Faculty Bibliography

CONTEXT/BACKGROUND:The biochemical basis for clinical variability in primary hyperparathyroidism (PHPT) is poorly understood. OBJECTIVES/OBJECTIVE:To define parathyroid tumor biochemical properties associated with calcium sensing failure in PHPT patients, and to relate differences in these profiles to variations in clinical presentation. DESIGN/METHODS:Pre-operative clinical data were evaluated for correlation to parathyroid tumor biochemical behavior. SETTING/METHODS:An endocrine surgery referral center at a large, public university hospital. PATIENTS AND OTHER PARTICIPANTS/METHODS:A sequential series of 39 patients undergoing surgery for PHPT. MAIN OUTCOME MEASURES/METHODS:An intact tissue, ex vivo interrogative assay was employed to evaluate the calcium-sensing capacity of parathyroid adenomas relative to normal donor glands. Tumors were functionally classified based on calcium dose-response curve profiles, and clinical parameters were compared among the respective classes. Changes in the relative expression of CASR, RGS5, and RCAN1, three key components in the calcium/PTH signaling axis were evaluated as potential mechanisms for calcium-sensing failure. RESULTS:Parathyroid adenomas grouped into three distinct functional classes. Tumors with diminished calcium sensitivity were the most common (18 of 39) and were strongly associated with reduced bone mineral density (p=0.0009). Tumors with no calcium sensing deficit (11 of 39) were associated with higher pre-operative PTH (p = 0.036). A third group (6/39) displayed a non-sigmoid calcium/PTH response curve; four of these six tumors expressed elevated RCAN1. CONCLUSIONS:Calcium-sensing capacity varies among parathyroid tumors but down-regulation of the calcium sensing receptor (CASR) is not an obligate underlying mechanism. Differences in tumor calcium responsiveness may contribute to variations in PHPT clinical presentation.

BACKGROUND:Primary hyperparathyroidism is associated with substantial morbidity, including osteoporosis, nephrolithiasis, and chronic kidney disease. Parathyroidectomy can prevent these sequelae but is poorly utilized in many practice settings. METHODS:We performed a retrospective cohort study using the national Optum de-identified Clinformatics Data Mart Database. We identified patients aged ≥35 with a first observed primary hyperparathyroidism diagnosis from 2004 to 2016. Multivariable logistic regression was used to determine patient/provider characteristics associated with parathyroidectomy. RESULTS:Of 26,522 patients with primary hyperparathyroidism, 10,101 (38.1%) underwent parathyroidectomy. Of the 14,896 patients with any operative indication, 5,791 (38.9%) underwent parathyroidectomy. Over time, there was a decreasing trend in the rate of parathyroidectomy overall (2004: 54.4% to 2016: 32.4%, P < .001) and among groups with and without an operative indication. On multivariable analysis, increasing age and comorbidities were strongly, inversely associated with parathyroidectomy (age 75-84, odds ratio 0.50 [95% confidence interval 0.45-0.55]; age ≥85, odds ratio 0.21 [95% confidence interval 0.17-0.26] vs age 35-49; Charlson Comorbidity Index ≥2 vs 0 odds ratio 0.62 [95% confidence interval 0.58-0.66]). CONCLUSION/CONCLUSIONS:The majority of US privately insured patients with primary hyperparathyroidism are not treated with parathyroidectomy. Having an operative indication only modestly increases the likelihood of parathyroidectomy. Further research is needed to address barriers to treatment and the gap between guidelines and clinical care in primary hyperparathyroidism.

