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BACKGROUND: Serum inflammation-based scores can predict clinical outcome in several cancer types, including adrenocortical carcinoma (ACC). It is unclear whether the extent of inflammation-based scores alterations in ACC reflects malignancy, steroid excess, or both. METHODS: We investigated a large retrospective cohort of adrenocortical adenomas (ACA, n = 429) and ACC (n = 61) with available baseline full blood count and hormonal evaluation. We examined the relationship between different inflammation-based scores [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI)] and both malignancy and steroid secretion patterns. RESULTS: All inflammation-based scores differed between ACC and ACA: patients with ACC had higher NLR, PLR, SII and lower LMR and PNI levels compared to ACA (all p values < 0.001). NLR showed a positive correlation with cortisol levels after overnight 1 mg-dexamethasone suppression test (1 mg-DST), both in ACC and ACA (p < 0.01). The ROC curve analysis determined NLR > 2.6 as the best cut-off to discriminate ACC from ACA [AUC = 0.846, p < 0.01]. At multivariable analysis, NLR > 2.6 was independently associated with ACC, 1 mg-DST cortisol levels and age, but not with tumour size. Considering the ACC, NLR and SII were higher and PNI was lower in patients with cortisol excess compared to those without cortisol excess (p = 0.002, p = 0.007, and p = 0.044 respectively). Finally, LMR and NLR differed between inactive-ACC (n = 10) and inactive-ACA (n = 215) (p = 0.040 and p = 0.031, respectively). CONCLUSION: Inflammation-based scores are related to steroid secretion both in ACC and ACA. ACCs present a higher grade of inflammation regardless of their hormonal secretion, likely as a feature of malignancy itself.
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BACKGROUND: Recurrence of acromegaly after successful surgery is a rare event, but no clear data are reported in the literature about its recurrence rates. This study aimed to evaluate the recurrence rate in a series of acromegalic patients treated by transsphenoidal surgery (TSS) with a long follow-up. METHODS: We retrospectively analyzed data from 283 acromegalic patients who underwent TSS at two pituitary units in Milan (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and IRCCS Humanitas Research Hospital). The diagnosis and recurrence of acromegaly were defined by both elevated IGF-1 levels and a lack of GH suppression based on appropriate criteria for the assay used at the time of diagnosis. RESULTS: After surgery, 143 patients (50%) were defined as not cured, 132 (47%) as cured and 8 (3%) as partially cured because of normalization of only one parameter, either IGF1 or GH. In the cured group, at the last follow-up (median time 86.8 months after surgery), only 1 patient (0.7%) showed full recurrence (IGF-1 + 5.61 SDS, GH nadir 1.27 µg/l), while 4 patients (3%) showed only increased IGF1. In the partially cured group at the last follow-up, 2/8 (25%) patients showed active acromegaly (IGF-1 SDS + 2.75 and + 3.62; GH nadir 0.6 and 0.5 µg/l, respectively). CONCLUSIONS: In the literature, recurrence rates range widely, from 0 to 18%. In our series, recurrence occurred in 3.7% of patients, and in fewer than 1%, recurrence occurred with elevation of both IGF-1 and the GH nadir. More frequently (25%), recurrence came in the form of incomplete normalization of either IGF-1 or GH after surgery.
