Are Higher Body Mass Index and Worse Metabolic Parameters Associated with More Aggressive Differentiated Thyroid Cancer? A Retrospective Cohort Study.

Obesity is a risk factor for differentiated thyroid cancer (DTC), but the association with DTC aggressiveness is controversial. To evaluate the association between preoperative body mass index (BMI)/other metabolic parameters and DTC aggressiveness in our surgical cohort, we retrospectively evaluated patients following thyroid surgery who were diagnosed with DTC between December 2013 and January 2021. Baseline characteristics, histopathological features, treatment modalities, and follow-up data were studied. We conducted logistic regression to analyze the association between BMI/other metabolic parameters and adverse DTC features. The final study cohort included 211 patients (79.6% women; mean age± standard deviation 48.7 ± 15.9 years): 66 (31.3%) with normal weight, 81 (38.4%) with overweight, and 64 (30.3%) with obesity. The median follow-up was 51 months (range 7-93). Complete versus partial thyroidectomy was more common among patients living with overweight or obesity than in normal weight patients (79.7% versus 61.7%, p = 0.017, respectively). Logistic regression demonstrated that higher BMI was associated with mildly increased risk for lymph nodes metastases (odds ratio [OR] 1.077, 95% CI: 1.013-1.145), and higher triglycerides/high-density lipoprotein-cholesterol (TG/HDL-C) ratio was associated with aggressive histological variants of DTC (OR 1.269, 95% CI 1.001-1.61). To conclude, specific adverse clinical and histopathological DTC features were indeed associated with higher BMI and higher TG/HDL-C ratio.

Novel Susceptibility Genes Drive Familial Non-Medullary Thyroid Cancer in a Large Consanguineous Kindred.

Familial non-medullary thyroid cancer (FNMTC) is a well-differentiated thyroid cancer (DTC) of follicular cell origin in two or more first-degree relatives. Patients typically demonstrate an autosomal dominant inheritance pattern with incomplete penetrance. While known genes and chromosomal loci account for some FNMTC, the molecular basis for most FNMTC remains elusive. To identify the variation(s) causing FNMTC in an extended consanguineous family consisting of 16 papillary thyroid carcinoma (PTC) cases, we performed whole exome sequence (WES) analysis of six family patients. We demonstrated an association of ARHGEF28, FBXW10, and SLC47A1 genes with FNMTC. The variations in these genes may affect the structures of their encoded proteins and, thus, their function. The most promising causative gene is ARHGEF28, which has high expression in the thyroid, and its protein-protein interactions (PPIs) suggest predisposition of PTC through ARHGEF28-SQSTM1-TP53 or ARHGEF28-PTCSC2-FOXE1-TP53 associations. Using DNA from a patient's thyroid malignant tissue, we analyzed the possible cooperation of somatic variations with these genes. We revealed two somatic heterozygote variations in XRCC1 and HRAS genes known to implicate thyroid cancer. Thus, the predisposition by the germline variations and a second hit by somatic variations could lead to the progression to PTC.

Zinc in microscopic calcifications isolated from thyroid fine needle aspiration may serve as a biomarker of thyroid nodule malignancy: A promising proof-of-concept.

