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Gender medicine studies how health status and diseases differ between men and women in terms of prevention, therapeutic approach, prognosis, and psychological and social impact. Sex and gender analyses have been demonstrated to improve science, contributing to achieving real appropriateness and equity in the cure for each person. Therefore, it is fundamental to consider, both in preclinical and clinical research, the different clinical and biological features associated with sex and/or gender, where sex differences are mainly influenced by biological determinants and gender ones by socio-cultural and economic matters. This article was developed to provide knowledge and methodological tools for the development of studies/research protocols in which sex and gender should be taken into account. [ABSTRACT FROM AUTHOR]

Inositols have demonstrated a role in cancer prevention and treatment in many kinds of neoplasms. Their molecular mechanisms vary from the regulation of survival and proliferative pathways to the modulation of immunity and oxidative stress. The dysregulation of many pathways and mechanisms regulated by inositols has been demonstrated in endocrine and neuroendocrine tumors but the role of inositol supplementation in this context has not been clarified. The aim of this review is to summarize the molecular basis of the possible role of inositols in endocrine and neuroendocrine tumors, proposing it as an adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background:d-Chiro-inositol is a natural molecule that, in association with its well-studied isomer myo-inositol, may play a role in treating various metabolic and gynecological disorders. Objectives: This perspective seeks to explore the mechanisms and functions of d-chiro-inositol, laying the foundations to discuss its use in clinical practice, across dysmetabolism, obesity, and hormonal dysregulation. Methods: A narrative review of all the relevant papers known to the authors was conducted. Outcome:d-Chiro-inositol acts through a variety of mechanisms, acting as an insulin sensitizer, inhibiting the transcription of aromatase, in addition to modulating white adipose tissue/brown adipose tissue transdifferentiation. These different modes of action have potential applications in a variety of therapeutic fields, including PCOS, dysmetabolism, obesity, hypoestrogenic/hyperandrogenic disorders, and bone health. Conclusions:d-Chiro-inositol mode of action has been studied in detail in recent years, resulting in a clear differentiation between d-chiro-inositol and its isomer myo-inositol. The insulin-sensitizing activities of d-chiro-inositol are well understood; however, its potential applications in other fields, in particular obesity and hyperestrogenic/hypoandrogenic disorders in men and women, represent promising avenues of research that require further clinical study. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. Study registration: This protocol was registered in clinicaltriasl.gov (NCT04282083). [ABSTRACT FROM AUTHOR]

Thyroid cancer is more aggressive in elderly patients due to biological causes related to age, histotype, and the advanced stage at diagnosis. In the elderly, both the diagnosis and treatment of thyroid cancer impact quality of life. This review aimed to collect and discuss the different therapeutic approaches in elderly patients affected by thyroid cancer. Our analysis examined the therapeutic surgical approach according to age and how this affects the prognosis of patients with thyroid cancer, along with how iodine 131 therapy is tolerated and how effective it is. Furthermore, we investigated whether levothyroxine suppressive therapy is always necessary and safe in elderly patients with thyroid cancer and the safety and efficacy of systemic therapy in the elderly. We also intended to identify peculiar features of thyroid cancer in elderly subjects and to evaluate how the disease and its treatment affect their quality of life. [ABSTRACT FROM AUTHOR]

Introduction: Mitotane, the only drug approved by the Food and Drug Administration (FDA) for the treatment of adrenocortical carcinoma, is associated with several side effects including neurotoxicity. The aim of our study is to investigate the relationship between mitotane plasma levels and neurological toxicity. Methods: We have considered five patients affected by adrenocortical carcinoma treated with mitotane. The neurological assessment included a neurological examination, an electroencephalogram, event-related potentials (P300), and a neuropsychological assessment. All of the patients were first considered at the onset of symptoms of neurotoxicity or when mitotanemia levels were above 18 mg/L, for the second time at mitotanemia normalization and subsequently at its further increase, or in case of persistent neurological abnormalities, some months after normalization. Results: At the first neurotoxicity, four patients showed impaired neurological examination, electroencephalogram, and P300; three patients had impaired neuropsychological assessment; one patient, only P300. At mitotanemia normalization, the neurological examination became normal in all patients and electroencephalogram normalized in one patient, improved in another one, continuing to be altered in the other three. P300 latency and neuropsychological assessment normalized in two patients and persisted altered in the patient experiencing long-term mitotane toxicity. At the third evaluation, in the patient with prolonged mitotane toxicity, the normal mitotanemia in the previous 9 months restored P300 and improved the electroencephalogram but not the neuropsychological assessment. In the two patients experiencing a further rise of mitotanemia, neurological examination was normal but P300 and electroencephalogram were altered. Conclusion: The results of our study highlighted the presence of neurophysiological and neuropsychological abnormalities associated with mitotane values above 18 mg/L. [ABSTRACT FROM AUTHOR]