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Following a comparison of nutrient total-tract digestibility estimates in lactating buffaloes using single-point undigestible NDF (uNDF) or acid-insoluble ash (AIA) as internal markers, the potential of fecal near-infrared spectroscopy (NIRS) to provide calibration equations for the assessment of the chemical composition of feces and nutrient total-tract digestibility estimated with internal markers was explored. Chemical analyses were performed on 147 fecal samples from lactating buffaloes reared on 5 farms in central Italy (Naples). Each farm fed a silage-based TMR to the buffaloes, and the TMR was sampled in the 2 d before the fecal collection. The TMR and individual fecal samples were collected and analyzed for DM, OM, ash, AIA, ether extract (EE), starch, fiber fractions (amylase-treated NDF without residual ash [aNDFom], amylase-treated NDF inclusive of residual ash [aNDF], ADF without residual ash [ADFom], ADF, hemicellulose, cellulose, ADL, uNDF), N, CP and CP bound to aNDF (NDICP) and to ADF (ADICP). The uNDF content was determined through a 240-h in vitro fermentation and employed, together with AIA as markers, to estimate the total-tract apparent digestibility and total-tract digestibility of DM, OM, ash, N, CP, EE, aNDFom, aNDF, NDIP, ADFom, and ADF, ADIN, ADL, hemicellulose, cellulose, starch, NFC, and the B3 fraction of N (NB3). No correlation was found between DM and OM digestibility estimated with AIA and uNDF as internal markers. Weak correlations were detected for all the other nutients digestibilities, and strong correlations were observed for EE, ADFom, hemicellulose, NDIN, ADIN, NB3, NFC, and starch. The sample set (n = 147) was divided in a calibration set (n = 111) and a validation set (n = 36) to "train" and "validate" the fecal NIRS curve through an external validation process. An estimation usable for preliminary or initial evaluation was obtained for N, CP, and aNDF fecal content. An excellent prediction was obtained for total tract digestibility of ADIN (R2 = 0.90) when estimated with uNDF as the internal marker. The NIRS technology was not able to accurately predict all the other traits and the estimated nutrient digestibility of lactating buffalo diets from fecal spectra.
Subject(s)
Buffaloes , Dietary Fiber , Digestion , Feces , Lactation , Spectroscopy, Near-Infrared , Animals , Feces/chemistry , Female , Spectroscopy, Near-Infrared/veterinary , Diet/veterinary , Animal Feed/analysis , Nutrients/analysis , SilageABSTRACT
AIM: Evaluate the influence of occlusal loading on the stress distribution of endodontically treated teeth after root canal preparation with different file's sizes and tapers by means of finite element analysis. METHODOLOGY: Seven three-dimensional models of a single-rooted, single-canal lower second premolar were established, one healthy control and six endodontically treated and restored models. The shape of root canal preparations followed file configurations 30/.05, 30/.09, 35/.04, 35/.06, 40/.04, and 40/.06. Von- Mises equivalent stresses were calculated by applying 30 N, 90 N and 270 N loads to the buccal cusp tip, each one at 90º, 45º and 20º angles from the occlusal plane simulating occlusion, dental interference and laterality, respectively. RESULTS: 45º loading was more prone to formation of higher stress values. The simulation of occlusion and laterality resulted in maximum stress areas located at the inner side of the root curvature, while under occlusal interference they were on the lingual surface over the tooth's long axis. CONCLUSIONS: The angulation of occlusal loading and magnitude were determinants for stress distribution on dental structure. Both variations of size and taper were not determinants for the increase in the maximum stress areas.
Subject(s)
Tooth, Nonvital , Humans , Tooth, Nonvital/therapy , Finite Element Analysis , Dental Occlusion , Computer Simulation , Root Canal Preparation , Dental Stress Analysis/methods , Stress, MechanicalABSTRACT
PURPOSE: Hypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro. METHODS: C2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl2 0.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated. RESULTS: The combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells. CONCLUSIONS: Our results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.
Subject(s)
Hyperphosphatemia , Hypocalcemia , Hypoparathyroidism , Humans , Hypocalcemia/etiology , Calcium , Insulin-Like Growth Factor I , Parathyroid Hormone , Hypoparathyroidism/etiology , Cell Differentiation , Muscles/metabolismABSTRACT
Introduction: Orbital surgery has always been disputed among specialists, mainly neurosurgeons, otorhinolaryngologists, maxillofacial surgeons and ophthalmologists. The orbit is a borderland between intra- and extracranial compartments; Krönlein's lateral orbitotomy and the orbitozygomatic infratemporal approach are the historical milestones of modern orbital-cranial surgery. Research question: Since its first implementation, endoscopy has significantly impacted neurosurgery, changing perspectives and approaches to the skull base. Since its first application in 2009, transorbital endoscopic surgery opened the way for new surgical scenario, previously feasible only with extensive tissue dissection. Material and methods: A PRISMA based literature search was performed to select the most relevant papers on the topic. Results: Here, we provide a narrative review on the current state and future trends in endoscopic orbital surgery. Discussion and conclusion: This manuscript is a joint effort of the EANS frontiers committee in orbital tumors and the EANS skull base section.
