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Introduction Treatment of acromegaly resistant to first generation somatostatin analogues (first gen-SSA) is often difficult. We aimed to investigate the role of partial response and resistance to first gen-SSA in the choice of second line treatments and their outcomes. Patients and methods A retrospective and multicenter study was conducted on 100 SSA-resistant acromegaly patients and treated with Pasireotide Lar (Pasi-Lar), Peg-V in monotherapy (m-Peg-V) or in combination with first gen-SSA (c-Peg-V). Results Thirty-three patients (33%) were treated with m-Peg-V, 36 (36%) with c-Peg-V and 31 with Pasi-Lar (31%). According to logistic regression, m-Peg-V was chosen in older patients (p = 0.01) and with not-invasive adenomas (p = 0.009), c-Peg-V therapy in younger patients (p = 0.001), with invasive adenomas (p = 0.02), Pasi-Lar was in invasive adenomas (p = 0.01) and in patients partially responsive to first-gen SSA (p = 0.01). At the last follow-up, 68 patients (68%) reached the acromegaly control: 22 with m-Peg-V (32.4%), 23 with c-Peg-V (33.8%) and 23 with Pasi-Lar (33.8%). Patients non-responsive to c-Peg-V had higher IGF-I levels (median 3.2 x ULN, IQR: 1.6, p p = 0.002) as compared to responsive patients (median IGF-I x ULN: 2.1 IQR: 1.4; median Peg-V dosage 20 mg/daily IQR: 10). All patients responsive to Pasi-Lar were partially responsive to first gen-SSAs (p = 0.02). Conclusion Our data showed that c-Peg-V and Pasi-Lar are chosen for the treatment of invasive tumors. The partial response to first gen-SSA seems to be the main determinant for the choice of Pasi-Lar and positively predicts the treatment outcome.

Purpose In presence of indeterminate lesions by fine needle aspiration (FNA), thyroid cancer cannot always be easily diagnosed by conventional cytology. As a consequence, unnecessary removal of thyroid gland is performed in patients without cancer based on the lack of optimized diagnostic criteria. Aim of this study is identifying a molecular profile based on long noncoding RNAs (lncRNAs) expression capable to discriminate between benign and malignant nodules. Methods Patients were subjected to surgery (n = 19) for cytologic suspicious thyroid nodules or to FNA biopsy (n = 135) for thyroid nodules suspicious at ultrasound. Three thyroid-specific genes (TG, TPO, and NIS), six cancer-associated lncRNAs (MALAT1, NEAT1, HOTAIR, H19, PVT1, MEG3), and two housekeeping genes (GAPDH and P0) were analyzed using Droplet Digital PCR (ddPCR). Results Based on higher co-expression in malignant (n = 11) but not in benign (n = 8) nodules after surgery, MALAT1, PVT1 and HOTAIR were selected as putative cancer biomarkers to analyze 135 FNA samples. Cytological and histopathological data from a subset of FNA patients (n = 34) were used to define a predictive algorithm based on a Naïve Bayes classifier using co-expression of MALAT1, PVT1, HOTAIR, and cytological class. This classifier exhibited a significant separation capability between malignant and benign nodules (P Conclusions ddPCR analysis of selected lncRNAs in FNA biopsies appears a suitable molecular tool with the potential of improving diagnostic accuracy.

Classification schemes for reporting thyroid cytology of fine needle aspiration (FNA) of thyroid nodules are largely used in clinical practice, but the level of inter-observer agreement among cytopathologists is poorly acknowledged. The present study aimed to explore the inter-observer agreement among the experienced authors of the 2014 Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC). A stratified randomization was performed in order to obtain a sample homogeneously distributed and representative of all ICCRTC classes. Four high-experience raters were randomly selected among the extensors of the Italian consensus. They independently reviewed 60 FNA samples blindly of the initial cytological report and clinical features. Their overall agreement was evaluated according to Fleiss' kappa. The overall inter-observer agreement was moderate (κ 0.46). Specifically, a good agreement was found when the samples were consistent for malignancy (TIR5) or were not adequate for diagnosis (TIR1) (κ 0.67 and κ 0.73, respectively). A moderate agreement was present for suspicious-for-malignant category (TIR4), and a fair agreement was recorded in the two intermediate ones (TIR3A and TIR3B) (κ 0.36 and κ 0.35, respectively). For clinical purposes, the agreement was good (κ 0.74) in differentiating cases with surgical indication (TIR4/TIR5) from those in which surgery is not essential or requires limited extension (TIR3B/TIR3A/TIR2). In conclusion, the present study confirms the reliability of ICCRTC. These data represent a reference for cytopathologists using this system and are useful for the practice of clinicians and surgeons.

