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.

The Obesity Paradox in Thyroid Surgery: Is Higher BMI Protective Against Hypoparathyroidism?

BACKGROUND: With a demonstrated association between adiposity and parathyroid hormone (PTH) levels, we hypothesized that patients with a higher body mass index (BMI) would have lower rates of postoperative hypoparathyroidism following total thyroidectomy. METHODS: retrospective review of patients undergoing total thyroidectomy from 2015 to 2021. Demographics, BMI, surgical indications, and laboratory data including pre- and postoperative PTH values were examined. RESULTS: Of the 352 patients with complete clinicopathologic data, most were female (n = 272, 77.3%) with an average age of 42.7 (SD+/-19.4). Obese (BMI 30-39.99) was most common BMI group (n = 108, 30.8%), with 11.7% (n = 41) morbidly obese (BMI > 40). Morbidly obese patients had significantly higher postoperative PTH levels than BMI < 18.5 (46.0 vs 19.3 pg/mL, P = .004). Patient race was significantly associated with pre- and postoperative PTH (P = .03, P = .004.) On multivariable analysis, preoperative PTH, race, and BMI were independent predictors of higher postoperative PTH (P < .05 for all). DISCUSSION: Patients with higher BMI and non-white race have relative protection from postoperative hypoparathyroidism.

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.

Thresholds for surgical referral in primary hyperparathyroidism: A conjoint analysis.

BACKGROUND: Primary hyperparathyroidism (PHPT) can be cured through surgery, but referral for treatment is often provider dependent. A conjoint analysis was performed to identify factors influencing referral for surgery. METHODS: Online survey assessed endocrinologists and other physicians who reviewed 10 patient scenarios. They decided whether to refer for surgery or medical management based on clinical (age, comorbidities, etc) and biochemical factors (mild or classic disease). RESULTS: Classic PHPT, age below 50, absence of comorbidities, presence of osteoporosis, and seeing a surgical provider significantly increased the likelihood of surgery referral (p < 0.001). Physician characteristics such as gender, practice duration, and setting did not have a significant influence. CONCLUSION: Despite published benefits of surgery, non-surgical physicians were less likely to refer PHPT patients for surgical treatment if patients were older (age ≥ 50), had comorbid conditions, or had mild disease. More education and advocacy are needed for improved access to surgery.

Surgical Treatment of Hyperthyroidism Can Be Performed Safely Before a Euthyroid State is Achieved.

Background: The 2016 American Thyroid Association guidelines recommend that hyperthyroid patients should be euthyroid before thyroidectomy. This recommendation is based on low-quality evidence. In this retrospective cohort study, we compare peri- and post-operative outcomes of patients with hyperthyroidism who were controlled versus uncontrolled at the time of thyroidectomy. Methods: A retrospective cohort study was performed on 275 hyperthyroidism patients at a single institution from December 2015 to November 2022. Patients were defined as hyperthyroid if they had a diagnosis of hyperthyroidism with at least one suppressed thyrotropin (TSH). Patients were considered uncontrolled if triiodothyronine or thyroxine (T4) was elevated immediately before surgery. Patient demographics, perioperative data, and postoperative outcomes were compared with Chi-square and Wilcoxon Rank Sum tests, as appropriate. Results: Of the 275 patients, 84.3% were women and 51.3% were uncontrolled at time of surgery. Controlled patients had higher median [interquartile range] TSH (0.4 [0.0, 2.4] mIU/L vs. 0.0 [0.0, 0.0] mIU/L, p < 0.001) and lower free T4 (fT4) (0.9 [0.7, 1.1] ng/dL vs. 3.1 [1.9, 4.4] ng/dL, p < 0.001), respectively. Uncontrolled patients were more likely to be diagnosed with Grave's disease (85.1% vs. 67.9%, p < 0.001) and to undergo surgery due to medication intolerance (12.1% vs. 6%) or history of thyroid storm (6.4% vs. 1.5%) (p = 0.008). Uncontrolled patients were also more likely to take a larger number of preoperative medications (2.3 vs. 1.4, p < 0.001). No patient in either group experienced thyroid storm precipitated by surgery. Controlled patients had shorter operative times (7.3% vs. 19.8% <1 hour, p < 0.014) and decreased median estimated blood loss (15.0 [5.0, 30.0] mL vs. 20.0 [10.0, 50.0] mL, p = 0.002). Both groups experienced similar, low rates of postoperative complications, apart from an increase in temporary hypocalcemia in the uncontrolled group (13.4% vs. 4.7%, p = 0.013). Conclusion: Our study is the largest to date examining the postoperative outcomes of patients with uncontrolled hyperthyroidism who undergo thyroidectomy. Our results affirm that thyroidectomy in actively thyrotoxic patients is safe and will not precipitate thyroid storm.