Thyroid nodules (TNs) are common neck ultrasonography (US) findings, yet only 5-10% of these nodules harbor thyroid cancer (TC). When US characteristics are consistent with an intermediate or high suspicion for TN malignancy, fine needle aspiration for cytology (FNAC) is indicated. The main limitation of FNAC is that cytological results can be indeterminate in up to 30% of cases, necessitating reevaluation through repeated FNAC, expensive molecular testing, or diagnostic thyroid lobe resection. As such, there is a need for further refinement of current diagnostic algorithms for TNs without subjecting patients to additional invasive procedures. As calcifications detected during thyroid US are considered a high-risk feature for malignancy, we used the material remaining following routine thyroid FNAC to isolate microscopic calcifications (MCs). We then characterized the elemental composition, morphology, and crystal phases of these MCs, ultimately revealing differences between the MCs from benign and malignant TNs. Specifically, thyroid MCs were identified as calcium phosphate crystals containing varying levels of magnesium, sodium, iron, and zinc. MCs obtained from malignant TNs, mainly papillary thyroid carcinoma, were composed of sub-micrometer spherical particles, whereas MCs from benign TNs consisted of faceted particles. While samples from most patients with a final diagnosis of malignant TNs (50% of them with indeterminate cytology) harbored zinc-containing MCs, zinc was largely absent in MCs from benign TNs (23% with indeterminate or non-diagnostic cytology). Together, these data suggest that the presence of zinc in MCs isolated from samples collected during routine FNAC may potentially offer value as a biomarker of TN malignancy. STATEMENT OF SIGNIFICANCE: As up to 40% of patients assessed for thyroid malignancy do not receive a definite diagnosis following thyroid nodule (TN) fine needle aspiration (FNA), there is a pressing need to improve the accuracy of current diagnostic algorithms. Chemical analyses of microscopic calcifications (MCs) may serve as a diagnostic target. We developed a straightforward protocol to chemically characterize MCs from excess material collected from TNs during routine FNA and found that these MCs differed between benign and malignant TNs. Specifically, zinc in TN-derived MCs may indicate a higher nodule malignancy risk, thus increasing the diagnostic accuracy of the FNA procedure, reducing the need for recurrent biopsies and diagnostic surgical procedures, and decreasing the costs, uncertainty, and stress faced by affected patients.

Rates of Malignancy in Cytology Indeterminate Thyroid Nodules: A Single Center Surgical Series.

BACKGROUND: Due to the high variability in malignancy rate among cytologically indeterminate thyroid nodules (Bethesda categories III-V), the American Thyroid Association recommends that each center define its own categorical cancer risk. OBJECTIVES: To assess cancer risk in patients with cytologically indeterminate thyroid nodules who were operated at our center. METHODS: In a retrospective study, we analyzed the pathology results of all the patients whose fine needle aspiration results showed Bethesda III-V cytology and who subsequently underwent total thyroidectomy or lobectomy from December 2013 to September 2017. RESULTS: We analyzed 56 patients with indeterminate cytology on fine needle aspiration. Twenty-nine (52%) were defined as Bethesda III, 19 (34%) Bethesda IV, and 8 (14%) Bethesda V category. Malignancy rates were 38%, 58%, and 100% for Bethesda categories III, IV, and V, respectively. Most malignancies in Bethesda categories III and IV were follicular in origin (follicular thyroid carcinoma and follicular type papillary thyroid carcinoma), while 100% of the patients with Bethesda category V were diagnosed with classical papillary thyroid carcinoma. No correlation was found between sonographic and cytological criteria of nodules with Bethesda categories III and IV and rates of malignancy. CONCLUSIONS: We found higher than expected rates of malignancy in indeterminate cytology. This finding reinforces the guidelines of the American Thyroid Association to establish local malignancy rates for thyroid nodules with indetermined cytology.

Thyroglobulin is a poor predictor of differentiated thyroid cancer in patients who undergo surgery for thyroid nodular diseases.

OBJECTIVES: Thyroglobulin, produced exclusively by thyroid follicular cells, serves as a specific tumor marker for the follow-up of differentiated thyroid cancer (DTC) patients after thyroidectomy. However, its role as a predictor of malignancy in patients with thyroid nodules is controversial. We assessed the potential role of preoperative serum thyroglobulin concentration to predict DTC in patients without a preoperative diagnosis of malignancy who underwent partial or total thyroidectomy. METHODS: This retrospective study included patients with a preoperative diagnosis of benign multinodular goiter (MNG) or a thyroid nodule with indeterminate cytology (INC) (Bethesda system categories III/IV) who underwent partial or total thyroidectomy between January 2014 and May 2019. We compared the patients' demographic, clinical, imaging, and biochemical data according to their final diagnosis: DTC or benign thyroid nodular disease. Further statistical analysis included odds ratio calculation and receiver operating characteristic (ROC) curve analysis. RESULTS: Of 131 patients who met inclusion and exclusion criteria, the indication for surgery was benign MNG in 69 patients and a thyroid nodule with INC in 62 patients. A final diagnosis of DTC was reported in 18 of the 69 benign MNG patients (26%) and in 30 of the 62 thyroid nodule with INC patients (48%). The preoperative measurements of nodule diameter and serum thyroid-stimulating hormone and thyroglobulin concentrations did not significantly differ between patients with a final diagnosis of DTC and those with benign histology. CONCLUSIONS: Preoperative serum thyroglobulin alone is insufficient to differentiate between malignant and benign thyroid nodular disease.