Neck pain is a common complain, being in most cases due to non-thyroidal causes. However, a minority of patients suffer from painful thyroid diseases. Among them, sub-acute thyroiditis (SAT) is the most frequent one. Rare thyroid-related causes of neck pain include hemorrhage within a thyroid nodule as well as Riedel's thyroiditis and suppurative thyroiditis. In the last 30 years, a few cases of a painful variant of Hashimoto's thyroiditis (HT) have been described. Biochemical, ultrasound, and histologic features were clearly suggestive for HT in all of the published cases and definitely ruled out the diagnosis of SAT. While sound descriptions of painful HT are present in the literature, it is important to emphasize that only 20 cases were reported from the year 2000 until now. The condition, however, is clinically relevant because neck pain was reported to be refractory both to steroids and to other analgesic drugs, being thyroidectomy the only effective treatment for pain relief in these patients. This short review analyzes currently available data supporting a role for HT as a rare cause of neck pain.

Background Many tumor-related factors have shown the ability to affect metabolic pathways by paving the way for cancer-specific metabolic features. Here, we investigate the regulation of mTORC1 by MDM4, a p53-inhibitor with oncogenic or anti-survival activities depending on cell growth conditions. Method MDM4-mTOR relationship was analysed through experiments of overexpression or silencing of endogenous proteins in cell culture and using purified proteins in vitro. Data were further confirmed in vivo using a transgenic mouse model overexpressing MDM4. Additionally, the Cancer Genome Atlas (TCGA) database (N = 356) was adopted to analyze the correlation between MDM4 and mTOR levels and 3D cultures were used to analyse the p53-independent activity of MDM4. Results Following nutrient deprivation, MDM4 impairs mTORC1 activity by binding and inhibiting the kinase mTOR, and contributing to maintain the cytosolic inactive pool of mTORC1. This function is independent of p53. Inhibition of mTORC1 by MDM4 results in reduced phosphorylation of the mTOR downstream target p70S6K1 both in vitro and in vivo in a MDM4-transgenic mouse. Consistently, MDM4 reduces cell size and proliferation, two features controlled by p70S6K1, and, importantly, inhibits mTORC1-mediated mammosphere formation. Noteworthy, MDM4 transcript levels are significantly reduced in breast tumors characterized by high mTOR levels. Conclusion Overall, these data identify MDM4 as a nutrient-sensor able to inhibit mTORC1 and highlight its metabolism-related tumor-suppressing function. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0626-7) contains supplementary material, which is available to authorized users.

Background Endometriosis is a chronic gynecological inflammatory disease characterized by the presence of functional endometrial glands and stroma outside of the uterine cavity. It affects 7–10% of women of reproductive age and up to 50% of women with infertility. The current gold standard for the diagnosis combines laparoscopic evaluation and biopsy of the visualized lesions. However, laparoscopy requires general anesthesia and developed surgical skills and it has a high procedural cost. In addition, it is associated with the risk, although rare, of potential intraoperative or postoperative complications. To date, several noninvasive biomarkers have been proposed; however, no definite diagnostic biomarker is yet available. The aim of this study was to characterize the CM proteome in patients with endometriosis using high resolution mass spectrometry—based proteomics, implemented by bioinformatic tools for quantitative analysis, in order to investigate the pathophysiological mechanisms of endometriosis. Methods Cervical mucus samples were collected from patients affected by endometriosis and fertile controls. An aliquot of the soluble acidic fraction of each cervical mucus sample, corresponding to 0.5 mg of total protein, was left to digest with sequencing grade modified porcine trypsin. The peptides were analyzed by LC–MS/MS on a high resolution Orbitrap Elite mass spectrometer and data were evaluated using bioinformatic tools. Results We aimed at the first total profiling of the cervical mucus proteome in endometriosis. From the list of identified proteins, we detected a number of differentially expressed proteins, including some functionally significant proteins. Six proteins were quantitatively increased in endometriosis, almost all being involved in the inflammatory pattern. Nine proteins were quantitatively reduced in endometriosis, including some proteins related with local innate immunity (CRISP-3 and Pglyrp1) and protection against oxidative stress (HSPB1). Fifteen proteins were not detected in endometriosis samples including certain proteins involved in antimicrobial activity (SLURP1 and KLK13) and related to seminal plasma liquefaction and male fertility (KLK13). Conclusions This is the first application of high resolution mass spectrometry—based proteomics aimed in detecting an array of proteins in CM to be proposed for the noninvasive diagnosis of endometriosis. This chronic disease presents in CM an inflammatory protein pattern. Electronic supplementary material The online version of this article (doi:10.1186/s12014-017-9142-4) contains supplementary material, which is available to authorized users.

