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This review delved into the intricate relationship between circadian clocks and physiological processes, emphasizing their critical role in maintaining homeostasis. Orchestrated by interlocked clock genes, the circadian timekeeping system regulates fundamental processes like the sleep-wake cycle, energy metabolism, immune function, and cell proliferation. The central oscillator in the hypothalamic suprachiasmatic nucleus synchronizes with light-dark cycles, while peripheral tissue clocks are influenced by cues such as feeding times. Circadian disruption, linked to modern lifestyle factors like night shift work, correlates with adverse health outcomes, including metabolic syndrome, cardiovascular diseases, infections, and cancer. We explored the molecular mechanisms of circadian clock genes and their impact on metabolic disorders and cancer pathogenesis. Specific associations between circadian disruption and endocrine tumors, spanning breast, ovarian, testicular, prostate, thyroid, pituitary, and adrenal gland cancers, are highlighted. Shift work is associated with increased breast cancer risk, with PER genes influencing tumor progression and drug resistance. CLOCK gene expression correlates with cisplatin resistance in ovarian cancer, while factors like aging and intermittent fasting affect prostate cancer. Our review underscored the intricate interplay between circadian rhythms and cancer, involving the regulation of the cell cycle, DNA repair, metabolism, immune function, and the tumor microenvironment. We advocated for integrating biological timing into clinical considerations for personalized healthcare, proposing that understanding these connections could lead to novel therapeutic approaches. Evidence supports circadian rhythm-focused therapies, particularly chronotherapy, for treating endocrine tumors. Our review called for further research to uncover detailed connections between circadian clocks and cancer, providing essential insights for targeted treatments. We emphasized the importance of public health interventions to mitigate lifestyle-related circadian disruptions and underscored the critical role of circadian rhythms in disease mechanisms and therapeutic interventions.

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BACKGROUND: In recent years, nuclear medicine imaging methods have proven to be of paramount importance in a wide variety of diseases, particularly in oncology, where they are crucial for assessing the extent of disease when conventional methods fall short. Moreover, nuclear imaging modalities are able to better characterize lesions using target agents related to specific pathways (e.g. glucose metabolism, cellular proliferation, amino acid transport, lipid metabolism, specific receptor ligands). The clinical presentation of endocrine diseases encompasses a broad spectrum of sign and symptoms. Moreover, endocrine tumors show varying degrees of aggressiveness from well differentiated and indolent to highly aggressive cancers, respectively. RATIONALE: With the application of new medicinal radio-compounds and increasingly advanced tomographic imaging technology, the utility of Positron Emission Tomography/Computed Tomography (PET/CT) in the field of endocrine diseases is expanding. AIM: This review aims to analyze and summarize the primary indications of PET/CT, providing a practical approach for clinicians. A comprehensive literature search on PubMed was conducted to provide an updated overview of the available evidence regarding the use of PET/CT in endocrinology. Within this review, we will discuss the applications of PET/CT, compare different radiopharmaceuticals and highlight the uptake mechanism, excluding neuroendocrine carcinomas from discussion. CONCLUSIONS: PET/CT is a valuable tool in diagnosing and managing endocrine disorders due to its capacity to furnish both functional and anatomical information, facilitate early lesion detection, guide treatment decisions, and monitor treatment response. Its non-invasive nature and precision make it an integral component of modern endocrine healthcare. This review aims to provide physicians with a clear perspective on the role of PET/CT imaging, discussing its emerging opportunities and appropriateness of use in endocrinological diseases.

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Somatostatin, a somatotropin release inhibiting factor (SST, SRIF), is a widely distributed multifunctional cyclic peptide and acts through a transmembrane G protein-coupled receptor (SST1-SST5). Over the past decades, research has begun to reveal the molecular mechanisms underlying the anticancer activity of this hormonal peptide. Among gastrointestinal tract (GIT) tumors, direct and indirect antitumor effects of SST have been documented best in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and less well in non-endocrine cancers, including sporadic colorectal cancer (CRC). In the latter, the signaling pathways involved in the antitumor function of SST are primarily MAPK/ERK/AKT and Wnt/ß-catenin. Direct (involving the MAPK pathway) and indirect (VEGF production) antiangiogenic effects of SST in CRC have also been described. The anti-inflammatory role of SST in CRC is emphasized, but detailed molecular mechanisms are still being explored. The role of SST in tumor genome/tumor microenvironment (TME)/host's gut microbiome interactions is only partially known. The results of SST analogues (SSAs)' treatment of sporadic CRC in monotherapy in vivo are not spectacular. The current review aims to present the state-of-the-art mechanisms and antitumor activity of endogenous SST and its synthetic analogues in CRC, with particular emphasis on sporadic CRC.