Importance/UNASSIGNED:Parathyroidectomy provides definitive management for primary hyperparathyroidism (PHPT), reducing the risk of subsequent fracture, nephrolithiasis, and chronic kidney disease (CKD), but its use among older adults in the US is unknown. Objective/UNASSIGNED:To identify patient characteristics associated with the use of parathyroidectomy for the management of PHPT in older adults. Design, Setting, and Participants/UNASSIGNED:This population-based, retrospective cohort study used 100% Medicare claims from beneficiaries with an initial diagnosis of PHPT from January 1, 2006, to December 31, 2016. Patients were considered to meet consensus guideline criteria for parathyroidectomy based on diagnosis codes indicating osteoporosis, nephrolithiasis, or stage 3 CKD. Multivariable logistic regression was used to identify patient characteristics associated with parathyroidectomy. Data were analyzed from February 11, 2020, to October 8, 2020. Main Outcomes and Measures/UNASSIGNED:The primary outcome was parathyroidectomy within 1 year of diagnosis. Results/UNASSIGNED:Among 210 206 beneficiaries with an incident diagnosis of PHPT (78.8% women; mean [SD] age, 75.3 [6.8] years), 63 136 (30.0%) underwent parathyroidectomy within 1 year of diagnosis. Among the subset of patients who met consensus guideline criteria for operative management (n = 131 723), 38 983 (29.6%) were treated with parathyroidectomy. Patients treated operatively were younger (mean [SD] age, 73.5 [5.7] vs 76.0 [7.1] years) and more likely to be White (90.1% vs 86.0%), to be robust or prefrail (92.1% vs 85.7%), and to have fewer comorbidities (Charlson Comorbidity Index score of 0 or 1, 54.6% vs 44.1%), in addition to being more likely to live in socioeconomically disadvantaged (46.9% vs 40.3%) and rural (18.1% vs 13.6%) areas (all P < .001). On multivariable analysis, increasing age had a strong inverse association with parathyroidectomy among patients aged 76 to 85 years (unadjusted rate, 25.9%; odds ratio [OR], 0.68 [95% CI, 0.67-0.70]) and older than 85 years (unadjusted rate, 11.2%; OR, 0.27 [95% CI, 0.26-0.29]) compared with those aged 66 to 75 years (unadjusted rate, 35.6%), as did patients with moderate to severe frailty (unadjusted rate, 18.9%; OR, 0.60 [95% CI, 0.56-0.64]) compared with robust patients (unadjusted rate, 36.1%) and those with a Charlson Comorbidity Index score of 2 or greater (unadjusted rate, 25.9%; OR, 0.77 [95% CI, 0.75-0.79]) compared with a Charlson Comorbidity Index score of 0 (unadjusted rate, 37.0%). With regard to operative guidelines, a history of nephrolithiasis increased the odds of parathyroidectomy (OR, 1.43 [95% CI, 1.39-1.47]); stage 3 CKD decreased the odds of parathyroidectomy (OR, 0.71 [95% CI, 0.68-0.74]); and osteoporosis showed no association (OR, 1.01 [95% CI, 0.99-1.03]). Conclusions and Relevance/UNASSIGNED:In this cohort study, most older adults with PHPT did not receive definitive treatment with parathyroidectomy. Older age, frailty, and multimorbidity were associated with nonoperative management, and guideline recommendations had minimal effect on treatment decisions. Further research is needed to identify barriers to surgical care and develop tools to target parathyroidectomy to older adults most likely to benefit.

BACKGROUND:Accurate prediction of thyroidectomy complications is necessary to inform treatment decisions. Ensemble machine learning provides one approach to improve prediction. METHODS:We applied the Super Learner (SL) algorithm to the 2016-2018 thyroidectomy-specific NSQIP database to predict complications following thyroidectomy. Cross-validation was used to assess model discrimination and precision. RESULTS:For the 17,987 patients undergoing thyroidectomy, rates of recurrent laryngeal nerve injury, post-operative hypocalcemia prior to discharge or within 30 days, and neck hematoma were 6.1%, 6.4%, 9.0%, and 1.8%, respectively. SL improved prediction of thyroidectomy-specific outcomes when compared with benchmark logistic regression approaches. For postoperative hypocalcemia prior to discharge, SL improved the cross-validated AUROC to 0.72 (95%CI 0.70-0.74) compared to 0.70 (95%CI 0.68-0.72; p < 0.001) when using a manually curated logistic regression algorithm. CONCLUSION/CONCLUSIONS:Ensemble machine learning modestly improves prediction for thyroidectomy-specific outcomes. SL holds promise to provide more accurate patient-level risk prediction to inform treatment decisions.

