Paget Disease of Bone Harboring Bone Metastatic Neuroendocrine Cancer: A Case Report.

In this case report, we describe an uncommon case of neuroendocrine cancer of unknown origin began with cauda equina syndrome in a patient affected by Paget disease of bone (PDB). A 76-year-old man with diagnosis of PDB, without history of pain or bone deformity, developed sudden severe low back pain. Bone alkaline phosphatase was increased and MRI and whole-body scintigraphy confirmed the localization of the disease at the third vertebra of the lumbar spine. Treatment with Neridronic Acid was started, but after only 2 weeks of therapy anuria and bowel occlusion occurred together with lower limb weakness and walking impairment. Cauda equina syndrome consequent to spinal stenosis at the level of L2-L3 was diagnosed after admission to Emergency Department and the patient underwent neurosurgery for spinal medulla decompression. The histologic results showed a complete subversion of bone structure in neoplastic tissue, consistent with metastatic neuroendocrine carcinoma of unknown origin. In conclusion, low back pain in the elderly may require deep investigation to individuate rare diseases. In asymptomatic patients with apparently stable PDB, the sudden appearance of pain or neurologic symptoms may alert the clinician for the possibility of other superimposing diseases, like bone metastases.

Autoantibody and T cell responses to oxidative post-translationally modified insulin neoantigenic peptides in type 1 diabetes.

AIMS/HYPOTHESIS: Antibodies specific to oxidative post-translational modifications (oxPTM) of insulin (oxPTM-INS) are present in most individuals with type 1 diabetes, even before the clinical onset. However, the antigenic determinants of such response are still unknown. In this study, we investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in type 1 diabetes. We also assessed the concordance between antibody and T cell responses to the oxPTM-INS neoantigenic peptides. METHODS: oxPTM-INS was generated by exposing insulin to various reactive oxidants. The insulin fragments resulting from oxPTM were fractionated by size-exclusion chromatography further to ELISA and LC-MS/MS analysis to identify the oxidised peptide neoepitopes. Immunogenic peptide candidates were produced and then modified in house or designed to incorporate in silico-oxidised amino acids during synthesis. Autoantibodies to the oxPTM-INSPs were tested by ELISA using sera from 63 participants with new-onset type 1 diabetes and 30 control participants. An additional 18 fresh blood samples from participants with recently diagnosed type 1 diabetes, five with established disease, and from 11 control participants were used to evaluate, in parallel, CD4+ and CD8+ T cell activation by oxPTM-INSPs. RESULTS: We observed antibody and T cell responses to three out of six LC-MS/MS-identified insulin peptide candidates: A:12-21 (SLYQLENYCN, native insulin peptide 3 [Nt-INSP-3]), B:11-30 (LVEALYLVCGERGFFYTPKT, Nt-INSP-4) and B:21-30 (ERGFFYTPKT, Nt-INSP-6). For Nt-INSP-4 and Nt-INSP-6, serum antibody binding was stronger in type 1 diabetes compared with healthy control participants (p≤0.02), with oxidised forms of ERGFFYTPKT, oxPTM-INSP-6 conferring the highest antibody binding (83% binders to peptide modified in house by hydroxyl radical [●OH] and >88% to in silico-oxidised peptide; p≤0.001 vs control participants). Nt-INSP-4 induced the strongest T cell stimulation in type 1 diabetes compared with control participants for both CD4+ (p<0.001) and CD8+ (p=0.049). CD4+ response to oxPTM-INSP-6 was also commoner in type 1 diabetes than in control participants (66.7% vs 27.3%; p=0.039). Among individuals with type 1 diabetes, the CD4+ response to oxPTM-INSP-6 was more frequent than to Nt-INSP-6 (66.7% vs 27.8%; p=0.045). Overall, 44.4% of patients showed a concordant autoimmune response to oxPTM-INSP involving simultaneously CD4+ and CD8+ T cells and autoantibodies. CONCLUSIONS/INTERPRETATION: Our findings support the concept that oxidative stress, and neoantigenic epitopes of insulin, may be involved in the immunopathogenesis of type 1 diabetes.

