Tumor size and molecular risk group are associated with differentiated thyroid cancer recurrence.

BACKGROUND: The threshold at which active surveillance can be considered is variable, with some algorithms proposing nonoperative treatment for differentiated thyroid carcinomas ≤2 cm and lobectomy alone for lesions 2.1-4 cm. To inform both decision for and extent of initial surgery, we aim to evaluate whether molecular results can complement tumor size to identify differentiated thyroid carcinomas associated with disease recurrence. METHODS: Patients from 2007-2013 and 2017-2021 who had initial thyroidectomy (differentiated thyroid carcinoma size 1-4 cm, clinical N0M0) were included. When available, molecular testing results were categorized into 3 previously described molecular risk groups (low, intermediate, and high). Primary outcome was structural recurrence. RESULTS: Recurrence was diagnosed in 3.8% of 1,739 patients with differentiated thyroid carcinomas. Preoperative variables including size (1-2 cm vs 2.1-4 cm, P = .43), age >55 years (P = .92), and male sex (P = .31) were not associated with recurrence. Molecular testing results were available for 1,020, and after excluding molecular risk group high-risk differentiated thyroid carcinoma, structural recurrences were associated with molecular risk group intermediate risk (7.2% vs molecular risk group low, 0.7%, P < .001), and most likely in differentiated thyroid carcinoma, which were both 2.1-4 cm and molecular risk group intermediate risk (11.3% vs size 1-2 cm 5.8%, P = .04). CONCLUSION: Overall, structural recurrences for differentiated thyroid carcinomas ≤4 cm were low (<5%) and molecuar testing was the only preoperative variable associated with recurrence. However, when molecular risk group intermediate risk was present, larger tumor size (2.1-4 cm) had a 2-fold greater risk of recurrence compared with tumors 1-2 cm, and size may still be helpful to guide management. When considering de-escalated treatment for the proposed guidelines with a cutoff of 2 cm, initial decision-making may be further optimized with identification of preoperative molecular risk groups.

Effect of Delayed Parathyroidectomy on Risk of Future Cardiovascular and Nephrolithiasis Interventions in Adults with Primary Hyperparathyroidism [Original Study].

OBJECTIVE: To determine whether the timing of parathyroid surgery impacts the risk of renal stone retreatment and cardiovascular interventions. SUMMARY BACKGROUND DATA: Long-term, untreated primary hyperparathyroidism is associated with significant morbidity including nephrolithiasis and cardiovascular disease. METHODS: We conducted a Population-based Cohort study of New York and California state-wide data from 2000-2020. Adult patients who underwent renal stone treatment and subsequently diagnosed with primary hyperparathyroidism (pHPT) and underwent parathyroidectomy (PTX) were included. Patients were excluded if PTX was prior to index stone procedure, they underwent second stone treatment within 6 months, with stage V CKD, with secondary or tertiary hyperparathyroidism, with prior kidney transplant or hemodialysis, or with prior cancer diagnosis. Rate of renal stone retreatment and cardiovascular interventions after PTX in pHPT patients with nephrolithiasis who underwent parathyroid surgery at ≤ 2 years and >2 years after index stone procedure was measured. RESULTS: We identified 2,093 patients who underwent first-time stone treatment and subsequent PTX. The median time to PTX was 560 days (IQR 187-1477) and follow-up was 7.4 years (IQR 4.5-13.1). Delaying PTX for more than 2 years increased the risk of renal stone retreatment by 59% (HR 1.59; P<0.001), increased the risk of experiencing coronary disease or associated interventions by 118% (HR=2.18; P=0.01), and increased the risk of experiencing an overall cardiovascular event by 52% (HR 1.52; P<0.01). CONCLUSIONS AND RELEVANCE: In symptomatic pHPT, delaying PTX significantly increases the risk of requiring future stone retreatment and cardiac/vascular surgical interventions. This highlights the importance of early surgical referral and multidisciplinary approaches to optimize outcomes and resource utilization in pHPT.

Molecular-derived risk of malignancy and the related positive call rate of indeterminate thyroid cytology diagnoses as quality metrics for individual cytopathologists.