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Pulmonary delivery offers a non-invasive route for the administration of biotherapeutics. In this context, understanding and control of a transport into, and across cellular barriers is central to the design of delivery systems. Here, we report our study on receptor mediated delivery of protein cargo by a formulation comprising sub-300 nm sized non-covalent protein complexes with biotin-conjugated PEG-poly(glutamic acid) (biotin-PEG2k-b-GA10) and PEG2k-b-GA30 copolymers blend as targeting and complexing functionalities. Designed complexes achieve intracellular delivery of the cargo in lung derived A549 epithelial cells in vitro via sodium-dependent multivitamin transporter (biotin receptor). We further show that biotin receptor driven endocytosis preferentially involves dynamin- and caveolae-dependent vesicular internalization, switching the transport pathway away from predominantly clathrin-dependent entry of free protein. Significantly for a protective intracellular delivery of biotherapeutics based on non-covalent complexation with polymeric excipients, the study provides evidence of intracellular presence of the complexing copolymer; demonstrated exploiting biotin in biotin-PEG2k-b-GA10 copolymer as a tag for binding with fluorescently labelled avidin. Moreover, analysis of intracellular localization of constitutive species shortly following cellular internalization suggests a co-localization of biotin-PEG2k-b-GA10 copolymer and protein constitutive species. The study demonstrates intracellular delivery of biotin targeted non-covalent complexes with a protein cargo, the result with important implications in a design of enabling technology platforms for protective, receptor mediated intracellular delivery of biotherapeutics.
Subject(s)
Biotin , Receptors, Growth Factor , Biotin/chemistry , Peptides , Avidin , EndocytosisABSTRACT
INTRODUCTION: Severe short stature is a feature of acrodysostosis, but data on growth are sparse. Treatment with recombinant human growth hormone (rhGH) is used in some centers to increase final height, but no studies have been published so far. Our objective was to conduct a multicenter, retrospective, cohort study to investigate growth in individuals with both types of acrodysostosis, treated with rhGH or not; we used the new nomenclature to describe acrodysostosis, as this disease belongs to the large group of inactivating PTH/PTHrP signaling disorders (iPPSD); acrodysostosis refers to iPPSD4 (acrodysostosis type 1 due to PRKAR1A mutations) and iPPSD5 (acrodysostosis type 2, due to PDE4D mutations). METHODS: We present auxological data from individuals with genetically characterized iPPSD4, and participants with clinical features of iPPSD5. RESULTS: We included 20 and 17 individuals with iPPSD4 and iPPSD5, respectively. The rhGH-treated iPPSD4 patients (n = 9) were smaller at birth than those who did not receive rhGH (median - 2.2 SDS vs. - 1.7 SDS); they showed a trend to catch-up growth during rhGH therapy (median 0.5 SDS in the first year). The rhGH-treated patients (n = 5) reached a better final height compared to those who did not receive rhGH (n = 4) (median - 2.8 SDS vs. - 3.9 SDS), suggesting that rhGH is efficient to increase height in those patients. The difference in target height to final height ranged between 1.6 and 3.0 SDS for iPPSD4 not treated with rhGH (n = 4), 2.1-2.8 SDS for rhGH-treated iPPSD4 (n = 5), 0.6-5.5 SDS for iPPSD5 not treated with rhGH (n = 5) and 2.5-3.1 for rhGH-treated iPPSD5 (n = 2). CONCLUSION: Final height may be positively influenced by rhGH in patients with acrodysostosis/iPPSD. Our rhGH-treated cohort started therapy relatively late, which might explain, at least in part, the limited effect of rhGH on height.