Usefulness of Color Doppler Ultrasonography in the Risk Stratification of Thyroid Nodules.

INTRODUCTION: Thyroid ultrasound (US) is crucial for clinical decision in the management of thyroid nodules. In this cross-sectional study, we aimed to test if the evaluation of thyroid nodules' vascularization could improve the risk stratification ability of the American College of Radiology (ACR) TI-RADS classification system. METHODS: A total of 873 thyroid nodules undergoing fine-needle aspiration were classified according to ACR TI-RADS US classification. Three types of vascularization were identified: type 0, no vascular signals; type 1, peripheral vascular signals; type 2, peripheral and intralesional vascular signals. Cytology specimens were evaluated conforming to the Italian Reporting System for Thyroid Cytology, and TIR3b, TIR4, and TIR5 were defined as high risk for malignancy. Odds ratios (ORs) with 95% confidence intervals (CI) and the areas under the receiver operating characteristic curves (ROC-AUC) for high-risk cytology categories were calculated. RESULTS: The 3 vascular patterns were differently distributed within the cytology categories: 52.4% of TIR1c, 15.9% of TIR2, 5.9% of TIR3a, 6.7% of TIR3b, 12.5% of TIR4, and 28.9% of TIR5 nodules had no vascular signals (p < 0.001). Nodule vascularity alone was not associated with a higher risk of malignant cytology (OR [95% CI] 0.75 [0.43-1.32], p = 0.32), without differences between peripheral (OR [95% CI] 0.65 [0.35-1.20]) and intranodular (OR [95% CI] 0.88 [0.48-1.62]) vascularization (p = 0.22). The ROC-AUC (95% CI) for the diagnosis of malignant cytology was similar when considering TI-RADS classification alone (0.736 [0.684-0.786]) and when considering TI-RADS classification plus the presence/absence of vascular signals (0.736 [0.683-0.789], p value for differences between the ROC-AUCs: 0.91). Among TR1, TR2, and TR3 TI-RADS classes, no nodules without vascular signals showed a malignant cytology, allowing the identification of nodules with benign cytology with 100% specificity within these US classes. CONCLUSIONS: Color Doppler study of thyroid nodules does not improve the risk stratification ability of the ACR TI-RADS US classification system.

Proton Pump Inhibitors and Fractures in Adults: A Critical Appraisal and Review of the Literature.

Despite the large number of patients worldwide being on proton pump inhibitors (PPIs) for acid-related gastrointestinal disorders, uncertainty remains over their long-term safety. Particularly, the potential side effects of these drugs on bone health have been evaluated in the last years. The purpose of our narrative review is to gather and discuss results of clinical studies focusing on the interactions between PPIs and fracture risk. Data generated mainly from nested case-control studies and meta-analysis suggest that long-term/high-dose PPIs users are characterized by an increased risk of fragility fractures, mainly hip fractures. However, in these studies, the PPIs-induced bone impairment is often not adjusted for different confounding variables that could potentially affect bone health, and exposure to PPIs was reported using medical prescriptions without adherence evaluation. The mechanisms of the PPI-related bone damage are still unclear, but impaired micronutrients absorption, hypergastrinemia, and increased secretion of histamine may play a role. Clinicians should pay attention when prescribing PPIs to subjects with a preexistent high risk of fractures and consider antiosteoporotic drugs to manage this additive effect on the bone. However, further studies are needed to clarify PPIs action on the bone.

Risk of cardiac autonomic neuropathy in latent autoimmune diabetes in adults is similar to type 1 diabetes and lower compared to type 2 diabetes: A cross-sectional study.

