Disparities in Thyroid Cancer Diagnosis Based on Residence and Distance From Medical Facility.

Context: Rural-urban disparities have been reported in cancer care, but data are sparse on the effect of geography and location of residence on access to care in thyroid cancer. Objective: To identify impact of rural or urban residence and distance from treatment center on thyroid cancer stage at diagnosis. Methods: We evaluated 800 adults with differentiated thyroid cancer in the iCaRe2 bioinformatics/biospecimen registry at the Fred and Pamela Buffett Cancer Center. Participants were categorized into early and late stage using AJCC staging, and residence/distance from treating facility was categorized as short (≤ 12.5 miles), intermediate (> 12.5 to < 50 miles) or long (≥ 50 miles). Multivariable logistic regression was used to identify factors associated with late-stage diagnosis. Results: Overall, 71% lived in an urban area and 29% lived in a rural area. Distance from home to the treating facility was short for 224 (28%), intermediate for 231 (28.8%), and long for 345 (43.1%). All 224 (100%) short, 226 (97.8%) intermediate, and 120 (34.7%) long distances were for urban patients; in contrast, among rural patients, 5 (2.16%) lived intermediate and 225 (65.2%) lived long distances from treatment (P < .0001). Using eighth edition AJCC staging, the odds ratio of late stage at diagnosis for rural participants ≥ 55 years was 2.56 (95% CI, 1.08-6.14) (P = .03), and for those living ≥ 50 miles was 4.65 (95% CI, 1.28-16.93) (P = .0075). Results were similar using seventh edition AJCC staging. Conclusion: Older age at diagnosis, living in rural areas, and residing farther from the treatment center are all independently associated with late stage at diagnosis of thyroid cancer.

Endocrinopathies Associated With Immune Checkpoint Inhibitor Use.

OBJECTIVE: To provide a clinical approach towards immune checkpoint inhibitor (ICI)-associated endocrinopathies, their link with cancer outcomes, factors which differentiate them from other immune related adverse events, and health systems innovation to improve care for these patients. METHODS: A literature search for articles pertaining to ICIs and endocrinopathies was performed and supplemented by expert opinions of the authors. RESULTS: While immune related adverse events can affect almost any organ, they frequently target the endocrine glands, most commonly thyroid. Different classes of ICIs have varying frequencies of endocrinopathies related to hypophysitis, thyroiditis, diabetes mellitus, and rarely hypoadrenalism and hypoparathyroidism. ICI-associated endocrinopathies share some features with classic endocrine autoimmunity but appear to be a distinct entity. They can be challenging to diagnose and manage due to nonspecific clinical features, use of exogenous glucocorticoids, and at times rapid and severe hormone deficiency. The role of anti-inflammatory high-dose glucocorticoids is minimal, and the ICI does not usually require permanent discontinuation. ICI-associated endocrinopathies usually cause permanent hormone deficiency necessitating long-term management and patient engagement. ICI-thyroiditis has been associated with improved survival, while other endocrinopathies have not shown a significant association with outcomes in cancer patients receiving ICIs. Oncoendocrinology teams can improve the care of patients with ICI-associated endocrinopathies. CONCLUSION: This narrative review provides guidance to clinicians prescribing ICIs and those managing ICI-associated endocrinopathies, and complements the frameworks provided by major scientific societies in this field.

Outcomes of cytologically indeterminate thyroid nodules managed with Genomic Sequencing Classifier.

