Evaluation of interleukin-18 levels in patients affected by multiple myeloma and monoclonal gammopathy of undetermined significance: analysis and review of the literature.

OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is a preneoplastic disease that often precedes multiple myeloma. The multistep evolutionary pattern of multiple myeloma is driven by genetic instability, a pro-inflammatory and immunosuppressive microenvironment, and tumor growth. Inflammation has long been recognized as a factor in both the onset and progression of cancer. PATIENTS AND METHODS: In this study, interleukin-18 plasma levels were compared in patients with multiple myeloma and monoclonal gammopathy of undetermined significance, as well as in a group of healthy controls. RESULTS: Our study shows that monoclonal gammopathy of undetermined significance patients have lower levels of interleukin-18 than healthy controls (521.657 ± 168.493 pg/ml vs. 1,266.481 ± 658.091 pg/ml for controls, p < 0.001). Thus, we discovered a significant difference in interleukin-18 levels between multiple myeloma patients and controls (418.177 ± 197.837 pg/ml; p = 0.001). CONCLUSIONS: In our work, we identified a reduction of interleukin-18 in monoclonal gammopathies. Furthermore, in this paper, we aimed to evaluate the existing literature on the potential mechanisms of action of this pro-inflammatory cytokine in the development of these diseases.

Predictors of thyroid adverse events during cancer immunotherapy: a real-life experience at a single center.

BACKGROUND: Thyroid dysfunction is among the most common immune-related adverse events (irAEs) of immune checkpoint inhibitors (ICIs) therapy. Data regarding potential predictors of the development of thyroid irAEs are still limited and sometimes conflicting. PATIENTS AND METHODS: We assessed potential risk factors and clinical outcomes associated with the onset of thyroid irAEs in a cohort of patients with different types of cancer treated with ICIs at a single center. Clinical and biochemical data, including thyroid function tests and autoantibodies at baseline and during treatment, were collected, and the onset of thyroid irAEs was recorded. Patients with thyroid dysfunction and/or under levothyroxine therapy before starting ICI were excluded. RESULTS: 110 patients (80 M, 30 F, aged 32-85 years; 56.4% non-small-cell lung cancer, 87% treated with anti-PD-1) with complete information were included in the study. Among them, 32 (29%) developed thyroid irAEs during ICIs therapy. Primary hypothyroidism was the most common irAEs, occurring in 31 patients (28.18% of the whole cohort), including 14 patients who experienced a transient thyrotoxicosis. About 60% of irAEs occurred within the first 8 weeks of therapy. At multivariate analysis, anti-thyroid autoantibodies positivity at baseline (OR 18.471, p = 0.022), a pre-existing (autoimmune and non-autoimmune) thyroid disorder (OR 16.307, p < 0.001), and a family history of thyroid diseases (OR = 9.287, p = 0.002) were independent predictors of the development of thyroid irAEs. CONCLUSION: Our data confirm the high frequency of thyroid dysfunctions (mostly hypothyroidism) during ICIs, and provide data on valuable predictors of thyroid toxicities that may help clinicians in identifying patients at risk for developing irAEs.

The effect of obesity-related allostatic changes on cardio-metabolic risk in euthyroid children.

PURPOSE: The hormonal thyroid changes related to obesity, even when in the euthyroid state, may contribute to the unfavorable cardio-metabolic profile of obese patients. In this retrospective study, we aim to investigate the biochemical thyroid changes and the association between serum TSH, FT4, FT3 and cardio-metabolic risk factors in euthyroid obese youths. METHODS: Four hundred ninety-one Caucasian euthyroid obese children and adolescents aged 9.93 ± 2.90 years were recruited. Each patient underwent clinical and auxological examination and laboratory workup including an OGTT and the measurement of thyroid function and lipid profile. Homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride to high-density lipoprotein cholesterol ratio, total cholesterol to HDL ratio, atherogenic index of plasma, insulinogenic index, area under the glucose and insulin curves were calculated. RESULTS: We found that TSH was positively correlated with BMI-SDS values and significantly associated with hypercholesterolemia and hyperinsulinemia; FT4 resulted negatively correlated with BMI-SDS; FT3 was positively correlated with BMI-SDS and the area under the curve of insulin and negatively correlated with HDL. FT3 and FT4 resulted significantly associated with severe obesity. In addition, children with high-normal TSH values showed higher triglyceride to high-density lipoprotein cholesterol ratio values than those with normal TSH levels. CONCLUSIONS: Our data showed that thyroid hormones could influence obesity, lipid and glycemic parameters in euthyroid youths. These findings could carry implications regarding optimal TSH levels in obese children and confirm the importance of evaluating the thyroid function as possible adjunctive cardio-metabolic risk factor related to obesity.