Subject(s)
Human Growth Hormone , Infant, Newborn , Humans , Human Growth Hormone/therapeutic use , Human Growth Hormone/pharmacology , Growth Hormone/therapeutic use , Retrospective Studies , Cohort Studies , Growth Disorders/drug therapy , Growth Disorders/etiology , Body Height , Recombinant Proteins/therapeutic useABSTRACT
Patients with cardiovascular autonomic failure (AF) may suffer from neurogenic supine hypertension (nSH), defined as systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, after 5 min of rest in the supine position, combined with neurogenic orthostatic hypotension (nOH) in approximately 50% of the cases. nSH may be the manifestation of central or peripheral autonomic lesions. Long-term risks are hypothesized with SH, including renal dysfunction, left ventricular hypertrophy, cerebrovascular disease and cognitive impairment. Yet, large longitudinal studies investigating long-term outcomes of nSH are lacking. In clinical practice, nSH should be investigated in patients with nOH. Office screening should be performed measuring supine BP immediately after lying down and 5 min later, combined with BP measurement on active or passive standing. Home BP recordings performed by patients themselves may also be useful, while 24 h-Ambulatory Blood Pressure Monitoring (ABPM) may allow for detection of nocturnal hypertension and confirm the diagnosis. Current expert recommendations suggest treatment interventions if SBP exceeds 160-180 mmHg. Non-pharmacological strategies represent the first-line treatment approach and include head-up sleeping, avoiding supine position during the daytime, and having a snack before bedtime to lower supine BP using post-prandial hypotension. Pharmacological treatments may be considered if severe nSH persists. Short-acting antihypertensive medications administered at bedtime are preferably used in order to selectively lower supine BP and reduce pressure diuresis without worsening daytime hypotension.
Subject(s)
Hypertension , Hypotension, Orthostatic , Hypotension , Blood Pressure/physiology , Blood Pressure Monitoring, Ambulatory , Humans , Hypertension/diagnosis , Hypertension/drug therapy , Hypotension, Orthostatic/diagnosis , Hypotension, Orthostatic/therapy , Supine Position/physiologyABSTRACT
PURPOSE: The main purpose of this study was to investigate the effects of 12 months of rhPTH (1-84) (Natpar®) treatment in a cohort of patients selected according to the indications of hypoparathyroidism guidelines. The use of recombinant human PTH (1-84) [rhPTH (1-84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy. METHODS: It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers, members of Hypoparathyroidism Working Group of the Italian Society of Endocrinology (HypoparaNET) were involved. Main outcome measures were serum and urinary calcium and phosphate concentration, calcium-phosphate product, renal function, oral calcium and vitamin D doses, and clinical manifestations. RESULTS: Fourteen adult subjects, affected by chronic hypoparathyroidism, were treated with rhPTH (1-84) for 12 months. At 12 months of rhPTH (1-84) treatment, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean albumin-adjusted total serum calcium levels quickly normalized after initiation of rhPTH (1-84) treatment compared to baseline (p = 0.009), remaining in the normal range until 12 months. Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p = 0.014). No severe adverse events were described. CONCLUSIONS: Biochemical and clinical results confirm the efficacy and safety of rhPTH (1-84) therapy, which represents an important option for hypoparathyroid patients unresponsive to conventional therapy.
