studies with 1,602 patients and 3,064 nerves at risk were identified. Methodological quality assessment showed high risk of bias in most items. Funnel plot did not reveal publication bias. The risk difference for temporary RLN palsy, definitive RLN palsy, temporary EBSLN palsy, and definitive EBSLN palsy were -2% (95% confidence interval -5.1 to 1); 0% (-1 to 1); -9% (-15 to -2) and -1% (-4 to 2), respectively. Quality was rated low or very low in most outcomes due to methodological flaws. Meta-analysis did not demonstrate a statistically significant decrease in the risk of temporary or definitive RLN injury and definitive EBSLN injury with the use of neuromonitoring. The neuromonitoring group had a statistically significant decrease in the risk of temporary EBSLN injury.

Neuromonitoring of the laryngeal nerves in thyroid surgery: a critical appraisal of the literature.

One of the most significant complication of thyroid surgery is injury of the recurrent laryngeal nerve. Injury of the external branch of the superior laryngeal nerve is a less obvious but occasionally significant problem. Recently, neuromonitoring during thyroidectomy has received considerable attention because of literature encouraging its use, but there is no consensus about its advantages and utility. A critical assessment of the literature on neuromonitoring was conducted in order to define its effectiveness, safety, cost-effectiveness and medical-legal impact. Available data does not show results superior to those obtained by traditional anatomical methods of nerve identification during thyroid surgery. Data about cost-effectiveness is scarce. The literature shows inconsistencies in methodology, patient selection and randomization in various published studies which may confound the conclusions of individual investigations. The current recommendation for use in "high risk" patients should be assessed because definition heterogeneity makes identification of these patients difficult. As routine use of neuromonitoring varies according to geography, its use should not be considered to be the standard of care.

Adolescent Perceptions of Adult-Mediated Healthcare Communication.

Adolescence is a time of rapid growth and development and may be accompanied by increased risk-taking behaviors and independence. Youth are particularly at risk for high levels of stress, decreased physical activity, unsafe sexual activity, abuse, depression, and suicide. Considering the unique health risks adolescents face, healthcare service access and utilization can play a pivotal role in promoting positive long term health outcomes throughout adulthood. At the same time, adolescents must often rely on parents/caregivers to mediate their healthcare access. Understanding how adolescents perceive adult interactions within healthcare is important for developing interventions that increase youth access to healthcare. We found that adolescents perceived adult-mediated healthcare experiences as either supportive (Subthemes: Recognition Builds Trust and Validation) or unsupportive (Subthemes: Adult-Focused Communication and Lack of Privacy). Based on our findings, we argue that prevention-focused interventions should include communication-based strategies. We discuss social work and healthcare practice and policy implications of these findings.

Management of Recurrent Well-Differentiated Thyroid Carcinoma in the Neck: A Comprehensive Review.

Surgery has been historically the preferred primary treatment for patients with well-differentiated thyroid carcinoma and for selected locoregional recurrences. Adjuvant therapy with radioactive iodine is typically recommended for patients with an intermediate to high risk of recurrence. Despite these treatments, locally advanced disease and locoregional relapses are not infrequent. These patients have a prolonged overall survival that may result in long periods of active disease and the possibility of requiring subsequent treatments. Recently, many new options have emerged as salvage therapies. This review offers a comprehensive discussion and considerations regarding surgery, active surveillance, radioactive iodine therapy, ultrasonography-guided percutaneous ablation, external beam radiotherapy, and systemic therapy for well-differentiated thyroid cancer based on relevant publications and current reference guidelines. We feel that the surgical member of the thyroid cancer management team is empowered by being aware and facile with all management options.

Long-term safety and efficacy of clobazam for Lennox-Gastaut syndrome: interim results of an open-label extension study.

In an ongoing open-label extension (OV-1004), patients with Lennox-Gastaut syndrome who had completed 1 of 2 randomized controlled trials (OV-1002 [Phase II] or OV-1012 [Phase III]) are receiving clobazam at dosages ≤2.0 mg/kg/day (≤80 mg/day). Of 306 eligible patients from OV-1002 or OV-1012, 267 entered the open-label extension. As of the interim date, July 1, 2010, 213 patients (79.8%) had remained in the trial, and 189 had received clobazam for ≥12 months, 128 for ≥18 months, and 94 for ≥24 months. Median percentage decreases in average weekly rates of drop seizures were 71.1% and 91.6% at Months 3 and 24. Mean modal and mean maximum daily dosages were 0.94 mg/kg and 1.22 mg/kg for those who had received clobazam for ≥1 year. The 4 most common adverse events were upper respiratory tract infection (18.4%), fall (14.2%), pneumonia (13.9%), and somnolence (12.7%). Clobazam's adverse event profile was consistent with its profile in controlled trials.

The surgical management of renal hyperparathyroidism.

Secondary and tertiary hyperparathyroidism (HPT) develop in patients with renal failure due to a variety of mechanisms including increased phosphorus and fibroblast growth factor 23 (FGF23), and decreased calcium and 1,25-dihydroxy vitamin D levels. Patients present with various bone disorders, cardiovascular disease, and typical laboratory abnormalities. Medical treatment consists of controlling hyperphosphatemia, vitamin D/analog and calcium administration, and calcimimetic agents. Improved medical therapies have led to a decrease in the use of parathyroidectomy (PTX). The surgical indications include parathyroid hormone (PTH) levels >800 pg/ml associated with hypercalcemia and/or hyperphosphatemia despite medical therapy. Other indications include calciphylaxis, fractures, bone pain or pruritis. Transplant recipients often show decreased PTH, calcium and phosphorus levels, but some will have persistent HPT. Evidence suggests that PTX may cause deterioration in renal graft function in the short-term calling into the question the indications for PTX in these patients. Pre-operative imaging is only occasionally helpful except in re-operative PTX. Operative approaches include subtotal PTX, total PTX with or without autotransplantation, and possible thymectomy. Each approach has its proponents, advantages and disadvantages which are discussed. Intraoperative PTH monitoring has a high positive predictive value of cure but a poor negative predictive value and therefore is of limited utility. Hypocalcemia is the most common complication requiring aggressive calcium administration. Benefits of surgery may include improved survival, bone mineral density and alleviation of symptoms.