BACKGROUND:Based on current evidence, the benefit of intraoperative nerve monitoring (IONM) in thyroid surgery is equivocal. METHODS:All patients who underwent planned thyroid surgery in the 2016-2018 ACS NSQIP procedure-targeted thyroidectomy dataset were included. Multivariable regression analyses were performed to examine the association between nerve monitoring and recurrent laryngeal nerve (RLN) injury while adjusting for patient demographics, extent of surgery, and perioperative variables. RESULTS:In total, 17,610 patients met inclusion criteria: 77.8% were female, and the median age was 52 years. IONM was used in 63.9% of cases. Of the entire cohort, 6.1% experienced RLN injury. Cases with IONM use had a lower rate of RLN injury compared to those that did not use IONM (5.7% vs. 6.8%, p = 0.0001). After adjustment, IONM was associated with reduced risk of RLN injury (OR 0.69, 95% CI 0.59-0.82, p < 0.0001). CONCLUSIONS:Nationally, IONM is used in nearly two thirds of thyroid surgeries. IONM is associated with a lower risk of recurrent laryngeal nerve injury. SUMMARY/CONCLUSIONS:In this contemporary U.S. study of 17,610 thyroidectomy cases, intraoperative nerve monitoring was used in nearly two thirds of cases. Recurrent laryngeal nerve injury occurred in 6.1% of the cohort. Intraoperative nerve monitoring was associated with a lower risk of recurrent laryngeal nerve injury.

Molecular mechanisms mediating tonic secretion of parathyroid hormone (PTH) in response to hypocalcaemia and hyperparathyroidism (HPT) are unclear. Here we demonstrate increased heterocomplex formation between the calcium-sensing receptor (CaSR) and metabotropic γ-aminobutyric acid (GABA) B₁ receptor (GABA_B1R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABA_B1R or glutamic acid decarboxylase 1 and 2 in PTGs produces hypocalcaemia and hypoparathyroidism, and prevents PTH hypersecretion in PTGs cultured from mouse models of hereditary HPT and dietary calcium-deficiency. Cobinding of the CaSR/GABA_B1R complex by baclofen and high extracellular calcium blocks the coupling of heterotrimeric G-proteins to homomeric CaSRs in cultured cells and promotes PTH secretion in cultured mouse PTGs. These results combined with the ability of PTG to synthesize GABA support a critical autocrine action of GABA/GABA_B1R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABA_B1R heteromer to HPT.

BACKGROUND:Surgeons have the responsibility to continuously enhance surgical practice. Standardized processes for institutions to validate and approve the introduction of innovative surgical techniques do not exist. The objective of this work was to develop a model for the introduction of innovative surgical techniques, which assists the innovating surgeons and institution with safe implementation. METHOD:A staged model for the institutional introduction of innovative surgical techniques was developed. Relevant concepts were introduced and defined, a framework for preparation and implementation was established, and an oversight structure was delineated. RESULTS:Systematic literature review and expert opinion revealed broad agreement on the core principles and theory of surgical innovation, but also noted a lack of specific processes. Our efforts aimed to both codify principles and provide a model for specific, best-practice workflows. Important concepts and outputs included: (1) appropriate definition of a sufficiently "new technique" requiring oversight; (2) the appropriate groundwork to be performed to plan for the implementation of the new technique; (3) patient-facing responsibilities, including informed consent; and (4) division of the introduction/adoption process into defined phases, starting from initial discovery and preparation to piloting and transition to standard practice, each with distinct, phase-specific tasks. CONCLUSION:We present a generalizable framework for approaching the safe introduction and adoption of innovative surgical techniques.