Resistant prolactinomas: a case series of 26 patients.

PURPOSE: Prolactin (PRL)-secreting tumors are the most common functional pituitary adenomas. They usually respond to dopamine agonist (DA) treatment, with PRL normalization and adenoma shrinkage. Our aim was to characterize patients with prolactinoma resistant to DA treatment. METHODS: This retrospective case series included patients diagnosed with DA-resistant prolactinomas between 1993-2017 in three medical centers. Resistance was defined as PRL levels above three times the upper limit of normal (ULN) despite a weekly dose of ≥2 mg cabergoline (CAB). Clinical and biochemical information, and response to treatment, were retrieved from medical records. RESULTS: Twenty-six patients were identified; 20 males. Of 25 macroadenomas, three were giant tumors (>40 mm) and 15 (57.7%) were invasive. The mean age at diagnosis was 31.8 ± 14.9 years (range: 13-62). The median maximal CAB dose was 3.5 mg/week (IQR, 2.5-5). Half the patients received only CAB in escalating doses, nine received CAB and underwent transsphenoidal surgery, and four underwent surgery and radiotherapy in addition to CAB treatment. PRL levels at baseline between patients treated only with CAB and those operated were (91.6 [51.1-296.7] vs. 73.1 [22.6-170.9] XULN p = 0.355), and under maximal CAB dose PRL levels between patients treated only with CAB and those operated were similar (5.77 [1.27-11.27] vs 5.27 (2.9-26) XULN p = 0.317). At the last visit patients who received combined therapy achieved lower PRL levels than those treated with DA only (5.22 [1.7-21.6] vs 1.1 [0.44-3.99] XULN p = 0.017) PRL normalization was attained in seven patients and levels below 3 × ULN in fourteen patients; the overall response was 56%. CONCLUSIONS: Resistant prolactinomas usually require a multi-modal treatment strategy. We were able to control 14/25 (56%) of resistant tumors.

Bone mineral density in women newly diagnosed with breast cancer: a prospective cohort study.

Estrogen may have opposing effects on health, namely increasing the risk of breast cancer and improving bone health by increasing bone mineral density (BMD). The objective of this study was to compare dual-energy X-ray absorptiometry (DXA) BMD between women newly diagnosed with breast cancer and matched controls without breast cancer. Women newly diagnosed with breast cancer treated between April 2012 and October 2017 were prospectively enrolled. A control group was established of women with negative mammography or breast ultrasound, matched 1:1 by age, body mass index, parity, and the use of hormone replacement therapy. All those included had DXA BMD, and lab assessments at enrollment. Of 869 women with newly diagnosed breast cancer, 464 signed informed consent. Of the 344 who completed the study protocol, 284 were matched to controls. Overall, the mean age was 58 years. Compared to the control group, for the breast cancer group, the mean vitamin D level was lower (48.9 ± 19.0 vs. 53.8 ± 28.8 nmol/L, p = 0.022); and mean values were higher of total hip BMD (0.95 ± 0.14 vs. 0.92 ± 0.12 g/cm2, p = 0.002), T score (-0.38 ± 1.17 vs. -0.68 ± 0.98, p = 0.002), and Z score (0.32 ± 1.09 vs. 0.01 ± 0.88, p < 0.001). Among the women with breast cancer, no correlations were found of baseline BMD with tumor size or grade, nodal involvement, or breast cancer stage. We concluded that women with newly diagnosed breast cancer tend to have higher BMD than women with similar characteristics but without breast cancer. This implies that BMD might be considered a biomarker for breast cancer risk.

High parathyroid hormone levels after parathyroidectomy for parathyroid adenoma are not related to the cellularity of the remaining glands.