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Microbial metabolites have been indicated to communicate with the host's endocrine system, regulating hormone production, immune-endocrine communications, and interactions along the gut-brain axis, eventually affecting the occurrence of endocrine cancer. Furthermore, microbiota metabolites such as short-chain fatty acids (SCFAs) have been found to affect the tumor microenvironment and boost immunity against tumors. SCFAs, including butyrate and acetate, have been demonstrated to exert anti-proliferative and anti-protective activity on pancreatic cancer cells. The employing of microbial metabolic products in conjunction with radiation and chemotherapy has shown promising outcomes in terms of reducing treatment side effects and boosting effectiveness. Certain metabolites, such as valerate and butyrate, have been made known to improve the efficiency of CAR T-cell treatment, whilst others, such as indole-derived tryptophan metabolites, have been shown to inhibit tumor immunity. This review explores the intricate interplay between microbial metabolites and endocrine tumorigenesis, spanning mechanistic insights to the discovery of potential therapeutic biomarkers.

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PURPOSE: Postmenopausal hyperandrogenism is a rare condition that requires identifying those women bearing a life-threatening tumor. We aimed to study diagnostic work-up and management of postmenopausal androgen excess, proposing an algorithm for clinical decision supporting. METHODS: We conducted an observational cross-sectional study and longitudinal follow-up including 51 consecutive menopausal patients reported for hyperandrogenism between 2003 and 2023 to our clinics. We assessed diagnostic testing accuracy and performance by receiver operating characteristic curves, their respective areas under the curve (AUCROC), and 95% confidence intervals (95%CI), for distinguishing between benign and malignant conditions, and androgen excess source. RESULTS: Most commonly, postmenopausal hyperandrogenism derived from benign conditions such as ovarian hyperthecosis (n = 9). However, four (8%) patients had borderline/malignant tumors arising at the ovaries (n = 3) or adrenals (n = 1). These latter were more likely to develop virilization than those with benign disorders [specificity(95%CI)]: 0.87 (0.69; 0.92)]. Circulating total testosterone [AUCROC(95%CI): 0.899 (0.795; 1.000)] and estradiol [AUCROC(95%CI): 0.912 (0.812; 1.000)] concentrations showed good performances for discriminating between both conditions. Transvaginal-ultrasonography found two out of three potentially malignant ovarian neoplasms, and another was apparent on a pelvic computed tomography scan. An adrenal computed tomography scan also located an androgen-secreting carcinoma. CONCLUSIONS: Clinical or biochemical features of an aggressive androgen-secreting tumor should lead to urgently obtaining a targeted imaging. At first, an abdominal-pelvic CT scan represents the best choice to perceive adrenal malignancy, and may identify aggressive ovarian tumors. When warning signs are lacking, a calm and orderly work-up allows properly addressing the diagnostic challenge of postmenopausal hyperandrogenism.

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PURPOSE: Brain metastases rarely complicate the natural history of patients with adrenocortical carcinoma (ACC). No information is available regarding the life expectancy and efficacy of treatments in ACC patients with brain involvement. METHODS: A pooled analysis was performed by searching on PubMed and using the keywords: "brain metastases in adrenocortical carcinoma", and "leptomeningeal metastases in adrenocortical carcinoma". Four patients diagnosed at Spedali Civili Hospital in Brescia were added to the analysis. Data concerning demographic, disease characteristics, adopted treatments and patient prognosis were collected. RESULTS: A total of 27 patients (18 adults and 9 children) were included in this study, 22 of them had an adequate follow-up. Brain metastases occurred late in the natural history of adult patients but not in that of children. Surgery plus/minus radiation therapy was the treatment of choice. Adult patients with brain metastases had a poor prognosis with a median progression-free survival (PFS) and overall survival (OS) of 2 and 7 months, respectively. Median PFS and OS were not attained in children. CONCLUSION: Brain metastases in ACC patients are rare and are associated with poor prognosis, particularly in adults. Surgery plus/minus radiotherapy is the only therapeutic approach that can offer patients a chance to obtain durable local disease control.

