Oncolytic vaccinia virus GLV-1h68 exhibits profound antitumoral activities in cell lines originating from neuroendocrine neoplasms.

BACKGROUND: Oncolytic virotherapy is an upcoming treatment option for many tumor entities. But so far, a first oncolytic virus only was approved for advanced stages of malignant melanomas. Neuroendocrine tumors (NETs) constitute a heterogenous group of tumors arising from the neuroendocrine system at diverse anatomic sites. Due to often slow growth rates and (in most cases) endocrine non-functionality, NETs are often detected only in a progressed metastatic situation, where therapy options are still severely limited. So far, immunotherapies and especially immunovirotherapies are not established as novel treatment modalities for NETs. METHODS: In this immunovirotherapy study, pancreatic NET (BON-1, QGP-1), lung NET (H727, UMC-11), as well as neuroendocrine carcinoma (NEC) cell lines (HROC-57, NEC-DUE1) were employed. The well characterized genetically engineered vaccinia virus GLV-1 h68, which has already been investigated in various clinical trials, was chosen as virotherapeutical treatment modality. RESULTS: Profound oncolytic efficiencies were found for NET/NEC tumor cells. Besides, NET/NEC tumor cell bound expression of GLV-1 h68-encoded marker genes was observed also. Furthermore, a highly efficient production of viral progenies was detected by sequential virus quantifications. Moreover, the mTOR inhibitor everolimus, licensed for treatment of metastatic NETs, was not found to interfere with GLV-1 h68 replication, making a combinatorial treatment of both feasible. CONCLUSIONS: In summary, the oncolytic vaccinia virus GLV-1 h68 was found to exhibit promising antitumoral activities, replication capacities and a potential for future combinatorial approaches in cell lines originating from neuroendocrine neoplasms. Based on these preliminary findings, virotherapeutic effects now have to be further evaluated in animal models for treatment of Neuroendocrine neoplasms (NENs).

Synthesis and biological evaluation of some novel triazole hybrids of curcumin mimics and their selective anticancer activity against breast and prostate cancer cell lines.

The anti-cancer property of curcumin, an active component of turmeric, is limited due to its poor solubility, stability and bioavailability. To enhance its efficacy, we designed a novel series of twenty-four monocarbonyl curcumin analogue-1,2,3-triazole conjugates and evaluated their anti-cancer activity towards endocrine related cancers. The new compounds (17-40) were synthesized through CuAAC click reaction and SAR analysis carried out. Out of these all, compound 17 showed most significant anti-cancer activity against prostate cancer cells with IC50 values of 8.8µM and 9.5µM in PC-3 and DU-145 cells, respectively. Another compound 26 showed significant anti-cancer activity against breast cancer cells with IC50 of 6µM, 10µM and 6.4µM in MCF-7, MDA-MB-231 and 4T1 cells, respectively while maintaining low toxicity towards non-cancer originated cell line, HEK-293. Compounds 17 and 26 arrested cell cycle and induced mitochondria-mediated apoptosis in cancer cells. Further, both of these compounds significantly down-regulated cell proliferation marker (PCNA), inhibited activation of cell survival protein (Akt phosphorylation), upregulated pro-apoptotic protein (Bax) and down-regulated anti-apoptotic protein (Bcl-2) in their respective cell lines. In addition, in vitro stability, solubility and plasma binding studies of the compounds 17 and 26 showed them to be metabolically stable. Thus, this study identified two new curcumin monocarbonyl-1,2,3-triazole conjugate compounds with more potent activity than curcumin against breast and prostate cancers.

Endocrine cancer trends 1990-2021: global disparities and health inequalities.

This study provides a comprehensive analysis of global, continental, and national trends in the prevalence and mortality of prostate cancer (PC), breast cancer (BC), and thyroid cancer (TC). Utilizing 2021 Global Burden of Diseases (GBD2021) data, prevalence and death rates for 2021 were examined, with temporal trends from 1990 to 2021 analyzed via Joinpoint regression. Annual percentage change (APC) and average APC (AAPC) were calculated with 95% CI. Distributive inequalities were quantified using the slope index of inequality and concentration index. In 2021, PC, BC, and TC showed higher global age-standardized prevalence rates (ASPR) in Europe and America compared to Africa and Asia, while higher age-standardized death rates (ASDR) for PC and BC were noted in Africa. Over the study period, significant global increases in ASPR were observed for PC (AAPC = 0.78, 95% CI: 0.67 to 0.89), BC (AAPC = 0.31, 95% CI: 0.24 to 0.37), and TC (AAPC = 1.42, 95% CI: 1.31 to 1.52). Conversely, ASDR significantly decreased for PC (AAPC = -0.83, 95% CI: -0.92 to -0.74), BC (AAPC = -0.48, 95% CI: -0.56 to -0.39), and TC (AAPC = -0.23, 95% CI: -0.29 to -0.17). Variations were observed across continents and time periods, affecting 204 countries and territories. Higher Social Development Index (SDI) levels were associated with a more pronounced burden of these cancers. The findings highlight significant global heterogeneity in prevalence, death rates, and temporal trends of endocrine cancers, with important implications for epidemiology and public health policies.