Background: To evaluate the ability of therapeutic intensity score (TIS) in predicting the clinical outcomes of partial (PA) and total adrenalectomy (TA) for UPA. Methods: Between 2011 and 2022, a four-center adrenalectomy dataset was queried for "unilateral adrenal mass" and "UPA" (n = 90). Preoperative TIS of each antihypertensive medication were individually calculated and merged to create a single, cumulative variable. Probability of complete clinical, partial, and absent pooled success rates according to TIS were assessed for the overall cohort by Kaplan–Meier. Cox analyses were used to identify predictors of complete clinical and partial/absent success, respectively. For all analyses, a two-sided p < 0.05 was considered significant. Results: At a median follow-up of 42 months (IQR 27–54) complete partial, and absent clinical success were observed in 60%, 17.7%, and 22.3%, respectively. On Kaplan–Meier analysis, TIS < 1 predicted higher complete success rates (p < 0.001), while TIS ≥ 1 was predictor of either partial and absent clinical success (p = 0.008). On multivariable analysis, TIS < 1 (HR 0.25; 95% CI 0.11–0.57; p = 0.001) and adenoma size (HR 1.11; 95% CI 1–1.23; p = 0.0049) were independent predictors of complete clinical success, while TIS ≥ 1 (HR 2.84; 95% CI 1.32–6.1; p = 0.007) was the only independent predictor of absent clinical success. Conclusions: TIS score and adenoma size may help to identify patients who are likely to be at risk of persistent hypertension after surgery. [ABSTRACT FROM AUTHOR]

Introduction. Several predictive scores to evaluate outcomes of adrenal surgery for unilateral primary aldosteronism (UPA), have been conceived. We compared a novel trifecta that summarizes outcomes of adrenal surgery for UPA with the clinical cure proposed by Vorselaars. Material and methods. Between March 2011 and January 2022, a multi-institutional dataset was queried for UPA. Baseline, perioperative and functional data were collected. Clinical and biochemical complete and partial success rates according to Primary Aldosteronism Surgical Outcome (PASO) criteria were assessed for the overall cohort. Clinical cure was defined either as normotension without antihypertensive medications or normotension with lower or equal use of antihypertensive medications. Trifecta was defined as the coexistence of =50% antihypertensive therapeutic intensity score (TIS) reduction (ΔTIS), no electrolyte impairment at 3-months and no Clavien-Dindo (2-5) complications. Cox regression analyses were used to identify predictors of long-term clinical and biochemical success. For all analyses, a two-sided p <0.05 was considered significant. Results Baseline, perioperative and functional outcomes were analyzed. Out of 90 patients, at a median follow-up of 42 months (IQR 27-54) a complete and partial clinical success was observed in 60% and 17.7% of cases while a complete and partial biochemical success was achieved in 83.3% and 12.3% of cases, respectively. Overall trifecta and clinical cure rates were 21.1% and 58.9%, respectively. On multivariable Cox regression analysis, trifecta achievement (HR 2.87; 95% CI 1.45-5.58; p = 0.02) was the only independent predictor of complete clinical success at long-term follow-up. Conclusions Despite its complex estimation and more restrictive criteria, trifecta but not clinical cure allows to independently predict composite PASO endpoints on the long run. [ABSTRACT FROM AUTHOR]

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs has been used for over two decades for the treatment of well-differentiated neuroendocrine tumors (NETs), and the publication of the NETTER-1 trials has further strengthened its clinical use. However, many aspects of this treatment are still under discussion. The purpose of this review is to collect and discuss the new available evidence, published in 2021, on the use of 177Lu-Oxodotreotide (DOTATATE) or 90Y-Edotreotide (DOTATOC) in adult patients with NETs focusing on the following hot topics: 1) PRRT use in new clinical settings, broaden its indications; 2) the short- and long-term safety; and 3) the identification of prognostic and predictive factors. The review suggests a possible future increase of PRRT applications, using it in other NETs, as a neoadjuvant treatment, or for rechallenge. Regarding safety, available studies, even those with long follow-up, supported the low rates of adverse events, even though 1.8% of treated patients developed a second malignancy. Finally, there is a lack of prognostic and predictive factors for PRRT, with the exception of the crucial role of nuclear imaging for both patient selection and treatment response estimation. [ABSTRACT FROM AUTHOR]

Abstract Background ChromograninA in prostate carcinoma (PC) indicate NE differentiation. This tumour is more aggressive and resistant to hormone therapy. Patients and methods We analyzed the incidence of pre-operative ChromograninA serum levels in non metastatic PC patients. Serum PSA and ChromograninA were analyzed before treatment. Clinicopathological parameters were evaluated in relation to serum ChromograninA. 486 patients were enrolled. Results We found 352 pT2 and 134 pT3. 21 patients were N+. 278 patients had Gleason score levels 7. Median PSA pre-operative level was 7.61 ng/ml. PSA was significantly associated with pT stage (pT2 with PSA abnormal 23.6% vs pT3 48.5%, p < 0.0001) and with a Gleason score (PSA abnormal 60% in the Gleason score was >7 vs 29.5% in the Gleason score = 7 vs 27.3% in the Gleason score 7 (31.4%) (p = 0.12). The serum ChromograninA levels in the two groups of patients were subdivided before and after 2005 on the basis of different used assays, showing no correlation with serum ChromograninA and other parameters. Conclusions This study showed that ChromograninA levels correlated to NE differentiation and possible aggressiveness of PC. Pre-operative circulating ChromograninA could complement PSA in selecting more aggressive PC cases, particularly in the presence of a higher Gleason score. Complementary information is provided by the absence of a correlation between serum ChromograninA and PSA levels.