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The endocrine component of the pancreas is located primarily in the islets of Langerhans, but is also found as single cells among the acinar cells and duct epithelium. It currently is thought that endocrine tumors of the pancreas (PETs) arise from pluripotent stem cells located within the ductal epithelium rather than from existing endocrine cells. Islet cell components include alpha, beta, PP, delta and epsilon cells, which secrete glucagon, insulin, pancreatic polypeptide, somatostatin and ghrelin, respectively. We investigated immunohistochemical labeling of 24 formalin fixed paraffin embedded PETs to identify which hormones were produced most frequently. Glucagon was the most frequently secreted hormone (83%) in PETS followed by insulin, ghrelin, pancreatic polypeptide and somatostatin.

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Endocrine neoplasia represents an increasingly broad spectrum of disorders. Endocrine neoplasms range from incidental findings to potentially lethal malignancies. In this paper, we cover the impact of pathology in the interpretation of the clinic-pathological, genetic, and radiographic features underpinning these neoplasms. We highlight the critical role of multidisciplinary interactions in structuring a rational diagnostic and efficient therapeutic plan and emphasize the role of histopathological input in decision-making. In this context, standardized pathology reporting and second opinion endocrine pathology review represent relevant tools to improve the overall diagnostic workup of patients affected by endocrine tumors in every specific scenario. In fact, although a relevant proportion of cases may be correctly identified based on clinical presentation and biochemical/imaging investigations, a subset of cases presents with atypical findings that may lead to an inappropriate diagnosis and treatment plan based on a wrong pathological diagnosis if all pieces of the puzzle are not correctly considered. Pathologists have a responsibility to actively guide clinicians before and during surgical procedures to prevent unnecessary interventions. In all areas of endocrine pathology, pathologists must understand the complexity of tissue preservation and assay sensitivities and specificities to ensure the optimal quality and interpretation of diagnostic material. Finally, pathologists are central actors in tumor tissue biobanking, which is an expanding field in oncology that should be promoted while adhering to strict ethical and methodological standards.

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INTRODUCTION: The pathogenic role of deregulated histone (de-)acetylation by histone deacetyles (HDACs) has been demonstrated in several human cancers. While some HDAC inhibitors (HDACi) have been approved for individual entities, for endocrine tumors such translation into clinical practice has not yet been achieved. AREAS COVERED: Relevant results identified by structured searches in PubMed as well as in reference lists are summarized in a narrative review to discuss the current knowledge of HDAC involvement and their therapeutic relevance in endocrine tumors. For thyroid, neuroendocrine, and adrenal tumors, various oncogenic mechanisms of HDAC deregulation and effects of HDAC inhibitors (HDACi) have been identified in preclinical studies including direct cancer cell toxicity and modification of differentiation status. EXPERT OPINION: Based on positive pre-clinical results, the research on HDAC (inhibition) in the various endocrine tumors should be intensified - yet, it needs to be considered that i) HDACs' oncogenic actions might constitute only a part of epigenetic mechanisms driving cancer, ii) individual HDAC has different roles in different endocrine tumor entities, iii) inhibition of HDACs might be especially attractive in combination with conventional or other targeted therapies, and iv) new HDAC-inhibiting drugs with improved specificity or functionally modified HDACi might further improve their efficacy.

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BACKGROUND: Multidisciplinary clinics are expected to improve patient care by enhancing efficiency for both patients and care providers. We hypothesized that while these clinics are an efficient use of time for patients, they can limit a surgeon's productivity. METHODS: A retrospective review was performed for patients evaluated in a Multidisciplinary Endocrine Tumor Clinic (MDETC) and Multidisciplinary Thyroid Cancer Clinic (MDTCC) from 2018 to 2021. Time from evaluation to surgery and prevalence of surgery were evaluated. Patients were compared to those evaluated in a surgeon-only endocrine surgery clinic (ESC) from 2017 to 2021. Chi-square and t-tests were used to test significance. RESULTS: Patients referred to the ESC underwent surgery more often than those referred to either multidisciplinary clinic (ESC 79.5%, MDETC 24.6%, MDTCC 7%; P < .001) but had a significantly longer delay between appointment and operation (ESC 19.9 days, MDETC 3.3 days, MDTCC 16.4 days; P < .001). Patients had a longer wait from referral to appointment for the MDCs (ESC 22.6 days, MDETC: 44.5, MDTCC 33; P < .05). There was no significant difference in miles traveled by patients to any clinic. CONCLUSION: Multidisciplinary clinics can provide fewer appointments and faster time to surgery for patients but may lead to longer wait time from referral to appointment and fewer overall surgeries than endocrine surgeon-only clinics.

