A MODEL TO PREDICT DIAGNOSIS OF PANCREATIC NEUROENDOCRINE TUMORS BASED ON EUS IMAGING FEATURES.

Background: This study aimed to determine predictive clinical and endoscopic ultrasound (EUS) features for pancreatic neuroendocrine tumor (PNET) diagnosis, utilizing EUS-guided tissue acquisition. Methods: A prospective study from 2018-2022 included patients with pancreatic masses undergoing EUS with elastography. Univariate binomial logistic regression followed by multiple logistic regression with significant predictors was employed. A forward selection algorithm identified optimal models based on predictor numbers. Variables encompassed EUS tumor characteristics (e.g., location, size, margins, echogenicity, vascularity on Doppler, main pancreatic duct dilation, elastography appearance, vascular invasion, and hypoechoic rim), alongside demographic and risk factors (smoking, alcohol, diabetes). Results: We evaluated 165 patients (24 PNETs). EUS features significantly linked with PNET diagnosis were well-defined margins (79% vs. 26%, p < 0.001), blue elastography appearance (46% vs. 9.9%, p < 0.001), vascularization (67% vs. 25%, p < 0.001), hypoechoic rim (46% vs. 10%, p < 0.001). The top-performing model, with 89.1% accuracy, included two predictors: a homogeneous lesion (OR, 95% CI) and a hypoechoic rim (OR, 95% CI). Conclusions: EUS appearance can differentiate PNETs from non-PNETs, with the hypoechoic rim being an independent predictor of PNET diagnosis. The most effective predictive model for PNETs combined the homogeneous lesion and presence of the hypoechoic rim.

Is it time to consider population screening for fracture risk in postmenopausal women? A position paper from the International Osteoporosis Foundation Epidemiology/Quality of Life Working Group.

The IOF Epidemiology and Quality of Life Working Group has reviewed the potential role of population screening for high hip fracture risk against well-established criteria. The report concludes that such an approach should strongly be considered in many health care systems to reduce the burden of hip fractures. INTRODUCTION: The burden of long-term osteoporosis management falls on primary care in most healthcare systems. However, a wide and stable treatment gap exists in many such settings; most of which appears to be secondary to a lack of awareness of fracture risk. Screening is a public health measure for the purpose of identifying individuals who are likely to benefit from further investigations and/or treatment to reduce the risk of a disease or its complications. The purpose of this report was to review the evidence for a potential screening programme to identify postmenopausal women at increased risk of hip fracture. METHODS: The approach took well-established criteria for the development of a screening program, adapted by the UK National Screening Committee, and sought the opinion of 20 members of the International Osteoporosis Foundation's Working Group on Epidemiology and Quality of Life as to whether each criterion was met (yes, partial or no). For each criterion, the evidence base was then reviewed and summarized. RESULTS AND CONCLUSION: The report concludes that evidence supports the proposal that screening for high fracture risk in primary care should strongly be considered for incorporation into many health care systems to reduce the burden of fractures, particularly hip fractures. The key remaining hurdles to overcome are engagement with primary care healthcare professionals, and the implementation of systems that facilitate and maintain the screening program.

HIGH RISK OF PARATHYROID CARCINOMA AND GENETIC SCREENING IN THE FIRST DIAGNOSED ROMANIAN FAMILY WITH HYPERPARATHYROIDISM-JAW TUMOR SYNDROME AND A GERMLINE MUTATION OF THE CDC73 GENE.