Abstract Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are rare tumours that present many clinical features. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. In 2000 the WHO developed a new classification which gives a better description of the characteristics and biological behaviour of the tumour. Surgical resection is the treatment of first choice for a patient with a GEP NET. In metastatic disease multiple therapeutic approaches are possible. In these cases the goal is to improve quality of life and to extent survival. GEP NETs express somatostatin receptors (SSTRs), which are bound by somatostatin (SST) or its synthetic analogues, although the subtypes and number of SSTRs expressed is very variable. Somatostatin analogues are used frequently to control hormone-related symptoms while their anti-neoplastic activity, even if it has not been widely studied and the regarding data are discordant, seems to result prevalently in tumour stabilisation. A few patients who fail to respond or cease to respond to standard SST analogues treatment seem to have a response to higher doses of these drugs. The use of higher doses of somatostatin analogues or the development of new subtype selective agonists and chimaeric somatostatin analogues, or pan-somatostatin will probably improve the clinical management of these patients. This review provides an update on the use of somatostatin analogues in the management of GEP NETs and discusses novel clinical strategies based on SSTR 2 gene transfer therapy.

Background: Immune checkpoint inhibitors (ICIs), by unleashing the anticancer response of the immune system, can improve survival of patients affected by several malignancies, but may trigger a broad spectrum of adverse events, including autoimmune hypophysitis. ICI-related hypophysitis mainly manifests with anterior hypopituitarism, while the simultaneous involvement of both anterior and posterior pituitary (i.e., panhypophysitis) has rarely been described. Case Presentation: In June 2015, a 64-year-old man affected by liver metastases of a uveal melanoma was referred to us due to polyuria and polydipsia. Two months prior, he had started ipilimumab therapy (3 mg/kg iv every 21 days). The treatment was well-tolerated (only mild asthenia and diarrhea were reported). A few days before the fourth cycle, the patient complained of intense headaches, profound fatigue, nocturia, polyuria (up to 10 L urine/daily), and polydipsia. Laboratory tests were consistent with adrenal insufficiency, hypothyroidism, and transient central diabetes insipidus. The pituitary MRI showed an enlarged gland with microinfarcts, while the hypophyseal stalk was normal, and the neurohypophyseal 'bright signal' in T1 sequences was not detected. The treatment included dexamethasone (then cortisone acetate at replacement dose), desmopressin, and levothyroxine. Within the next five days, the symptoms resolved, and blood pressure, electrolytes, glucose, and urinalysis were stable within the normal ranges; desmopressin was discontinued while cortisone acetate and levothyroxine were maintained. The fourth ipilimumab dose was entirely administered in the absence of further side effects. Conclusion: As ICIs are increasingly used as anticancer agents, the damage to anterior and/or posterior pituitary can be progressively encountered by oncologists and endocrinologists in their clinical practice. Patients on ICIs and their caregivers should be informed about that risk and be empowered to alert the referring specialists early, at the onset of panhypopituitarism symptoms, including polyuria/polydipsia. [ABSTRACT FROM AUTHOR]

Introduction: Pituitary metastases (PM) are rare events and to date only very few cases of melanoma PM have been described in literature up to now. Case Presentation: We describe the clinical history of a 33-year-old male patient who underwent surgical excision of an inter-scapular melanoma in 2008. The subsequent follow-up was negative for ~10 years. In September 2018, due to the onset of a severe headache, the patient underwent a brain magnetic resonance imaging, which showed an expansive mass in the saddle and suprasellar region with a maximum diameter of 17 mm. Pituitary function tests and visual field were normal. Worsening of the headache and the appearance of a left eye ptosis led the patient to surgical removal of the lesion in October 2018. The histological examination unexpectedly showed metastasis of the melanoma. Post-operative hormonal assessment showed secondary hypothyroidism and hypoadrenalism, which were both promptly treated, and a mild hypogonadism. Three months after surgery, a sellar MRI showed a persistent, increased pituitary mass (3 cm of diameter); fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) detected an increased radiopharmaceutical uptake in the sellar region. Due to the persistence of the disease and the evidence of a BRAF V600E mutation, in February 2019, the patient underwent a combined treatment with dabrafenib (a BRAF inhibitor) and trametinib (mitogen-activated extracellular signal-regulate kinase inhibitor). Sellar MRI performed 6 months later showed no evidence of mass in the sellar region. The patient was in a good clinical condition and did not complain of headaches or other symptoms; there were no significant side-effects from the anticancer therapy. After 13 months of treatment, the patient showed no recurrence of the disease on morphological imaging. Anticancer therapy was confirmed, replacement therapies with hydrocortisone and levothyroxine continued and the pituitary-gonadal axis was restored. Conclusion: This is a very interesting case, both for the rarity of the pituitary melanoma metastasis and for the singular therapeutic course carried out by the patient. This is the first case of a pituitary melanoma metastasis with BRAF mutation, successfully treated with the combination of dabrafenib and trametinib after incomplete surgical removal. [ABSTRACT FROM AUTHOR]