Subject(s)
Calcium , Hypoparathyroidism , Adult , Humans , Parathyroid Hormone , Phosphates/therapeutic use , Prospective Studies , Treatment OutcomeABSTRACT
PURPOSE: Octreotide (OCT) is a first-generation somatostatin analog (SSA) used in the treatment of acromegaly and neuroendocrine tumors (NETs). In both diseases, OCT interacts with somatostatin receptors 2 and 5 (SSTR2 and SSTR5), inhibiting hormone hypersecretion and cell proliferation. Skeletal health is an important clinical concern in acromegaly and NETs, since acromegalic osteopathy and NET bone metastasis occur in a remarkable number of patients. While OCT's effect on NET and pituitary cells has been extensively investigated, its direct action on bone cells remains unknown. METHODS: Here, we investigated OCT direct effects on cell proliferation, differentiation, mineralization, and chemoattractant capacity of murine primary osteoblasts and osteoblast cell line MC3T3-E1. RESULTS: OCT inhibited osteoblasts and MC3T3-E1 cell proliferation (- 30 ± 16%, and - 22 ± 4%, both p < 0.05 vs control) and increased MC3T3-E1 cell apoptosis (+ 76 ± 32%, p < 0.05 vs control). The anti-proliferative action of OCT was mediated by SSTR2 and SSTR5 in MC3T3-E1, while its pro-apoptotic effect was abrogated in SSTR2-silenced cells. The analysis of genes related to the early and late phases of osteoblast differentiation showed that OCT did not affect Alp, Runx2, Bglap, Spp1, and Sost levels in MC3T3-E1 cells. Similarly, OCT did not affect ALP activity, mineralization, and osteoclastogenic induction. Finally, Vegfa expression decreased in OCT-treated MC3T3-E1 cells and OCT inhibited pancreatic NET cell migration toward the osteoblast-conditioned medium. CONCLUSION: This study provides the first evidence of the direct action of OCT on osteoblasts which may have clinically relevant implications for the management of skeletal health in subjects with acromegaly and metastatic NETs.
Subject(s)
Acromegaly , Octreotide , Acromegaly/metabolism , Animals , Cell Differentiation , Cell Proliferation , Humans , Mice , Octreotide/pharmacology , Osteoblasts , OsteogenesisABSTRACT
PURPOSE: Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing's syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing's disease (CD). METHODS: Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome. RESULTS: Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6-10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78). CONCLUSIONS: CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.
Subject(s)
Adrenocorticotropic Hormone/blood , Cushing Syndrome/diagnosis , Magnetic Resonance Imaging/methods , Petrosal Sinus Sampling/methods , Pituitary ACTH Hypersecretion , Pituitary Function Tests/methods , Pituitary Neoplasms , Adult , Cushing Syndrome/epidemiology , Diagnosis, Differential , Diagnostic Techniques, Endocrine , Female , Humans , Hypophysectomy/methods , Hypophysectomy/statistics & numerical data , Italy/epidemiology , Male , Pituitary ACTH Hypersecretion/blood , Pituitary ACTH Hypersecretion/diagnosis , Pituitary ACTH Hypersecretion/epidemiology , Pituitary ACTH Hypersecretion/surgery , Pituitary Neoplasms/diagnostic imaging , Pituitary Neoplasms/pathology , Pituitary Neoplasms/surgery , Retrospective StudiesABSTRACT
OBJECTIVE: Patients with Cushing's syndrome (CS) are at high risk of venous thromboembolism related to a hypercoagulability due to procoagulant imbalance. However, whether these alterations are reversible after disease remission is still unclear. The endogenous thrombin potential (ETP) measured with and without the addition of thrombomodulin provides a global representation of coagulation and previous data confirmed hypercoagulable profile in patients with active hypercortisolism. Aim of this study was to assess the short- and long-term modification of ETP in patients with CS after disease remission. DESIGN AND METHODS: Nineteen patients with CS for whom surgical remission was achieved, were prospectively evaluated for clinical characteristics, cortisol secretion profile and ETP at different time points: (i) before surgical intervention; (ii) after 6 months and (iii) 5 years from the time of persistent remission. Nineteen healthy subjects matched for age and gender were also evaluated as control group. RESULTS: Before surgery, patients showed higher ETP-ratio (with/without thrombomodulin) than controls (0.62 ± 0.09-vs-0.56 ± 0.09, p = 0.034). No significant correlation between ETP-ratio and cortisol secretion was found. 6 months after remission, ETP-ratio was still significantly increased compared to controls (0.64 ± 0.09-vs-0.56 ± 0.09, p = 0.01), but was similar to baseline (0.64 ± 0.09-vs-0.62 ± 0.09, p = 0.87). At 5 years, ETP-ratio showed a significant decrease (0.55 ± 0.14-vs-0.62 ± 0.09, p = 0.02) and was comparable to controls (0.55 ± 0.14-vs-0.56 ± 0.09, p = 0.7). CONCLUSIONS: Plasma hypercoagulability detected in patients with active hypercortisolism persists at short-term evaluation and seems to be completely reversible after long-term remission of disease. These data, as part of a whole evaluation of thrombotic risk, can contribute to make appropriate therapeutic choice in these patients.