AIMS: Microvascular complications' risk differs between people with latent autoimmune diabetes in adults (LADA) and people with type 2 diabetes. We aimed to investigate whether the prevalence of cardiac autonomic neuropathy, a life-threatening complication of diabetes, also varies depending on diabetes type. METHODS: In this cross-sectional study, 43 adults with LADA, 80 with type 1 diabetes and 61 with type 2 diabetes were screened for cardiac autonomic neuropathy with recommended tests. Logistic regression models were used to test differences between diabetes types adjusting for confounders. RESULTS: Cardiac autonomic neuropathy was diagnosed in 17 (40%) participants with LADA, 21 (26%) participants with type 1 diabetes and 39 (64%) participants with type 2 diabetes (p < 0.001). The odds ratio (OR) for cardiac autonomic neuropathy in type 1 diabetes and in type 2 diabetes compared to LADA were 0.54 (95% CI: 0.25-1.20, p-value: 0.13) and 2.71 (95% CI: 1.21-6.06, p-value 0.015) respectively. Smoking (adj OR 3.09, 95% CI: 1.40-6.82, p-value: 0.005), HDL cholesterol (adj OR 0.29, 95% CI: 0.09-0.93, p-value: 0.037) and hypertension (adj OR 2.11, 95% CI: 1.05-4.24, p-value: 0.037) were independent modifiable risk factors for cardiac autonomic neuropathy. Differences among diabetes types did not change after correction for confounders. CONCLUSIONS: This is the first study offering a comparative evaluation of cardiac autonomic neuropathy among LADA, type 1 and type 2 diabetes, showing a lower risk of cardiac autonomic neuropathy in LADA compared to type 2 diabetes and similar compared to type 1 diabetes. This disparity was not due to differences in age, metabolic control or cardiovascular risk factors.

Clinical, Biochemical, and Radiological Profile of Normocalcemic Primary Hyperparathyroidism.

CONTEXT: The clinical and radiological aspects of normocalcemic hyperparathyroidism (NHPT) are confounded by the differing methods used to rule out secondary hyperparathyroidism and by the small sample size. OBJECTIVE: To assess the clinical, biochemical, and radiological profile of NHPT compared with primary hyperparathyroidism (PHPT) and control subjects. DESIGN: Multicentric cross-sectional study. SETTING: Outpatient clinic. PATIENTS: 47 NHPT, 41 PHPT, and 39 age- and sex-matched control subjects. MAIN OUTCOME MEASURES: Calcium metabolism and bone turnover markers (BTMs). Lumbar spine, total hip, femoral neck, one-third distal radius bone mineral density (BMD). Morphometric vertebral fracture (VF) assessed by dual-energy X-ray absorptiometry. RESULTS: NHPT patients had significantly higher parathyroid hormone, 25(OH)-vitamin D levels and lower calcium × phosphorus product than controls (P < .001). Compared with PHPT, the NHPT group had significantly higher 25(OH) vitamin D levels (P = .016). NHPT had BTM levels similar to controls and PHPT. NHPT, PHPT, and controls have similar lumbar spine and femoral neck BMD. NHPT and controls had a similar radial BMD, while patients with PHPT had a lower radial BMD than both patients with NHPT (P = .031) and controls (P < .05). Using the control group as the reference, after adjustment for interacting factors, there was no increase in risk of moderate-severe VF in NHPT (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.25-4.55), while PHPT had an increased risk (OR 3.81,95% CI 1.15-15.12). Seventy-nine percent of NHPT and 59% of PHPT patients fulfilled the criteria for asymptomatic hyperparathyroidism. CONCLUSIONS: The biochemical phenotype of NHPT is intermediate between PHPT and controls. In contrast, the bone phenotype resembles controls with normal bone turnover, no significant BMD impairment, and no increased risk of VF.

PTH(1-34) for the Primary Prevention of Postthyroidectomy Hypocalcemia: The THYPOS Trial.