Resistin levels and inflammatory and endothelial dysfunction markers in obese postmenopausal women with type 2 diabetes mellitus.

BACKGROUND: Obesity-associated coronary heart disease (CHD) risk is higher in women than in men with type 2 diabetes (T2DM). Resistin, an adipokine secreted by adispose tissue, may contribute to this higher risk. AIMS: To explore the relationships among resistin levels and common inflammatory and endothelial dysfunction markers and CHD risk in obese post-menopausal T2DM women. METHODS: Serum levels of resistin, hsCRP, IL-6, Soluble vascular cell adhesion molecule (sVCAM), homocysteine (tHcy), HOMA-IR and metabolic parameters were determined in a group of 132 T2DM women with and without documented CHD and in 55 non-diabetic women. RESULTS: Resistin, sVCAM, IL-6 and tHcy levels were comparable in T2DM and controls. CHD women showed higher resistin, sVCAM and tHcy levels than those without CHD, and for resistin this difference remained significant after age-adjustment (P = 0.013); conversely hsCRP were ~ 2X higher in T2DM women than in controls (P = 0.0132) without any difference according to CHD history. At univariate analysis resistin levels were significantly associated with age, waist circumference, hypertension, tHcy, hsPCR, sVCAM, IL-6, HDL-cholesterol, triglycerides and creatinine levels, but only creatinine, triglycerides, hsCRP, IL-6 and sVCAM were independently associated to resistin levels at stepwise regression analysis. Resistin levels were independently associated to CHD, increasing the risk by 1.15 times (0.986-1.344 95% CI), together with age, tHcy, LDL-C and hypertension. CONCLUSIONS: Circulating resistin levels were comparable in obese/overweight T2DM and control women. In T2DM women, resistin levels correlated with markers of renal function, systemic inflammation and endothelial dysfunction and were independently associated with a higher CHD risk.

Serum levels of advanced glycation end products (AGEs) are increased and their soluble receptor (sRAGE) reduced in Hashimoto's thyroiditis.

PURPOSE: Advanced glycation end products (AGEs) are increased in conditions of oxidative stress and promote inflammation by interacting with their receptor RAGE on cell membrane. By contrast, the soluble receptor sRAGE exerts protective effects by competing with RAGE for ligand binding. AGEs/sRAGEs interaction is involved in the pathogenesis of several diseases related to oxidative stress. In the present study, we evaluated the AGEs/sRAGEs oxidative balance in Hashimoto' thyroiditis (HT). METHODS: We measured the levels of sRAGE, by ELISA, and AGEs, by spectrophotometric method, in the serum of 50 HT patients (5 M, 45 F; mean age 38.5 ± 12 years) and 50 age-, sex- and BMI-matched healthy controls. All subjects were euthyroid at recruitment and none was on LT-4 therapy. RESULTS: Serum sRAGEs were significantly lower (median 424 vs 738 pg/ml; p = 0.001) and AGEs higher (205 vs 114 AU/g prot; p = 0.001) in HT patients compared to controls, and the two parameters were inversely correlated (p = 0.016). Accordingly, the AGEs/sRAGEs ratio was threefold higher in HT patients than controls (0.48 vs 0.15; p = 0.0001). In regression analysis models, serum TPO-Ab were the main predictors for AGEs and sRAGEs levels and AGEs/sRAGEs ratio (p < 0.0001), irrespective of TSH and/or FT4 values. CONCLUSION: sRAGEs were decreased and AGEs increased, suggesting a dysregulation of AGE/sRAGEs-related oxidative homeostasis in HT patients, even when in euthyroid status. Autoimmunity per se seems to play an important role in AGEs/sRAGE imbalance, irrespective of thyroid function alterations.

MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs). PURPOSE: In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features. METHODS: Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation. RESULTS: All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and 'atypical' morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043). CONCLUSIONS: In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.

Non-specific rheumatic manifestations in patients with Hashimoto's thyroiditis: a pilot cross-sectional study.

PURPOSE: Hashimoto's thyroiditis (HT) is often associated with rheumatic disorders (arthritis, etc.), but many HT patients report non-specific rheumatic signs and symptoms in the absence of clinically evident rheumatic diseases. Aim of this study was to evaluate the prevalence of non-specific rheumatic manifestations (RMs) in HT subjects without classified autoimmune comorbidities. METHODS: 500 HT patients (467 F, 33 M; median age 41 years, range 14-69) and 310 age- and sex-matched controls, consecutively referred to the Endocrine Unit of Messina University Hospital, were evaluated for non-specific RMs. None took L-thyroxine. EXCLUSION CRITERIA: autoimmune comorbidities, infectious, and/or inflammatory diseases, history of neoplasia, BMI > 30 kg/m2. RESULTS: In our HT cohort, 100 patients (20%) complained of one or more RMs, vs 21 controls (6.8%; P < 0.001). There were minimal differences between the manifestations recorded in the two groups, the most common being polyarthralgias and myalgias/fibromyalgia, but non-specific RMs occurred threefold more in HT patients. Comparing HT patients with RMs (96 F and 4 M) with those affected by HT alone, female sex was prevalent (F:M ratio 24:1 vs 5:1) with higher age at diagnosis (median 43 vs 37 years; P < 0.001). HT patients with RMs (62%) were mostly euthyroid (median TSH 2.0 µIU/L) and only 7% overtly hypothyroid, discouraging a possible causal relationship between thyroid dysfunction per se and RMs. CONCLUSIONS: A significant percentage of HT patients complains of non-specific rheumatic signs and symptoms, in the absence of other diagnosed systemic comorbidities and regardless of thyroid functional status, deserving careful evaluation and prolonged follow-up.

Pediatric urolithiasis.

Urolithiasis is a well-known condition that can affect any part of the urinary tract. With a rate of 3-5% the incidence of upper urinary tract for long has been higher in adults (1-3), but recently it has increased among children reaching 3,3% . Indeed, more than 1% of all urinary stones are seen in patients aged less than 18 years (4). Pediatric urolithiasis is endemic in Turkey and Far East and it is probably due to malnutrition and racial factors (5). The spontaneous stone passage is more likely in children than in adults, indeed ureteral calculi spontaneously pass into 41-63% of children (1). Rate of stone passage depends on size and stone location in the urinary system. Stones sized less than 5 mm have a passage rate ranging from 40% to 98%, whilst stones > 5 mm have between 55% and 50% (6). In the last decade, the use of alpha blockers has proven well efficacious in helping spontaneous passage of distal ureteric stones in adults (7-9). The latest EAU guidelines support their use in adults while remain vague about their use in children because of unclear safety and efficacy (4). In search of evidence supporting or not the use of medical expulsive therapy in children we reviewed the literature dealing with the management of urolithiasis in pediatric patients. The primary aim of the present study was to evaluate the efficacy of medical expulsive therapy (MET), defined as stone expulsion rate, with a-blockers compared to a control group. The secondary aim was to assess the safety, defined as side effects rate, of MET compared to a control group.

Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience.