CONTEXT: Molecular testing can refine the risk of malignancy in thyroid nodules with indeterminate cytology to decrease unnecessary diagnostic surgery. OBJECTIVE: This study was performed to evaluate the outcomes of cytologically indeterminate thyroid nodules managed with Afirma genomic sequencing classifier (GSC) testing. DESIGN, SETTING, PATIENTS, AND INTERVENTION: Adult patients who underwent a biopsy at three major academic centers between July 2017 and June 2021 with Bethesda III or IV cytology were included. All patients had surgery or minimum follow-up of 1 year ultrasound surveillance. MAIN OUTCOME MEASURES: The primary outcomes were the sensitivity, specificity, PPV, and NPV of GSC in Bethesda III and IV nodules. RESULTS: The median nodule size of the 834 indeterminate nodules was 2.1 cm and the median follow-up was 23 months. GSC's sensitivity, specificity, PPV, and NPV across all institutions were 95%, 81%, 50%, and 99% for Bethesda III nodules and 94%, 82%, 65%, and 98% for Bethesda IV nodules, respectively. The overall false negative rate was 2%. The NPV of GSC in thyroid nodules with oncocytic predominance was 100% in Bethesda III nodules and 98% in Bethesda IV nodules. However, the PPV of oncocytic nodules was low (17% in Bethesda III nodules and 45% in Bethesda IV nodules). Only 22% of thyroid nodules with benign GSC results grew during surveillance. CONCLUSIONS: GSC is a key tool for managing patients with indeterminate cytology, including the higher-risk Bethesda IV category. GSC benign thyroid nodules can be observed similarly to thyroid nodules with benign cytology.

Excellent Response to Therapy Occurs for Most Patients With Thyroid Cancer Treated With Lobectomy.

INTRODUCTION: American Thyroid Association (ATA) Guidelines for Management of Thyroid Nodules and Thyroid Cancer indicate that thyroid lobectomy (TL) or total thyroidectomy (TT) are appropriate surgery for low- and intermediate-risk well-differentiated thyroid carcinoma. We sought to determine outcomes of TL or TT by ATA response to therapy (RTT) classification. METHODS: This is a single-institution retrospective cohort study of adults with unilateral suspicious or malignant thyroid nodules under 4 cm from January 2016 through December 2021. Our primary outcome was ATA RTT. RESULTS: During the study period, 118 met inclusion criteria: 37 (31%) underwent TL and 81 (69%) TT. Of the TL patients, 7 (19%) underwent completion thyroidectomy. Response to therapy (RTT) was similar with TT versus TL: excellent response 56 (69%) versus 30 (81%), indeterminate response 20 (25%) versus 5 (14%), and biochemically incomplete response 5 (6%) versus 2 (5%), P = 0.20. There were no differences between the groups for age, sex, race or ethnicity, tumor size, histologic type, or complications. Thyroidectomy (TT) was associated with multiple nodules 47% versus 22% for TL (P = 0.009), bilateral nodules 43% versus 16% (P = 0.004), central neck lymph nodes removed median 3 (interquartile range [IQR] 1-8) versus 0 (IQR 0-2) P < 0.001, lymph node metastases median 0 (IQR 0-1) versus 0 (0-0) P = 0.02. Median follow-up was 32.5 mo (IQR 17-56 mo) and was similar between the groups. CONCLUSIONS: Patients with TL for well-differentiated thyroid carcinoma without high-risk features have an RTT similar to patients undergoing TT. In this cohort, 81% of patients treated with TL have not required additional intervention.

Thyroglobulin Cutoff Values for Detecting Excellent Response to Therapy in Patients With Differentiated Thyroid Cancer.

