Decreased bone mass in adolescents with bone fragility fracture but not in young children: a case-control study.

Background: The incidence of distal forearm fracture due to minimal/moderate trauma shows a bimodal distribution for age at event, with one peak occurring during early adolescence, in both boys and girls and the other one in postmenopausal females. The aim of this study was, therefore, to document whether the relationship between bone mineral density and fracture is different in young children compared with adolescents. Methods: A matched-pair, case-control study has been conducted to evaluate bone mineral density in 469 young children and 387 adolescents of both sexes, with/without fracture due to minimal/moderate trauma with assurance that the compared groups were equally susceptible to the outcome event. All fractures were radiographically confirmed. The study utilized bone mineral areal density of the total body, spine, hips, and forearm; volumetric bone mineral density of the forearm; and metacarpal radiogrammetry measurements. The study controlled for skeletal development, bone geometry, body composition, hand grip strength, calcium intake, and vitamin D status. Results: Adolescents with distal forearm fracture have reduced bone mineral density at multiple skeletal regions of interest. This was documented by the bone mineral areal density measurements at multiple skeletal sites (p < 0.001), volumetric bone mineral density measurements of the forearm (p < 0.0001), and metacarpal radiogrammetry (p < 0.001). Adolescent females with fracture had reduced cross-sectional areas of the radius and metacarpals. The bone status of young female and male children with fracture was no different to its controls. Increased body fatness was more prevalent among fracture cases than in controls. Around 72% of young female and male children with fracture had serum 25-hydroxyvitamin D levels below the threshold of 31 ng/ml, compared with only 42% of female controls and to 51% of male controls. Conclusions: Adolescents with bone fragility fracture had reduced bone mineral density at multiple skeletal regions of interest, whereas this was not the case with younger children. The results of the study may have implications for the prevention of bone fragility in this segment of the pediatric population.

Utilizing Dynamic Risk Stratification in Patients With Tall Cell Variant Papillary Thyroid Cancer.

OBJECTIVES: Tall cell variant (TCV) papillary thyroid cancer (PTC) is a subtype of PTC associated with aggressive tumor behavior, advanced stage, and higher rates of recurrence and mortality. The present study aimed to test an established dynamic risk stratification tool in the TCV population, with the goal of better predicting the postoperative course of these patients. STUDY DESIGN: Retrospective chart review. METHODS: A total of 94 patients with TCV who underwent total thyroidectomy with radioactive iodine ablation were retrospectively reviewed from 1998 through 2020. Biochemical, structural, and overall response to treatment was determined for each patient, based on postoperative thyroglobulin levels and imaging findings. Primary outcomes were locoregional and distant recurrence, presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. RESULTS: Patients with TCV who were stratified as having an excellent overall response to treatment had lower rates of locoregional recurrence than indeterminate, biochemical incomplete, and structural incomplete responses (2.0%, 33.3%, 55.0%, and 85.7% at 5 years respectively, p < 0.001). The same was true for distant recurrence as well (2.0%, 9.0%, 35.1%, and 42.9%, p < 0.001). An excellent response was also associated with lower rates of presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. CONCLUSIONS: Although TCV is an aggressive subtype associated with worse clinical outcomes than classical PTC, patients with an excellent overall response to treatment have significantly improved outcomes when compared to indeterminate, biochemical incomplete, and structural incomplete responses. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2430-2438, 2023.

Association of Treatment Strategies and Tumor Characteristics With Overall Survival Among Patients With Anaplastic Thyroid Cancer: A Single-Institution 21-Year Experience.