In aggressive pituitary tumors (PT) showing local invasion or growth/recurrence despite multimodal conventional treatment, temozolomide (TMZ) is considered a further therapeutic option, while little data are available on peptide receptor radionuclide therapy (PRRT). We analyzed PRRT effectiveness, safety and long-term outcome in three patients with aggressive PT, also reviewing the current literature. Patient #1 (F, giant prolactinoma) received five cycles (total dose 37 GBq) of 111In-DTPA-octreotide over 23 months, after unsuccessful surgery and long-term dopamine-agonist treatment. Patient #2 (M, giant prolactinoma) underwent two cycles (12.6 GBq) of 177Lu-DOTATOC after multiple surgeries, radiosurgery and TMZ. In patient #3 (F, non-functioning PT), five cycles (29.8 GBq) of 177Lu-DOTATOC followed five surgeries, radiotherapy and TMZ. Eleven more cases of PRRT-treated aggressive PT emerged from literature. Patient #1 showed tumor shrinkage and visual/neurological amelioration over 8-year follow-up, while the other PTs continued to grow causing blindness and neuro-cognitive disorders (patient #2) or monolateral amaurosis (patient #3). No adverse effects were reported. Including the patients from literature, 4/13 presented tumor shrinkage and clinical/biochemical improvement after PRRT. Response did not correlate with patients' gender or age, neither with used radionuclide/peptide, but PRRT failure was significantly associated with previous TMZ treatment. Overall, adverse effects occurred only in two patients. PRRT was successful in 1/3 of patients with aggressive PT, and in 4/5 of those not previously treated with TMZ, representing a safe option after unsuccessful multimodal treatment. However, at present, considering the few data, PRRT should be considered only in an experimental setting.

Effects of three treatment modalities (diet, myoinositol or myoinositol associated with D-chiro-inositol) on clinical and body composition outcomes in women with polycystic ovary syndrome.

OBJECTIVE: To evaluate, in overweight/obese PCOS women, which of three distinct treatment modalities achieved the greatest clinical benefits in terms of clinical and body composition outcomes. PATIENTS AND METHODS: Forty-three polycystic ovary syndrome (PCOS) overweight/obese patients were randomly treated for 6 months with: only diet (Group 1, n = 21); diet and myo-inositol (MI) 4 g + folic acid 400 µg daily (group 2, n = 10); diet in association with MI 1.1 g + D-chiroinositol (DCI) 27.6 mg + folic acid 400 µg daily (group 3, n = 13). Menstrual cycle, Ferriman-Gallwey score, body mass index (BMI), waist circumference, hip circumference, waist-hip ratio (WHR), and body composition by bioimpedentiometry were measured at baseline, 3 and 6 months. RESULTS: Body weight, BMI, waist and hip circumferences decreased significantly in all groups. There was a significant difference between the 3 groups regarding the restoration of menstrual regularity (p = 0.02) that was obtained in all patients only in-group 3. CONCLUSIONS: MI+DCI in association with diet seems to accelerate the weight loss and the fat mass reduction with a slight increase of percent lean mass, and this treatment contributes significantly in restoring the regularity of the menstrual cycle.

Vigilance on use of drugs, herbal products, and food supplements during pregnancy: focus on fosfomycin.

PURPOSE: Urinary tract infection (UTI) is defined as a common bacterial infection that can lead to significant morbidity such as stricture, fistula, abscess formation, bacteremia, sepsis, pyelonephritis, and kidney dysfunction with a mortality rates reported of 1% in men and 3% in women because of development of pyelonephritis. UTIs are more common in women and the 33% of them require antimicrobials treatment for at least one episode by the age of 24 years. UTIs are the most common infections observed during pregnancy and up to 30% of mothers with not treated asymptomatic bacteriuria may develop acute pyelonephritis which consequently can be associated to adverse maternal and fetal outcomes. All bacteriuria in pregnancy should be treated with antimicrobial treatments being safe for both the mother and the fetus. Approximately one every four women receives prescription of antibiotic treatment during pregnancy, nearly 80% of all the prescription medications during gestation. The use of fosfomycin to treat cystitis in pregnancy generally considered safe and effective. Even though use on antibiotics for urinary tract infections is considered generally safe for the fetus and mothers, this opinion is not based on specific studies monitoring the relationship of among urinary infections, consumption of antibiotics, and pregnancy outcomes. MATERIALS AND METHODS: On this basis we decided to analyze data from the database of our multicenter study PHYTOVIGGEST, reporting data from 5362 pregnancies, focusing on use of fosfomycin. Principal outcomes of pregnancy in women treated with fosfomycin were taken into consideration. RESULTS: Women who have been treated with urinary antibiotics during the pregnancy were 183. With respect to the total number of pregnancies of our sample, these women represented the percentage of 3.49% (187/5362). Analysis of different outcomes of pregnancy such as gestational age, neonatal weight, and neonatal Apgar index did not show any significant difference. At the same time, analysis of data of pregnancy complicancies (such as urgent cesarean delivery, use of general anesthesia, need to induce labor) did not show any difference in women taking fosfomycin during pregnancy and those not taking it. CONCLUSIONS: Our data, based on a large number of pregnancies, confirm the safety use of fosfomycin use in pregnancy.