Context: Serum thyroglobulin (Tg) is a biochemical marker for detecting persistent or recurrent differentiated thyroid carcinoma (DTC) post-thyroidectomy. Tg can indicate DTC before structural disease (SD) is visible with imaging procedures. Objective: This work aimed to evaluate the clinical performance of the Elecsys® Tg II assay at a Tg cutoff of 0.2 ng/mL for ruling out SD in adults with DTC after total/near-total thyroidectomy, with or without radioiodine ablation (RAI). Methods: Patients were enrolled into 2 cohorts: longitudinal (Tg assessed every 6 months over 2 years under thyroid-stimulating hormone [TSH] suppression therapy following thyroidectomy with or without RAI) and cross-sectional with confirmed SD (Tg assessed once >12 weeks after thyroidectomy). Analyses were performed for both cohorts combined and in the longitudinal cohort. Results: The study included 530 clinically evaluable samples, the majority (n = 424 samples) from patients who had not received RAI treatment. Following correction for SD prevalence (4.97% in the longitudinal cohort), an Elecsys Tg II cutoff of 0.2 ng/mL ruled out SD with a negative predictive value of 99.9% (95% CI, 99.5%-100%). The assay had excellent sensitivity (98.5%-100%) and acceptable specificity (53.4%-53.5%) for detecting SD (Tg ≥ 0.2 ng/mL) for both cohorts combined and in the longitudinal cohort, with similar findings in RAI-treated and non-RAI-treated subgroups. Conclusion: In this cohort of DTC patients post-thyroidectomy, a Tg cutoff of 0.2 ng/mL was highly effective for ruling out the presence of SD under TSH-suppressed conditions, including in patients who had not received RAI treatment.

Endocrine Dysfunction From Immune Checkpoint Inhibitors: Pearls and Pitfalls in Evaluation and Management.

Immune checkpoint inhibitors (ICPis) have proven extremely efficacious in cancer therapy but also lead to a plethora of immune-related adverse events (irAEs). The endocrine irAEs are not only quite common but also may pose a challenge to the clinician while managing a patient with cancer treated with ICPis. The clinical features of endocrine dysfunction are usually nonspecific and may overlap with concurrent illnesses, underlying the importance of accurate hormone testing and efforts toward case-finding. The management of endocrine irAEs is unique in the focus being on hormone replacement rather than curtailing the autoimmune process. Although the management of thyroid irAEs appears straightforward, adrenal insufficiency and insulin-dependent diabetes can be life-threatening if not promptly recognized and treated. This clinical review synthesizes the studies to provide pearls and pitfalls in the evaluation and management of endocrine irAEs with specific reference to guidelines from oncologic societies.

Hypophysitis and Secondary Adrenal Insufficiency From Immune Checkpoint Inhibitors: Diagnostic Challenges and Link With Survival.

BACKGROUND: Hypophysitis is a serious adverse event stemming from immune checkpoint inhibitor (ICI) therapy for malignancy. This study aimed to characterize ICI-induced hypophysitis, identify diagnostic challenges, and evaluate an association with survival in a large cancer cohort. METHODS: We performed a retrospective cohort study of adult patients with cancer who received ICIs between December 1, 2012, and December 31, 2019. We identified 839 patients who received CTLA-4, PD-1, or PD-L1 inhibitors or a combination thereof who were followed for a median of 19.4 months. Hypophysitis was defined as MRI evidence of pituitary gland and/or stalk enlargement or biochemical evidence of hypopituitarism if not explained by another etiology. RESULTS: A total of 16 (1.9%) patients developed hypophysitis a median of 7 months after ICI initiation, with most patients having melanoma (9/16; 56.2%) or renal cell carcinoma (4/16; 25%). Two patients also had exogenous glucocorticoid exposure but exhibited secondary hypothyroidism and secondary adrenal insufficiency (AI). Median age at the start of ICI was 61.3 years and 57% were men. Patients who developed hypophysitis were younger compared with those who did not develop hypophysitis (median age, 57 vs 65 years; P=.011). Hypophysitis occurred most frequently after combination therapy (13.7%) compared with CTLA-4 monotherapy (1.9%), PD-1 monotherapy (1.2%), and PD-L1 monotherapy (0.8%) (P<.0001). Pituitary gland enlargement on MRI occurred more frequently after CTLA-4 inhibitor monotherapy or combination therapy (5/7; 71.4%) compared with PD-1/PD-L1 inhibitor monotherapy (1/6; 16.7%). The survival benefit of hypophysitis was not apparent after addressing immortal time bias and adjusting for other variables affecting patient outcomes. CONCLUSIONS: Secondary AI occurred in all patients, and secondary hypothyroidism occurred in half. Classic pituitary gland enlargement is usually absent in PD-1/PD-L1 inhibitor-induced hypophysitis. Further pituitary evaluation must be conducted to differentiate secondary AI resulting from exogenous glucocorticoids and hypophysitis in patients with cancer receiving ICIs. The link between hypophysitis and ICI efficacy needs further investigation.