CONTEXT: Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is a rare autosomal dominant cause of familial hyperparathyroidism associated with ossifying fibromas (OF) of the maxillofacial bones and increased risk of parathyroid carcinoma, caused by inactivating germline mutation of the cell division cycle 73 (CDC73) gene. OBJECTIVE: To report the first Romanian family with HPT-JT and genetic screening of CDC73 gene. SUBJECTS AND METHODS: Mutational analysis of the CDC73 gene and genetic screening of the family of a proband with HPT-JT. Histological diagnosis of parathyroid tumors (WHO criteria) and immunohistochemistry (parafibromin) were performed. RESULTS: Three of the six screened family members had evidence of PHPT and surgically proven parathyroid tumours. Two of the three affected members had parathyroid carcinomas and one had two parathyroid adenomas. Genetic screening of CDC73 gene revealed that 4 of 6 patients showed a heterozygous germline deletion of one nucleotide: c.128-IVS1+1 delG. All the three affected patients, resulted to be carriers of the CDC73 mutation, but each one bearing a different CDC73 polymorphism. CONCLUSIONS: We identified a new CDC73 germline mutation in a Romanian family of HPT-JT. Analysis of clinical phenotypes in the four mutated individuals confirmed the incomplete penetrance and the variable clinical expression of the disease.

INCIDENCE AND TIME TREND OF HIP FRACTURES IN ROMANIA: A NATIONWIDE STUDY FROM 2008 TO 2018.

BACKGROUND: Hip fractures are a major issue of public health as they are responsible for high morbidity, excess mortality and costs. There are differences in Europe and worldwide in the incidence rates of hip fractures and time trends, in the context of the population aging. Ten years ago, we characterized the incidence of hip fracture in Romania using data from the national hospital discharge register. OBJECTIVE: This is the first Romanian study to assess the hip fracture incidence rates over a period of 11 years, between 2008 and 2018. SUBJECTS AND METHODS: This analysis is a nationwide retrospective study on hospitals reporting primary DRG data on hip fracture, using a rigorous definition with both diagnostic and surgical procedure codes. The population aged 40+ was stratified in 5-year intervals and both the crude incidence rates and the adjusted incidence rates of hip fracture using standardization on age for the 2018 reference population were calculated in women and men. RESULTS: From 2008 to 2018, the number of hip fractures rose by 53 % in women (from 7513 to 11512) and 22.4 % in men (from 4266 to 5220). Meanwhile, the Romanian population over 40 years increased by 12.5% in women and 14.2% in men. The crude incidence rate rose by 36.2% in women and 7.2% in men and the age-standardized incidence rates by 27.4% in women and 6% in men. These increases are mostly based on 85+ age populations' changes. CONCLUSIONS: In Romania, the hip fractures incidence continues to grow throughout an 11-year-period, especially in women, representing an increasing burden for our society.

THE CRUCIAL ROLE OF THE WNT SYSTEM IN BONE REMODELLING.

The maintenance of bone mass is critically dependent on the balance between bone formation by osteoblasts and bone resorption by osteoclasts, processes in which osteocytes play also an important role. The activities of these bone cells are regulated by a variety of endocrine and paracrine factors of which sex steroids, parathyroid hormone, 1.25(OH)2-vitamin D3, glucocorticoids, retinoids and thyroid hormones are the most well known systemic factors. To the long list of locally acting factors belong cytokines and growth factors. This list was extended some 15 years ago by the discovery of the very important role of the WNT signalling system for the maintenance of bone mass. The first evidence of its role was the findings that mutations in the LRP5 gene, encoding a co-receptor in WNT-signaling, could result in either gain or loss of bone mass, i.e. either high bone mass or osteoporosis. This was a most unexpected observation since no indications existed prior to this discovery that the WNT signalling system had a role in bone remodeling. Since then, many observations have been made demonstrating the important role of different WNTs in regulating bone formation and resorption. Interestingly, some of these findings have demonstrated that trabecular and cortical bone are regulated by different mechanisms. It is the aim of the present overview to give the readers an insight into the WNT signalling system and its role in bone remodeling.

TRABECULAR BONE SCORE (TBS) HAS A POOR DISCRIMINATIVE POWER FOR VERTEBRAL FRACTURES IN 153 ROMANIAN PATIENTS WITH PRIMARY HYPERPARATHYROIDISM.