Background: The 2015 American Thyroid Association (ATA) guidelines proposed a three-category system for estimating the risk of recurrence of differentiated thyroid carcinoma (DTC). This system includes several perioperative features, but not age at diagnosis. However, age has traditionally been recognized as a critical factor in the survival of DTC patients, and the eighth edition of TNM stated that patients older than 55 years were at higher risk of death. In this study, we raised the question of whether age at DTC diagnosis impacts on its risk of recurrence. Specifically, the present study aimed to (i) evaluate the association between age at diagnosis and structural recurrence and (ii) investigate whether age at diagnosis could improve the performance of the ATA system. Methods: During the study period, four institutions selected DTC patients treated with both thyroidectomy and radioiodine and who had follow-up for at least one year. Patients with proven structural evidence of disease during follow-up were identified, and disease-free survival (DFS) was calculated accordingly. Results: The study involved 1603 DTC patients with a median age of 49 years and DFS of 44 months. Disease recurred in 8%. The shortest DFS was found in the oldest patients. The Kaplan–Meier curves were calculated for each decade of age, and there was a significant association with DFS (p = 0.0014). Patients older than 55 years had significantly higher risk (hazard ratio [HR] 1.78, 95% confidence interval [CI 1.23–2.56]). The Kaplan–Meier curves of DFS in high-, intermediate- and low-risk groups showed a significant association only in the high-risk group (p = 0.0058). Patients older than 55 years had significantly higher risk of relapse over time only in the high-risk group (HR 2.15 [CI 2.01–4.53]). Cox's proportional analysis showed that the age cutoff of 55 years and the ATA system were significant predictors of relapse. Adding age at diagnosis above 55 years to the ATA system identified a subgroup of patients at highest risk for relapse. Conclusions: The age threshold adopted in the eighth edition of TNM staging system for DTC patients' prognosis also identifies cases at higher risk of relapse. Applying age at diagnosis, with a cutoff of 55 years, to the ATA risk stratification system identifies cases at highest risk of relapse. [ABSTRACT FROM AUTHOR]

In recent years, endocrine disrupting chemicals have gained interest in human physiopathology and more and more studies aimed to explain how these chemicals compounds affect endocrine system. In human populations, the majority of the studies point toward an association between exposure to endocrine disrupting chemicals and the disorders affecting endocrine axis. A great number of endocrine disrupting chemicals seem to be able to interfere with the physiology of hypothalamus-pituitary-gonadal axis; however, every endocrine axis may be a target for each EDCs and their action is not limited to a single axis or organ. Several compounds may also have a negative impact on energy metabolic homeostasis altering adipose tissue and promoting obesity, metabolic syndrome, and diabetes. Different mechanism have been proposed to explain these associations but their complexity together with the degree of occupational or environmental exposure, the low standardization of the studies, and the presence of confounding factors have prevented to establish causal relationship between the endocrine disorders and exposure to specific toxicants so far. This manuscript aims to review the state of art of scientific literature regarding the effects of endocrine-disrupting chemicals (EDCs) on endocrine system. [ABSTRACT FROM AUTHOR]

Background: Surgery is the standard treatment for cervical metastases of medullary thyroid cancer (MTC) diagnosed after initial surgical treatment. Repeated neck dissections, however, carry an elevated risk of complications, have an adverse impact on the quality of life, and sometimes do not achieve cure of the disease Clinical case: In a patient who had undergone two cervical neck dissections complicated by accessory nerve injury, an US-guided laser ablation (LA) of a lymph node metastasis of MTC was performed. LA was performed with two treatments during a five month period. The procedure was carried out with one optical fiber and an energy delivery of 3300 and 360 Joules. Treatments were well tolerated and resulted in complete structural and biochemical cure during a 12 month follow-up. No major complication was registered. Conclusions: LA is a promising tool for the management of relapsing cervical metastases that are localized in non- critical areas and are characterized by low progression rate. Advantages of LA are the outpatient setting, the absence of general anesthesia, the tolerability and the safety of the procedure. Thus, LA may be considered as an alternative approach to surgery or active surveillance for the management of local recurrences of MTC in selected patients. [ABSTRACT FROM AUTHOR]

Abstract: Whole exome sequencing (WES) was used to investigate two Italian siblings with wild‐type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild‐type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto‐oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET‐negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co‐driven by a MET mutation has potential management implications, since the tyrosine‐kinase inhibitor cabozantinib—approved for treating advanced MTCs—is a specific MET inhibitor. [ABSTRACT FROM AUTHOR]