Increased serum interleukin-37 (IL-37) levels correlate with oxidative stress parameters in Hashimoto's thyroiditis.

PURPOSE: Interleukin-37 (IL-37), member of the IL-1 family, is a natural suppressor of immune and inflammatory responses. Increased serum IL-37 levels were observed in several autoimmune diseases, including Graves' disease. To our knowledge, no data on Hashimoto's thyroiditis (HT) are available in the literature. METHODS: Aim of our study was to measure serum IL-37 levels and evaluate their relationship, if any, with oxidative stress markers in HT patients. We enrolled 45 euthyroid HT patients (5 M e 40 F, median age 40 years) and 50 age- and sex-matched healthy controls. None was under L-thyroxine therapy. Serum IL-37 levels were measured by ELISA. Specific serum tests, such as derived reactive oxygen metabolites (d-ROMs), and biological anti-oxidant potential (BAP) test were performed in all subjects to investigate the changes in oxidative balance, and advanced glycation end products (AGEs) were determined as a specific marker of oxidative stress. RESULTS: IL-37 levels were significantly higher in HT than in controls (median 475 vs. 268 pg/ml, P = 0.018). In the same patients, serum oxidants (d-ROMs) were increased and anti-oxidants (BAP) decreased compared with controls (P = 0.011 and < 0.0001, respectively), clearly indicating an enhanced oxidative stress. In addition, AGEs levels were higher in HT patients than in controls (210 vs. 140 AU/g prot, P < 0.0001) and directly correlated with IL-37 levels (P = 0.048). At multivariate analysis, the main independent predictors that influenced IL-37 levels were both anti-thyroid antibodies (P = 0.026) and AGEs levels (P = 0.001). CONCLUSIONS: IL-37 is up-regulated in HT and may exert a protective role by counteracting oxidative stress and inflammation.

GSTP1 gene methylation and AHR rs2066853 variant predict resistance to first generation somatostatin analogs in patients with acromegaly.

PURPOSE: Biomarkers of clinical and therapeutic outcome in acromegaly are needed. Polymorphisms or epigenetic changes of detoxification genes, such as those coding for the aryl hydrocarbon receptor (AHR) and the glutathione-S-transferase-P1 (GSTP1), could have a role in GH secreting pituitary tumors' pathophysiology and clinical expression. In this study, we assessed the contribution of GSTP1 gene promoter methylation status, per se or in combination with the occurrence of the AHR gene rs2066853 variant, on clinical features and response to somatostatin analogs (SSA) treatment in acromegaly patients. METHODS: This is an observational, retrospective study, carried out in the Endocrine Unit of an Italian University Hospital. We enrolled 77 wild-type AIP gene acromegaly patients, who have been screened for germline AHR rs2066853 variant and GSTP1 gene promoter methylation. Clinical and biochemical parameters were compared after patients' stratification according to GSTP1 methylation status and the presence of AHR rs2066853. We also evaluated the response to SSA treatment in 71 cases. RESULTS: 17 patients carried the AHR rs2066853 variant and 26 had methylated GSTP1 (GSTP1-methyl) gene promoter. GSTP1-methyl patients showed a higher prevalence of diabetes mellitus (p = 0.01), colonic polyps (p = 0.05), and were more resistant to SSA (p = 0.02) as compared to GSTP1 unmethylated patients (GSTP1-unmethyl). Patients GSTP1-unmethyl and AHR wild-type were the most sensitive to SSA treatment, while those with both GSTP1-methyl and AHR rs2066853 variant were all resistant to SSA (p = 0.01). CONCLUSIONS: In acromegaly, GSTP1 gene methylation associates with resistance to SSA treatment, especially in patients carrying also the AHR rs2066853 variant, and with increased prevalence of colonic polyps and diabetes mellitus.