BACKGROUND: Indeterminate thyroid cytopathology diagnoses represent differing degrees of risk that are corroborated by follow-up studies. However, traditional cytologic-histologic correlation may overestimate the risk of malignancy (ROM) because only a subset of cases undergo resection. Alternatively, some molecular tests provide probability of malignancy data to calculate the molecular-derived risk of malignancy (MDROM) and the positive call rate (PCR). The authors investigated MDROMs and PCRs of indeterminate diagnoses for individual cytopathologists as quality metrics. METHODS: This study was approved by the Department of Pathology Quality Improvement Program. Thyroid cytopathology diagnoses and ThyroSeq v3 results were retrieved for each cytopathologist for a 2-year period with at least 3 years of follow-up for the atypia of undetermined significance (AUS), follicular neoplasia (FN), and follicular neoplasia, oncocytic-type (ONC) cytopathologic diagnoses. MDROMs and PCRs were compared with reference ROMs and cytologic-histologic correlation outcomes. RESULTS: The overall MDROMs (and ranges for cytopathologists) for the AUS, FN, and ONC categories were 13.4% (range, 5.8%-20.8%), 28.1% (range, 22.1%-36.7%), and 27.0% (range, 19.5%-41.5%), respectively, and most individual cytopathologists' MDROMs were within reference ROM ranges. However, PCRs more effectively parsed the differences in cytopathologists' ROM performance. Although the overall PCRs were not significantly different across cytopathologists (p = .06), the AUS PCRs were quite different (p = .002). By cytologic-histologic correlation, six of 55 resected cases (10.9%) were falsely negative, and there were no false-positive cases. CONCLUSIONS: MDROMs and PCRs evaluate concordance with reference ROMs and with one another and provide individual feedback, which potentially facilitates quality improvement.

Outcomes of subtotal parathyroidectomy for renal hyperparathyroidism.

BACKGROUND: Renal hyperparathyroidism due to end-stage kidney disease is associated with considerable morbidity, and when refractory is treated with parathyroidectomy. Recurrent renal hyperparathyroidism is a major surgical complication, yet initial target parathyroid remnant size and outcomes, including rates of recurrence are not well elucidated. METHODS: This is a single-institution retrospective cohort study of patients who underwent initial subtotal parathyroidectomy for renal hyperparathyroidism on dialysis, from 1990-2022. The subtotal parathyroidectomy was defined as resection of 3 parathyroid glands ± partial resection of the fourth gland leaving a remnant of ∼75-100 mg, and postresection intraoperative parathyroid hormone goal was 150-250 pg/mL. Clinical data were examined for outcomes. RESULTS: Among 204 patients who met inclusion criteria, 139 (68%) had follow-up data; 58% (80/139) were women and median age was 45 years. Surgical complications included 2 hematomas (1.4%), 1 recurrent laryngeal nerve injury (<1%), and no patient required readmission for intravenous calcium. Using a target remnant size of 75-100 mg, recurrent renal hyperparathyroidism was uncommon (14/139, 10%) and arose at a median interval of 58.6 months (range, 8-180). In cases of recurrence, the postresection intraoperative parathyroid hormone level was less likely to drop <250 pg/mL (40%, 4/10 vs nonrecurrence 65%, 80/123; P = .11) with a slightly lower median decrease (70% vs 81% in nonrecurrence, P = .8); however, neither were significant. Recurrence did not occur in the 19 patients who later received kidney transplantation (P = .2). CONCLUSION: In subtotal parathyroidectomy for renal hyperparathyroidism, use of a target 75-100 mg remnant size results in low complication rates. Durable cure appears to be more likely with renal transplantation.

Sex differences in patients with primary hyperparathyroidism.