Hereditary Endocrine Tumor Registries.

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.

Aberrant PI3Kδ splice isoform as a potential biomarker and novel therapeutic target for endocrine cancers.

Introduction: PI3K/AKT signaling pathway is upregulated in a broad spectrum of cancers. Among the class I PI3Ks (PI3Kδ/ß/δ isoforms), PI3Kδ has been implicated in hematologic cancers and solid tumors. Alternative splicing is a post-transcriptional process for acquiring proteomic diversity in eukaryotic cells. Emerging evidence has highlighted the involvement of aberrant mRNA splicing in cancer development/progression. Methods: Our previous studies revealed that PIK3CD-S is an oncogenic splice variant that promotes tumor aggressiveness and drug resistance in prostate cancer (PCa). To further evaluate the potential of utilizing PI3Kδ-S (encoded from PIK3CD-S) as a cancer biomarker and/or drug target, comprehensive analyses were performed in a series of patient samples and cell lines derived from endocrine/solid tumors. Specifically, IHC, immunofluorescence, western blot and RT-PCR assay results have demonstrated that PI3Kδ isoforms were highly expressed in endocrine/solid tumor patient specimens and cell lines. Results: Differential PIK3CD-S/PIK3CD-L expression profiles were identified in a panel of endocrine/solid tumor cells. SiRNA knockdown of PIK3CD-L or PIK3CD-S differentially inhibits AKT/mTOR signaling in PCa, breast, colon and lung cancer cell lines. Moreover, siRNA knockdown of PTEN increased PI3Kδ levels and activated AKT/mTOR signaling, while overexpression of PTEN reduced PI3Kδ levels and inhibited AKT/mTOR signaling in cancer cells. Intriguingly, PI3Kδ-S levels remained unchanged upon either siRNA knockdown or overexpression of PTEN. Taken together, these results suggested that PTEN negatively regulates PI3Kδ-L and its downstream AKT/mTOR signaling, while PI3Kδ-S promotes AKT/mTOR signaling without regulation by PTEN. Lastly, PI3Kδ inhibitor Idelalisib and SRPK1/2 inhibitor SRPIN340 were employed to assess their efficacies on inhibiting the PI3Kδ-expressing endocrine/solid tumors. Our results have shown that Idelalisib effectively inhibited PI3Kδ-L (but not PI3Kδ-S) mediated AKT/mTOR signaling. In contrast, SRPIN340 reversed the aberrant mRNA splicing, thereby inhibiting AKT/mTOR signaling. In-vitro functional assays have further demonstrated that a combination of Idelalisib and SRPIN340 achieved a synergistic drug effect (with drastically reduced cell viabilities/growths of tumor spheroids) in inhibiting the advanced tumor cells. Conclusion: In summary, our study has suggested a promising potential of utilizing PI3Kδ-S (an oncogenic isoform conferring drug resistance and exempt from PTEN regulation) as a prognostic biomarker and drug target in advanced endocrine cancers.

Metabolomics-A Tool to Find Metabolism of Endocrine Cancer.

Clinical endocrinology entails an understanding of the mechanisms involved in the regulation of tumors that occur in the endocrine system. The exact cause of endocrine cancers remains an enigma, especially when discriminating malignant lesions from benign ones and early diagnosis. In the past few years, the concepts of personalized medicine and metabolomics have gained great popularity in cancer research. In this systematic review, we discussed the clinical metabolomics studies in the diagnosis of endocrine cancers within the last 12 years. Cancer metabolomic studies were largely conducted using nuclear magnetic resonance (NMR) and mass spectrometry (MS) combined with separation techniques such as gas chromatography (GC) and liquid chromatography (LC). Our findings revealed that the majority of the metabolomics studies were conducted on tissue, serum/plasma, and urine samples. Studies most frequently emphasized thyroid cancer, adrenal cancer, and pituitary cancer. Altogether, analytical hyphenated techniques and chemometrics are promising tools in unveiling biomarkers in endocrine cancer and its metabolism disorders.