Accuracy of Periapical Radiography and CBCT in Endodontic Evaluation.

INTRODUCTION: A radiological evaluation is essential in endodontics, for diagnostic purposes, planning and execution of the treatment, and evaluation of the success of therapy. The periapical radiography is nowadays the main radiographic investigations used but presents some limits as 3D anatomic alteration, geometric compression, and possible anatomical structures overlapping that can obscure the area of interest. CBCT (cone beam computed tomography) in endodontics allows a detailed assessment of the teeth and surrounding alveolar anatomy for endodontic diagnosis, treatment planning, and follow-up. OBJECTIVE: The purpose of this study was to evaluate the accuracy of CBCT in comparison with conventional intraoral radiographs used in endodontic procedures. MATERIALS AND METHODS: Statistical analysis was performed on 101 patients with previous endodontic treatments with the relative radiographic documentation (preoperative, postoperative, and follow-up intraoral X-ray) that had underwent at CBCT screening for surgical reasons. The CBCT scans were evaluated independently by two operators and compared with the corresponding periapical images. RESULTS: Our analysis shows that the two radiological investigations statistically agree in 100% of cases in the group of patients without any endodontic sign. In the group of patients with an endodontic pathology, detected with CBCT, endodontic under extended treatments (30.6%), MB2 canals in nontreated maxillary molars (20.7%), second canals in nontreated mandibular incisors (9%), root fractures (2.7%), and root resorption (2.7%) were not always visible in intraoral X-ray. Otherwise, positivity in the intraoral X-ray was always confirmed in CBCT. A radiolucent area was detected in CBCT exam in 46%, while the intraoral X-ray exam was positive only in 18%. CONCLUSIONS: Our study shows that some important radiological signs acquired using CBCT are not always visible in periapical X-ray. Furthermore, CBCT is considered as a II level exam and could be used to solve diagnostic questions, essential to a proper management of the endodontic problems.

Clinical and metabolic outcomes in pregnant women at risk for gestational diabetes mellitus supplemented with myo-inositol: a secondary analysis from 3 RCTs.

BACKGROUND: Gestational diabetes mellitus is defined as carbohydrate intolerance that begins or is first recognized during pregnancy. Insulin sensitizing substances such as myo-inositol have been considered for the prevention of gestational diabetes mellitus and related complications. OBJECTIVE: Because previous studies failed to show a clear reduction of gestational diabetes mellitus complications, the aim of this study was to evaluate clinical and metabolic outcomes in women who are at risk for gestational diabetes mellitus supplemented with myo-inositol since the first trimester. STUDY DESIGN: A secondary analysis of databases from 3 randomized, controlled trials (595 women enrolled) in which women who were at risk for gestational diabetes mellitus (a parent with type 2 diabetes mellitus, obese, or overweight) were supplemented with myo-inositol (4 g/d) throughout pregnancy. Main measures were the rate of adverse clinical outcomes: macrosomia (birthweight, ≥4000 g), large-for-gestational-age babies (fetal growth, ≥90 percentile), fetal growth restriction (fetal growth, ≤3 percentile), preterm birth (delivery before week 37 since the last menstruation), gestational hypertension, and gestational diabetes mellitus. RESULTS: A significant reduction was observed for preterm birth (10/291 [3.4%] vs 23/304 [7.6%]; P=.03), macrosomia (6/291 [2.1%] vs 16/304 [5.3%]; P=.04), Large-for-gestational-age babies (14/291 [4.8%] vs 27/304 [8.9%]; P=.04) with only a trend to significance for gestational hypertension (4/291 [1.4%] vs 12/304 [3.9%]; P=.07). Gestational diabetes mellitus diagnosis was also decreased when compared with the control group (32/291 [11.0%] vs 77/304 [25.3%]; P<.001). At univariate logistic regression analysis, myo-inositol treatment reduced the risk for preterm birth (odds ratio, 0.44; 95% confidence interval, 0.20-0.93), macrosomia (odds ratio, 0.38; 95% confidence interval, 0.14-0.98), and gestational diabetes mellitus diagnosis (odds ratio, 0.36; 95% confidence interval, 0.23-0.57). CONCLUSION: Myo-inositol treatment in early pregnancy is associated with a reduction in the rate of gestational diabetes mellitus and in the risk of preterm birth and macrosomia in women who are at risk for gestational diabetes mellitus.