BACKGROUND: Differences in presenting symptoms of primary hyperparathyroidism and outcomes of parathyroidectomy between sexes have been described, but whether these can be assessed by perioperative use of a validated tool, such as the Pasieka Parathyroidectomy Assessment Score, is unknown. METHOD: All patients with primary hyperparathyroidism were asked to complete symptom assessment at the preoperative and postoperative visits. The assessment included a query for 13 Pasieka Parathyroidectomy Assessment Score parameters evaluated using a visual analog scale as described by Pasieka (summative score 0-1,300), and general quality of life and wellness. A review of a prospectively maintained database of primary hyperparathyroidism patients (January 2016-December 2019) was performed, and those who had a 6-month cure after initial parathyroidectomy were included. RESULTS: The study cohort was mostly women (77%, 541/701). The median preoperative Pasieka Parathyroidectomy Assessment Score was higher in women (155, 0-1,190) than in men (80.5, 0-855, P < .001), although there were similar rates of asymptomatic primary hyperparathyroidism (Pasieka Parathyroidectomy Assessment Score = 0, 12.5% vs 7%, P = .042). After curative parathyroidectomy, women reported a substantial reduction in symptomatology, with Pasieka Parathyroidectomy Assessment Score declining by 35% at initial postoperative visit (median, 155 vs 100, P < .001), further decreasing to 48% by 6 months (155 vs 80, P < .001). The Pasieka Parathyroidectomy Assessment Score in men did change but to a much smaller degree at both the initial postoperative visit (80.5 vs 70; P = .036) and at 6 months (80.5 vs 57.5; P = .048). CONCLUSION: When assessed with the Pasieka Parathyroidectomy Assessment Score, improvement in symptoms was clearly demonstrated for women after curative parathyroidectomy. Whether symptom improvement also occurs in men is less apparent but may be due to disparities in the development and validation of outcomes tools in general.

Normocalcemic hyperparathyroidism: Intervention to differentiate primary from secondary hyperparathyroidism.

BACKGROUND: Normocalcemic hyperparathyroidism can occur, but surgery should not be considered until common etiologies for secondary hyperparathyroidism are comprehensively excluded. Calcium deficiency is an underrecognized cause of normocalcemic parathyroid hormone elevation, and we aim to determine if the implementation of a preoperative calcium challenge can be used to reduce unnecessary parathyroidectomy. METHODS: Consecutive patients referred for parathyroidectomy (1/21-6/22) with normocalcemia (serum calcium <10 mg/dL) and concurrently elevated parathyroid hormone levels were routinely treated with supplemental calcium and vitamin D3, and follow-up laboratory studies were assessed. RESULTS: A total of 29/314 (9%) patients had normocalcemic parathyroid hormone elevation with mean calcium, parathyroid hormone, and vitamin D 25OH levels of 9.5 ± 0.3 mg/dL, 109.9 ± 34.9 pg/mL, and 42.7 ± 23.8 ng/mL respectively. Confounding factors included estimated glomerular filtration rate <60 in 2, loop diuretic use in 4, and prior gastric bypass or gastric sleeve surgery in 4. Follow-up biochemical evaluation was available in 27 (92%); results were unchanged in 7 patients (26%); normalization of parathyroid hormone levels with persistently normal calcium levels occurred in 15 (55%), thus confirming secondary hyperparathyroidism and hypercalcemia with elevated parathyroid hormone levels (classic primary hyperparathyroidism) was diagnosed in 5 (19%). Parathyroid exploration has been completed for 3 of 5 patients with classic primary hyperparathyroidism to date. CONCLUSION: A preoperative calcium challenge was prospectively initiated in normocalcemic patients with parathyroid hormone elevation, and there was high compliance (92%). Short-interval calcium supplementation revealed ∼50% to have resolved secondary hyperparathyroidism due to insufficient calcium intake, which avoided unnecessary surgery. In contrast, classic patients were unveiled in 20%, allowing for prompt and correct surgical intervention.

Molecular Testing Predicts Incomplete Response to Initial Therapy in Differentiated Thyroid Carcinoma Without Lateral Neck or Distant Metastasis at Presentation: Retrospective Cohort Study.

Background: Molecular testing (MT) is emerging as a potential prognostic factor that can be available before treatment of differentiated thyroid carcinoma begins. Among patients eligible for either lobectomy or total thyroidectomy as their initial therapy, our study aims were to assess (1) if conventionally available preoperative factors are associated with incomplete response to initial therapy, and (2) if MT results can be a surrogate for the ATA Risk Stratification System (RSS) to estimate risk of recurrence. Methods: The data of consecutive thyroid cancer patients without preoperative lateral neck disease or distant metastasis who underwent index thyroidectomy between November 1, 2017 and October 31, 2021 were reviewed. Logistic regression models including preoperative variables such as MT and/or the postoperatively available RSS were constructed to predict disease recurrence, either structural or biochemical. Model discrimination using the c-statistic and goodness-of-fit test were compared. Results: Among 945 patients studied, 50 (5.2%) recurred with 18-month median follow-up. Recurrences were detected in 17 (2.9%), 20 (6.7%), and 13 (22.8%) patients with RSS-low, -intermediate, and -high cancers, respectively (p < 0.001). In multivariable analysis, only tumor size was associated with recurrence (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.1-1.5). In a different model analyzing 440 (46.6%) patients with available MT results, recurrence was associated with both larger tumor size (OR 1.4 [95% CI 1.1-1.8]) and MT results (p < 0.001). Including MT improved the c-statistic by 27%, which was statistically no different than the model incorporating only the RSS (p = 0.15). Conclusions: Disease recurrence was observed across all ATA RSS categories in short-term follow-up, and tumor size was the only conventional preoperative factor associated with recurrence. When MT results were incorporated, they not only improved predictive ability beyond tumor size alone, but also yielded similar ability as the gold standard ATA RSS. Thus, MT results might aid the development of novel preoperative risk stratification algorithms.