Parathyroid Carcinoma: a Review.

Parathyroid cancer is a rare endocrine malignancy with only a few thousand cases reported worldwide. As a result, there exists considerable controversy regarding the various aspects of this disease, viz., etiology, diagnosis, and management. We hereby attempt to review the literature on parathyroid carcinoma (PC) and summarize the practices based on the current evidence available. The majority of the PC are sporadic although an association with hyperparathyroidism-jaw tumor syndrome, multiple endocrine neoplasia (MEN) 1 and 2, and isolated familial hyperparathyroidism has been shown. As preoperative diagnosis is challenging, PC should be suspected in patients presenting with a neck mass with signs and symptoms of invasion to surrounding structures. Skeletal and renal symptoms are often associated with PC as presenting complaints. The biochemical parameters are more pronounced in the case of PC compared with benign countpart. Due to its rarity, the American Joint Committee of cancer control (AJCC) acknowledges that as yet a clear distinct staging system to prognosticate the disease would be premature. Complete excision with negative margins at first surgery offers the best chance of cure. The role of radiotherapy (RT) is still unclear; however few series have suggested a better locoregional control with adjuvant RT. Recurrences are common and are most significantly associated with an incomplete clearance at initial surgery. Surgical salvage of recurrent/metastatic disease with medical management of hypercalcemia is the treatment of choice. Large prospective studies and trials need to be conducted to understand the pathology better and improve management protocols; however this is a challenge due to rarity of cases.

Clinical decision making in small non-functioning VHL-related incidentalomas.

The optimal treatment strategy for patients with small non-functioning VHL-related incidentalomas is unclear. We searched the Freiburg VHL registry for patients with radiologic evidence of pheochromocytoma/paraganglioma (PHEO/PGL). In total, 176 patients with single, multiple, and recurrent tumours were identified (1.84 tumours/patient, range 1-8). Mean age at diagnosis was 32 ± 16 years. Seventy-four percent of tumours were localised to the adrenals. Mean tumour diameter was 2.42 ± 2.27 cm, 46% were <1.5 cm. 24% of tumours were biochemically inactive. Inactive tumours were significantly smaller than active PHEO/PGL at diagnosis (4.16 ± 2.80 cm vs 1.43 ± 0.45 cm; P < 0.025) and before surgery (4.89 ± 3.47 cm vs 1.36 ± 0.43 cm; P < 0.02). Disease was stable in 67% of 21 patients with evaluable tumours ≤1.5 cm according to RECIST and progressed in 7. Time till surgery in these patients was 29.5 ± 20.0 months. A total of 155 patients underwent surgery. PHEO/PGL was histologically excluded in 4 and proven in 151. Of these, one had additional metastatic disease, one harboured another tumour of a different type, and in 2 a second surgery for suspected disease recurrence did not confirm PHEO/PGL. Logistic regression analysis revealed 50% probability for a positive/negative biochemical test result at 1.8 cm tumour diameter. Values of a novel symptom score were positively correlated with tumour size (Rs = 0.46, P < 0.0001) and together with a positive biochemistry a linear size predictor (P < 0.01). Results support standardised clinical assessment and measurement of tumour size and metanephrines in VHL patients with non-functioning incidentalomas <1.5 cm at one year following diagnosis and at individualised intervals thereafter depending on evolving growth dynamics, secretory activity and symptomatology.

Replication of newly proposed TNM staging system for medullary thyroid carcinoma: a nationwide study.

A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38-4.57) vs 3.04 (95% CI: 1.38-6.67) for stage II, 2.06 (95% CI: 0.45-9.39) vs 3.59 (95% CI: 1.61-8.03) for stage III and 5.87 (95% CI: 2.02-17.01) vs 59.26 (20.53-171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.

The role of mTOR pathway as target for treatment in adrenocortical cancer.

Adrenocortical carcinomas (ACCs) are rare tumors with scant treatment options for which new treatments are required. The mTOR pathway mediates the intracellular signals of several growth factors, including the insulin-like growth factors (IGFs), and therefore represents a potential attractive pathway for the treatment of several malignancies including ACCs. Several mTOR inhibitors, including sirolimus, temsirolimus and everolimus, have been clinically developed. This review summarizes the results of the studies evaluating the expression of the mTOR pathway components in ACCs, the effects of the mTOR inhibitors alone or in combination with other drugs in preclinical models of ACCs and the early experience with the use of these compounds in the clinical setting. The mTOR pathway seems a potential target for treatment of patients with ACC, but further investigation is still required to define the potential role of mTOR inhibitors alone or in combination with other drugs in the treatment of ACC patients.