CONTEXT: There are no studies evaluating teriparatide for prevention of post-thyroidectomy hypocalcemia. OBJECTIVE: Our objective was to evaluate whether teriparatide can prevent postsurgical hypocalcemia and shorten the hospitalization in subjects at high risk of hypocalcemia following thyroid surgery. DESIGN: This was a prospective phase II randomized open-label trial. SETTING: This trial was set on a surgical ward. PATIENTS: Twenty-six subjects (six males, 20 females) with intact PTH lower than10 pg/ml 4 hours after thyroidectomy were included. INTERVENTION: Subjects were randomized (1:1) to receive SC administration of 20 mcg of teriparatide every 12 hours until the discharge (treatment group) or to follow standard clinical care (control group). MAIN OUTCOME MEASURE: Adjusted serum calcium, duration of hospitalization, and calcium/calcitriol supplementation were measured. RESULTS: Overall, the incidence of hypocalcemia was 3/13 in treatment group and 11/13 in the control group (P = .006). Treated patients had a lower risk of hypocalcemia than controls (relative risk, 0.26 [95% confidence interval, 0.09-0.723)]). The median duration of hospitalization was 3 days (interquartile range, 1) in control subjects and 2 days (interquartile range, 0) in treated subjects (P = .012). One month after discharge, 10/13 subjects in the treatment group had stopped calcium carbonate supplements, while only 5/13 in the control group had discontinued calcium. The ANOVA for repeated measures showed a significant difference in calcium supplements between groups at 1-month visit (P = .04) as well as a significant difference between discharge and 1-month visit in the treatment group (P for interaction time group = .04) Conclusions: Teriparatide may prevent postsurgical hypocalcemia, shorten the duration of hospitalization, and reduce the need for calcium and vitamin D supplementation after discharge in high risk subjects after thyroid surgery.

Irisin is associated with osteoporotic fractures independently of bone mineral density, body composition or daily physical activity.

BACKGROUND: Although there is an evidence of correlation between irisin and osteoporotic fractures, previous studies have not elucidated the relationship between irisin and either lean or fat mass. The main aim of this study is to investigate the relationship between irisin and body composition in postmenopausal women with osteoporosis and the impact of irisin levels on fragility vertebral fractures. METHODS: In this cross-sectional study, 36 overweight subjects affected by at least one vertebral osteoporotic fracture confirmed by an X-ray vertebral morphometry and 36 overweight nonosteoporotic subjects were enrolled. Serum irisin levels were measured using an irisin competitive ELISA. We evaluated lumbar spine and hip BMD and body composition using dual energy X-ray absorptiometry. To measure and monitor daily physical activity, each subject wore an armband for approximately 72 h. RESULTS: No significant correlations were found between irisin and BMD at any site and between irisin with either lean or fat mass. Serum levels of irisin were not correlated with the daily physical activity. Serum irisin levels were lower in subjects with previous osteoporotic fractures than in controls (P = 0·032), and the difference in irisin levels remained significant after adjustment for creatinine (P = 0·037), vitamin D (P = 0·046), lean mass (P = 0·02), lumbar BMD (P = 0·023) and femoral BMD (P = 0·032). CONCLUSION: Our data confirm an inverse correlation between irisin levels and vertebral fragility fractures, but no significant correlation was found with BMD or lean mass. Irisin may play a protective role on bone health independent of BMD but further studies are needed to clarify the relationship between irisin and bone metabolism.

Severe hypophosphatemic osteomalacia secondary to fanconi syndrome due to adefovir: a case report.

OBJECTIVE: Generalized proximal, type 2, renal tubular acidosis, also known as Fanconi syndrome, is a generalized dysfunction of the proximal renal tubule characterized by impaired reabsorption and increased urinary loss of phosphate and other solutes, such as uric acid, glucose, amino acids, and bicarbonate. Chronic hypophosphatemia is the second most common cause of osteomalacia after vitamin D deficiency in adult patients and can have a heterogeneous presentation, ranging from mild symptoms such as muscle weakness and skeletal pain to more severe presentation, such as disabling myopathy, severe bone and joint pain, difficulty walking, and even bone fractures. METHODS: This report describes a case of severe hypophosphatemic osteomalacia with multiple fragility fractures induced by adefovir, which was worsened and confounded by a previous treatment with zoledronic acid and required prolonged intravenous potassium phosphate administration. RESULTS: We highlight the limited diagnostic value of dual X-ray absorptiometry and bone scintigraphy in this challenging diagnosis. Bone metabolism should always be assessed in patients treated with adefovir for early detection of osteomalacia due to Fanconi syndrome. CONCLUSION: Although rare, this condition may be life-threatening and mimic other bone metabolic disorders that are treated with drugs that may further impair phosphate balance.