Oxidative stress, a condition defined as unbalancing between production of free radicals and antioxidant defenses, is an important pathogenetic mechanism in different diseases. Despite the abundant literature, many aspects of hormone role in regulating antioxidant synthesis and activity still remain obscure. Therefore, we reviewed experimental data, in vivo and in vitro, about the effects of the different pituitary- dependent axes on antioxidant levels, trying to give a broad view from hormones which also have antioxidant properties to the classic antioxidants, from the lipophilic antioxidant Coenzyme Q10, strictly related to thyroid function, to total antioxidant capacity, a measure of non-protein non-enzymatic antioxidants in serum and other biological fluids. Taken together, these data underline the importance of oxidative stress in various pituitary-dependent disorders, suggesting a possible clinical usefulness of antioxidant molecules.

The aim of this longitudinal study was to evaluate the echocardiographic outcome of acromegalic heart disease in patients undergoing different therapeutic approaches, in order to investigate whether SSA could provide therapeutic advantages as compared with neurosurgery. In total of 36, consecutive patients undergoing SSA treatment after neurosurgery were enrolled in this study (Gr.Surg.-SSA). After 12 months of treatment, 21 patients had a controlled disease, while the remaining 15 patients displayed uncontrolled disease. Twelve acromegalic patients who did not undergo SSA treatment due to controlled disease after neurosurgery were enrolled as control group (Gr.Surg). The echocardiographic-Doppler study was performed before neurosurgery and after 12-months of follow-up. After follow-up, a significant reduction in serum GH and IGF-I values, Left Ventricular Mass index (LVMi) and LVH rate with an improvement in diastolic function was observed in both groups of patients. We found a significant reduction of LVMi either in patients with controlled disease or in those with poorly controlled disease undergoing SSA treatment. Diastolic function and of LVH percentage improved in all groups, but significantly so only in controlled patients, no significant difference in any echocardiographic parameters and in the prevalence of the LVH rate were observed between the three groups of patients at the end of follow-up. Therefore, our data appear to show that for echographic parameters medical treatment additive beneficial effects is compared to neurosurgery alone. SSA also appears to contribute to the improvement of acromegalic cardiomyopathy also in patients who did not achieve biochemical control of the disease.

We evaluated the prevalence and features of colonic polyps in a population of acromegalic subjects, compared to a control group of patients with irritable bowel syndrome (IBS). Colonic polyps were found in 30 acromegalic subjects (40%) and in 10 controls (13%) (P < 0.0001). Among the acromegalic patients, polyps were of the hyperplastic type in 27 subjects (90%) and adenomatous in 3 (10%). In the control group, polyps were hyperplastic in nine subjects (90%) and adenomatous in one (10%). We also observed a significant association (P < 0.0001) between the presence of hyperplastic polyps and the older age in both the acromegalic and the control groups. There were no differences between the two groups regarding sex, site, size, or macroscopic and histological types of polyps. Acromegalic patients have a higher prevalence of colonic hyperplastic polyps than IBS subjects, while the prevalence of adenomatous polyps is similar in the two groups.

Management of subclinical Cushing’s syndrome (SCS) remains controversial; it is not possible to predict which patients would benefit from adrenalectomy. In the present study we aimed to evaluate the role of adrenocortical scintigraphy (ACS) in the management of patients with SCS. The medical records of 33 consecutive patients with adrenal “incidentaloma” and proven or suspected SCS who underwent 131I-19-iodocholesterol ACS between 2004 and 2010 were reviewed. Sixteen underwent laparoscopic adrenalectomy (surgical group—S-group) and 17 were medically managed (medical group—M-group). Follow-up evaluation was obtained by outpatient consultation. Overall 25 patients (15 in the S-group and 10 in the M-group) had concordant unilateral uptake at ACS (ACS+). In the S-group, the mean follow-up duration was 30.9 ± 16.1 months and, irrespective of the presence of hormonal diagnosis of SCS, in patients who were ACS+ adrenalectomy resulted in a significant increase in HDL cholesterol and decreases in body mass index, glycemia, and blood pressure (BP). One patient reduced antihypertensive medication and three others were able to discontinue it altogether. Prolonged postoperative hypoadrenalism (PH) occurred in 14 patients in the S-group. The overall accuracy in predicting PH was 93.7 % for ACS and 68.7 % for laboratory findings. In the M-group, the mean follow-up duration was 31.5 ± 26.3 months and no patient developed overt Cushing’s syndrome, although ACS+ patients experienced a worsening in glycemia and diastolic BP. Adrenal scintigraphy seems the most accurate diagnostic test for SCS. It is able to predict the metabolic outcome and the occurrence of PH, identifying the patients who could benefit from adrenalectomy irrespective of hormonal diagnosis.