The avian chorioallantoic membrane as an alternative tool to study medullary thyroid cancer.

Preclinical trials of medullary thyroid cancer (MTC) therapeutics require both in vitro and in vivo analyses. Human tumour xenografted rodent models, which are considered the 'gold standard' to study and validate the efficacy and toxicity of lead compounds before translation to clinical trials, are very expensive, subject to organismal variability and ethical controversies. The avian chorioallantoic membrane (CAM) assay provides an alternative versatile, cost-effective and ethically less objectionable short-term, in vivo model for reliable screening of drugs. In this work, we grafted two MTC cell lines and patient-derived MTC tumour samples onto the avian CAM and characterised the resulted tumours histologically and immunohistochemically. Our findings provide the evidence that the CAM assay is a suitable model for studying the pathophysiology of MTC and can even be used as in vivo system for drug testing.

Metabolic Regulation of Epithelial to Mesenchymal Transition: Implications for Endocrine Cancer.

The last few decades have witnessed an outstanding advancement in our understanding of the hallmarks of endocrine cancers. This includes the epithelial to mesenchymal transition (EMT), a process that alters the morphology and functional characteristics of carcinoma cells. The mesenchymal stem cell like phenotype produced by EMT allows the dislocation of cancer cells from the primary tumor site with inheritance of motility, metastatic and invasive properties. A fundamental driver thought to initiate and propagate EMT is metabolic reprogramming that occur during these transitions. Though there remains a paucity of data regarding the alterations that occur during EMT in endocrine cancers, the contribution of deregulated metabolism is a prominent feature. This mini review focuses on metabolic reprogramming events that occur in cancer cells and in particular those of endocrine origin. It highlights the main metabolic reprogramming outcomes of EMT, encompassing glycolysis, mitochondria oxidative phosphorylation and function, glutamine and lipid metabolism. Comprehending the metabolic changes that occur during EMT will help formulate potential bioenergetic targets as therapies for endocrine cancer metastasis.

Evaluation of A Novel GLP-1R Ligand for PET Imaging of Prostate Cancer.

BACKGROUND: Glucagon-like peptide 1 receptor (GLP-1R) is an important biomarker for diagnosis and therapy of the endocrine cancers due to overexpression. Recently, in human prostate cancer cell lines the receptor was also observed, therefore it may be a potential target for the disease. 18F-Al-NOTA-MAL-Cys39- exendin-4 holds great promise for GLP-1R. Therefore, the feasibility of the 18F-labeled exendin-4 analog for prostate cancer imaging was investigated. METHODS: New probe 18F-Al-NOTA-MAL-Cys39-exendin-4 was made through one-step fluorination. Prostate cancer PC3 cell xenograft model mice were established to primarily evaluate the imaging properties of the tracer via small animal PET studies in vivo. Pathological studies and Western Blots were also performed. RESULTS: PC-3 prostate xenografts were clearly imaged under baseline conditions. At 30 and 60 min postinjection, the tumor uptakes were 2.90±0.41%ID/g and 2.26±0.32 %ID/g respectively. The presence of cys39-exendin-4 significantly reduced the tumor uptake to 0.82±0.10 %ID/g at 60 min p.i. Findings of ex vivo biodistribution studies were similar to those of in vivo PET imaging. The tumors to blood and muscles were significantly improved with the increase of time due to rapid clearance of the tracer from normal organs. Low levels of radioactivity were also detected in the GLP-1R positive tumor and normal organs after coinjection with excessive unlabeled peptides. Immunohistochemistry and Western Blots results confirmed that GLP-1R was widely expressed in PC-3 prostate cancers. CONCLUSION: 18F-Al labeled exendin-4 analog might be a promising tracer for in vivo detecting GLP-1R positive prostate cancer with the advantage of facile synthesis and favorable pharmacokinetics. It may be useful in differential diagnosis, molecularly targeted therapy and prognosis of the cancers.

Targeted next-generation sequencing of cancer genes in poorly differentiated thyroid cancer.