CONTEXT: Trabecular Bone Score (TBS) has been recently proposed as a good tool to investigate secondary osteoporosis. OBJECTIVE: The aim of this study was to assess TBS from spine DXA images in patients with primary hyperparathyroidism (PHPT) and look at its correlates. SUBJECTS AND METHODS: 153 patients, mean age 59.1 ± 12.1 yrs, females and males (10%), mean BMI 26.2 ± 4.8 kg/m2, mean serum calcium and PTH of 11.3 ± 1.2 mg/dL and 232 ± 329 pg/mL, respectively; 89% had osteoporosis/osteopenia by LS DXA and 46% had renal involvement. There were 7.6% patients with vertebral fractures, 13.2% patients with nonvertebral fractures. TBS indices were derived from LS-DXA images and cutoff points used were those previously reported. RESULTS: Mean TBS was in the partially degraded range (1.258 ± 0.115); 32% of patients had degraded microarchitecture (TBS ≤ 1.20), 51% had partially degraded microarchitecture (TBS > 1.20 and < 1.35) and 17% had normal TBS. TBS was significantly correlated with areal BMD both at the LS (r=0.544; p<0.001) and FN (r = 0.315; p < 0.001), and negatively with age (r= - 0.354; p < 0.001) and years since menopause - YSM (r = - 0.257, p = 0.005). Patients with vertebral fractures had mean values of TBS in the degraded range, significantly lower than those without vertebral fractures (1.173 ± 0.076 vs. 1.263 ± 0.115; p = 0.006). The presence of vertebral fracture was independently associated only with YSM (OR = 1.131, 95% CI = 0.032 - 0.214, p = 0.008) but not with TBS. CONCLUSIONS: In a cohort of symptomatic PHPT patients, including postmenopausal, premenopausal and male patients, we have shown that TBS was in the partially degraded range, but it was not independently associated with fractures.

SUSPECTED NON-LRP5 MUTATION ASSOCIATED WITH HIGH BONE MASS UNALTERED BY CONCURRENT SYMPTOMATIC PRIMARY HYPERPARATHYROIDISM OF LONG DURATION.

BACKGROUND: Unexplained high bone mass (HBM) (Bone Mineral Density-BMD Z-score at the lumbar spine or hip of ≥+3.2 SD, or a combined spine and hip Z score ≥4 SD) after routine bone densitometry occurs with a prevalence of approximately 2 out of 1.000 and is currently believed to be a mild form of skeletal dysplasia (1). RESULTS: We present the case of a patient with unexplained HBM (Z-scores at L3, L1-L4, total hip and radius total were +3, +2.7, +2 and +1.8, respectively) and concurrent symptomatic primay hyperparathyroidism (total serum calcium 11.9 mg/dL, serum Parathyroid Hormone - PTH 189.3 pg/mL) of long duration. There were no significant BMD changes at any skeletal site after the surgical cure of hyperparathyroidism. Testing for LRP (low density lipoprotein receptor-related proteins) 5 gene mutations was negative. CONCLUSIONS: We presented an unusual case of the association of a HBM with primary hyperparathyroidism with resistance to the catabolic action of PTH. In spite of the negative result of LRP5 testing we do believe that a mutation of a gene involved in the Wnt pathway in bone is responsible.

Circulating osteoprotegerin and leptin levels in postmenopausal women with and without osteoporosis.