Glycemic Variability in Patients With Stage II-III Colon Cancer Treated With Surgery and Adjuvant Chemotherapy.

OBJECTIVES: To examine glycemic variability within one month and one year following surgery and throughout adjuvant chemotherapy among patients with stage II-III colon cancer, with and without type 2 diabetes (T2D). SAMPLE & SETTING: 58 patients with stage II-III colon cancer treated with surgery and chemotherapy. METHODS & VARIABLES: A retrospective analysis of electronic health record data over one year showed glycemic variability, measured as standard deviation and coefficient of variation. Chi-square, Fisher's exact, and Mann-Whitney U tests and Spearman's correlation coefficient were calculated. RESULTS: Patients with T2D had higher glycemic variability throughout chemotherapy and within one year following surgery. A significant increase in glycemic variability throughout chemotherapy was observed in patients without T2D. Significant associations between glycemic variability and demographic and clinical characteristics differed by T2D status, standard deviation, and coefficient of variation. IMPLICATIONS FOR NURSING: Nurses need to assess serial blood glucose levels in patients with and without T2D. Teaching patients how to maintain glycemic control during treatment is a priority. Research should include predictive models to identify risk factors for higher glycemic variability and cancer-related symptoms and outcomes.

Thyroid Carcinoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).

Serum Thyroglobulin Measurement Following Surgery Without Radioactive Iodine for Differentiated Thyroid Cancer: A Systematic Review.

Background: The utility of serum thyroglobulin (Tg) measurement following partial thyroidectomy or total/near-total thyroidectomy without radioactive iodine (RAI) for differentiated thyroid cancer is unclear. This systematic review examines the diagnostic accuracy of serum Tg measurement for persistent, recurrent, and/or metastatic cancer in these situations. Methods: Ovid MEDLINE, Embase, and Cochrane Central were searched in October 2021 for studies on Tg measurement following partial thyroidectomy or total/near-total thyroidectomy without or before RAI. Quality assessment was performed, and evidence was synthesized qualitatively. Results: Thirty-seven studies met inclusion criteria. Four studies (N = 561) evaluated serum Tg measurement following partial thyroidectomy, five studies (N = 751) evaluated Tg measurement following total/near-total thyroidectomy without RAI, and 28 studies (N = 7618) evaluated Tg measurement following total or near-total thyroidectomy before RAI administration. Following partial thyroidectomy, Tg measurement was not accurate for diagnosing recurrence or metastasis, or estimates were imprecise. Following total/near-total thyroidectomy without RAI, evidence was limited due to few studies with very low rates of recurrence or metastasis, but indicated that Tg levels were usually stable and low. For Tg measurements before RAI administration, diagnostic accuracy for metastatic disease or persistence varied, although sensitivity appeared high (but specificity low) at a cutoff of >1 to 2.5 ng/mL. However, applicability to patients who do not undergo RAI is uncertain because patients selected for RAI are likely to represent a higher risk group. The evidence was very low quality for all scenarios. All studies had methodological limitations, and there was variability in the Tg thresholds evaluated, patient populations, outcomes assessed, and other factors. Conclusions: Very limited evidence suggests low utility of Tg measurement for identifying recurrent or metastatic disease following partial thyroidectomy. Following total/near-total thyroidectomy, Tg levels using a cutoff of 1-2.5 ng/mL might identify patients at low risk for persistent or metastatic disease. Additional research is needed to clarify the role of Tg measurement in these settings, determine optimal Tg thresholds, and determine appropriate measurement intervals.

Glycemic Variability Within 1 Year Following Surgery for Stage II-III Colon Cancer.