BACKGROUND: Patients with primary hyperparathyroidism (PHPT) treated surgically occasionally have normalized calcium, but persistently high parathyroid hormone (PTH). We hypothesized that a possible explanation for this phenomenon is an underlying hyperplasia rather than adenoma. METHODS: Retrospective cohort of patients who underwent parathyroidectomy for PHPT with biopsy of a normal-appearing parathyroid gland were included. Cellularity level of each biopsy and of the adenoma's rim was determined. RESULTS: Forty-seven patients were included. Of them, 19 (40%) had postoperative normocalcemia but elevated PTH. There was no correlation between cellularity either in the rim or of the normal-appearing parathyroid gland and postoperative PTH. The postoperative high PTH group had higher preoperative PTH (P = 0.001) and larger adenomas (P = 0.025). CONCLUSIONS: High PTH levels after successful parathyroidectomy in patients with primary hyperparathyroidism do not appear to result from underlying hyperplasia. A possible alternative explanation is that these patients have a higher preoperative burden of disease.

Limitations of ultrasound in predicting bilaterality vs unilaterality of well-differentiated carcinoma of the thyroid.

PURPOSE: The purpose of this study is to assess the efficacy of ultrasonography in the differentiation of a bilateral and a unilateral WDTC to help physicians decide on performing a total or a partial thyroidectomy. MATERIALS AND METHODS: Retrospective chart review of all patients diagnosed with papillary thyroid carcinoma following a total thyroidectomy or a complete thyroidectomy between January 2013 and December 2015 at the Department of Otorhinolaryngology and Head and Neck Surgery in Soroka University Medical Center in southern Israel. The preoperative ultrasound images of the thyroid were compared to the final pathology in the contralateral lobe. RESULTS: Seventy seven patients (77) were included in this study, There was no correlation between the sonography in the contralateral lobe and the malignancy on that side (p = 0.479). US had a 39% false negative rate and 69% false positive rate. CONCLUSION: The patients with a well-differentiated carcinoma of the thyroid, a benign nodule detected sonographically in the contralateral lobe should not bear a high weight in decision making regarding the extent of surgery.

Hyperprolactinemia diagnosis in elderly men: a cohort of 28 patients over 65 years.

PURPOSE: To characterize a cohort of elderly men with prolactinomas and their response to treatment. METHODS: We have identified 28 elderly men diagnosed after the age of 65 with prolactinomas at seven different endocrine clinics in Israel. A retrospective electronic chart review identified a control group of 76 younger men with macroprolactinomas treated in one of the centers. RESULTS: Mean age at diagnosis was 71.3 ± 5.6 (range 65-86) years, and current age 76.6 ± 7.5 years. Initial complaints leading to diagnosis included sexual dysfunction in 17 males (61%), headaches in two patients (7%), and visual abnormalities in two (7%). Three men presented with osteoporosis. Ten patients (36%) were diagnosed incidentally following brain imaging for unrelated reasons. Seventeen patients (61%) had macroadenoma, while eleven (39%) presented with a microadenoma or no visible adenoma. Mean prolactin (PRL) at presentation was 1594 (median 382; range 50-18,329) ng/ml. Testosterone was low in 21 men. Patients were treated with cabergoline (max dose, 1.1 ± 0.5 mg/week), except for one given bromocriptine; none required pituitary surgery or radiotherapy. Treatment normalized PRL in 24 patients, and in three men PRL suppressed to <2 ULN. Fifteen men normalized testosterone, three improved without normalization, and in three the normal baseline level increased. After a mean follow-up of 5.3 years, 14/15 patients harboring a macroadenoma showed significant adenoma shrinkage. Most patients reported improvement of low libido/erectile dysfunction. In the control group 60 men (79%) achieved PRL normalization. CONCLUSIONS: Elderly men with prolactinomas are diagnosed incidentally in 36% of cases. Long-term medical therapy is successful, achieving biochemical remission, adenoma shrinkage, and clinical improvement in almost all patients.

A rare cause of postpartum acute hyponatremia.