Parathyroid Imaging Practices for Primary Hyperparathyroidism Without Previous Operations Among Endocrine Surgery Program Directors.

BACKGROUND: Attempts at preoperative localization of abnormal parathyroid gland(s) in primary hyperparathyroidism (pHPT) can be performed with a variety of modalities. Study utilization is surgeon-specific with highly variable opinions in parathyroid surgery. As more people are diagnosed with pHPT, the complexity of the disease has given rise to variation in management. This heterogeneity raises the question of the true clinical practice of imaging among individual endocrine surgeons. METHODS: To better understand the preoperative parathyroid imaging practices of endocrine surgeons, an email-based survey was disseminated to the program directors of 22 American Association of Endocrine Surgeons fellowship programs querying them on their initial diagnostic test of choice for pHPT. Clinical support team members from each respective program were subsequently contacted and answers were compared. RESULTS: Sixty-eight percent (15/22) of clinical team members recommended either an additional (12/15) or different imaging test (3/15) than what was recommended by their institution's endocrine surgeon. The most common initial imaging test that was repeated by both the endocrine surgeon and clinical team member was neck ultrasound; 33% of clinical team members (7/22) responded concordantly to their surgeon with ultrasound as the initial recommendation. DISCUSSION: Significant variability exists in the preoperative approach to patients with hyperparathyroidism. Here, we demonstrate that inconsistency in preoperative imaging recommendations even extends to within an individual surgeon's practice based on the impact of the clinical support team, highlighting the role for improved clinical protocols within an institution's clinical team.

Association of comprehensive thyroid cancer molecular profiling with tumor phenotype and cancer-specific outcomes.

BACKGROUND: Molecular testing improves the diagnostic accuracy of thyroid cancer. Whether specific molecular testing results are associated with tumor phenotype or provide prognostic information needs further delineation. METHODS: Consecutive thyroid cancer patients after index thyroidectomy with ThyroSeq version 3 (Rye Brook, NY) molecular testing obtained on preoperative fine-needle aspiration or thyroidectomy specimens from patients with thyroid cancer were categorized into 3 molecular risk groups based on detected mutations, fusions, copy number alterations, and/or gene expression alterations and correlated with histopathology and recurrence, defined as biochemical or structural. RESULTS: Of 578 patients, 49.9%, 37.5%, and 12.6% had molecular risk group-low, molecular risk group-intermediate, and molecular risk group-high cancers, respectively. With a median 19-month follow-up, 9.1% patients recurred. Compared with molecular risk group-low, molecular risk group-intermediate cancers were diagnosed in younger patients and more often had microscopic extrathyroidal extension, involved margins, and nodal disease. Compared with molecular risk group-intermediate, molecular risk group-high cancers were diagnosed in older patients and more often had gross extrathyroidal extension and vascular invasion. In multivariable analysis, recurrence was more likely in molecular risk group-high cancers than in molecular risk group-intermediate (hazard ratio = 4.0; 95% confidence interval, 1.9-8.6; P < .001) and more likely in molecular risk group-intermediate than in molecular risk group-low (hazard ratio = 5.0; 95% confidence interval, 2.0-12.5; P < .001). CONCLUSION: Using modern comprehensive genotyping, the genetic profile of thyroid cancers can be categorized into 3 novel molecular risk groups that were associated with histopathologic phenotype and recurrence in short-term follow-up.

Changes in thyroid nodule cytology rates after institutional implementation of the Thyroid Imaging Reporting and Data System.