OBJECTIVE: To examine glycemic variability within 1 month and 1 year following surgery among adult patients, with and without Type 2 Diabetes (T2D), treated for stage II-III colon cancer. METHOD: A retrospective analysis of electronic health record data was conducted. Glycemic variability (i.e., standard deviation [SD] and coefficient of variation [CV] of > 2 blood glucose measures) was assessed within 1 month and within 1 year following colon surgery. Chi-square (χ2), Fisher's exact, and Mann-Whitney U tests were used for the analyses. RESULTS: Among the sample of 165 patients with stage II-III colon cancer, those with T2D had higher glycemic variability compared to patients without T2D (p < .001), with values within 1 month following surgery (SD = 44.69 mg/dL, CV = 27.4%) vs (SD = 20.55 mg/dL, CV = 17.53%); and within 1 year following surgery (SD = 45.04 mg/dL, CV = 29.04%) vs (SD = 21.36 mg/dL, CV = 18.6%). Associations were found between lower body mass index and higher glycemic variability (i.e., SD [r = -.413, p < .05] and CV [r = -.481, p < .01]) within 1 month following surgery in patients with T2D. Higher preoperative glucose was associated with higher glycemic variability (i.e., SD r = .448, p < .01) within 1 year in patients with T2D. Demographic and clinical characteristics were weakly associated with glycemic variability in patients without T2D. CONCLUSIONS: Patients with stage II-III colon cancer with T2D experienced higher glycemic variability within 1 month and within 1 year following surgery compared to those without T2D. Associations between glycemic variability and demographic and clinical characteristics differed by T2D status. Further research in prospective studies is warranted.

Comparison of Afirma GEC and GSC to Nodules Without Molecular Testing in Cytologically Indeterminate Thyroid Nodules.

BACKGROUND: Analysis of cytologically indeterminate thyroid nodules with Afirma Gene Expression Classifier (GEC) and Genomic Sequencing Classifier (GSC) can reduce surgical rate and increase malignancy rate of surgically resected indeterminate nodules. METHODS: Retrospective cohort analysis of all adults with cytologically indeterminate thyroid nodules from January 2013 through December 2019. We compared surgical and malignancy rates of those without molecular testing to those with GEC or GSC, analyzed test performance between GEC and GSC, and identified variables associated with molecular testing. RESULTS: 468 indeterminate thyroid nodules were included. No molecular testing was performed in 273, 71 had GEC, and 124 had GSC testing. Surgical rate was 68% in the group without molecular testing, 59% in GEC, and 40% in GSC. Malignancy rate was 20% with no molecular testing, 22% in GEC, and 39% in GSC (P = 0.022). GEC benign call rate (BCR) was 46%; sensitivity, 100%; specificity, 61%; and positive predictive value (PPV), 28%. GSC BCR was 60%; sensitivity, 94%; specificity, 76%; and PPV, 41%. Those with no molecular testing had larger nodule size, preoperative growth of nodules, and constrictive symptoms and those who underwent surgery in the no molecular testing group had higher body mass index, constrictive symptoms, higher Thyroid Imaging Reporting and Data System and Bethesda classifications. Type of provider was also associated with the decision to undergo surgery. CONCLUSION: Implementation of GEC showed no effect on surgical or malignancy rate, but GSC resulted in significantly lower surgical and higher malignancy rates. This study provides insight into the factors that affect the real-world use of these molecular markers preoperatively in indeterminate thyroid nodules.

Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

Patient Reported Outcome Measures of Health-Related Quality of Life and Asthenia after Thyroidectomy.