A previously healthy 24-year-old female underwent an emergent caesarean section without a major bleeding described. During the first post-operative days (POD) she complained of fatigue, headache and a failure to lactate with no specific and conclusive findings on head CT. On the following days, fever rose with a suspicion of an obstetric surgery-related infection, again with no evidence to support the diagnosis. On POD5 a new-onset hyponatremia was documented. The urine analysis suggested SIADH, and following a treatment failure, further investigation was performed and demonstrated both central hypothyroidism and adrenal insufficiency. The patient was immediately treated with hydrocortisone followed by levothyroxine with a rapid resolution of symptoms and hyponatremia. Further laboratory investigation demonstrated anterior hypopituitarism. The main differential diagnosis was Sheehan's syndrome vs lymphocytic hypophysitis. Brain MRI was performed as soon as it was available and findings consistent with Sheehan's syndrome confirmed the diagnosis. Lifelong hormonal replacement therapy was initiated. Further complaints on polyuria and polydipsia have led to a water deprivation testing and the diagnosis of partial central insipidus and appropriate treatment with DDAVP. Learning points: Sheehan's syndrome can occur, though rarely, without an obvious major post-partum hemorrhage. The syndrome may resemble lymphocytic hypophysitis clinically and imaging studies may be crucial in order to differentiate both conditions. Hypopituitarism presentation may be variable and depends on the specific hormone deficit. Euvolemic hyponatremia workup must include thyroid function test and 08:00 AM cortisol levels.

INTRAMEDULLARY SPINAL CORD METASTASIS AS THE PRESENTING FEATURE OF PAPILLARY THYROID CARCINOMA.

OBJECTIVE: The objective of this report is to present an unusual case of intramedullary spinal cord metastasis (ISCM) as the presenting feature of papillary thyroid carcinoma (PTC). METHODS: The presented case includes clinical, biochemical, and imaging findings as well as surgical and pathology reports. Treatment with radioactive iodine (RAI) and the response to this treatment are presented. RESULTS: A 71-year-old woman was evaluated for debilitating low back pain and walking disability. Magnetic resonance imaging demonstrated an oval, lumbar, intramedullary mass with benign features and surgery was scheduled. On preoperative evaluation for the lumbar mass, a multinodular thyroid goiter (unfortunately overlooked previously) was noticed, causing severe narrowing of the trachea. Total thyroidectomy was performed with a pathology diagnosis of PTC. In a second operation, the lumbar lesion was removed and proved to represent metastatic PTC. External beam radiation was subsequently administered to the thyroid bed, lumbar spine, and other skeletal metastases, followed by 150 milliCurie of RAI. A post-treatment scan showed high uptake over the lumbar spine, and skeletal and lung lesions. Clinically, the patient restored her walking ability and back pain improved. CONCLUSION: ISCM rarely is the presenting feature of PTC. Our patient presented with back pain which is the typical, though non-specific symptom, of ISCM. She showed good clinical response to multimodal treatment which is in line with the few other differentiated thyroid cancer patients with ISCM reported in the literature. Prompt surgical resection, followed by external beam radiation and RAI, may improve neurological signs, alleviate pain, and improve quality of life.

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Utility of Pit-1 Immunostaining in Distinguishing Pituitary Adenomas of Primitive Differentiation from Null Cell Adenomas.

Pit-1 immunostaining is not routinely used in the characterization of pituitary adenomas, and its utility in distinguishing adenomas dedicated towards the lactotroph, somatotroph, and thyrotroph lineage from null cell adenomas warrants further evaluation. Pituitary adenomas that were negative for expression of a basic panel of hormonal markers (ACTH, prolactin, and growth hormone) were further evaluated for TSH, SF-1, and Pit-1 expression using a tissue microarray. Among the 147 identified pituitary adenomas that were negative for ACTH, prolactin, growth hormone, and TSH, expression of SF-1 was present in 68 cases (46%). Of the remaining 72 cases with sufficient tissue for further analysis, four were Pit-1 positive (6% of the adenomas negative for ACTH, prolactin, growth hormone, TSH, and SF-1); the remaining 68 were potentially null cell adenomas. Two of the Pit-1-positive adenomas displayed a paranuclear CAM 5.2 staining pattern suggestive of a sparsely granulated somatotroph adenoma; however, only one case contained fibrous bodies within a majority of the adenoma cells. Our data suggests that Pit-1 can be utilized as a second tier immunostain in cases of clinically non-functioning adenomas that are immunonegative for ACTH, prolactin, growth hormone, TSH, and SF-1 in order to further segregate rare cases of Pit-1-positive adenomas from null cell adenomas. Pit-1 immunostaining can recognize rare cases of sparsely granulated somatotroph adenomas that appear immunonegative for growth hormone, as well as rare cases of other Pit-1-positive adenomas that are negative for Pit-1 lineage hormones. Overall, pituitary adenomas of the Pit-1 lineage that do not produce prolactin, growth hormone, or TSH are rare, with only four cases identified in the current study.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.

IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Diagnostic Computed Tomography Coregistration With In-111-DTPA-Octreotide Single Photon Emission Tomography/Low-Dose Computed Tomography.

OBJECTIVES: In-111-DTPA-octreotide (OctreoScan) is still pivotal for neuroendocrine tumor imaging, despite the introduction of Ga-68-octreotide tracers. Low-dose computed tomography (LDCT) assists in the localization of SPECT findings but often results in uncertain interpretation. This retrospective study evaluates the impact of coregistration of In-111-DTPA-octreotide SPECT/LDCT with diagnostic CT on interpretation. METHODS: Thirty-five consecutive studies, in which coregistration was performed because of uncertain interpretation, were evaluated. Presence of somatostatin receptors was categorized retrospectively as definitely positive, probably positive, probably negative, or definitely negative with and without rigid registration with diagnostic CT, and possible added value of coregistration was evaluated. RESULTS: Coregistration was performed in 35 studies. However, on subsequent reading, 4 SPECT/CTs yielded definite results and were omitted. Coregistration was helpful in 30 of the remaining 31 cases, changing reading to definitely positive (7) or to definitely negative (23). In 13 of the 23 cases, diagnosis changed from probably positive to definitely negative. Coregistration contributed in 42 of 48 sites, with greatest benefit in the liver (13/14), pancreas (10/10), and lymph nodes (6/6). CONCLUSIONS: Coregistration is becoming increasingly easier and may be utilized when SPECT/LDCT is inconclusive.

UTILITY OF A GLUCOCORTICOID SPARING STRATEGY IN THE MANAGEMENT OF PATIENTS FOLLOWING TRANSSPHENOIDAL SURGERY.

OBJECTIVE: Following transsphenoidal surgery (TSS), it is important to assess for and manage adrenal insufficiency (AI). The goal of this study is to assess the efficacy and safety of a glucocorticoid (GC) sparing protocol to limit GC exposure in patients undergoing TSS. METHODS: Adult patients undergoing TSS (excluding Cushing disease) with adequate adrenal function prior to surgery underwent TSS without perioperative GC coverage. Following TSS, daily morning fasting serum cortisol levels were tested. GCs were administered at stress doses for serum cortisol <5 mcg/dL, between 5 and 12 mcg/dL in the presence of clinically significant symptoms of AI, or >12 mcg/dL with severe headache, nausea or vomiting, fatigue, anorexia, or hyponatremia. The primary endpoint was the use of GCs in the immediate postoperative period. RESULTS: Of 178 subjects, GCs were administered to 80 (45%) patients for the following indications: 31.3% for serum cortisol <5 mcg/dL; 36.3% for cortisol between 5 and 12 mcg/dL accompanied by symptoms or signs of AI; 8.8% for moderate to severe postoperative hyponatremia; and 7.5% for severe headache, nausea and vomiting, fatigue, or anorexia with cortisol >12 mcg/dL. Logistic regression analysis showed that longer length of hospital stay (odds ratio [OR] 1.22, confidence interval [CI] 1.02-1.45) and the presence of new postoperative anterior pituitary hormone deficiency (OR 3.3, CI 1.26-8.67) were associated with postoperative GC use. By 12 weeks, only 14% of subjects remained on GCs. There were no adverse events related to withholding GCs. CONCLUSION: Our protocol for managing GC replacement is both safe and effective for limiting GC exposure in patients undergoing TSS. ABBREVIATIONS: AI = adrenal insufficiency CI = confidence interval FSH = follicle-stimulating hormone GC = glucocorticoid GH = growth hormone IGF-1 = insulin-like growth factor-1 IV = intravenous LH = luteinizing hormone LOS = length of hospital stay OR = odds ratio TSS = transsphenoidal surgery.

Epidemiology of Neuroendocrine Tumors.