Purpose: Recombinant human TSH (rhTSH) is currently used in follow-up of patients affected by differentiated thyroid cancer (DTC). Age, sex, weight, body mass index, body surface area (BSA) and renal function are known factors affecting serum TSH peak levels, but the proper rhTSH dose to deliver to single patient remains elusive. In this study, the correlations of basal metabolic rates with serum TSH peak following rhTSH administration were investigated. Methods: We evaluated 221 patients affected by thyroid cancer that received a standard dose rhTSH. Blood samples were collected at pre-established time points. Data on body weight, height, and BSA were collected. The Mifflin-St Jeor and Fleisch equations were used to assess basal metabolism. Results: The median value (range) of serum TSH peaks was 142 ± 53 ìU/ml. Serum TSH peaks were significantly lower in males than in females (p = 0.04). TSH values also increased with age. Data showed a significant decrease of TSH peak levels at day 3 from the administration of rhTSH when basal metabolic rates increased (p = 0.002 and p = 0.009, respectively). Similar findings were observed at day 5 (p = 0.004 and p = 0.04, respectively). A multivariate analysis of several factors revealed that patients' basal metabolism (obtained using the Mifflin-St Jeor but not Fleisch equation) predicts serum TSH level peak at day 3 (p < 0.001). These results were used to generate a new formula based on Mifflin-StJeor equation which reveals as a promising tool in tailoring rhTSH dose. Conclusion: Basal metabolism appears an improving factor in tailoring diagnostic rhTSH dose in patients affected by DTC. [ABSTRACT FROM AUTHOR]

Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth. AMPK, the main molecular target of metformin, is emerging as a target for cancer prevention and treatment. PCOS may be correlated to an increased risk for developing ovarian and endometrial cancer (up to threefold). Several studies have demonstrated an increase in mortality rate from ovarian cancer among overweight/obese PCOS women compared with normal weight women. Long-term use of metformin has been associated with lower rates of ovarian cancer. Considering the evidence supporting a higher risk of gynaecological cancer in PCOS women, we discuss the potential use of insulin-sensitizers as a potential tool for chemoprevention, hypothesizing a possible rationale through which insulin-sensitizers may inhibit tumourigenesis. [ABSTRACT FROM AUTHOR]

Background: Variant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Costs and time of sequencing and ATM variant complexity make large-scale, general population screenings not cost-effective yet. Recently, we developed a straightforward, rapid, and inexpensive test based on p53 mitotic centrosomal localization (p53-MCL) in peripheral blood mononuclear cells (PBMCs) that diagnoses mutant ATM zygosity and recognizes tumor-associated ATM polymorphisms. Methods: Fresh PBMCs from 496 cancer patients were analyzed by p53-MCL: 90 cases with familial BRCA1/2- positive and -negative breast and/or ovarian cancer, 337 with sporadic cancers (ovarian, lung, colon, and post-menopausal breast cancers), and 69 with breast/thyroid cancer. Variants were confirmed by ATM sequencing. Results: A total of seven individuals with ATM variants were identified, 5/65 (7.7 %) in breast cancer cases of familial breast and/or ovarian cancer and 2/69 (2.9 %) in breast/thyroid cancer. No variant ATM carriers were found among the other cancer cases. Excluding a single case in which both BRCA1 and ATM were mutated, no p53-MCL alterations were observed in BRCA1/2-positive cases. Conclusions: These data validate p53-MCL as reliable and specific test for germline ATM variants, confirm ATM as breast cancer susceptibility gene, and highlight a possible association with breast/thyroid cancers. [ABSTRACT FROM AUTHOR]

Background: Several of the currently used anticancer drugs may variably affect thyroid function, with impairment ranging from modified total but not free concentration of thyroid hormones to overt thyroid disease. Summary: Cytotoxic agents seem to alter thyroid function in a relatively small proportion of adult patients. Anticancer hormone drugs may mainly alter serum levels of thyroid hormone-binding proteins without clinically relevant thyroid dysfunction. Old immunomodulating drugs, such as interferon-α and interleukin-2, are known to induce variably high incidence of autoimmune thyroid dysfunction. Newer immune checkpoint inhibitors, such as anti-CTLA4 monoclonal antibodies, are responsible for a relatively low incidence of thyroiditis and may induce secondary hypothyroidism resulting from hypophysitis. Central hypothyroidism is a well-recognized side effect of bexarotene. Despite their inherent selectivity, tyrosine kinase inhibitors may cause high rates of thyroid dysfunction. Notably, thyroid toxicity seems to be restricted to tyrosine kinase inhibitors targeting key kinase-receptors in angiogenic pathways, but not other kinase-receptors (e.g., epidermal growth factor receptors family or c-KIT). In addition, a number of these agents may also increase the levothyroxine requirement in thyroidectomized patients. Conclusions: The pathophysiology of thyroid toxicity induced by many anticancer agents is not fully clarified and for others it remains speculative. Thyroid dysfunction induced by anticancer agents is generally manageable and dose reduction or discontinuation of these agents is not required. The prognostic relevance of thyroid autoimmunity, overt and subclinical hypothyroidism induced by anticancer drugs, the value of thyroid hormone replacement in individuals with abnormal thyrotropin following anticancer systemic therapy, and the correct timing of replacement therapy in cancer patients need to be defined more accurately in well-powered prospective clinical trials. [ABSTRACT FROM AUTHOR]