BACKGROUND: After thyroidectomy some patients experience a chronic fatigue syndrome called asthenia. The purpose of this study was to determine the post-operative health related quality of life (HRQOL) and risk of asthenia in patients undergoing thyroidectomy. METHODS: A single institution prospective observational cohort study of adults undergoing thyroidectomy from September 2016 to July 2019 with four HRQOL surveys: preoperative baseline, 2 wk-, 6 mo- and 12 mo-postoperatively. Patients were surveyed using the Short Form 36 version 2 and Brief Fatigue Inventory. Asthenia was defined as Brief Fatigue Inventory > 60 at 12 mo. HRQOL was compared between patients undergoing thyroid lobectomy (TL) or total thyroidectomy (TT) with benign (-B) or malignant (-Ca) final pathology. RESULTS: A total of 182 patients were included: 67 (37%) with TL-B, 32 (17%) with TL-Ca, 40 (22%) with TT-B, and 43 (24%) with TT-Ca. The incidence of asthenia was 42% for TT and 4% for TL. In the TL-B group, 2 patients (3%) developed asthenia, compared with 2 patients (6.25%) in the TL-Ca group, 14 patients (35%) in the TT-B group, and 21 (48.8%) in the TT-Ca group (P = 0.0001). The odds ratio of asthenia for TT compared to TL was 10.4 (95% CI 3.86-28.16) and for patients with malignancy compared to benign disease was 2.05 (95% CI 1.17-3.61). CONCLUSIONS: Patients undergoing TT have a higher risk of developing asthenia than those undergoing TL, particularly if the final pathology shows malignancy.

The Association of Diabetes and Hyperglycemia on Inpatient Readmissions.

OBJECTIVE: To evaluate the association between inpatient glycemic control and readmission in individuals with diabetes and hyperglycemia (DM/HG). METHODS: Two data sets were analyzed from fiscal years 2011 to 2013: hospital data using the International Classification of Diseases, Ninth Revision (ICD-9) codes for DM/HG and point of care (POC) glucose monitoring. The variables analyzed included gender, age, mean, minimum and maximum glucose, along with 4 measures of glycemic variability (GV), standard deviation, coefficient of variation, mean amplitude of glucose excursions, and average daily risk range. RESULTS: Of 66 518 discharges in FY 2011-2013, 28.4% had DM/HG based on ICD-9 codes and 53% received POC monitoring. The overall readmission rate was 13.9%, although the rates for individuals with DM/HG were higher at 18.9% and 20.6% using ICD-9 codes and POC data, respectively. The readmitted group had higher mean glucose (169 ± 47 mg/dL vs 158 ± 46 mg/dL, P < .001). Individuals with severe hypoglycemia and hyperglycemia had the highest readmission rates. All 4 GV measures were consistent and higher in the readmitted group. CONCLUSION: Individuals with DM/HG have higher 30-day readmission rates than those without. Those readmitted had higher mean glucose, more extreme glucose values, and higher GV. To our knowledge, this is the first report of multiple metrics of inpatient glycemic control, including GV, and their associations with readmission.

Postoperative thyroid hormone supplementation rates following thyroid lobectomy.

BACKGROUND: Thyroid lobectomy is performed for symptomatic benign nodules, indeterminate nodules, or low-risk well differentiated thyroid cancer. We aimed to determine factors associated with thyroid stimulating hormone over goal (TH) following lobectomy. METHODS: We performed a retrospective single-institution cohort study of patients undergoing thyroid lobectomy from January 2016 to December 2017. TH was defined as need for thyroid hormone in accordance with guidelines. Univariate and multivariate logistic regression analysis was performed. RESULTS: One hundred patients were included and 47% developed. TH: 73% of those with cancer, 38% with benign pathology (p = 0.002). Patients with TH were more likely to have thyroiditis 26% versus 3.8% (p = 0.002); higher preoperative TSH: mean 1.88mIU/L (SD 1.17) versus 1.16mIU/L (SD 0.77) (p = 0.0002), and smaller remnant thyroid lobe adjusted for body surface area 2.99ml/m2 versus 3.72ml/m2 (p = 0.003). CONCLUSIONS: After thyroid lobectomy, TH is associated with preoperative TSH level, thyroiditis, remnant thyroid volume, and malignancy. The majority of patients with final pathology of carcinoma will require thyroid hormone supplementation to achieve TSH goal.