Postoperative Hypocalcemia in Hyperthyroid Patients: The Parathyroids Aren't Always to Blame.

INTRODUCTION: Hypocalcemia is commonly reported after thyroidectomy and has multiple possible etiologies including: parathyroid devascularization, reactive hypoparathyroidism from relative hypercalcemia in thyrotoxicosis, and abrupt reversal of thyrotoxic osteodystrophy. In patients that are actively hyperthyroid and undergoing thyroidectomy, it is not known how many experience hypocalcemia from nonhypoparathyroidism etiologies. Therefore, our aim was to examine the relationship among thyrotoxicosis, hypocalcemia, and hypoparathyroidism. METHODS: A retrospective review was performed of prospectively-collected data from all patients undergoing thyroidectomy for hyperthyroidism by 4 surgeons from 2016 to 2020. All patients carried a diagnosis of Graves' disease or toxic multinodular goiter. Patient demographics, preoperative medications, laboratory reports, and postoperative medications were reviewed. Hypocalcemia within the first month of surgery despite a normal parathyroid hormone (PTH) level was the primary outcome of interest and was compared between patients with and without thyrotoxicosis. Secondary outcomes were duration of postoperative calcium use and the relationship between preoperative calcium supplementation and postoperative calcium supplementation. Descriptive statistics, Wilcoxon rank-sum, and chi-square tests were used for bivariate analysis, as appropriate. RESULTS: A total of 191 patients were identified, with mean age of 40.5 y (range 6-86). Most patients were female (80%) and had Graves' disease (80%). At the time of surgery, 116 (61%) had uncontrolled hyperthyroidism (thyrotoxic group, Free Thyroxine >1.64 ng/dL or Free Triiodothyronine > 4.4 ng/dL), with the remaining 75 (39%) considered euthyroid. Postoperative hypocalcemia (calcium < 8.4 mg/dL) developed in 27 (14%), while hypoparathyroidism (PTH < 12 pg/mL) was observed in 39 (26%). Thyrotoxic patients comprised a majority of those with hypocalcemia (n = 22, 81%, P = 0.01) and hypoparathyroidism immediately following surgery (n = 14, 77%, P = 0.04). However, a majority of initially hypocalcemic, thyrotoxic patients had normal PTH values within the first month after surgery (n = 17, 85%), pointing to a potential nonparathyroid etiology. On bivariate analysis, no significant relationship was found for thyrotoxic patients with initial postoperative hypocalcemia (18%) and hypoparathyroidism <1-month after surgery (29%, P = 0.29) or between 1 and 6 mo after surgery (2%, P = 0.24). Of the 19 patients in the nonhypoparathyroidism group, 17 (89%) were off all calcium supplements by 6 mo postop. CONCLUSIONS: In patients with hyperthyroidism, those in active thyrotoxicosis at time of surgery have a higher rate of postoperative hypocalcemia compared to euthyroid patients. When hypocalcemia lasts >1 mo postoperatively, data from this study suggest that hypoparathyroidism may not be the primary etiology in many of these patients, who typically require calcium supplementation no more than 6 mo postoperatively.

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.

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.

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.

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.

Vitamin D deficiency is associated with single gland parathyroid disease.

BACKGROUND: Primary hyperparathyroidism (PHPT) with low preoperative vitamin D levels is thought to be related to 4-gland hyperplasia. We reviewed final parathyroid pathology in relationship to preoperative vitamin D levels. METHODS: A retrospective review was performed for all PHPT patients undergoing parathyroidectomy from 2001 to 2019. Patient demographics, laboratory studies, and final pathology were reviewed. RESULTS: 2230 patients were included in the analysis, 78.1% were female with a mean age of 59 years. Patients were stratified into 3 groups based on their preoperative 25-hydroxy vitamin D levels; "deficient" (<20 ng/mL) (n = 319), "insufficient" (20-30 ng/mL) (n = 1108), or "sufficient" (>30 ng/mL) (n = 803). Patients with deficient vitamin D had a higher frequency of single adenoma (71%) compared to sufficient vitamin D patients (62%) (p < 0.001) and fewer hyperplastic glands (19%) compared to sufficient vitamin D level patients (25%) (p < 0.001). CONCLUSIONS: Vitamin D deficiency is more strongly associated with single-gland parathyroid disease than 4-gland hyperplasia. Further investigation into the complex interplay between vitamin D levels and autonomous parathyroid function is warranted.