Osteoprotegerin (OPG) is a recently identified citokine with an important role in bone remodeling, that acts as a decoy receptor for RANKL; OPG was shown to be an important inhibitor of osteoclast differentiation and activation. Leptin influences bone metabolism by acting on differentiated osteoblasts, having an anabolic effect on bone. The relationship between circulating OPG levels and osteoporosis in postmenopausal women is controversial. Thus, one of the aims of our study was to investigate the relationships between OPG levels and biochemical markers of bone turnover and bone density in women with and without osteoporosis. We have investigated 135 postmenopausal women, including a group with osteoporosis (n=76, mean age 59+/-8 years) and a group with severe osteoporosis (n=31, mean age 64+/-8 years), using healthy postmenopausal women (n=28, mean age 48+/-9 years) as controls. The serum concentrations of OPG were determinated by ELISA. Serum estradiol was measured by Enzyme Immunoassay (EIA). The markers of bone formation and resorption were measured by standard methods. Leptin was measured by ELISA. Bone mineral density at lumbar spine and femoral neck was measured by dual energy x-ray absorptiometry (DEXA). There was a significant positive association between serum OPG levels and age (r=0.27; p<0.001), both in the postmenopausal women as a whole and in the cohort with osteoporosis. Circulating OPG levels were significantly higher in both osteoporotic groups (p<0.005 and p<0.01, respectively) than in the control group. There were no significant associations between serum OPG levels and bone density, bone markers and serum estradiol. Serum leptin levels were significantly associated with age (r=0.18, p<0.03), estradiol (r=0.2, p<0.05) and BMD (r=0.25, p<0.008); there was no significant relationship between leptin and bone turnover markers. We conclude that serum OPG levels increase with age, both in healthy and osteoporotic postmenopausal women. This could represent a possible protective mechanism against bone loss. Serum leptin levels also increase with age and are positively associated with estradiol and BMD and not significantly associated with bone turnover markers.

Differential effects of glucocorticoids on bone resorption in neonatal mouse calvariae stimulated by peptide and steroid-like hormones.

Differential effects on in vitro bone resorption were observed when the glucocorticoids, hydrocortisone and dexamethasone, were added to neonatal mouse calvariae treated with either parathyroid hormone (PTH), 1,25(OH)2-vitamin D3, all trans-retinoic acid (t-RA), or prostaglandin E2 (PGE2). Bone resorption was assessed by analyzing either the release of 45Ca from [45Ca]CaCl2 prelabeled calvarial bones or the release of 3H from [3H]proline prelabeled calvariae. At PGE2 concentrations of 3 x 10(-8) and 3 x 10(-7) mol/l, co-treatment with either 10(-6) mol/l dexamethasone or 10(-6) mol/l hydrocortisone caused additive 45Ca release from neonatal mouse calvariae. In contrast, synergistic release from mouse calvarial bones of both 45Ca and 3H was found after either 10(-6) mol/l hydrocortisone or 10(-6) mol/l dexamethasone was combined with 3 x 10(-11) mol/l PTH treatment for 120 h. Dose-response studies indicated that the synergistic stimulation of 45Ca release from neonatal mouse calvariae by glucocorticoids and PTH could be elicited at glucocorticoid concentrations of 10(-8) to 10(-6) mol/l and at PTH concentrations of 10(-11) to 10(-9) mol/l. Progesterone and RU 38486 (a derivative of 19-nortestosterone with antiglucocorticoid activity) blocked the synergism noted with glucocorticoid and PTH co-treatment, suggesting that interaction between the steroids and PTH was dependent on glucocorticoid receptor interaction. Addition of either 10(-6) mol/l hydrocortisone or 10(-6) mol/l dexamethasone to neonatal mouse calvariae treated with 1,25(OH)2-vitamin D3 (10(-11) and 10(-10) mol/l) also resulted in synergistic stimulation of 45Ca release. In contrast to these observations, the stimulatory effect of t-RA (10(-8) mol/l) on 45Ca release from calvarial bones was abolished in the presence of 10(-6) mol/l dexamethasone. These results suggest that an important role of glucocorticoids may be to synergistically potentiate bone resorption stimulated by PTH and 1,25(OH)2-vitamin D3, but indicate an opposing interaction between the glucocorticoids and bone resorptive retinoids.

Stimulation of neonatal mouse calvarial bone resorption by the glucocorticoids hydrocortisone and dexamethasone.

