Clinical characteristics and outcomes of adrenal hemorrhage.

BACKGROUND: Although uncommon, adrenal hemorrhage has multiple etiologies. Because clinical characteristics, management, and outcomes of patients with adrenal hemorrhage are inadequately described, we examined the underlying etiology, need for intervention, evolution of imaging characteristics, and adequacy of subsequent evaluation. METHODS: We performed a retrospective review of patients diagnosed with adrenal hemorrhage (radiologist-confirmed density consistent with hemorrhage on computed tomography) from 2005 to 2021 at a university-based institution. Demographic characteristics, hemorrhage etiology, and subsequent follow-up were analyzed. RESULTS: Of 193 adrenal hemorrhage patients, the mean age was 49.2 ± 18.3 years, and 35% were female. Clinical presentations included trauma (47%), abdominal or flank pain (28%), incidental findings on imaging acquired for other reasons (12%), postoperative complication (8%), or shock (3%). Hemorrhage outside of the gland was present in 62% of patients. Unilateral hemorrhage was more frequent (93%) than bilateral (7%). A total of 12% of patients had nodules, but only 70% of these were identified on initial imaging, and only 43% had hormonal evaluation. Of 7 patients who had adrenalectomy or biopsy, pathology was either benign (57%) or nonadrenal malignancy (43%). No adrenocortical carcinomas were identified. Follow-up imaging was performed in 56% of patients and revealed decreased, stable, resolved, or increased adrenal hemorrhage size in 39%, 19%, 30%, and 12% of patients, respectively. CONCLUSION: Adrenal hemorrhage is secondary to multiple etiologies, most commonly trauma. In the setting of adrenal hemorrhage, many adrenal nodules were not identified on initial imaging. Only a minority of patients with nodules underwent "complete" biochemical evaluation. Follow-up imaging may improve the identification of underlying nodules needing hormonal evaluation.

Bioengineered in vitro three-dimensional tumor models in endocrine cancers.

Abstract: Endocrine tumors are a heterogeneous cluster of malignancies that originate from cells that can secrete hormones. Examples include, but are not limited to, thyroid cancer, adrenocortical carcinoma, and neuroendocrine tumors. Many endocrine tumors are relatively slow to proliferate, and as such, they often do not respond well to common antiproliferative chemotherapies. Therefore, increasing attention has been given to targeted therapies and immunotherapies in these diseases. However, in contrast to other cancers, many endocrine tumors are relatively rare, and as a result, less is understood about their biology, including specific targets for intervention. Our limited understanding of such tumors is in part due to a limitation in model systems that accurately recapitulate and enable mechanistic exploration of these tumors. While mouse models and 2D cell cultures exist for some endocrine tumors, these models often may not accurately model nuances of human endocrine tumors. Mice differ from human endocrine physiology and 2D cell cultures fail to recapitulate the heterogeneity and 3D architectures of in vivo tumors. To complement these traditional cancer models, bioengineered 3D tumor models, such as organoids and tumor-on-a-chip systems, have advanced rapidly in the past decade. However, these technologies have only recently been applied to most endocrine tumors. In this review we provide descriptions of these platforms, focusing on thyroid, adrenal, and neuroendocrine tumors and how they have been and are being applied in the context of endocrine tumors.

Heterogeneous parathyroid near-infrared autofluorescence patterns are associated with single adenomas in primary hyperparathyroidism.

BACKGROUND: Primary adenoma (PA) and multi-gland hyperplasia (MGH) account for 85% and 15% of primary hyperparathyroidism (PHPT) cases, respectively. Near-infrared autofluorescence (NIRAF) enhances intraoperative parathyroid identification. We hypothesized that PA would display a more heterogeneous NIRAF pattern compared to MGH. METHODS: Patients undergoing surgery for sporadic PHPT were categorized based on the presence of PA or MGH. To quantify heterogeneity, we utilized ratios of (1) mean parathyroid gland (PG) NIRAF over background NIRAF (mean ratio), (2) minimum and (3) maximum PG NIRAF over mean PG NIRAF (minimum and maximum ratios). Additionally, a heterogeneity score was quantified using mean ratio (mean PG NIRAF over background NIRAF), and overall NIRAF (mean NIRAF of eight random 15 × 15 pixel areas). A point was assigned to ratios <0.8 or >1.2. Images were quantified by ImageJ software. Mann-Whitney test was performed for all comparisons. RESULTS: Of 78 patients, 63 had a single PA and 15 had MGH, totaling 102 PGs. There was no difference between their mean ratios. PA had a lower minimum ratio compared to that of MGH (0.86 ± 0.01 vs. 0.93 ± 0.01, p = 0.001) and a brighter maximum ratio (1.21 ± 0.02 vs. 1.12 ± 0.01, p = 0.0008). PA also scored higher on their heterogeneity scores compared to MGH (1.27 ± 0.23 vs. 0.33 ± 0.15, p = 0.001). CONCLUSION: Single parathyroid adenomas display a more heterogeneous autofluorescence pattern compared to that of multi-gland hyperplasia. Intraoperative characterization of PGs by real-time NIR imaging patterns may be a beneficial adjunct during parathyroid surgery.