Importance: Survival outcomes for anaplastic thyroid cancer (ATC), the most aggressive subtype of thyroid cancers, have remained poor. However, targeted therapies and immunotherapies present new opportunities for treatment of this disease. Evaluations of survival outcomes over time with new multimodal therapies are needed for optimizing treatment plans. Objective: To evaluate the association of treatment strategies and tumor characteristics with overall survival (OS) among patients with ATC. Design, Setting, and Participants: This retrospective case series study evaluated the survival outcomes stratified by treatment strategies and tumor characteristics among patients with ATC treated at a tertiary level academic institution from January 1, 2000, to December 31, 2021. Demographic, tumor, treatment, and outcome characteristics were analyzed. Kaplan-Meier method and log rank test modeled OS by treatment type and tumor characteristics. Data were analyzed in May 2022. Main Outcomes and Measures: Overall survival (OS). Results: The study cohort comprised 97 patients with biopsy-proven ATC (median [range] age at diagnosis, 70 [38-93] years; 60 (62%) female and 85 [88%] White individuals; 59 [61%] never smokers). At ATC diagnosis, 18 (19%) patients had stage IVA, 19 (20%) had stage IVB, and 53 (55%) had stage IVC disease. BRAF status was assessed in 38 patients; 18 (47%) had BRAF-V600E variations and 20 (53%), BRAF wild type. Treatment during clinical course included surgery for 44 (45%) patients; chemotherapy, 41 (43%); definitive or adjuvant radiation therapy, 34 (RT; 35%); and targeted therapy, 28 (29%). Median OS for the total cohort was 6.5 (95% CI, 4.3-10.0) months. Inferior OS was found in patients who did not receive surgery (hazard ratio [HR], 2.12; 95% CI, 1.35-3.34; reference, received surgery), chemotherapy (HR, 3.28; 95% CI, 1.99-5.39; reference, received chemotherapy), and definitive or adjuvant RT (HR, 2.47; 95% CI, 1.52-4.02; reference, received definitive/adjuvant RT). On multivariable analysis, age at diagnosis (HR, 1.03; 95% CI, 1.01-1.06), tumor stage IVC (HR, 2.65; 95% CI, 1.35-5.18), and absence of definitive or adjuvant RT (HR, 1.90; 95% CI, 1.01-3.59) were associated with worse OS. Conclusions and Relevance: This retrospective single-institution study found that lower tumor stage, younger age, and the ability to receive definitive or adjuvant RT were associated with improved OS in patients with ATC.

Use of Preoperative Imaging in Primary Hyperparathyroidism.

CONTEXT: Preoperative imaging is performed routinely to guide surgical management in primary hyperparathyroidism, but the optimal imaging modalities are debated. OBJECTIVE: Our objectives were to evaluate which imaging modalities are associated with improved cure rate and higher concordance rates with intraoperative findings. A secondary aim was to determine whether additive imaging is associated with higher cure rate. DESIGN, SETTING, AND PATIENTS: This is a retrospective cohort review of 1485 adult patients during a 14-year period (2004-2017) at an academic tertiary referral center that presented for initial parathyroidectomy for de novo primary hyperparathyroidism. MAIN OUTCOME MEASURES: Surgical cure rate, concordance of imaging with operative findings, and imaging performance. RESULTS: The overall cure rate was 94.1% (95% confidence interval, 0.93-0.95). Cure rate was significantly improved if sestamibi/single-photon emission computed tomography (SPECT) was concordant with operative findings (95.9% vs. 92.5%, P = 0.010). Adding a third imaging modality did not improve cure rate (1 imaging type 91.8% vs. 2 imaging types 94.4% vs. 3 imaging types 87.2%, P = 0.59). Despite having a low number of cases (n = 28), 4-dimensional (4D) CT scan outperformed (higher sensitivity, specificity, positive predictive value, negative predictive value) all imaging modalities in multiglandular disease and double adenomas, and sestamibi/SPECT in single adenomas. CONCLUSIONS: Preoperative ultrasound combined with sestamibi/SPECT were associated with the highest cure and concordance rates. If pathology was not found on ultrasound and sestamibi/SPECT, additional imaging did not improve the cure rate or concordance. 4D CT scan outperformed all imaging modalities in multiglandular disease and double adenomas, and sestamibi/SPECT in single adenomas, but these findings were underpowered.

Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors: a PreCIS database study.

BACKGROUND: Thyroid hormones have profound effect on the heart and peripheral vasculature. Hypothyroidism is associated with an increase in a number of coronary heart disease (CHD) risk factors including dyslipidemia, hypertension, and elevated levels of homocysteine. Our objective was to assess the effects of hypothyroidism (thyroid-stimulating hormone [TSH]: >10 µ U/mL), moderate subclinical hypothyroidism (SCH; TSH: 6.1-10 µ U/mL), and mild SCH (TSH: 3.1-6.0 µ U/mL) on cardiovascular risk factors, CHD prevalence, and all-cause mortality in patients at high risk for CHD seen in a preventive cardiology clinic. METHODS: All patients seen in the Cleveland Clinic Preventive Cardiology clinic have demographic and laboratory tests including TSH and multiple CHD risk factors obtained at the baseline visit. All data are entered into a database (called PreCIS). The social security death index is queried monthly to determine all-cause mortality. RESULTS: Several CHD risk factors including age, male gender, systolic blood pressure, triglycerides, and fibrinogen were more common in hypothyroid patients. Prevalence of CHD was more common in hypothyroid and moderate SCH patients. All-cause mortality was higher in hypothyroid and moderate SCH patients, but not in mild SCH patients. Higher mortality in these groups was observed in both genders, patients under 65 years of age, and patients not on thyroid replacement therapy, but was not observed in patients over 65 years of age. CONCLUSIONS: Hypothyroidism and moderate, but not mild, SCH are associated with increased CHD prevalence and all-cause mortality. These observations suggest patients with moderate, but not mild, SCH and patients at high risk for CHD should be treated with thyroid replacement therapy.

Risk factors for low bone mass in patients with ulcerative colitis following ileal pouch-anal anastomosis.

OBJECTIVES: Bone mineral density (BMD) can be adversely affected by the chronic nature of inflammatory bowel disease. Ileal pouch-anal anastomosis (IPAA) is the surgical treatment of choice for patients with ulcerative colitis (UC) who require proctocolectomy. There are few data on BMD in UC patients with IPAA. The aim of the study was to assess the prevalence and risk factors associated with low BMD in UC patients after IPAA. METHODS: A total of 327 eligible patients with UC and IPAA from the Pouchitis Clinic were enrolled. Dual-energy X-ray absorptiometry was performed. Patients were classified as having normal or low BMD, based on the criteria by the International Society for Clinical Densitometry. A total of 39 demographic and clinical variables were evaluated with logistic regression models. RESULTS: Of 327 patients with a median of 4 years after IPAA, 105 (32.1%) had low BMD. Fragility fracture was documented in 11 patients (10.5%) in the low BMD group and in 13 of 222 patients (5.9%) in the normal BMD group (P=0.14). In the multivariable analysis, covariate-adjusted factors associated with a low BMD were advanced age (odds ratio (OR) =1.64 per 5 years; 95% CI, 1.44-1.87), low body mass index (OR=0.43 per 5 kg/m(2); 95% CI, 0.30-0.62), and non-use of daily calcium supplement (OR=0.53; 95% CI, 0.29-0.96). Pouch-associated factors were not found to be significantly associated with the bone loss. CONCLUSIONS: Low BMD was common in patients with UC, even after colectomy and IPAA. Low BMD in this patient population was associated with certain risk factors, some of which may be modifiable.

The utility of peripheral thyrotropin mRNA in the diagnosis of follicular neoplasms and surveillance of thyroid cancers.