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Context: Endocrine neoplasia syndromes are phenotypically complex, and there is a misconception that they are universally rare. Genetic alterations are increasingly recognized; however, true prevalence is unknown. The purpose of a clinical registry is to monitor the quality of health care delivered to a specified group of patients through the collection, analysis, and reporting of relevant health-related information. This leads to improved clinical practice, decision-making, patient satisfaction, and outcome. Objective: This review aims to identify, compare, and contrast active registries worldwide that capture data relevant to hereditary endocrine tumors (HETs). Methods: Clinical registries were identified using a systematic approach from publications (Ovid MEDLINE, EMBASE) peer consultation, clinical trials, and web searches. Inclusion criteria were hereditary endocrine tumors, clinical registries, and English language. Exclusion criteria were institutional audits, absence of clinical data, or inactivity. Details surrounding general characteristics, funding, data fields, collection periods, and entry methods were collated. Results: Fifteen registries specific for HET were shortlisted with 136 affiliated peer-reviewed manuscripts. Conclusion: There are few clinical registries specific to HET. Most of these are European, and the data collected are highly variable. Further research into their effectiveness is warranted. We note the absence of an Australian registry for all HET, which would provide potential health and economic gains. This review presents a unique opportunity to harmonize registry data for HET locally and further afield.

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Background: Parathyroid carcinoma is an infrequent neoplasm of the endocrine system, constituting roughly 0.5% to 5% of cases of primary hyperparathyroidism. The diagnosis of this condition presents a unique challenge for healthcare professionals. Case report: We present a case of a 77-year-old female patient who presented with a longstanding right-sided neck tumor. The Positron emission tomography-computed tomography (PET-CT) scan detected a substantial tumor situated at the inferior border of the thyroid gland. A surgical procedure was conducted, resulting in the total excision of the tumor. The diagnosis of parathyroid carcinoma was confirmed through pathological investigation. At the six-month follow-up, the patient exhibited favorable post-operative outcomes with no evidence of recurrence. Conclusion: The primary approaches for managing parathyroid carcinoma involve precise diagnosis and surgical removal. This case report provides confirmation that the implementation of rigorous treatment measures can yield a substantial improvement in the prognosis.

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Non-endocrine findings in patients with MEN1 (multiple endocrine neoplasia) syndrome also include skin lesions, especially tumor-type lesions. This is a narrative review of the English-language medical literature including original studies concerning MEN1 and dermatological issues (apart from dermatologic features of each endocrine tumor/neuroendocrine neoplasia), identified through a PubMed-based search (based on clinical relevance, with no timeline restriction or concern regarding the level of statistical significance). We identified 27 original studies involving clinical presentation of patients with MEN1 and cutaneous tumors; eight other original studies that also included the genetic background; and four additional original studies were included. The largest cohorts were from studies in Italy (N = 145 individuals), Spain (N = 90), the United States (N = 48 and N = 32), and Japan (N = 28). The age of patients varied from 18 to 76 years, with the majority of individuals in their forties. The most common cutaneous tumors are angiofibromas (AF), collagenomas (CG), and lipomas (L). Other lesions are atypical nevi, basocellular carcinoma, squamous cell carcinoma, acrochordons, papillomatosis confluens et reticularis, gingival papules, and cutaneous T-cell lymphoma of the eyelid. Non-tumor aspects are confetti-like hypopigmentation, café-au-lait macules, and gingival papules. MEN1 gene, respective menin involvement has also been found in melanomas, but the association with MEN1 remains debatable. Typically, cutaneous tumors (AF, CG, and L) are benign and are surgically treated only for cosmetic reasons. Some of them are reported as first presentation. Even though skin lesions are not pathognomonic, recognizing them plays an important role in early identification of MEN1 patients. Whether a subgroup of MEN1 subjects is prone to developing these types of cutaneous lesions and how they influence MEN1 evolution is still an open issue.

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Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old. It is primarily associated with Li-Fraumeni and Beckwith-Wiedemann tumor predisposition syndromes in children. The incidence of pediatric ACC is 10-15fold higher in southern Brazil due to a higher prevalence of TP53 mutation associated with Li-Fraumeni syndrome in that population. Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.