A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity.

Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture. Organoids and other small 3D in vitro models of tissues or tumors can model certain complexities of human in vivo biology; however, this technology has largely yet to be applied to ACC. In this study, we describe the generation of 3D tumor constructs from an established ACC cell line, NCI-H295R. NCI-H295R cells were encapsulated to generate 3D ACC constructs. Tumor constructs were assessed for biomarker expression, viability, proliferation, and cortisol production. In addition, matrix metalloproteinase (MMP) functionality was assessed directly using fluorogenic MMP-sensitive biosensors and through infusion of NCI-H295R cells into a metastasis-on-a-chip microfluidic device platform. ACC tumor constructs showed expression of biomarkers associated with ACC, including SF-1, Melan A, and inhibin α. Treatment of ACC tumor constructs with chemotherapeutics demonstrated decreased drug sensitivity compared to 2D cell culture. Since most tumor cells migrate through tissue using MMPs to break down extracellular matrix, we validated the utility of ACC tumor constructs by integrating fluorogenic MMP-sensitive peptide biosensors within the tumor constructs. Lastly, in our metastasis-on-a-chip device, NCI-H295R cells successfully engrafted in a downstream lung cell line-based construct, but invasion distance into the lung construct was decreased by MMP inhibition. These studies, which would not be possible using 2D cell cultures, demonstrated that NCI-H295R cells secreted active MMPs that are used for invasion in 3D. This work represents the first evidence of a 3D tumor constructs platform for ACC that can be deployed for future mechanistic studies as well as development of new targets for intervention and therapies.

Adrenal Near-Infrared Autofluorescence.

Context: Parathyroid tissue is one of the few tissues to have strong near-infrared (NIR) autofluorescence, which has been exploited to improve intraoperative parathyroid identification. The US Food and Drug Administration has approved 2 devices for this purpose. Adrenal glands can be difficult to distinguish from surrounding fat, an issue during total adrenalectomy. Objective: We hypothesized adrenal tissue may also possess considerable NIR autofluorescence. Methods: Resected patient adrenal specimens were examined after robotic adrenalectomy with an NIR camera intraoperatively. Patients did not receive fluorescent dye. Images were taken of both gross and sectioned specimens. Post hoc image analysis was performed with ImageJ software. Confocal microscopy was performed on selected tissues using immunofluorescence and hematoxylin-eosin staining. Results: Resected tissue was examined from 22 patients undergoing surgery for pheochromocytomas (6), primary aldosteronism (3), adrenocorticotropin-independent hypercortisolism (10), and a growing or suspicious mass (3). Normal adrenal tissue demonstrated strong NIR autofluorescence. The intensity ratio compared to background (set as 1) for gross images was 2.03 ±â€…0.51 (P < .0001) compared to adjacent adipose of 1.24 ±â€…0.18. Autofluorescence from adrenal tumors was also detected at variable levels of intensity. Cortisol-producing tumors had the highest fluorescence ratio of 3.01 ±â€…0.41. Confocal imaging localized autofluorescence to the cytosol, with the highest intensity in the zona reticularis followed by the zona fasciculata. Conclusion: Normal and abnormal adrenal tissues possess natural NIR autofluorescence. Highest autofluorescence levels were associated with cortisol-producing tumors. Confocal imaging demonstrated the highest intensity in the zona reticularis. NIR cameras may have the potential to improve identification of adrenal tissue during surgery.

Smaller parathyroids have higher near-infrared autofluorescence intensity in hyperparathyroidism.