In vitro stimulation of bone resorption was observed with the glucocorticoids hydrocortisone and dexamethasone. Dosage-dependent release of 45Ca from neonatal mouse calvarial bones was found for both steroids, with half-maximal responses for hydrocortisone and dexamethasone of 0.3 and 0.08 microM, respectively. Significant release of stable calcium (Ca2+), inorganic phosphate (Pi), and the lysosomal enzyme beta-N-acetylglucosaminidase was noted following treatment of mouse calvariae with either 1 microM hydrocortisone or 1 microM dexamethasone. Additionally, both 1 microM hydrocortisone and 1 microM dexamethasone elicited release of 3H from calvarial bones prelabeled with [3H]proline. The stimulation of bone resorption by the glucocorticoids, as assessed by 45Ca release, was sustained over 120 h of culture. Inhibition of 45Ca release from calvariae treated with either 1 microM hydrocortisone or 0.1 microM dexamethasone was observed with 0.01-30 nM salmon calcitonin (sCT), 0.1 mM acetazolamide, and 0.1 mM of the bisphosphonate AHPrBP. Inhibition of glucocorticoid-induced bone resorption by sCT occurred without "escape from calcitonin-induced inhibition." The 45Ca release stimulated by 1 microM hydrocortisone and 0.1 microM dexamethasone was also inhibited by 10 microM progesterone in a competitive manner and by 1 microM of the antiglucocorticoid RU38486, both of which are modulators of glucocorticoid binding. Prostaglandin E2 (PGE2) formation by 10 nM parathyroid hormone (PTH) in neonatal mouse calvarial bones was inhibited by both 1 microM hydrocortisone and 1 microM dexamethasone, but neither compound altered basal PGE2 formation. Exposure of calvarial bones to the mitotic inhibitors hydroxyurea and mitomycin C inhibited 45Ca release stimulated by 1 microM hydrocortisone and 1 microM dexamethasone. In contrast, addition of 1 ng/ml of recombinant murine granulocyte macrophage colony stimulating factor (rmGM-CSF) had no effect on 45Ca release elicited by the glucocorticoids. These results suggest that hydrocortisone and dexamethasone stimulate osteoclastic resorption in neonatal mouse calvariae by a receptor-mediated mechanism that is dependent on cellular replication.

Graves'-Basedow's disease--asthma association. Presentation of five cases.

Thyroid hormones have a non-selective permissive action on adrenergic receptors (including beta 2). Asthma is an immune disease in which some pathological pathways include beta 2 adrenergic receptor blockade. In theoretical terms, that would mean that in hyperthyroidism asthma would ameliorate. In 5 cases with Graves-Basedow's disease--asthma association this phenomenon has not appeared. The similar clinical features and follow-up of these patients suggest a narrow etiopathogenic group. In all cases, asthma has occurred previous to Graves-Basedow's disease, and the thyroid disease has been suspected because of paradoxical aggravation of asthma crises. In all cases the immune thyroid disease appeared in women over 40 years of age (two over 60 yrs). The thyromegaly was diffuse but small (and absent in one case), thyroid hormone levels have been expectedly high (T3 slightly higher than in other cases). No eye proptosis over Werner's 3rd degree has been recorded. The therapeutical problems have been as follows: contraindication of non-selective antitachycardia beta-blockers (we have administered reserpine), contraindication of non-selective adrenergic bronchodilatory agents (we have administered very low doses of aminophylline), early radical antithyroid therapy (we have administered 111-185 MBq of 131I). Thyroid function after 6 mos to 7 years follow-up have been within normal range (except one case who became hypothyroid). The asthma ameliorated early after 131I administration.

Effects of radioiodine therapy in hyperthyroidism (thyroid function, thyroid volume, Graves' ophtalmopathy, thyrotoxic heart disease).