Formerly named carcinoids, neuroendocrine tumors originate from diffuse endocrine cells, can involve any part of the gastrointestinal tract, endocrine pancreas and bronchopulmonary (BP) tree, and have a wide range of malignant potential. This chapter summarizes the data available on the epidemiology of neuroendocrine neoplasia (NEN) from around the world, including the relative frequency according to organ of origin, annual incidence rates (IR) and trends in IR at the various anatomic sites, age and stage at presentation, racial and gender differences in IR and 5-year survival rates. Over time, changes have been made in the classification and registration of NEN, both in the same registry and across the globe, thus confounding the possibility to draw conclusions as to the true rise in IR of NEN that is observed all over the world. BP NEN has become the most common site in many western countries, while NEN of the rectum is more common in the Far East. In some countries, appendiceal NEN is the most common site in females. When compared to adenocarcinoma of the same location, the prognosis of NEN patients is better. Five-year survival rates are highest for NEN originating in the rectum and appendix, but lower in small intestinal and pancreatic NEN. Future research is needed to understand the contribution of genetic and environmental factors to NEN epidemiology.

Breast cancer survivors are at an increased risk for osteoporotic fractures not explained by lower BMD: a retrospective analysis.

BACKGROUND: An association between higher bone mineral density (BMD) and the diagnosis of breast cancer (BC) has been reported. Data on the risk of osteoporotic fractures in women with BC are conflicting. AIMS: The objective of this study was to assess fracture risk adjusted for BMD in women with and without BC, and to assess whether fracture risk in BC patients is attributed to BMD or BC characteristics. METHODS: Using electronic medical records of patients who underwent dual energy X-ray absorptiometry BMD studies at Soroka University Medical Center between February 2003 and March 2011, we identified women with subsequent diagnosis of osteoporotic fractures. BC status, demographic, health characteristics, BMD, and other laboratory findings were assessed. In BC patients data on grade, stage, and treatment were collected. Primary outcome was osteoporotic fracture, analyzed by Cox proportional hazards regression models. RESULTS: During a median follow-up of 4.9 years in 17,110 women with BMD testing (658 BC patients), 1,193 women experienced an osteoporotic fracture (62 in BC and 1,131 in no-BC groups). In multivariate analysis adjusted for age, body mass index (BMI) and BMD, hazard ratio (HR) for any osteoporotic fracture in women with BC was 1.34 (P=0.026). BMD was similar among women with and without BC who fractured. BC patients who experienced an osteoporotic fracture had a trend for less-advanced BC, lower rates of chemotherapy treatment, and higher rates of tamoxifen treatment. CONCLUSIONS: BC survivors are at increased risk of an osteoporotic fracture, which is not explained by worse BMD. Chemotherapy or aromatase inhibitors did not contribute substantially to fracture risk among our BC survivors.

Association between bone mineral density and incidence of breast cancer.

INTRODUCTION: Previous studies have suggested an inverse relationship between bone mineral density (BMD) and breast cancer incidence. The primary objective of this study was to assess whether BMD is associated with risk of subsequent breast cancer occurrence in the female population of southern Israel. METHODS: The electronic medical charts of women who underwent BMD at the Soroka Medical Center (SMC) between February 2003 and March 2011 were screened for subsequent breast cancer diagnoses. Women were divided by tertiles of BMD at 3 skeletal sites: lumbar spine (LS, L1-4), total hip (TH) and femoral neck (FN). The incidence of breast cancer was calculated. RESULTS: Of 15268 women who underwent BMD testing, 86 were subsequently diagnosed with breast cancer. Most women in the study were older than 50 years (94.2% and 92.7%, respectively; p = 0.597). Women who subsequently developed breast cancer had a higher mean body-mass index (BMI) (30.9 ± 5.5 vs. 29.1 ± 5.7 p = 0.004) and the mean BMD Z-score was significantly higher than in those without breast cancer for all 3 skeletal sites (LS: 0.36 ± 1.58 vs. -0.12 ± 1.42, p = 0.002; TH: 0.37 ± 1.08 vs. 0.03 ± 1.02, p = 0.002; FN: 0.04 ± 0.99 vs. -0.18 ± 0.94; p = 0.026). Women in the highest Z-score tertiles at the FN and TH had a higher chance of developing breast cancer compared to the lowest tertile; odds ratio of 2.15, 2.02, respectively (P = 0.004 and 0.01 respectively). No association was found between the BMD Z-score and the stage, histology, grade or survival from breast cancer. CONCLUSIONS: This study provides additional support for an inverse association between BMD and the risk of breast cancer.