BACKGROUND: Intraoperative parathyroid gland identification can be challenging. Parathyroid glands have an intrinsic autofluorescence when excited by wavelengths in the near-infrared region. Studies using near-infrared cameras to detect parathyroid gland near-infrared autofluorescence have suggested improved identification. The pathologic parathyroid glands in primary hyperparathyroidism have variable near-infrared autofluorescence intensity, but how this correlates with different characteristics of hyperparathyroidism is unknown. Our objective was to correlate the fluorescent intensity of excited glands with clinical variables to enhance a surgeon's ability to identify parathyroid glands. METHODS: The data on patients undergoing surgery for primary hyperparathyroidism were collected. The images were collected intraoperatively with a handheld near-infrared device and analyzed. The data consisted of the ratio of mean parathyroid gland near-infrared autofluorescence over background (white gauze) near-infrared autofluorescence. The variables assessed for correlation with autofluorescence intensity were gland volume and weight, preoperative serum calcium and parathyroid hormone, age, body mass index, and sex. The images were quantified by Image J software (National Institutes of Health, Bethesda, MD). The lasso regression was analyzed by R version 4.1.3 to calculate adjusted P values (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: From 2017 to 2021, 131 patients with primary hyperparathyroidism underwent parathyroidectomies of 151 parathyroid glands. The mean near-infrared autofluorescence intensity of parathyroid glands had a negative correlation with weight with lighter glands fluorescing more (P = .019) and a positive correlation with age with glands from older patients fluorescing more (P = .013). There were no significant correlations with preoperative serum calcium and parathyroid hormone, body mass index, and sex (P > .05). CONCLUSION: In patients with primary hyperparathyroidism, we found that autofluorescence intensity correlated with parathyroid gland weight and patient age. This suggested that near-infrared camera use may be particularly helpful in identifying smaller adenomas and in older patients.

Near-infrared Autofluorescence Features of Parathyroid Carcinoma.

Introduction: Parathyroid carcinoma is very rare, and intraoperative definitive diagnosis can be elusive with currently available diagnostics. Near-infrared (NIR) autofluorescence is an emerging tool that identifies parathyroid glands in real time. It is not known whether NIR autofluorescence can detect parathyroid carcinoma intraoperatively. Methods: Patients with preoperative suspicion for parathyroid carcinoma were identified from ongoing studies examining parathyroid autofluorescence with a NIR camera and probe. Specimens from these patients were examined intraoperatively to determine their autofluorescence patterns. Results: Three patients with suspected parathyroid carcinoma were identified preoperatively. Intraoperative NIR autofluorescence imaging showed a relative lack of autofluorescence for all cases, in contrast to parathyroid adenomas and normal parathyroid glands, which typically exhibit significant autofluorescence. Final pathology confirmed parathyroid carcinoma in all cases. Conclusion: Parathyroid carcinoma can be difficult to confirm prior to final pathology review. Our 3 cases suggest that absence of NIR autofluorescence may suggest the likelihood of parathyroid carcinoma, but more studies are needed to investigate this experience.

Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling.

Vertical sleeve gastrectomy (VSG) results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium; however, the mechanism remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the nuclear bile acid receptor farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express EGFP in ISC/progenitor cells and performed RNA-Seq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by glucagon-like peptide-1, GLP-1) in mouse intestinal organoids following treatment with bile acids, an FXR agonist, and an FXR antagonist. RNA-Seq of ISCs revealed that bile acid receptors are expressed in ISCs and that VSG explicitly alters expression of several genes that regulate EEC differentiation. Mouse intestinal organoids treated with bile acids and 2 different FXR agonists increased GLP-1-positive cell numbers, and administration of an FXR antagonist blocked these effects. Taken together, these data indicate that VSG drives ISC fate toward EEC differentiation through bile acid signaling.

Ambiguous and Incomplete: Natural Language Processing Reveals Problematic Reporting Styles in Thyroid Ultrasound Reports.