Different concentration of human cord blood HMGB1 according to delivery and labour: A pilot study.

OBJECTIVE: Oxidative stress is involved in several maternal conditions characterized both by an increase in free radicals synthesis and a parallel decrease in the antioxidant activity. Parturition induces considerable oxidative stress and many inflammatory mediators, among which HMGB1, are involved from the beginning of pregnancy to the birth of the infant. We evaluated serum cord blood HMGB1 levels in a population of neonates to investigate correlation with mode of delivery, as well as the influence of labour. SETTING AND PATIENTS: The study subjects were 325 neonates delivered at University Hospital "G. Martino" of Messina over an 18-month period. Following cord separation, venous blood sampling was performed on umbelical cords. RESULTS: In the cord venous blood, we found HMGB1 values significantly more elevated in spontaneous vaginal group when compared to elective or emergency caesarean section group. Regarding labour, umbilical cord venous blood HMGB1 levels were significantly higher in the spontaneous and induced labour group, compared to non-labouring women. CONCLUSION: These results could highlight a possible role of HMGB1 during birth time related to mode of delivery and labour.

Pasireotide treatment reduces cardiometabolic risk in Cushing's disease patients: an Italian, multicenter study.

PURPOSE: Patients with Cushing's disease (CD) experience metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue dysfunction (ATD) and of the related cardiometabolic risk. We aimed to evaluate the impact of 12-month pasireotide treatment on cardiometabolic risk in CD patients. METHODS: This is a multicentre, prospective, and observational study. Sixteen CD patients, referred to the Endocrine Units of the University Hospitals of Messina, Napoli, Padova, and Palermo (Italy), successfully treated with pasireotide for 12 month have been enrolled. In all patients, we assessed anthropometric, clinical, and biochemical parameters and calculated VAI, ATD severity, Framingham, and atherosclerotic cardiovascular disease (ASCVD) risk scores, before and after 6 and 12 months of treatment with pasireotide (1200-1800 mcg/daily). RESULTS: Before starting pasireotide treatment, ATD was present in 7/16 patients (mild in 2/16, moderate in 3/16, and severe 2/16). After 12 months of treatment: (i) 24h-urinary free cortisol levels (p = 0.003), BMI (p < 0.001), waist circumference (p = 0.001), LDL-cholesterol (p = 0.033), total-cholesterol (p = 0.032), triglycerides (p = 0.030), VAI (p = 0.015), and ATD severity (p = 0.026) were significantly decreased as compared to baseline; (ii) ATD was present in only 1/16 patients; (iii) prevalence of diabetes mellitus (p = 0.015) and HbA1c levels (p = 0.001) were significantly increased as compared to baseline; (iv) Framingham and ASCVD risk scores were not significantly different from pre-treatment values. CONCLUSIONS: Twelve-month pasireotide treatment significantly reduces VAI and ATD in CD patients. These positive effects on cardiometabolic risk occur despite no change in Framingham and ASCVD risk scores and the increase in the prevalence of diabetes mellitus.

How to improve effectiveness of pegvisomant treatment in acromegalic patients.

PURPOSE: Pegvisomant (PEGV) treatment in acromegaly patients resistant to somatostatin analogues is less effective in the real life than in clinical trials. This is a multicenter, observational, retrospective, longitudinal study. The aim was to detect characteristics which improve long-term PEGV effectiveness. METHODS: 87 acromegalic patients treated with PEGV have been enrolled in seven referral Italian centres. PEGV was administered for up to 4 years, at doses up titrated until IGF-1 normalization or to ≥ 30 mg/day. The rate of patients who reached IGF-1 normalization at last visit has been calculated. RESULTS: IGF-1 was normalized in 75.9% of patients after 1 year and in 89.6% at last visit. Disease control was associated with lower baseline GH, IGF-1 and IGF-1 xULN and was more frequent when baseline IGF-1 was < 2.7 × ULN (p < 0.02). PEGV dose was dependent on baseline IGF-1 > 2.7 × ULN (p < 0.05) and doses > 1.0 mg/BMI/day were administered more frequently when baseline IGF-1 was > 2.0 × ULN (p = 0.03). PEGV resistance was associated with higher BMI (p = 0.006) and was more frequent when BMI was > 30 kg/m2 (p = 0.07). There were no significant differences between patients treated with monotherapy or combined treatment. IGF-1 normalization, PEGV dose and rate of associated treatment were similar between males and females. PEGV effectiveness was independent from previous management. Diabetic patients needed higher doses of PEGV than non-diabetic ones. CONCLUSIONS: PEGV effectiveness improves when up titration is appropriate. Higher PEGV doses at start and a more rapid up-titration are necessary in patients with obesity and/or IGF-1 > 2.7 × ULN.