To gain insights into the role of iodine deficiency in favoring thyroid tumorigenesis (particularly of the follicular histotype), 22 Sicilian patients with thyroid tumors were selected for having lived permanently in either one of two areas of different iodine availability. Eleven patients (age 46.1 +/- 14.6 years, mean +/- SD; 10 females and 1 male) were from the iodine-deficient (ID) areas of the provinces of Messina and Catania (mean urinary excretion of iodine = 48.1 micrograms/24 hours). Thyroid tumors were follicular or Hürthle cell adenomas (no. = 3), follicular carcinomas (FC, no. = 4), papillary carcinomas (PC, no. = 2) and anaplastic carcinomas (no. = 2). Eleven patients (age 47.1 +/- 15.2 years; 10 females and 1 male) were from the metropolitan area of Messina, an area of relative iodine-sufficiency (IS) (urinary excretion of iodine = 95.2 micrograms/24 hours). These 11 patients had serum levels of TSH that were significantly lower than the corresponding values of the 11 patients from the ID area (0.76 +/- 0.33 vs 1.80 +/- 1.22 mU/l, p = 0.01) The tumors of the 11 patients from the IS area were: follicular or Hürthle cell adenomas (no. = 6), Hürthle cell carcinoma (no. = 1), FC (no. = 2), PC (no. = 2). Molecular biology studies revealed that both the normal as well as the tumor tissue of all 22 patients did not harbor any of the three classical activating mutations (codons 12, 13 and 61) in any of the three ras oncogenes. Similar negative results were obtained as far as loss of heterozygosity of the retinoblastoma (Rb) anti-oncogene is concerned. Immunohistochemistry studies were performed to investigate expression of c-met and basic fibroblast growth factor (bFGF) proto-oncogenes. Only one Hürthle cell carcinoma and the two PC from the IS group, and one FC and the two PC from the ID group stained for the c-met oncogene. Expression of c-met was greater (3+) in the four PC (concerning 70-80% of the tumor cells) than in the other two cancers (1+;5% of the tumor cells). In the IS group, positivity for bFGF was detected in 3/6 adenomas, 1/2 FC, the Hürthle cell carcinoma and the two PC. In the ID group, positivity for bFGF was observed in 2/3 adenomas, 2/4 FC, the two PC and the two anaplastic carcinomas. The 8 positive cases from the ID group had a greater level of bFGF expression than the 7 positive cases from the IS group (intensity of staining = 2.0+ vs 1.57+). Interestingly, the greatest expression of bFGF was seen in the cases with peri-tumoral lymphocytic infiltration from either group. In the ID group correlations between (i.) pre-intervention serum TSH and intensity of tumoral staining for bFGF, (ii.) serum TSH and per cent of tumoral cells reactive with anti-bFGF and (iii.) between intensity of staining for bFGF and per cent of tumoral cells bFGF +ve were higher than in the IS group. We conclude that activating mutations of ras, loss of DNA from the Rb locus and over-expression of both c-met and bFGF are of no pathogenetic relevance in driving thyroid tumorigenesis of iodine-deficient areas.

A clinical and pathological study was undertaken to define the prevalence, clinical presentation and outcome of thyroid carcinoma in children and adolescents. Clinical records from 48 patients under 20 years of age at diagnosis, out of 372 patients with thyroid cancer examined between 1980 and 1994, were retrospectively reviewed. Female/male ratio was 3.8/1. None had a previous positive history of head and neck irradiation. Patients underwent near-total (44 patients) or partial (4 patients) thyroidectomy followed by 131I ablation of residual thyroid tissue. The mean follow up period was 58.4 months, ranging between 2 and 190 months. Clinically a thyroid mass was present in 41 patients, 28 of whom also showed neck lymph node involvement. Node metastases were present in 50% of the patients and lung metastases in 4.2%. Histological type was papillary in 41, follicular in 6, and medullary in 1 case. Surgical complications were observed in 19 patients (40%). In 3 patients papillary thyroid cancer was associated with chronic lymphocytic thyroiditis. All patients were treated with l-thyroxine suppressive therapy. Recurrence of cancer after surgical and radio-iodine treatment was observed only in one patient 8 months after surgery. Conclusion Our experience demonstrates that thyroid carcinoma in childhood cannot be considered a rare occurrence, since it represents about 13% of all thyroid cancers, and is frequently associated with lymph node but rarely with distant metastases. Nevertheless, the prognosis of thyroid carcinoma in childhood is fairly good.