BACKGROUND: Thyroid cells in peripheral circulation express uniquely thyrotropin receptor (TSHR) mRNA, and their detection may aid thyroid cancer management. METHODS: Since 2002, 258 patients had prospective TSHR mRNA measurement by quantitative RT-PCR from peripheral blood before and/or after thyroidectomy. Thyroid cancer detection was assessed from known clinical diagnostic criteria and mRNA for patients with follicular neoplasms (n = 64) and long-term cancer follow-up (n = 13). RESULTS: Adding TSHR mRNA to fine-needle aspiration biopsy (FNAB) maintained high sensitivity (90%) but improved specificity (73%) for thyroid cancer diagnosis. When FNAB specimens indicated follicular neoplasm, a decision algorithm combining TSHR mRNA and abnormal thyroid ultrasound features correctly diagnosed all cancer patients (100% sensitivity) and would have spared operation for benign disease in 38%. Elevated TSHR mRNA on postoperative day 1 predicted persistent/recurrent cancer. During long-term thyroid cancer surveillance, TSHR mRNA had a 91% concordance with radioactive iodine whole body scan (WBS)-detectable disease, agreed with thyroglobulin (Tg) levels in 64% of patents, missed disease in 5%, but was more sensitive to detecting disease than Tg levels in 31% of patients, including all patients with Tg antibodies. CONCLUSIONS: Detecting circulating thyroid cancer cells is useful for initial thyroid cancer diagnosis and postoperatively predicts recurrent cancer. This novel test promises to enhance thyroid cancer patient care by management algorithms that combine histologic, genomic, and clinical criteria.

Thyroid-stimulating hormone receptor messenger ribonucleic acid measurement in blood as a marker for circulating thyroid cancer cells and its role in the preoperative diagnosis of thyroid cancer.

CONTEXT: Thyroid cancer cells express TSH receptor (TSHR) mRNA, and its measurement in the circulation may be useful in the diagnosis/management of differentiated thyroid cancer (DTC). OBJECTIVE: Our objective was to assess the diagnostic value of circulating TSHR mRNA for preoperative detection of DTC in patients with thyroid nodules. PATIENTS: We measured TSHR mRNA levels by RT-PCR in 258 subjects: 51 healthy subjects and 207 patients (thyroid nodules, n = 180; recurrent thyroid cancer, n = 27) with fine-needle aspirations (FNA) and/or thyroid/neck surgery. Eighty-nine patients also had d-1 postoperative levels assessed. OUTCOME MEASURES: TSHR mRNA levels were compared with FNA cytology for cancer detection preoperatively and serum thyroglobulin and/or whole-body 131I scans postoperatively. RESULTS: Based on cytology/pathology, 88 patients had DTC and 119 had benign thyroid disease. The TSHR mRNA levels in cancer patients were significantly higher than in benign disease (P < 0.0001). At a cutoff value of 1.02 ng/microg total RNA, the TSHR mRNA correctly classified 78.7% of patients preoperatively (sensitivity = 72.0%; specificity = 82.5%). Of 131 patients with FNA and surgery, 51 were FNA positive (all cancer), 17 were FNA negative (15 benign, two cancer), and 63 were indeterminate. TSHR mRNA correctly diagnosed DTC in 16 of 24 (67%) and benign disease in 29 of 39 (74%) patients with indeterminate FNA (combined sensitivity = 90%; specificity = 80%). Combining TSHR mRNA and ultrasound features for follicular lesions correctly classified all follicular cancers and could have spared surgery in 31% of these patients with benign disease. TSHR mRNA has a short life in circulation, and normalized levels on postoperative d 1 correlated with disease-free status, whereas elevated levels predicted residual/metastatic disease. CONCLUSIONS: TSHR mRNA measured with FNA enhances the preoperative detection of cancer in patients with thyroid nodules, reducing unnecessary surgeries, and immediate postoperative levels can predict residual/metastatic disease.

Giant invasive pituitary prolactinoma with falsely low serum prolactin: the significance of 'hook effect'.