BACKGROUND: The American College of Radiology Thyroid Imaging Reporting and Data System for ultrasound classification of malignancy risk was developed to better triage thyroid nodules for fine-needle aspiration biopsy. To examine further, we compared thyroid cytologic classification rates in nodules before and after institutional Thyroid Imaging Reporting and Data System implementation. METHODS: Cytology diagnoses by Bethesda criteria (categories I-VI) from January 2014 to October 2021 were retrieved; observed changes in yearly category frequency were analyzed by linear regression; and pooled cohorts of pre- (2014-2018) and post-Thyroid Imaging Reporting and Data System (2019-2021) cytology call rates were compared. RESULTS: Overall, 7,413 cytologic specimens were included (range/year 715-1,444). From 2014 to 2021, the proportion of benign (Bethesda category II) diagnosis per year declined stepwise from 49.7% to 19.4%, and atypia of undetermined significance/follicular lesion of undetermined significance (Bethesda category III) increased sequentially from 21.3% to 51.5%. Between 2014 and 2021, Bethesda category III diagnosis increased on average by 4.8% per year (95% confidence internal, 3.29-5.54; P < .001) and Bethesda category II results decreased on average by 4.4% per year (95% confidence interval, 6.29-3.42; P < .001). When comparing pre- and post-Thyroid Imaging Reporting and Data System, the proportion of Bethesda category II cytology results decreased (43.1% vs 21%; P = .001) while Bethesda category III (28.3% vs 47.7%; P = .002) and Bethesda category V (1.1% vs 1.7%; P = .015) results increased. CONCLUSION: After implementation of American College of Radiology Thyroid Imaging Reporting and Data System ultrasound criteria, we observed a 2.5-fold decline in the rate of benign cytology and an increase in the proportion of atypia of undetermined significance/follicular lesion of undetermined significance results.

Comparative utility of preoperative imaging in normocalcemic versus hypercalcemic primary hyperparathyroidism.

BACKGROUND: Normocalcemic primary hyperparathyroidism (PHPT) has been shown to benefit from parathyroidectomy. PHPT may be localized preoperatively with various imaging modalities, but the utility of preoperative imaging in normocalcemic PHPT compared to hypercalcemic PHPT is not well defined. METHODS: Retrospective review was performed on all PHPT patients who underwent parathyroidectomy from 2001 to 2019. Patients were stratified into normocalcemic and hypercalcemic groups. Patient and outcomes data were analyzed. RESULTS: All 2218 patients in this database were included. 433 patients had normocalcemic PHPT (19.5%) and 1785 had hypercalcemic PHPT (80.5%). Among normocalcemic patients, equivalent cure rates were seen between patients with preoperative imaging versus those without (100% vs 99%). No differences in postoperative complications were demonstrated except for a slightly increase in transient hypocalcemia in patients without imaging. CONCLUSIONS: Normocalcemic PHPT patients had equivalent cure and similar complication rates with or without preoperative imaging compared to hypercalcemic patients. Routine localization studies in normocalcemic PHPT may be safely omitted in favor of exploration with intraoperative adjuncts by experienced surgeons.

Thyroid hormone replacement following lobectomy: Long-term institutional analysis 15 years after surgery.

BACKGROUND: The decision to pursue lobectomy versus total thyroidectomy is highly individualized. The rate of thyroid hormone replacement therapy after lobectomy varies considerably (15%-48%) and studies are limited by short-term follow-up. We sought to assess long-term thyroid hormone replacement therapy-requirement for lobectomy. METHODS: Patients undergoing lobectomy from January 2005 to July 2010 at an academic institution were reviewed. Demographic, laboratory, pathology, and thyroid hormone replacement therapy use were compared. RESULTS: In total, 235 patients were included. The rate of thyroid hormone replacement therapy after lobectomy was 46.8% (110/235). The majority were female (84.7%), with a mean age of 52 ± 1 years, 97% with benign pathology, and the median duration of follow-up was 7.2 years. Among the 110 thyroid hormone replacement therapy, the mean postoperative thyroid stimulating hormone level 9.08 ± 0.96m IU/L and the time to thyroid hormone replacement therapy-initiation was 621 days; 24% started therapy ≥2 years after surgery. There was no difference in age, sex, or malignancy. Hashimoto thyroiditis was diagnosed in 21.8% patients who underwent thyroid hormone replacement therapy versus 8.0% of those without thyroid hormone replacement therapy (odds ratio 3.2; 95% confidence interval, 1.43-6.79; P < .001). On multivariate analysis, only Hashimoto thyroiditis was independently associated with thyroid hormone replacement therapy use (odds ratio 2.88; 95% confidence interval, 1.3-6.6; P = .012). CONCLUSION: With long-term follow-up, nearly 50% of patients who underwent lobectomy for benign disease required thyroid hormone replacement therapy and nearly one-quarter of these patients not starting until ≥2 years after surgery. Therefore, patients who undergo thyroid lobectomy should be counseled appropriately and thyroid function followed for a minimum of 2 years.