Subject(s)
Blood Coagulation Tests/methods , Cushing Syndrome , Hydrocortisone/blood , Thrombin/analysis , Thrombophilia , Venous Thromboembolism , Adrenalectomy/methods , Adult , Blood Coagulation , Cushing Syndrome/blood , Cushing Syndrome/complications , Cushing Syndrome/surgery , Female , Humans , Hypophysectomy/methods , Male , Postoperative Period , Remission Induction , Risk Assessment/methods , Thrombophilia/blood , Thrombophilia/etiology , Time , Venous Thromboembolism/blood , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & controlABSTRACT
CONTEXT: Acromegalic patients have an increased vertebral fracture (VFx) risk due to bone quality reduction, independently of bone mineral density (BMD). OBJECTIVE: The aim of the study is to describe bone quality in acromegaly, measured by trabecular bone score (TBS), a noninvasive index for assessing bone microarchitecture. METHODS: We collected data from 18 patients (13 female, age 56.2â ±â 15 years) newly diagnosed with acromegaly. Thirty-six age- and sex-matched healthy controls were also recruited. Pituitary function, bone and calcium-phosphorous metabolism, and BMD at spine and femur and TBS (by dual-energy x-ray absorptiometry) were assessed in acromegalic patients at diagnosis and 12 months after the achievement of insulin-like growth factor 1 (IGF-1) normalization. RESULTS: At diagnosis, BMD and the VFx prevalence were comparable between patients and controls (28.3â ±â 5.9 vs 27.6â ±â 3.7 and 11% vs 8.3%), whereas TBS was significantly lower in acromegalic patients (1.20â ±â 0.13 vs 1.30â ±â 0.06; Pâ <â .001) and carboxyterminal telopeptide (CTX) and osteocalcin were significantly higher compared to controls (707â ±â 365.7 vs 371â ±â 104.1 pg/mL; Pâ =â .001 and 31.6â ±â 15.4 vs 17.0â ±â 5.7 ng/mL; Pâ =â .001, respectively). One year after IGF-1 normalization, a significant reduction of bone turnover indexes was observed in the group of acromegalic patients surgically cured (osteocalcin decrease of 61.2%, CTX decrease of 60.3%) compared to the ones controlled by medical therapy (osteocalcin decrease of 39%, CTX decrease of 40.7%; Pâ =â .01 and Pâ =â .001, respectively). Despite these findings, no TBS or BMD variations were observed. CONCLUSION: Acromegalic patients have impaired bone quality despite normal density. Achieving normal growth hormone secretion rapidly leads to the normalization of bone turnover.
ABSTRACT
PURPOSE: A long-lasting remission of acromegaly after somatostatin analogues (SAs) withdrawal has been described in some series. Our aim was to update the disease evolution after SAs withdrawal in a cohort of acromegalic patients. METHODS: We retrospectively evaluated 21 acromegalic patients previously included in a multicentre study (Ronchi et al. 2008), updating data at the last follow-up. We added further 8 patients selected for SAs withdrawal between 2008-2018. Pituitary irradiation represented an exclusion criterion. The withdrawal was suggested after at least 9 months of clinical and hormonal disease control. Clinical and biochemical data prior and after SAs withdrawal were analysed. RESULTS: In the whole cohort (29 patients) mean age was 50 ± 14.9 years and 72.4% were females. In 69% pituitary surgery was previously performed. Overall, the median time of treatment before SAs withdrawal was 53 months (IQR = 24-84). At the last follow up in 2019, 23/29 patients (79.3%) had a disease relapse after a median time of 6 months (interquartile range or IQR = 3-12) from the drug suspension, while 6/29 (20.7%) were still on remission after 120 months (IQR = 66-150). IGF-1 levels were significantly lower before withdrawal in patients with persistent remission compared to relapsing ones (IGF-1 SDS: -1.5 ± 0.6 vs -0.11 ± 1, p = 0.01). We did not observe any other difference between patients with and without relapse, including SAs formulation, dosage and treatment duration. CONCLUSION: A successful withdrawal of SAs is possible in a subset of well-controlled acromegalic patients and it challenges the concept that medical therapy is a lifelong requirement.