Poorly differentiated thyroid carcinoma (PDTC) is a rare malignancy with higher mortality than well-differentiated thyroid carcinoma. The histological diagnosis can be difficult as well as the therapy. Improved diagnosis and new targeted therapies require knowledge of DNA sequence changes in cancer-relevant genes. The TruSeq Amplicon Cancer Panel was used to screen cancer genomes from 25 PDTC patients for somatic single-nucleotide variants in 48 genes known to represent mutational hotspots. A total of 4490 variants were found in 23 tissue samples of PDTC. Ninety-eight percent (4392) of these variants did not meet the inclusion criteria, while 98 potentially pathogenic or pathogenic variants remained after filtering. These variants were distributed over 33 genes and were all present in a heterozygous state. Five tissue samples harboured not a single variant. Predominantly, variants in P53 (43% of tissue samples) were identified, while less frequently, variants in APC, ERBB4, FLT3, KIT, SMAD4 and BRAF (each in 17% of tissue samples) as well as ATM, EGFR and FBXW7 (each in 13% of tissue samples) were observed. This study identified new potential genetic targets for further research in PDTC. Of particular interest are four observed ERBB4 (alias HER4) variants, which have not been connected to this type of thyroid carcinoma so far. In addition, APC and SMAD4 mutations have not been reported in this subtype of cancer either. In contrast to other reports, we did not find CTNNB1 variants.

Investigating the association of rs2910164 with cancer predisposition in an Irish cohort.

INTRODUCTION: MicroRNAs (miRNAs) are small noncoding RNA molecules that exert post-transcriptional effects on gene expression by binding with cis-regulatory regions in target messenger RNA (mRNA). Polymorphisms in genes encoding miRNAs or in miRNA-mRNA binding sites confer deleterious epigenetic effects on cancer risk. miR-146a has a role in inflammation and may have a role as a tumour suppressor. The polymorphism rs2910164 in the MIR146A gene encoding pre-miR-146a has been implicated in several inflammatory pathologies, including cancers of the breast and thyroid, although evidence for the associations has been conflicting in different populations. We aimed to further investigate the association of this variant with these two cancers in an Irish cohort. METHODS: The study group comprised patients with breast cancer (BC), patients with differentiated thyroid cancer (DTC) and unaffected controls. Germline DNA was extracted from blood or from saliva collected using the DNA Genotek Oragene 575 collection kit, using crystallisation precipitation, and genotyped using TaqMan-based PCR. Data were analysed using SPSS, v22. RESULTS: The total study group included 1516 participants. This comprised 1386 Irish participants; 724 unaffected individuals (controls), 523 patients with breast cancer (BC), 136 patients with differentiated thyroid cancer (DTC) and three patients with dual primary breast and thyroid cancer. An additional cohort of 130 patients with DTC from the South of France was also genotyped for the variant. The variant was detected with a minor allele frequency (MAF) of 0.19 in controls, 0.22 in BC and 0.27 and 0.26 in DTC cases from Ireland and France, respectively. The variant was not significantly associated with BC (per allele odds ratio = 1.20 (0.98-1.46), P = 0.07), but was associated with DTC in Irish patients (per allele OR = 1.59 (1.18-2.14), P = 0.002). CONCLUSION: The rs2910164 variant in MIR146A is significantly associated with DTC, but is not significantly associated with BC in this cohort.

Role of microRNAs in endocrine cancer metastasis.

The deregulation of transcription and processing of microRNAs (miRNAs), as well as their function, has been involved in the pathogenesis of several human diseases, including cancer. Despite advances in therapeutic approaches, cancer still represents one of the major health problems worldwide. Cancer metastasis is an aggravating factor in tumor progression, related to increased treatment complexity and a worse prognosis. After more than one decade of extensive studies of miRNAs, the fundamental role of these molecules in cancer progression and metastasis is beginning to be elucidated. Recent evidences have demonstrated a significant role of miRNAs on the metastatic cascade, acting either as pro-metastatic or anti-metastatic. They are involved in distinct steps of metastasis including epithelial-to-mesenchymal transition, migration/invasion, anoikis survival, and distant organ colonization. Studies on the roles of miRNAs in cancer have focused mainly on two fronts: the establishment of a miRNA signature for different tumors, which may aid in early diagnosis using these miRNAs as markers, and functional studies of specific miRNAs, determining their targets, function and regulation. Functional miRNA studies on endocrine cancers are still scarce and represent an important area of research, since some tumors, although not frequent, present a high mortality rate. Among the endocrine tumors, thyroid cancer is the most common and best studied. Several miRNAs show lowered expression in endocrine cancers (i.e. miR-200s, miR-126, miR-7, miR-29a, miR-30a, miR-137, miR-206, miR-101, miR-613, miR-539, miR-205, miR-9, miR-195), while others are commonly overexpressed (i.e. miR-21, miR-183, miR-31, miR-let7b, miR-584, miR-146b, miR-221, miR-222, miR-25, miR-595). Additionally, some miRNAs were found in serum exosomes (miR-151, miR-145, miR-31), potentially serving as diagnostic tools. In this review, we summarize studies concerning the discovery and functions of miRNAs and their regulatory roles in endocrine cancer metastasis, which may contribute for the finding of novel therapeutic targets. The review focus on miRNAs with at least some identified targets, with established functions and, if possible, upstream regulation.