Long-Term Outcomes for Patients with Multiple Endocrine Neoplasia Type 1 and Duodenopancreatic Neuroendocrine Neoplasms.

BACKGROUND: Liver metastasis from duodenopancreatic neuroendocrine neoplasms (DP-NENs) is a major cause of mortality in multiple endocrine neoplasia type 1 (MEN1) patients, yet much of their natural history is unknown. METHODS: This longitudinal, retrospective cohort study analyzed all MEN1 patients with imageable functional (F) and nonfunctional (NF) DP-NENs (1990-2021) for liver metastasis-free survival (LMFS) and overall survival (OS). RESULTS: Of 138 patients, 85 (61.6%) had imageable DP-NENs (28 F, 57 NF), and the mean largest tumor size was 1.8 ± 1.4 cm. Multifocality was present in 32 patients (37.7%). Surgery was performed for 49 patients (57.7%). During an 11-year median follow-up period (IQR, 6-17 years), 23 (27.1%) of the patients had liver metastasis, and 19 (22.4%) patients died. Death was attributed to liver metastasis in 60% of cases. The patients with F-DP-NENs versus NF-DP-NENs more often had liver metastasis (46.4% vs. 15.8%; p = 0.002) but had similar 10-year LMFS (80.9 vs. 87.0%; p = 0.44) and OS (82.7 vs. 94.3%; p = 0.69). The patients with NF-DP-NENs had surgery when their tumors were larger (p < 0.001). Tumor size was not associated with liver metastasis (p = 0.89). The average growth rate was 0.04 cm/year (SE, 0.02 cm/year; p = 0.01) during active surveillance for NF-DP-NENs (n = 38). Liver metastasis developed in four patients with tumors smaller than 2 cm. The risk of liver metastasis was independent of surgery (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.21-2.93; p = 0.72) and death (HR, 0.51; 95% CI, 0.08-3.06; p = 0.46). CONCLUSIONS: Although the observed outcomes in this study were better than historical data, small NF-DP-NENs still developed liver metastasis and liver metastasis remains a major cause of death. These results suggest that size as a sole criterion for surgery may be insufficient to predict tumor behavior.

Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis.

Expression of the tight junction-associated protein junctional adhesion molecule-A (JAM-A) is increased in sepsis, although the significance of this is unknown. Here, we show that septic JAM-A -/- mice have increased gut permeability, yet paradoxically have decreased bacteremia and systemic TNF and IL-1ß expression. Survival is improved in JAM-A-/- mice. However, intestine-specific JAM-A-/- deletion does not alter mortality, suggesting that the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A-/- mice have increased numbers of splenic CD44hiCD4+ T cells, decreased frequency of TNF+CD4+ cells, and elevated frequency of IL-2+CD4+ cells. Septic JAM-A-/- mice have increased numbers of B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A-/- × RAG-/- mice have improved survival compared with RAG-/- mice and identical mortality as WT mice. Gut neutrophil infiltration and neutrophil phagocytosis are increased in JAM-A-/- mice, while septic JAM-A-/- mice depleted of neutrophils lose their survival advantage. Therefore, increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A-/- mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.

Parathyroidectomy for Normocalcemic Tertiary Hyperparathyroidism: A 19-Year Experience.