Subject(s)
Acromegaly , Insulin-Like Growth Factor I/analysis , Secondary Prevention , Somatostatin , Withholding Treatment/statistics & numerical data , Acromegaly/blood , Acromegaly/diagnosis , Acromegaly/drug therapy , Duration of Therapy , Female , Hormones/pharmacology , Humans , Male , Middle Aged , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Remission Induction/methods , Secondary Prevention/methods , Secondary Prevention/statistics & numerical data , Somatostatin/analogs & derivatives , Somatostatin/pharmacology , Time , Treatment OutcomeSubject(s)
Biomarkers/metabolism , Diabetes Insipidus/diagnosis , Glycopeptides/metabolism , Neurosurgical Procedures/adverse effects , Pituitary Diseases/surgery , Postoperative Complications/diagnosis , Diabetes Insipidus/etiology , Diabetes Insipidus/metabolism , Female , Humans , Male , Middle Aged , Pituitary Diseases/pathology , Postoperative Complications/etiology , Postoperative Complications/metabolism , Prognosis , Prospective StudiesABSTRACT
Adrenocortical carcinomas (ACCs) overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, but IGF1R/IR-targeted therapies failed in ACC patients. The cytoskeleton actin-binding protein filamin A (FLNA) impairs IR signalling in melanoma cells. Aims of this study were to test FLNA involvement in regulating IGF1R and IR responsiveness to both IGF2 and inhibitors in ACC. In ACC cells H295R and SW13 and primary cultures (1ACC, 4 adenomas) we found that IGF1R and IR interacted with FLNA, and FLNA silencing increased IGF1R and reduced IR expression, with a downstream effect of increased cell proliferation and ERK phosphorylation. In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R. Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only. In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.
Subject(s)
Adrenal Cortex Neoplasms/pathology , Adrenocortical Carcinoma/pathology , Biomarkers, Tumor/metabolism , Filamins/metabolism , Insulin-Like Growth Factor II/metabolism , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/antagonists & inhibitors , Actin Cytoskeleton/metabolism , Adrenal Cortex Neoplasms/drug therapy , Adrenal Cortex Neoplasms/metabolism , Adrenocortical Carcinoma/drug therapy , Adrenocortical Carcinoma/metabolism , Apoptosis , Biomarkers, Tumor/genetics , Cell Proliferation , Filamins/genetics , Gene Expression Regulation, Neoplastic , Humans , Imidazoles/pharmacology , Insulin-Like Growth Factor II/genetics , Mitogens/pharmacology , Pyrazines/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Signal Transduction , Tumor Cells, CulturedSubject(s)
COVID-19/diagnosis , COVID-19/epidemiology , Pituitary ACTH Hypersecretion/diagnosis , Pituitary ACTH Hypersecretion/epidemiology , Tertiary Care Centers/trends , Adult , Aged , COVID-19/therapy , Cohort Studies , Female , Humans , Italy/epidemiology , Male , Middle Aged , Pituitary ACTH Hypersecretion/therapyABSTRACT
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine neoplasm of the parafollicular thyroid C cells. Although somatostatin receptors are expressed by MTCs, treatment with octreotide has shown poor efficacy, whereas recently pasireotide has demonstrated antiproliferative effects in persistent postoperative MTCs. Aim of this study was to test the effects of octreotide and pasireotide on MTC cells proliferation, cell cycle proteins expression, MAPK activation, apoptosis, calcitonin secretion, migration and invasion in TT cell line as well as in primary MTC cultured cells. Our results showed that both octreotide and pasireotide reduced TT cell proliferation (-35.2 ± 12.1%, p < 0.001, and -25.3 ± 24.8%, p < 0.05, at 10-8 M, respectively), with concomitant inhibition of ERK phosphorylation and cyclin D1 expression. This cytostatic effect was accompanied by a proapoptotic action, with an increase of caspase3/7 activity of 1.5-fold. Moreover, both octreotide and pasireotide inhibited cell migration (-50.9 ± 11.3%, p < 0.01, and -40.5 ± 17%, p < 0.05, respectively) and invasion (-61.3 ± 35.1%, p < 0.05, and -49.7 ± 18%, p < 0.01, respectively). No effect was observed on calcitonin secretion. We then tried to extend these observations to primary cultures (n = 5). Octreotide and/or pasireotide were effective in reducing cells proliferation in 3 out of 5 tumors, and to induce cell apoptosis in 1 out of 3 MTCs. Both octreotide and pasireotide were able to reduce cell migration in all MTC tested. SST2, SST3 and SST5 were expressed in all MTC, with a tendency to increased expression of SST2 in RET mutated vs wild type MTCs. In agreement, inhibition of mutated RET in TT cells reduced SST2 expression. In conclusion, we demonstrated that octreotide and pasireotide inhibited cell proliferation and invasiveness in a subset of MTC, supporting their potential use in the control of tumor growth.
Subject(s)
Carcinoma, Neuroendocrine/pathology , Octreotide/pharmacology , Somatostatin/analogs & derivatives , Thyroid Neoplasms/pathology , Apoptosis/drug effects , Calcitonin/metabolism , Cell Movement/drug effects , Cell Proliferation/drug effects , Humans , Mutation/genetics , Neoplasm Invasiveness , Proto-Oncogene Proteins c-ret/genetics , Somatostatin/metabolism , Somatostatin/pharmacology , Tumor Cells, CulturedABSTRACT
BACKGROUND: According to the European Society for Medical Oncology/ European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology (ESMO/ESGO/ESTRO) Consensus Conference, the role of preoperative risk groups (RGs) in endometrial cancer (EC) is to direct surgical nodal staging. We compared diagnostic accuracy and economic impact of three work-up strategies to identify RGs. METHODS: A retrospective multicentre study including patients with early-stage EC. The three different work-up strategies were as follows:-Mondovì Hospital: transvaginal ultrasonography, pelvic magnetic resonance imaging (MRI); frozen section examination of the uterus in case of imaging discordance. High-risk patients underwent abdominal computed tomography.-Gemelli Hospital: transvaginal ultrasonography, MRI, One-Step Nucleic Acid Amplification (OSNA) of sentinel lymph node (SLN); frozen section examination of the uterus in case of imaging discordance.-Negrar Hospital: positron emission tomography (PET), frozen section examination of the uterus and of SLN. For statistical purposes patients were assigned, preoperatively and postoperatively, to two groups: group A (high-risk) and group B (not high-risk). RESULTS: Three hundred eighty-five patients were included (93 Mondovì, 215 Gemelli, 77 Negrar). Endometrial biopsy errors led to 47.3% misclassifications. Test accuracy of Mondovì, Gemelli and Negrar strategies was 0.83 (95%CI 0.734-0.901), 0.95 (95%CI 0.909-0.975) and 0.94 (95%CI 0.866-0.985), respectively. Preoperative work-up mean cost per patient in group A was 514.5 at Mondovì, 868.5 at Gemelli, and 1212.8 at Negrar hospital (p-value < 0.001), while in group B was 378.8 at Mondovì, 941.2 at Gemelli, and 1848.4 at Negrar hospital (p-value < 0.001). CONCLUSIONS: In our study, work-up strategies with more relevant economic impact showed a better diagnostic accuracy. Upcoming guidelines should specify recommendations about the gold standard work-up strategy, including the role of SLN.