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PURPOSE: Since the role of [18F]FDG PET/CT in low-grade gastroenteropancreatic (GEP) neuroendocrine neoplasia (NET) is not well established, this study was aimed to evaluate the role of [18F]FDG PET/CT in grade 1 (G1) GEP-NETs. METHODS: This is a retrospective study including patients with G1 GEP-NETs who underwent [18F]FDG PET/CT. RESULTS: 55 patients were evaluated, including 24 (43.6%) with pancreatic NETs and 31 (56.4%) with gastrointestinal NETs. At the time of diagnosis, 28 (51%) patients had metastatic disease, and 50 (91%) patients were positive by 68-Ga sstr PET/CT. Overall, 27 patients (49%) had positive findings on [18F]FDG PET/CT. Following [18F]FDG PET/CT, therapeutic management was modified in 29 (52.7%) patients. Progression-free survival was longer in patients with negative [18F]FDG PET/CT compared with positive [18F]FDG PET/CT (median PFS was not reached and 24 months, respectively, p = 0.04). This significance was particularly evident in the pancreatic group (p = 0.008). CONCLUSIONS: Despite having low proliferative activity, approximately half of GEP-NETs G1 showed positive [18F]FDG PET/CT, with a corresponding negative impact on patients' clinical outcomes. These data are in favor of a more "open" attitude toward the potential use of [18F]FDG PET/CT in the diagnostic work-up of G1 GEP-NETs, which may be used in selected cases to detect those at higher risk for an unfavorable disease course.

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BACKGROUND: Many studies link G protein-coupled receptors (GPCRs) to cancer. Some endocrine tumors are unresponsive to standard treatment and/or require long-term and poorly tolerated treatment. This study explored, by bioinformatics analysis, the tumoral profiling of the GPCR transcriptome to identify potential targets in these tumors aiming at drug repurposing. METHODS: We explored the GPCR differentially expressed genes (DEGs) from public datasets (Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA)). The GEO datasets were available for two medullary thyroid cancers (MTCs), eighty-seven pheochromocytomas (PHEOs), sixty-one paragangliomas (PGLs), forty-seven pituitary adenomas and one-hundred-fifty adrenocortical cancers (ACCs). The TCGA dataset covered 92 ACCs. We identified GPCRs targeted by approved drugs from pharmacological databases (ChEMBL and DrugBank). RESULTS: The profiling of dysregulated GPCRs was tumor specific. In MTC, we found 14 GPCR DEGs, including an upregulation of the dopamine receptor (DRD2) and adenosine receptor (ADORA2B), which were the target of many drugs. In PGL, seven GPCR genes were downregulated, including vasopressin receptor (AVPR1A) and PTH receptor (PTH1R), which were targeted by approved drugs. In ACC, PTH1R was also downregulated in both the GEO and TCGA datasets and was the target of osteoporosis drugs. CONCLUSIONS: We highlight specific GPCR signatures across the major endocrine tumors. These data could help to identify new opportunities for drug repurposing.

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Endocrine tumors derive from endocrine cells with high heterogeneity in function, structure and embryology, and are characteristic of a marked diversity and tissue heterogeneity. There are still challenges in analyzing the molecular alternations within the heterogeneous microenvironment for endocrine tumors. Recently, several proteomic, lipidomic and metabolomic platforms have been applied to the analysis of endocrine tumors to explore the cellular and molecular mechanisms of tumor genesis, progression and metastasis. In this review, we provide a comprehensive overview of spatially resolved proteomics, lipidomics and metabolomics guided by mass spectrometry imaging and spatially resolved microproteomics directed by microextraction and tandem mass spectrometry. In this regard, we will discuss different mass spectrometry imaging techniques, including secondary ion mass spectrometry, matrix-assisted laser desorption/ionization and desorption electrospray ionization. Additionally, we will highlight microextraction approaches such as laser capture microdissection and liquid microjunction extraction. With these methods, proteins can be extracted precisely from specific regions of the endocrine tumor. Finally, we compare applications of proteomic, lipidomic and metabolomic platforms in the field of endocrine tumors and outline their potentials in elucidating cellular and molecular processes involved in endocrine tumors.

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Positron emission tomography/computed tomography (PET/CT) is increasingly becoming a mainstay in diagnosis and management of many malignant disorders. However, its role in the assessment of gastro-intestinal lesions is still evolving. The aim of this review was to demonstrate the areas, where PET/CT is impactful and where it has limitations. This will allow for us to reduce unnecessary investigations and develop methods to overcome the limitations.