INTRODUCTION: Parathyroidectomy is the standard management for patients with tertiary hyperparathyroidism (THPT) and hypercalcemia. However, a subset of patients with THPT have normal or mildly-elevated serum calcium levels in the setting of significantly elevated parathyroid hormone (PTH). The purpose of this study is to determine the effectiveness and safety of parathyroidectomy in normocalcemic THPT. MATERIALS AND METHODS: Retrospective review of 212 consecutive patients with THPT who subsequently underwent parathyroidectomy between 2001 and 2020 was performed. Patients were categorized as normocalcemic, "mild" (Ca ≤ 10.4 mg/dL) or hypercalcemic, "classic" THPT (Ca ≥ 10.5 mg/dL) and clinical data are compared. RESULTS: 71 of 212 (34%) were normocalcemic with median pre-operative Ca and PTH levels of 9.7 mg/dL and 225pg/mL, respectively and 141 of 212 (67%) were hypercalcemic with median preoperative Ca and PTH levels of 11 mg/dL and 211pg/mL, respectively. The mean length of stay was shorter in normocalcemic patients (0.33 versus 0.50 d; P = 0.03). 10 of 71 (14%) normocalcemic patients underwent reoperative parathyroidectomy, more than double that of hypercalcemic patients (5.6%; P = 0.06). Concomitant thymectomy was performed in 28.1% and 22.1% of normocalcemia and hypercalcemic patients, respectively (P = 0.44). No patient in either group required intravenous calcium or had undetectable PTH levels, but permanent hypocalcemia was more frequent in normocalcemic compared to hypercalcemic patients (11.2% versus 1.4%; P = 0.03). CONCLUSIONS: Parathyroidectomy for normocalcemic tertiary hyperthyroidism (HPT) can be performed safely. These data can help guide multidisciplinary discussions for earlier surgical referral and intervention. Future investigations are needed to evaluate the impact of parathyroidectomy on the renal allograft, bone health, and cardiovascular disease.

Mediastinal parathyroidectomy: Utilization of a multidisciplinary, robotic-assisted transthoracic approach in challenging cases.

BACKGROUND: The majority of ectopic mediastinal parathyroid adenomas are accessible transcervically and those not amenable to this approach pose a significant clinical and technical challenge. METHODS: Retrospective review of transthoracic robot-assisted mediastinal parathyroidectomy (TTRMP) for primary hyperparathyroidism between 2012 and 2019 at a single institution. RESULTS: 16 patients underwent TTRMP, 63% were female with a mean age of 64 ± 2.0 years. Nine of 16 had prior parathyroidectomy; 80% had persistent disease and a mean 2.8-year delay from index operation until TTRMP. Locations included: intrathymic (8), AP window (4), carina (3), and retroesophageal (1). Two patients underwent parathyroid reimplantation. Mean post-operative calcium and PTH were 9.2 ± 0.2 mg/dL and 20.2 ± 5.6 pg/mL, respectively. Complications included: temporary hypocalcemia (4), permanent hypocalcemia (1), DVT (1), hoarseness (1), and subcostal neuralgia (1). CONCLUSION: In experienced hands, TTRMP is a safe and effective approach to mediastinal parathyroids not accessible transcervically. A multidisciplinary approach should be used in reoperative cases.

Outpatient parathyroidectomy in the pediatric population: An 18-year experience.

BACKGROUND: Parathyroidectomy for primary hyperparathyroidism (pHPT) is safely performed in the outpatient setting in the adult population. However, concern that children and adolescents have higher complication rates and are unable to recognize and communicate symptoms of hypocalcemia has limited same-day discharges in the pediatric population. METHODS: Nineteen patients aged 8-18 years (14.1 ± 0.7) underwent outpatient parathyroidectomy for pHPT by a single high-volume endocrine surgeon from 2002-2020. Patient demographics, disease, operations, and complications were reviewed. RESULTS: Sixteen of 19 patients were symptomatic with fatigue (62.5%), joint pain (37.5%) and nephrolithiasis (18.7%) most common. Mean preoperative Ca and PTH were 11.7 ± 0.3 mg/dL and 102.3 ± 11.8pg/mL, respectively. Ten of 19 had a single adenoma and 9 had multigland hyperplasia including one MEN1 and one MEN2A patient. We performed 11 four-gland explorations, 8 unilateral parathyroidectomies; including 9 transcervical thymectomies, 1 total thyroidectomy, and 1 bilateral central neck dissection. Mean 6-month postoperative Ca and PTH levels were 9.5 ± 0.3 mg/dL (range 7.3-10.3) and 29±5.0pg/mL (range 6.3-77), respectively. One patient developed permanent hypoparathyroidism and 1 had temporary hypocalcemia. No temporary or permanent hoarseness, unplanned same-day admission, wound complications, or Emergency Department visits occurred. CONCLUSION: Outpatient parathyroidectomy can be safely and effectively performed in pediatric patients with primary HPT. LEVEL OF EVIDENCE: Treatment Study, Level III.