Background: Pegvisomant (PEGV) is widely used, alone or with somatostatin analogs (SSA), for GH-secreting pituitary tumors poorly controlled by SSAs alone. No information is available on specific indications for or relative efficacies of PEGV + SSA versus PEGV monotherapy. Aim of our study was to characterize real-life clinical use of PEGV vs. PEGV + SSA for SSA-resistant acromegaly (patient selection, long-term outcomes, adverse event rates, doses required to achieve control). Methods: A retrospective analysis of data collected in 2005-2010 in five hospital-based endocrinology centers in Rome was performed. Sixty-two adult acromegaly patients treated ⩾6 months with PEGV (Group 1, n = 35) or PEGV + SSA (Group 2, n = 27) after unsuccessful maximal-dose SSA monotherapy (⩾12 months) were enroled. Groups were compared in terms of clinical/biochemical characteristics at diagnosis and before PEGV or PEGV + SSA was started (baseline) and end-of-follow-up outcomes (IGF-I levels, adverse event rates, final PEGV doses). Results: Group 2 showed higher IGF-I and GH levels and sleep apnea rates, higher rates residual tumor tissue at baseline, more substantial responses to SSA monotherapy and worse outcomes (IGF-I normalization rates, final IGF-I levels). Tumor growth and hepatotoxicity events were rare in both groups. Final daily PEGV doses were similar and significantly increased with treatment duration in both groups. Conclusions: PEGV and PEGV + SSA are safe, effective solutions for managing SSA-refractory acromegaly. PEGV + SSA tends to be used for more aggressive disease associated with detectable tumor tissue. With both regimens, ongoing monitoring of responses is important since PEGV doses needed to maintain IGF-I control are likely to increase over time. [ABSTRACT FROM AUTHOR]

Fine-needle aspiration biopsy is regarded as an important tool for diagnosing thyroid lesions because of its simplicity, safety, and cost-effectiveness. Its role in correctly characterizing the group of indeterminate lesions or follicular-patterned neoplasms (FN) might be more decisive. Liquid-based cytology (LBC) is a technique based on the use of a semi-automated device that has gained popularity as a method of collecting and processing both gynecologic and non-gynecologic cytologic specimens. It achieves a diagnostic sensitivity as accurate as conventional preparations especially for its excellent cell preservation and for the lack of background which decrease the amount of inadequate diagnoses. Moreover, the cellular material which has been stored in the preservative solution could be effectively used for the application of immunocytochemical and molecular techniques especially for the Follicular proliferations. In many cases the cytologic features are similar in both methods but the colloid film and the lymphocytic component are more easily evaluated on direct smears whereas nuclear details and colloid globules are better evaluated in LBC slides. The LBC-processed biopsies represent a valid alternative to conventional cytology. The possibility of applying special techniques enhance the efficacy of the cytological diagnosis of thyroid lesions. [ABSTRACT FROM AUTHOR]

Cytotoxic anticancer treatment may induce amenorrhea or menopause to a variable extent. These side effects may not only impair or impede fertility but also cause sexual dysfunction, bone loss, and menopausal symptoms, with a strikingly negative effect on quality of life in many women. Aromatase inhibitors (AIs) are a recommended adjuvant endocrine treatment option in postmenopausal patients affected by early breast cancer (EBC) but are contraindicated in premenopausal women and in those with residual ovarian function. Women over 40 years of age with chemotherapy-induced amenorrhea (CIA) and routine hormonal levels consistent with menopause may receive an AI as adjuvant endocrine treatment. For these women, the tools available to identify menopause do not appear to be completely reliable. This review focused on the pathophysiology of ovarian toxicity induced by cytotoxic agents and on potentially useful methods to diagnose chemotherapy-induced menopause in patients treated with adjuvant chemotherapy for endocrine-responsive EBC. Moreover, practical approaches are proposed to distinguish true menopausal women, who would benefit from AIs, from those with transient or persistent CIA. [ABSTRACT FROM AUTHOR]

Background: ChromograninA in prostate carcinoma (PC) indicate NE differentiation. This tumour is more aggressive and resistant to hormone therapy. Patients and methods: We analyzed the incidence of pre-operative ChromograninA serum levels in non metastatic PC patients. Serum PSA and ChromograninA were analyzed before treatment. Clinicopathological parameters were evaluated in relation to serum ChromograninA. 486 patients were enrolled. Results: We found 352 pT2 and 134 pT3. 21 patients were N+. 278 patients had Gleason score levels <7; 173 patients had levels = 7 (122 were 3+4 and 51 4+3); and 35 patients with levels >7. Median PSA pre-operative level was 7.61 ng/ml. PSA was significantly associated with pT stage (pT2 with PSA abnormal 23.6% vs pT3 48.5%, p < 0.0001) and with a Gleason score (PSA abnormal 60% in the Gleason score was >7 vs 29.5% in the Gleason score = 7 vs 27.3% in the Gleason score <7, p < 0.0001). In 114 patients pre-operative ChromograninA levels were elevated (23.5%). Serum ChromograninA levels had no significant association with PSA (p = 0.44) and pT stage (p = 0.89). abnormal ChromograninA levels increased from a Gleason score of <7 (25.5%) to >7 (31.4%) (p = 0.12). The serum ChromograninA levels in the two groups of patients were subdivided before and after 2005 on the basis of different used assays, showing no correlation with serum ChromograninA and other parameters. Conclusions: This study showed that ChromograninA levels correlated to NE differentiation and possible aggressiveness of PC. Pre-operative circulating ChromograninA could complement PSA in selecting more aggressive PC cases, particularly in the presence of a higher Gleason score. Complementary information is provided by the absence of a correlation between serum ChromograninA and PSA levels. [ABSTRACT FROM AUTHOR]

Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are rare tumours that present many clinical features. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. In 2000 the WHO developed a new classification which gives a better description of the characteristics and biological behaviour of the tumour. Surgical resection is the treatment of first choice for a patient with a GEP NET. In metastatic disease multiple therapeutic approaches are possible. In these cases the goal is to improve quality of life and to extent survival. GEP NETs express somatostatin receptors (SSTRs), which are bound by somatostatin (SST) or its synthetic analogues, although the subtypes and number of SSTRs expressed is very variable. Somatostatin analogues are used frequently to control hormone-related symptoms while their anti-neoplastic activity, even if it has not been widely studied and the regarding data are discordant, seems to result prevalently in tumour stabilisation. A few patients who fail to respond or cease to respond to standard SST analogues treatment seem to have a response to higher doses of these drugs. The use of higher doses of somatostatin analogues or the development of new subtype selective agonists and chimaeric somatostatin analogues, or pan-somatostatin will probably improve the clinical management of these patients. This review provides an update on the use of somatostatin analogues in the management of GEP NETs and discusses novel clinical strategies based on SSTR 2 gene transfer therapy. [ABSTRACT FROM AUTHOR]

Background: To propose a trifecta that summarizes endpoints and predicts their maintenance after adrenalectomy (n = 90) for unilateral primary aldosteronism (UPA). Methods: Trifecta was defined as coexistence of: ≥50% antihypertensive therapeutic intensity score reduction (∆TIS), no hypokalemia at 3 months, and no Clavien grade 2–5. Logistic regression was used to identify predictors of trifecta. Probability of clinical, biochemical, and simultaneous success according to trifecta were assessed by Kaplan–Meier. Cox regression was used to identify predictors of long-term clinical, biochemical, and simultaneous success. For all analyses, a two-sided p < 0.05 was considered significant. Results: Simultaneous success rate was 50%. On multivariable analysis, TIS was an independent predictor of trifecta achievement (HR 3.28; 95% CI 1.07–10.9; p = 0.03). At Kaplan–Meier, trifecta predicted higher success for all endpoints (each p < 0.03). On multivariable Cox analysis, adenoma size (AS) ≥6 cm and trifecta were independent predictors of biochemical (AS: HR 2.87; 95% CI 1.53–5.36; trifecta: HR 2.1; 95% CI 1.13–3.90; each p < 0.02) and simultaneous success (AS: HR 3.81; 95% CI 1.68–8.65; trifecta: HR 4.29; 95% CI 2.08–8.86; each p < 0.01), while trifecta was an independent predictor of complete clinical success (HR 2.84; 95% CI 1.45–5.58; p < 0.01). Conclusions: Trifecta and AS are independent predictors of either long-term complete clinical, biochemical, or combined success after adrenalectomy for UPA. [ABSTRACT FROM AUTHOR]

Simple Summary: As no previous studies had assessed the risk of second malignant tumors in patients with pheochromocytomas/paragangliomas (PPGLs), we aimed to evaluate whether these patients could have an increased risk of additional malignancy, comparing them with patients in the general population who had a first malignancy and developed a second malignant tumor. We demonstrated that PPGL patients had higher incidence of additional malignant tumors and the risk of developing a second malignant tumor increased with age at diagnosis. As the main tumors were prostate, colorectal and lung/bronchial cancers in males, and breast cancer, differentiated thyroid cancer and melanoma in females, our findings could have an impact on the surveillance strategy. No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46–15.71) in males and 13.21 (95% CI 7.52–21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15–5.44, p = 0.021 for 50–59 vs. <50-year category; HR 3.46, 95% CI 1.67–7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10–0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy. [ABSTRACT FROM AUTHOR]

Simple Summary: This is, to our knowledge, the first systematic review conducted on the endocrine effects of mitotane, which aims to collect all available evidence in the literature and provide complete and useful information regarding the management of the endocrine and metabolic side effects of mitotane in clinical practice. Despite the pivotal role of mitotane in adrenocortical carcinoma (ACC) management, data on the endocrine toxicities of this treatment are lacking. The aim of this systematic review is to collect the available evidence on the side effects of mitotane on the endocrine and metabolic systems in both children and adults affected by adrenal carcinoma. Sixteen articles on 493 patients were included. Among the adrenal insufficiency, which is an expected side effect of mitotane, 24.5% of patients increased glucocorticoid replacement therapy. Mineralocorticoid insufficiency usually occurred late in treatment in 36.8% of patients. Thyroid dysfunction is characterized by a decrease in FT4, which occurs within 3–6 months of treatment in 45.4% of patients, while TSH seems to not be a reliable marker. Dyslipidemia is characterized by an increase in both LDL-c and HDL-c (54.2%). Few studies have found evidence of hypertriglyceridemia. In males, gynecomastia and hypogonadism can occur after 3–6 months of treatment (38.4% and 35.6%, respectively), while in pre-menopausal women, mitotane can cause ovarian cysts and, less frequently, menstrual disorders. Most of these side effects appear to be reversible after mitotane discontinuation. We finally suggest an algorithm that could guide metabolic and endocrine safety assessments in patients treated with mitotane for ACC. [ABSTRACT FROM AUTHOR]