OBJECTIVE: Natural language processing (NLP) systems convert unstructured text into analyzable data. Here, we describe the performance measures of NLP to capture granular details on nodules from thyroid ultrasound (US) reports and reveal critical issues with reporting language. METHODS: We iteratively developed NLP tools using clinical Text Analysis and Knowledge Extraction System (cTAKES) and thyroid US reports from 2007 to 2013. We incorporated nine nodule features for NLP extraction. Next, we evaluated the precision, recall, and accuracy of our NLP tools using a separate set of US reports from an academic medical center (A) and a regional health care system (B) during the same period. Two physicians manually annotated each test-set report. A third physician then adjudicated discrepancies. The adjudicated "gold standard" was then used to evaluate NLP performance on the test-set. RESULTS: A total of 243 thyroid US reports contained 6,405 data elements. Inter-annotator agreement for all elements was 91.3%. Compared with the gold standard, overall recall of the NLP tool was 90%. NLP recall for thyroid lobe or isthmus characteristics was: laterality 96% and size 95%. NLP accuracy for nodule characteristics was: laterality 92%, size 92%, calcifications 76%, vascularity 65%, echogenicity 62%, contents 76%, and borders 40%. NLP recall for presence or absence of lymphadenopathy was 61%. Reporting style accounted for 18% errors. For example, the word "heterogeneous" interchangeably referred to nodule contents or echogenicity. While nodule dimensions and laterality were often described, US reports only described contents, echogenicity, vascularity, calcifications, borders, and lymphadenopathy, 46, 41, 17, 15, 9, and 41% of the time, respectively. Most nodule characteristics were equally likely to be described at hospital A compared with hospital B. CONCLUSIONS: NLP can automate extraction of critical information from thyroid US reports. However, ambiguous and incomplete reporting language hinders performance of NLP systems regardless of institutional setting. Standardized or synoptic thyroid US reports could improve NLP performance.

Thyroid cancer, recent advances in diagnosis and therapy.

Over the past several decades, the approach to the diagnosis and management of patients with follicular cell-derived thyroid cancer has evolved based on improved classification of patients better matching clinical outcomes, as well as advances in imaging, laboratory, molecular technologies and knowledge. While thyroid surgery, radioactive iodine therapy and TSH suppression remain the mainstays of treatment, this expansion of knowledge has enabled de-escalation of therapy for individuals diagnosed with low-risk well-differentiated thyroid cancer; better definition of treatment choices for patients with more aggressive disease; and improved ability to optimize treatments for patients with persistent and/or progressive disease. Most recently, the advancement of knowledge regarding the molecular aspects of thyroid cancer has improved thyroid cancer diagnosis and has enabled individualized therapeutic options for selected patients with the most aggressive forms of the disease. Guidelines from multiple societies across the world reflect these changes, which focus on taking a more individualized approach to clinical management. In this review, we discuss the current more personalized approach to patients with follicular cell-derived thyroid cancer and point toward areas of future research still needed in the field.

Thyroid Ultrasound Reports: Will the Thyroid Imaging, Reporting, and Data System Improve Natural Language Processing Capture of Critical Thyroid Nodule Features?

BACKGROUND: Critical thyroid nodule features are contained in unstructured ultrasound (US) reports. The Thyroid Imaging, Reporting, and Data System (TI-RADS) uses five key features to risk stratify nodules and recommend appropriate intervention. This study aims to analyze the quality of US reporting and the potential benefit of Natural Language Processing (NLP) systems in efficiently capturing TI-RADS features from text reports. MATERIALS AND METHOD: This retrospective study used free-text thyroid US reports from an academic center (A) and community hospital (B). Physicians created "gold standard" annotations by manually extracting TI-RADS features and clinical recommendations from reports to determine how often they were included. Similar annotations were created using an automated NLP system and compared with the gold standard. RESULTS: Two hundred eighty-two reports contained 409 nodules at least 1-cm in maximum diameter. The gold standard identified three nodules (0.7%) which contained enough information to calculate a complete TI-RADS score. Shape was described most often (92.7% of nodules), whereas margins were described least often (11%). A median number of two TI-RADS features are reported per nodule. The NLP system was significantly less accurate than the gold standard in capturing echogenicity (27.5%) and margins (58.9%). One hundred eight nodule reports (26.4%) included clinical management recommendations, which were included more often at site A than B (33.9 versus 17%, P < 0.05). CONCLUSIONS: These results suggest a gap between current US reporting styles and those needed to implement TI-RADS and achieve NLP accuracy. Synoptic reporting should prompt more complete thyroid US reporting, improved recommendations for intervention, and better NLP performance.

Hormonal Evaluation of Incidental Adrenal Masses: The Exception, Not the Rule.