Hierarchically Multivalent Peptide-Nanoparticle Architectures: A Systematic Approach to Engineer Surface Adhesion.

The multivalent binding effect has been the subject of extensive studies to modulate adhesion behaviors of various biological and engineered systems. However, precise control over the strong avidity-based binding remains a significant challenge. Here, a set of engineering strategies are developed and tested to systematically enhance the multivalent binding of peptides in a stepwise manner. Poly(amidoamine) (PAMAM) dendrimers are employed to increase local peptide densities on a substrate, resulting in hierarchically multivalent architectures (HMAs) that display multivalent dendrimer-peptide conjugates (DPCs) with various configurations. To control binding behaviors, effects of the three major components of the HMAs are investigated: i) poly(ethylene glycol) (PEG) linkers as spacers between conjugated peptides; ii) multiple peptides on the DPCs; and iii) various surface arrangements of HMAs (i.e., a mixture of DPCs each containing different peptides vs DPCs cofunctionalized with multiple peptides). The optimized HMA configuration enables significantly enhanced target cell binding with high selectivity compared to the control surfaces directly conjugated with peptides. The engineering approaches presented herein can be applied individually or in combination, providing guidelines for the effective utilization of biomolecular multivalent interactions using DPC-based HMAs.

Bimodal liquid biopsy for cancer immunotherapy based on peptide engineering and nanoscale analysis.

Despite its high potential, PD-L1 expressed by tumors has not been successfully utilized as a biomarker for estimating treatment responses to immunotherapy. Circulating tumor cells (CTCs) and tumor-derived exosomes that express PD-L1 can potentially be used as biomarkers; however, currently available assays lack clinically significant sensitivity and specificity. Here, a novel peptide-based capture surface is developed to effectively isolate PD-L1-expressing CTCs and exosomes from human blood. For the effective targeting of PD-L1, this study integrates peptide engineering strategies to enhance the binding strength and specificity of a ß-hairpin peptide derived from PD-1 (pPD-1). Specifically, this study examines the effect of poly(ethylene glycol) spacers, the secondary peptide structure, and modification of peptide sequences (e.g., removal of biologically redundant amino acid residues) on capture efficiency. The optimized pPD-1 configuration captures PD-L1-expressing tumor cells and tumor-derived exosomes with 1.5-fold (p = 0.016) and 1.2-fold (p = 0.037) higher efficiencies, respectively, than their whole antibody counterpart (aPD-L1). This enhanced efficiency is translated into more clinically significant detection of CTCs (1.9-fold increase; p = 0.035) and exosomes (1.5-fold increase; p = 0.047) from patients' baseline samples, demonstrating stronger correlation with patients' treatment responses. Additionally, we confirmed that the clinical accuracy of our system can be further improved by co-analyzing the two biomarkers (bimodal CTC/exosome analysis). These data demonstrate that pPD-1-based capture is a promising approach for capturing PD-L1-expressing CTCs and exosomes, which can be used as a reliable biomarker for cancer immunotherapy.

Reply to "industry-informed perspectives on the benefits of rideshare-based medical transportation".

The authors of "Rideshare Transportation to Health Care: Evidence From a Medicaid Implementation" respond to a letter to the editor.

Primary hyperparathyroidism: Disease of diverse genetic, symptomatic, and biochemical phenotypes.

Genetic, symptomatic, and biochemical heterogeneity of patients with primary hyperparathyroidism (PHPT) has become apparent in recent years. An in-depth, evidence-based review of the phenotypes of PHPT was conducted. This review was intended to provide the resulting information to surgeons who operate on patients with hyperparathyroidism. This review revealed that the once relatively clear distinction between familial and sporadic PHPT has become more challenging by the finding of various germline mutations in patients with seemingly sporadic PHPT. On the one hand, the genetic and clinical characteristics of some syndromes in which PHPT is an important component are now better understood. On the other hand, knowledge is emerging about novel syndromes, such as the rare multiple endocrine neoplasia type IV (MEN4), in which PHPT occurs frequently. It also revealed that, currently, the classical array of symptoms of PHPT is seen rarely upon initial presentation for evaluation. More common are nonspecific, nonclassical symptoms and signs of PHPT. In areas of the world where serum calcium levels are checked routinely, most patients today are "asymptomatic" and they are diagnosed after an incidental finding of hypercalcemia; however, some of them have subclinical involvement of bones and kidneys, which is demonstrated on radiographs, ultrasound, and modern imaging techniques. Last, the review points out that there are three distinct biochemical phenotypes of PHPT. The classical phenotype in which calcium and parathyroid hormone levels are both elevated, and other disease presentations in which the serum levels of calcium or intact parathyroid hormone are normal. Today several, distinct phenotypes of the disease can be identified, and they have implications in the diagnostic evaluation and treatment of patients, as well as possible screening of relatives.