The study group consisted of 135 hyperthyroid patients--128 with Graves' disease and 7 with toxic multinodular goiter. A single dose of radioiodine was given in 110 cases (81.48%), two doses in 22 patients (16.3%) and three doses in 3 patients (2.22%); mean total dose was 6.8 mCi (range = 3-24 mCi). The main goal of radio iodine therapy is to achieve euthyroidism; after radioiodine treatment, 61 patients (45.2%) were euthyroid, 60 patients (44.4%) with permanent hypothyroidism and 14 (10.36%) with PERSISTING HYPERTHYROIDISM--the mean duration of follow-up being 4.2 years. After radioiodine therapy, goiter became absent in 30 patients (28%); in those patients, goiter was moderately enlarged or large before therapy. Around 63% (12 cases) of the patients with thyrotoxic atrial fibrillation reverted to sinus rhythm. During the last four years (1990-1994) the patients with Graves' ophthalmopathy from the study group were treated with Prednisone after radioiodine therapy; this corticotherapy contributes to the lower percentage (1.5%) of worsening Graves' ophthalmopathy after radioiodine therapy.

Inadequate cortisol synthesis in prophyria cutanea tarda.

Many common clinical features suggest that between corticosuprarenal insufficiency (CSRI) and porphyria cutanea tarda (PCT) there may be some pathogenic relationships. In order to further understand these relations we have performed the ACTH-depot stimulation test (1 mg, i.m.) in 9 patients (from 13 males) with PCT. In 8 patients cortisolemia was assayed 1, 2, (12) and 24 hours post-stimulation. In all 13 cases the basal eliminations of cortisol metabolite (17-OH-corticosteroids) were under normal limits: 2.88 mg/24 h/g creatinine vs 15 controls with 7.06 mg/24h/g creatinine. After ACTH four cases showed lack of stimulation, considered on the second day for 17-OH-corticosteroids. In one case, after one year of PCT treatment, the early post-stimulation level is only moderately decreased. In one case, the test was normal. In four cases the ACTH stimulation was over-normal, i.e., greater than on the first day, suggesting supraphysiological responses. In this group 2 patients showed unexpectedly low early stimulation slopes on cortisolemia (at 1 and 2 hours) associated with concordant high late stimulation levels. This later phenomenon suggests a functional impaired secretion of cortisol in PCT, which seems to be similar to that of insulinemia after glucose in NIDDM, as a receptor lesion. The lesions of cortisol secretion in PCT could have been made by porphyrin storage, impaired hem-enzyme synthesis (cyt P-450) and as a new and attractive hypothesis, could be due to mitochondrial porphyrin receptor decreased activity.

Bone scintigraphy in acromegaly. Preliminary report on 10 cases.

The present study investigates if bone scintigraphy could be used as a diagnostic and prognostic tool in acromegaly. Bone scintigraphy (99m Tc-diphosphonate) was performed in 10 acromegalic (7 active and 3 inactive acromegaly) vs 12 control patients. Isotope uptake (in counts/cell) was assessed in the area of interest 3-4 hours after diphosphonate administration. Three views were chosen: cranium lateral (I)/frontal (II), and the hands (III). Between the acromegalic and control patients there were significant differences (x = p less than 0.001; xx = p less than 0.05) for the following areas: I-parietal: 66.5 vs 24.82x; I-occipital: 58.4 vs 23x; I-mediosphenoidal temporal: 55.2 vs 21.36x: I-nasal: 55.9 vs 38.73 xx; II-frontal: 46.8 vs 16.64 x; II-nasal: 59.8 vs 40.27 xx; III-left metacarpal: 21.67 vs 15.36 xx; III-right metacarpal: 21.78 vs 16.18 xx. Surprisingly, bone isotope uptake at the mandibular level, both in lateral and frontal view, showed no significant differences between acromegalic and control patients (55.2 vs 45 and 59.8 vs 44.5). Between the active and nonactive acromegalic patients there were no significant differences in any area. Bone scintigraphy, therefore, does not represent a useful index for disease activity. However, the results gave rise to two interesting problems: the acromegalic bone seems to have the same metabolic activity irrespective of the disease status; why is bone isotope uptake the same in acromegalics with pronounced prognathism as in the controls with normal mandible?