Correlation of cardio-metabolic parameters with vitamin D status in healthy premenopausal women.

PURPOSE: Vitamin D has been associated with metabolic disorders and increasing risk of cardiovascular diseases, with conflicting results. Aim of our study was to evaluate the relationship, if any, between cardio-metabolic risk factors and serum 25(OH)D concentrations in healthy women in premenopausal age. METHODS: We enrolled 200 healthy women, aged 19-50 years (mean age ± SD, 38 ± 11 years). In each subject, we measured serum 25(OH)D in relation to metabolic biomarkers and cardiovascular parameters. RESULTS: A status of vitamin D deficiency was found in 48% of the study population, while 38% showed levels higher than 30 ng/ml. Fasting glucose and insulin levels were significantly higher in subjects with vitamin D deficiency/insufficiency (P = 0.034 and P = 0.049, respectively) as well as HOMA-IR (P = 0.05). HDL cholesterol was significantly lower (P = 0.024) and intima-media thickness (IMT) higher (P = 0.014) in the vitamin D deficient/insufficient subjects. Moreover, serum 25(OH)D levels inversely correlated with insulin levels (P = 0.0001) and intima-media thickness (P = 0.015), and directly with serum HDL cholesterol (P = 0.010). At univariate regression analysis, the parameters that were significantly associated with vitamin D levels were insulin (P = 0.050), HDL cholesterol (P = 0.016), and intima-media thickness (P = 0.015). At multivariate analysis adjusted for age and BMI, vitamin D was still significantly associated with HDL cholesterol and intima-media thickness. CONCLUSIONS: A positive association between vitamin D and HDL cholesterol was found in healthy women without any evidence of metabolic disorders, with a significant inverse correlation between vitamin D and IMT. These results suggest a possible protective role of 25(OH)D in cardiovascular disorders.

Autoimmune comorbidities in Hashimoto's thyroiditis: different patterns of association in adulthood and childhood/adolescence.

OBJECTIVE: Hashimoto's thyroiditis (HT), the most common autoimmune thyroid disease at any age, is often associated with other autoimmune diseases. The present study was aimed to describe the type and frequency of non-thyroidal autoimmune diseases (NTADs) in HT patients and to delineate the clinical pattern of diseases clustering in pediatric/adolescent and adult age. DESIGN: Cross-sectional study. METHODS: 1053 newly diagnosed HT patients (500 adults (467 F, mean age 40.2 ± 13.7 years) and 553 children/adolescents (449 F, mean age 11.1 ± 3.0 years)) were evaluated for common NTADs by means of careful recording of medical history, physical examination and assessment of selected autoantibody profiles. RESULTS: The prevalence of associated NTADs was significantly higher in adults than that in pediatric/adolescent HT patients (P < .0001). In addition, the number of adult patients suffering from two or more associated NTADs was significantly higher than that of children/adolescent (P < 0.0001). A female prevalence was evident in both cohorts, but was significant in the adults (P < 0.0001). The epidemiological distribution of NTADs was strongly different in the two cohorts, the most frequent associated diseases being arthropathies and connective tissue diseases in adults and type 1 diabetes and coeliac disease in children/adolescents. Skin diseases were represented with similar prevalence in both cohorts, vitiligo being the most common. CONCLUSIONS: Age at HT presentation may influence autoimmune diseases clustering, favoring the association of specific NTADs in different ages of life. Moreover, the association between HT and NTADs increases with age and occurs most frequently in adults.