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitor (ICPi)-induced thyroid dysfunction is a frequent immune-related adverse event (irAE). ICPi-induced thyrotoxicosis is usually the first stage of a biphasic thyroiditis with secondary hypothyroidism, whereas ICPi-induced Graves' disease (GD), due to the stimulating activity of TSH-receptor autoantibodies, is extremely rare. The aim of this study was to describe the characteristics and evolution of GD during ICPi therapy. We showed that in five patients with induced GD, two patients evolved into classical GD and the three other patients evolved as thyroiditis with short-term thyrotoxicosis and secondary long-term hypothyroidism, with the initial scintigraphic appearance seeming to predict their evolution. Three other patients had a diagnosis of GD before ICPi treatment: all evolved towards definitive hypothyroidism during treatment, without the appearance of irAE. None of the eight patients developed severe hyperthyroidism with life-threatening symptoms, nor significant Graves' orbitopathy. Use of ICPis in this population with induced or pre-existing autoimmune GD disease therefore appears to be safe. Thyrotoxicosis is an adverse event associated with immune checkpoint inhibitors (ICPis) that occurs in 0.6 to 3.2% of treated patients, depending on ICPi class. Presentation usually consists of a biphasic thyroiditis with transient thyrotoxicosis and secondary hypothyroidism. ICPi-induced Graves' disease (GD), due to the stimulating activity of TSH-receptor autoantibodies (TRAb), is extremely rare. The aim of this retrospective study was to describe the characteristics and evolution of GD during ICPi therapy. Five among 243 patients followed for ICPi-induced thyrotoxicosis showed TRAb positivity (2% of the cohort). GD occurred quickly after initiation of ICPis; its course was typical for two patients, with prolonged requirement for antithyroid drug treatment (ATD). The three other patients experienced biphasic thyroiditis with secondary hypothyroidism requiring long-term substitution. Three other patients had a diagnosis of GD before starting ICPis; they evolved toward hypothyroidism with early cessation of ATD and long-term substitution treatment during ICPi treatment. None developed significant Graves' orbitopathy. ICPi treatment was not interrupted for thyroid dysfunction. In conclusion, GD is a rare, immune-related adverse event of ICPis with an unusual course and frequent evolution to biphasic thyroiditis. In the case of ICPi-induced thyrotoxicosis in the presence of TRAb, observing the spontaneous evolution and performing a scintigraphy are useful before starting ATD treatment. Pre-existing GD is not exacerbated by ICPis and tends to evolve towards hypothyroidism. ICPi treatment can be maintained with adequate biochemical surveillance. [ABSTRACT FROM AUTHOR]

Background: The concomitant presence of papillary thyroid cancer (PTC) and medullary TC (MTC) is rare. In this multicentric study, we documented the epidemiological characteristics, disease conditions and clinical outcome of patients with simultaneous MTC/PTC. Methods: We collected data of patients with concomitant MTC/PTC at 14 Italian referral centers. Results: In total, 183 patients were enrolled. Diagnosis was mostly based on cytological examination (n = 58, 32%). At diagnosis, in the majority of cases, both PTC (n = 142, 78%) and MTC (n = 100, 54%) were at stage I. However, more cases of stage II–IV were reported with MTC (stage IV: n = 27, 15%) compared with PTC (n = 9, 5%). Information on survival was available for 165 patients: 109 patients (66%) were disease-free for both PTC and MTC at the last follow-up. Six patients died from MTC. Median time to progression was 123 months (95% confidence interval (CI): 89.3–156.7 months). Overall, 45% of patients were disease-free after >10 years from diagnosis (125 months); this figure was 72.5% for PTC and 51.1% for MTC. Conclusions: When MTC and PTC are concurrent, the priority should be given to the management of MTC since this entity appears associated with the most severe impact on prognosis. [ABSTRACT FROM AUTHOR]

The diagnosis of neuroendocrine tumors (NETs) is a challenging task: Symptoms are rarely specific, and clinical manifestations are often evident only when metastases are already present. However, several bioactive substances secreted by NETs can be included for diagnostic, prognostic, and predictive purposes. Expression of these substances differs between different NETs according to the tumor hormone production. Gastroenteropancreatic (GEP) NETs originate from the diffuse neuroendocrine system of the gastrointestinal tract and pancreatic islets cells: These tumors may produce many non-specific and specific substances, such as chromogranin A, insulin, gastrin, glucagon, and serotonin, which shape the clinical manifestations of the NETs. To provide an up-to-date reference concerning the different biomarkers, as well as their main limitations, we reviewed and summarized existing literature. [ABSTRACT FROM AUTHOR]