BACKGROUND: Incidental adrenal masses (IAMs) occur in approximately 4% of patients undergoing abdominal CT scans for any indication. Hormonal evaluation is recommended for all IAMs. The purpose of this study was to identify the rate of IAMs in a screening population and to determine the adequacy of endocrine evaluation of newly identified IAMs based on established guidelines. METHODS: This was a retrospective analysis of 6913 patients undergoing a non-contrast screening CT colonography at a single academic medical center between June 2004 and July 2012. RESULTS: The prevalence of IAMs in this asymptomatic screening population was 2.1% (n = 148). Of those patients, 8.8% (n = 11) underwent some form of hormonal evaluation and only 6.4% (n = 8) patients had a "complete" workup. Cortisol, metanephrines, and an aldosterone-renin ratio were evaluated in 8.0%, 7.2%, and 4.0% of patients, respectively. Of the patients (n = 11) who underwent hormonal evaluation, 27.3% had functional masses and 36.4% underwent surgery. Of those who did not have hormonal evaluation, 42.1% (n = 48) had comorbidities that should have prompted hormonal evaluation based on established guidelines. Hormonal evaluation was not performed in 89.4% of patients with hypertension and 21.1% of patients with diabetes. 88.9% of patients on three or more antihypertensive medications did not undergo any hormonal evaluation. CONCLUSIONS: Compliance with IAM workup guidelines is poor, which may result in missed diagnosis of functional adrenal masses. Establishment of a robust protocol and education on appropriate workup for IAMs is necessary for adequate hormonal evaluation.

COVID-19 Pandemic and Surgical Oncology: Preserving the Academic Mission.

BACKGROUND: The global pandemic of respiratory disease cause by the novel human coronavirus (SARS-CoV-2) has caused untold suffering, loss of life and upheaval in society. The pandemic has lead to massive redirection of health care resources to treat the surge of COVID-19 patients, and enforcement of social distancing to reduce the rate of transmission. METHODS: Editorial Board members provided observations of the implications of the pandemic on academic surgical oncology. RESULTS: Delivery of health care to other populations including cancer patients has been significantly disrupted. The implications both short term and long term threaten preservation of the academic mission in medicine at large, and certainly in the field of surgical oncology. CONCLUSIONS: The effects on surgical oncology training, research and clinical trials are major.

Outcomes after completion thyroidectomy versus total thyroidectomy for differentiated thyroid cancer: A single-center experience.

BACKGROUND: Thyroid cancer diagnoses are often discovered after diagnostic thyroid lobectomy. Completion thyroidectomy (CT) may be indicated for intermediate or high-risk tumors to facilitate surveillance and/or adjuvant treatment. The completeness of thyroid resection and the safety of CT compared to total thyroidectomy (TT) is unclear. We assessed outcomes after TT or CT to determine completeness of resection and risk of complications. METHODS: Patients undergoing TT or CT between 2000 and 2018 were retrospectively reviewed. Pathology, unstimulated thyroglobulin (uTg), parathyroid hormone (PTH), rates of hematoma, and recurrent laryngeal nerve (RLN) injury were compared. RESULTS: Differentiated thyroid cancer (DTC) was identified in 954 patients undergoing TT and 142 patients undergoing CT. Postoperative uTg at 6 months was not different between TT and CT, 0.2 vs 0.2 ng/mL, P = .37. Transient hypoparathyroidism with immediate postoperative PTH less than 10 was more common after TT, 14.3 vs 6.0% (P = .009). No differences were noted regarding postoperative hematoma, transient RLN injury, permanent hypoparathyroidism, and permanent RLN injury. CONCLUSIONS: If CT is required for DTC, a complete resection, as assessed by postoperative uTg, can be achieved. Furthermore, CT is significantly less likely to result in transient hypoparathyroidism and poses no additional risk of RLN injury, hematoma, or permanent hypoparathyroidism.

Telemedicine: Patient-Provider Clinical Engagement During the COVID-19 Pandemic and Beyond.

BACKGROUND: The novel coronavirus pandemic has drastically affected healthcare organizations across the globe. METHODS: We sought to summarize the current telemedicine environment in order to highlight the important changes triggered by the novel coronavirus pandemic, as well as highlight how the current crisis may inform the future of telemedicine. RESULTS: At many institutions, the number of telemedicine visits dramatically increased within days following the institution of novel coronavirus pandemic restrictions on in-person clinical encounters. Prior to the pandemic, telemedicine utilization was weak throughout surgical specialties due to regulatory and reimbursement barriers. As part of the pandemic response, the USA government temporarily relaxed various telemedicine restrictions and provided additional telemedicine funding. DISCUSSION: The post-pandemic role of telemedicine is dependent on permanent regulatory solutions. In the coming decade, telemedicine and telesurgery are anticipated to mature due to the proliferation of interconnected consumer health devices and high-speed 5G data connectivity.