The authors report a case of a patient with giant, invasive skull base tumor extending to the parasellar area discovered incidentally during the work-up for decreased memory. The patient's neurological exam was otherwise unremarkable. Endocrine evaluation performed at a local hospital showed a moderate hyperprolactinemia 103 ng/ml (normal up to 20 ng/ml). Given the large size of the tumor, the elevated prolactin (PRL) was interpreted to be secondary to stalk effect and patient underwent debulking surgery through a transcranial approach. Immunostaining of the excised tumor tissue was strongly positive for prolactin. His prolactin was found to be 13,144 ng/ml in our lab after surgery confirming the diagnosis of invasive giant prolactinoma. The patient developed a complete right third, fourth and sixth nerve palsy postoperatively. He was started on Cabergoline with normalization of his prolactin level and more than 50% decrease in residual tumor size over 9 months periods. There has been no clinically significant improvement in his right eye ophthalmoplegia since surgery. This case highlights the importance of 'Hook Effect' resulting in falsely low prolactin level, which may have significant therapeutic implication.

Successful treatment of sulfonylurea-induced prolonged hypoglycemia with use of octreotide.

OBJECTIVE: To report the successful use of octreotide in the management of prolonged hypoglycemia attributable to therapeutic doses of sulfonylureas. METHODS: We present a case series of 6 patients with sulfonylurea-induced hypoglycemia, along with pertinent serial laboratory data and review of the course of management. RESULTS: Most of our 6 study patients had diabetes mellitus, which had been managed with sulfonylurea therapy. In the context of renal failure or heart failure (or both), severe, prolonged hypoglycemia developed. Intermittent intravenous administration of 50% dextrose did not result in a sustained and adequate response. Continuous intravenous administration of dextrose-containing solutions was contraindicated because of fluid overload as a result of congestive heart failure or renal failure. Administration of octreotide, 50 microg subcutaneously every 8 hours, resulted in a prompt and sustained resolution of the hypoglycemia. In 3 of the 6 study subjects, measurements of insulin and C-peptide levels both before and after treatment confirmed the efficacy of the octreotide therapy. CONCLUSION: Our cases demonstrate that octreotide proves to be an effective treatment intervention for prolonged hypoglycemia caused by therapeutic doses of sulfonylureas. This is the first major report of the safe and effective use of octreotide in the management of sulfonylurea-induced hypoglycemia outside the emergency department setting.

Calcium supplementation and bone mineral density in females from childhood to young adulthood: a randomized controlled trial.

BACKGROUND: Short-term studies established that calcium influences bone accretion during growth. Whether long-term supplementation influences bone accretion in young adults is not known. OBJECTIVE: This study evaluated the long-term effects of calcium supplementation on bone accretion among females from childhood to young adulthood. DESIGN: A 4-y randomized clinical trial recruited 354 females in pubertal stage 2 and optionally was extended for an additional 3 y. The mean dietary calcium intake of the participants over 7 y was approximately 830 mg/d; calcium-supplemented persons received an additional approximately 670 mg/d. Primary outcome variables were distal and proximal radius bone mineral density (BMD), total-body BMD (TBBMD), and metacarpal cortical indexes. RESULTS: Multivariate analyses of the primary outcomes indicated that calcium-supplementation effects vary over time. Follow-up univariate analyses indicated that all primary outcomes were significantly larger in the supplemented group than in the placebo group at the year 4 endpoint. However, at the year 7 endpoint, this effect vanished for TBBMD and distal radius BMD. Longitudinal models for TBBMD and proximal radius BMD, according to the time since menarche, showed a highly significant effect of supplementation during the pubertal growth spurt and a diminishing effect thereafter. Post hoc stratifications by compliance-adjusted total calcium intake and by final stature or metacarpal total cross-sectional area showed that calcium effects depend on compliance and body frame. CONCLUSIONS: Calcium supplementation significantly influenced bone accretion in young females during the pubertal growth spurt. By young adulthood, significant effects remained at metacarpals and at the forearm of tall persons, which indicated that the calcium requirement for growth is associated with skeletal size. These results may be important for both primary prevention of osteoporosis and prevention of bone fragility fractures during growth.