Tumour diameter is not reliable for management of non-secreting pancreatic neuroendocrine tumours.

Small non-functioning pancreatic NETs (pNETs) ≤2 cm can pose a management dilemma in terms of surveillance or resection. There is evidence to suggest that a surveillance approach can be considered since there are no significant radiological changes observed in lesions during long-term follow-up. However, other studies have suggested loco-regional spread can be present in ≤2 cm pNETs. The aim of this study was to characterise the prevalence of malignant features and identify any useful predictive variables in a surgically resected cohort of pNETs. 418 patients with pNETs were identified from 5 NET centres. Of these 227 were included for main analysis of tumour characteristics. Mean age of patients was 57 years, 47% were female. The median follow-up was 48.2 months. Malignant features were identified in 38% of ≤2 cm pNETs. ROC analysis showed that the current cut-off of 20 mm had a sensitivity of 84% for malignancy. The rate of malignant features is in keeping with other surgical series and challenges the belief that small pNETs have a low malignant potential. This study does not support a 20 mm size cut-off as being a solitary safe parameter to exclude malignancy in pNETs.

Bilateral adrenal masses: a single-centre experience.

BACKGROUND: Bilateral adrenal masses may have aetiologies like hyperplasia and infiltrative lesions, besides tumours. Hyperplastic and infiltrative lesions may have coexisting hypocortisolism. Bilateral tumours are likely to have hereditary/syndromic associations. The data on clinical profile of bilateral adrenal masses are limited. AIMS: To analyse clinical, biochemical and radiological features, and management outcomes in patients with bilateral adrenal masses. METHODS: Retrospective analysis of 70 patients with bilateral adrenal masses presenting to a single tertiary care endocrine centre from western India (2002-2015). RESULTS: The most common aetiology was pheochromocytoma (40%), followed by tuberculosis (27.1%), primary adrenal lymphoma (PAL) (10%), metastases (5.7%), non-functioning adenomas (4.3%), primary bilateral macronodular adrenal hyperplasia (4.3%), and others (8.6%). Age at presentation was less in patients with pheochromocytoma (33 years) and tuberculosis (41 years) compared with PAL (48 years) and metastases (61 years) (P<0.001). The presenting symptoms for pheochromocytoma were hyperadrenergic spells (54%) and abdominal pain (29%), whereas tuberculosis presented with adrenal insufficiency (AI) (95%). The presenting symptoms for PAL were AI (57%) and abdominal pain (43%), whereas all cases of metastasis had abdominal pain. Mean size of adrenal masses was the largest in lymphoma (5.5cm) followed by pheochromocytoma (4.8cm), metastasis (4cm) and tuberculosis (2.1cm) (P<0.001). Biochemically, most patients with pheochromocytoma (92.8%) had catecholamine excess. Hypocortisolism was common in tuberculosis (100%) and PAL (71.4%) and absent with metastases (P<0.001). CONCLUSION: In evaluation of bilateral adrenal masses, age at presentation, presenting symptoms, lesion size, and biochemical features are helpful in delineating varied underlying aetiologies.

How genomic studies have improved our understanding of the mechanisms of transcriptional regulation by NR5A nuclear receptors.

SF-1 and LRH-1 are transcription factors that belong to the NR5A family of nuclear receptors that both have an essential role during development. Recent studies at the genome-wide scale have enabled the characterization of the cistrome and transcriptome regulated by SF-1 and LRH-1 in different cell lines and tissues. Those studies have allowed us to make a significant leap forward in our understanding of the mechanisms of transcriptional regulation of NR5A nuclear receptors in stem cells and cancer.

Steroid hormone receptors and prostate cancer: Role of structural dynamics in therapeutic targeting / 亚洲男科学杂志(英文版)

Steroid hormone receptors (SHRs) act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator (SRM) ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain (LBD)/AF2 and neglect intrinsically disordered (ID) N-terminal domain (NTD)/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor′s (AR′s) ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR′s structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer.