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Objective: To describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC)., Design: Electronic survey August 2020-May 2021., Results: 96% of 171 (121 APT, 50 PC), initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated aggressive behaviour after 5.5 years (IQR: 2.8-12). Of the patients, 63% were men. Adrenocorticotrophic hormone (ACTH)-secreting tumours constituted 30% of the APT/PC, and the gonadotroph subtypes were under-represented. Five out of 13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7-12.1) from diagnosis. At the first surgery, the Ki67 index was ≥3% in 74/93 (80%) and ≥10% in 38/93 (41%) tumours. An absolute increase of Ki67 ≥ 10% after median of 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67 ≥ 10% and ACTH-secretion were associated with worse prognosis., Conclusion: APT/PCs exhibit a wide and challenging spectrum of behaviour. Temozolomide is the first-line chemotherapy, and other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers.

Context: Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors., Objective: To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with those described in the current literature., Design/methods: Three case studies, including clinical presentation, germline, and tumor genetic analysis and family history., Setting: Two tertiary University Hospitals in Sydney, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia., Outcome: Phenotype of the 3 cases and their kindred; molecular analysis and tumor p27kip1 immunohistochemistry., Results: Family A: The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B: The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushing's syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G > A, p.Trp60*; c.475G > A, p.Asp159Asn) and 1 previously reported (c.374_375delCT, p.Ser125*)., Conclusions: Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Objective: Transsphenoidal surgery (TSS) is the first-line treatment for Cushing's disease. The objectives of the study were to determine remission and recurrence rates after TSS for Cushing's disease, identify factors that predict these outcomes, and define the threshold for postoperative morning serum cortisol (MSeC) that most accurately predicts sustained remission., Methods: Records were retrospectively reviewed for consecutive adults undergoing TSS for Cushing's disease at a tertiary centre (1990-2019). Remission was defined as MSeC <138 nmol/L by 6 weeks postoperatively. Recurrence was defined as elevated 24-h urine free cortisol, lack of suppression after dexamethasone or elevated midnight salivary cortisol., Results: In this study, 42 patients (age 47 ± 13 years, 83% female) were assessed with 55 ± 56 months of follow-up. Remission occurred after 77% of primary ( n  = 30) and 42% of revision operations ( n  = 12). After primary surgery, remission was associated with lower MSeC nadir (26 ± 36 nmol/L vs 347 ± 220 nmol/L, P   < 0.01) and lower adrenocorticotropin nadir (2 ± 3 pmol/L vs 6 ± 3 pmol/L, P  = 0.01). Sustained remission 5 years after surgery was predicted by MSeC <92 nmol/L within 2 weeks postoperatively (sensitivity 100% and specificity 100%). After revision surgery, remission was predicted by lower MSeC nadir (70 ± 45 nmol/L vs 408 ± 305 nmol/L, P  = 0.03), smaller tumour diameter (3 ± 2 mm vs 15 ± 13 mm, P  = 0.05) and absence of cavernous sinus invasion (0% vs 71%, P  = 0.03). Recurrence after primary and revision surgery occurred in 17% and 20% of patients respectively., Conclusions: Lower postoperative MSeC nadir strongly predicted remission after both primary and revision surgery. Following primary surgery, an MSeC <92 nmol/L within 2 weeks predicted sustained remission at 5 years. MSeC nadir was the most important prognostic marker following TSS for Cushing's disease., Competing Interests: Richard J Harvey is consultant with Medtronic, Stryker, Novartis, Meda, and NeilMed pharmaceuticals. Research grant funding received from Glaxo-Smith-Kline and Stallergenes. He has been on the speakers’ bureau for Glaxo-Smith-Kline, Meda Pharmaceuticals and Seqirus. Ann McCormack has received speaker honorarium for IPSEN, Pfizer and Novartis. Benjamin P Jonker has received speaker fees from Integra LifeSciences Corporation. All other authors have no financial disclosures or conflicts of interest., (© The authors.)

Objective: We have previously reported that human calcified aortic cusps have abundant expression of smooth muscle (SM) markers and co-activators. We hypothesised that cells in bicuspid aortic valve (BAV) cusps and those affected by rheumatic heart valve (RHV) disease may follow a similar phenotypic transition into smooth muscle cells, a process that could be regulated by transforming growth factors (TGFs)., Aims: Cusps from eight patients with BAV and seven patients with RHV were analysed for early and late SM markers and regulators of SM gene expression by immunocytochemistry and compared to healthy aortic valves from 12 unused heart valve donors. The ability of TGFs to induce these markers in valve endothelial cells (VECs) on two substrates was assessed., Results: In total, 7 out of 8 BAVs and all the RHVs showed an increased and atypical expression of early and late SM markers α-SMA, calponin, SM22 and SM-myosin. The SM marker co-activators were aberrantly expressed in six of the BAV and six of the RHV, in a similar regional pattern to the expression of SM markers. Additionally, regions of VECs, and endothelial cells lining the vessels within the cusps were found to be positive for SM markers and co-activators in three BAV and six RHV. Both BAVs and RHVs were significantly thickened and HIF1α expression was prominent in four BAVs and one RHV. The ability of TGFβs to induce the expression of SM markers and myocardin was greater in VECs cultured on fibronectin than on gelatin. Fibronectin was shown to be upregulated in BAVs and RHVs, within the cusps as well as in the basement membrane., Conclusion: Bicuspid aortic valves and RHVs expressed increased numbers of SM marker-positive VICs and VECs. Concomittantly, these cells expressed MRTF-A and myocardin, key regulators of SM gene expression. TGFβ1 was able to preferentially upregulate SM markers and myocardin in VECs on fibronectin, and fibronectin was found to be upregulated in BAVs and RHVs. These findings suggest a role of VEC as a source of cells that express SM cell markers in BAVs and RHVs. The similarity between SM marker expression in BAVs and RHVs with our previous study with cusps from patients with aortic stenosis suggests the existance of a common pathological pathway between these different pathologies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Latif, Sarathchandra, McCormack, Yacoub and Chester.)

Background: Endocrinology has one of the highest proportions of female specialists and trainees, however females have traditionally been underrepresented in leadership positions and as speakers at scientific meetings., Hypothesis: Females would represent less than half of invited speakers (plenary, symposium sessions) at endocrinology conferences and in leadership positions of endocrinology societies., Method: An audit of Australian diabetes and endocrinology societies and their respective annual scientific meetings between 2016 - 2020. Analysis of the gender of conference speakers across oral, symposium and plenary sessions, session chairs, program organising committees and society committees., Results: A total of 1638 speakers (females 856, 52.3%) across 550.4 hours (females 273.6, 49.7%) of presentations at the conferences were identified. Among plenary sessions of all 3 societies there were more male (61%) than female speakers. A total of 608 session chairs were identified, with 313 (51.5%) females. The majority of organising committee members (n=116) were female (56%), however the representation across each organising committee varied. There was a low proportion of society female council members (39% female)., Conclusion: There was an equal representation of females and males as conference speakers and session chairs. However, there was an underrepresentation of women in more prestigious roles of plenary speakers and society council members. We implore conscious efforts to address this disparity., Competing Interests: AM is the President-elect of the Endocrine Society of Australia. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Raven and McCormack.)

Purpose: In adults and children, transsphenoidal surgery (TSS) represents the cornerstone of management for most large or functioning sellar lesions with the exception of prolactinomas. Endocrine evaluation and management are an essential part of perioperative care. However, the details of endocrine assessment and care are not universally agreed upon., Methods: To build consensus on the endocrine evaluation and management of adults undergoing TSS, a Delphi process was used. Thirty-five statements were developed by the Pituitary Society's Education Committee. Fifty-five pituitary endocrinologists, all members of the Pituitary Society, were invited to participate in two Delphi rounds and rate their extent of agreement with statements pertaining to perioperative endocrine evaluation and management, using a Likert-type scale. Anonymized data on the proportion of panelists' agreeing with each item were summarized. A list of items that achieved consensus, based on predefined criteria, was tabulated., Results: Strong consensus (≥ 80% of panelists rating their agreement as 6-7 on a scale from 1 to 7) was achieved for 68.6% (24/35) items. If less strict agreement criteria were applied (ratings 5-7 on the Likert-type scale), consensus was achieved for 88% (31/35) items., Conclusions: We achieved consensus on a large majority of items pertaining to perioperative endocrine evaluation and management using a Delphi process. This provides an international real-world clinical perspective from an expert group and facilitates a framework for future guideline development. Some of the items for which consensus was not reached, including the assessment of immediate postoperative remission in acromegaly or Cushing's disease, represent areas where further research is needed., (© 2021. The Author(s).)

The success of tissue-engineered heart valves rely on a balance between polymer degradation, appropriate cell repopulation, and extracellular matrix (ECM) deposition, in order for the valves to continue their vital function. However, the process of remodeling is highly dynamic and species dependent. The carbon fibers have been well used in the construction industry for their high tensile strength and flexibility and, therefore, might be relevant to support tissue-engineered hearts valve during this transition in the mechanically demanding environment of the circulation. The aim of this study was to assess the suitability of the carbon fibers to be incorporated into tissue-engineered heart valves, with respect to optimizing their cellular interaction and mechanical flexibility during valve opening and closure. The morphology and surface oxidation of the carbon fibers were characterized by scanning electron microscopy (SEM). Their ability to interact with human adipose-derived stem cells (hADSCs) was assessed with respect to cell attachment and phenotypic changes. hADSCs attached and maintained their expression of stem cell markers with negligible differentiation to other lineages. Incorporation of the carbon fibers into a stand-alone tissue-engineered aortic root, comprised of jet-sprayed polycaprolactone aligned carbon fibers, had no negative effects on the opening and closure characteristics of the valve when simulated in a pulsatile bioreactor. In conclusion, the carbon fibers were found to be conducive to hADSC attachment and maintaining their phenotype. The carbon fibers were sufficiently flexible for full motion of valvular opening and closure. This study provides a proof-of-concept for the incorporation of the carbon fibers into tissue-engineered heart valves to continue their vital function during scaffold degradation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tseng, Grace, Aguib, Sarathchandra, McCormack, Ebeid, Shehata, Nagy, El-Nashar, Yacoub, Chester and Latif.)

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified., Competing Interests: Declaration of interests MF has received grants to her institution from Novartis, Strongbridge, Novo Nordisk, Crinetics, Millendo, Ascendis, and Pfizer; personal honoraria for consulting and advisory boards from Crinetics, HRA Pharma, Novartis, Recordati, Strongbridge, Sparrow, Ascendis, Novo Nordisk, and Pfizer; and has served on the Board of the Pituitary Society. RA has received grants to his institution from Strongbridge Biopharma, Novartis Pharmaceuticals, and Corcept Therapeutics, and personal honoraria for consulting and advisory boards from Strongbridge Biopharma, Recordati Rare Diseases, Corcept Therapeutics, and Novartis Pharmaceuticals. IB has received grants and fees for consulting, advisory boards, and authorship to her institution from the National Institutes of Health (NIH), Strongbridge, Corcept, HRA Pharma, Sparrow Pharmaceutics, Adrenas Pharmaceutics, and Elsevier, and non-financial support to her institution from HRA Pharma. AB-S has received personal honoraria for advisory boards from Recordati. JB has received grants to his institution from Novartis, HRA Pharma, and Recordati, and personal honoraria for consulting, lectures, and meeting attendance from Novartis, HRA Pharma, Ipsen, and Recordati. NRB has served on the Board or as an advisor for European Neuroendocrine Association and the European Reference Network on Rare Endocrine Conditions. CLB has received grants and personal honoraria for lectures from Novartis and served on the Board or as an advisor for Sociedade Brasileira de Endocrinologia e Metabologia, Endocrine Society, and European Society of Endocrinology. MDB has received grants as principal investigator from Novartis. JDC has received grants to his institution from Novartis, Strongbridge, and Crinetics; personal honoraria for consulting and authorship from Recordati, Novo Nordisk, Corcept, and Merck Manual; and served on the Board or as an advisor for Pituitary Society, Endocrine Society, and American Association of Clinical Endocrinologists. FFC has served on the Board of the Pituitary Society. FC has received personal honoraria for consulting, lectures, and support for meeting attendance from Recordati Rare Diseases, Ipsen, and HRA Pharma. PC has received grants and honoraria to his institution for consulting and lectures from Novartis and Recordati. JF has received grants to his institution from Novartis and personal honoraria for consulting and advisory boards from Corcept, Recordati, and Novartis. MGa has received non-financial support from Novartis and Recordati and served on the Board or as an advisor for Pituitary Society and Brazilian Society of Endocrinology and Metabolism. EBG has received grants and personal honoraria for consulting, lectures, and advisory boards from Novartis, Corcept, Strongbridge, Bristol-Myers Squibb, Recordati, and HRA Pharma; and has served as an advisor for Cushing's Support & Research Foundation. AGi has received grants to his institution from Pfizer and personal honoraria for consulting and advisory boards from Abiogen, Novo Nordisk, and Recordati; and has served on the Board or as an advisor to European Society of Endocrinology and Glucocorticoid Induced Osteoporosis Skeletal Endocrinology Group. AGr has served as an advisor to Novartis and as an editor for Neuroendocrinology and Journal of Neuroendocrinology. MGu has received personal honoraria for consulting and lectures from Recordati Rare Diseases UK, HRA Pharma, and Ipsen; and is a Board member or advisor for UK Society for Endocrinology and European Society of Endocrinology. AGI has received grants to her institution from Recordati, Novartis, and Strongbridge; and personal honoraria for consulting from Recordati, HRA Pharma, and Strongbridge. UBK has received grants as co-investigator from Corcept; personal honoraria for consulting, advisory board, and lectures from Acerus Pharmaceuticals and Novo Nordisk; and serves as editor for Journal of Clinical Endocrinology and Metabolism and as Board member for Endocrine Society. NK has received personal honoraria for consulting from Recordati Rare Diseases and HRA Pharma, and has served as Board member or advisor for Pituitary Society, European Neuroendocrine Association, Endocrine Society, and European Society of Endocrinology. LK has received personal honoraria for consulting from Strongbridge and Recordati. DFK has received royalties from Mizuho. AL has received grants from Recordati and Corcept; personal honoraria for lectures, support for meeting attendance, and advisory boards from Pfizer, Ipsen, Corcept, and the European Journal of Endocrinology; royalties from UpToDate Endocrinology; and served as a Board member for International Society of Endocrinology. AM has received grants and personal honoraria for lectures or presentations and support for meeting attendance from Pfizer, Ipsen, Novartis, and Novo Nordisk, and served as a Council member for Endocrine Society of Australia. SM has received grants to his institution from US Food and Drug Administration and non-financial support from Cyclacel. MM has received grants to his institution from Corcept, Novartis, and Strongbridge; fees for expert testimony from Janssen and Corcept; and personal honoraria for advisory boards for Merck, Pfizer, Recordati, and Strongbridge. JN-P has received grants and honoraria to the institution for consulting and advisory boards from Diurnal Ltd and HRA Pharma, Recordati, and Novartis; and served as a Board member or advisor for Pituitary Foundation and Endocrine Society. LN has received royalties from UpToDate and support for meeting attendance from the NIH, and has served as a Board member for Endocrine Society. AMP has received grants to his institution from HRA Pharma and served as advisor for European Reference Network on Rare Endocrine Conditions and European Endocrine Society. SP has received personal honoraria for lectures and advisory boards from HRA Pharma, Recordati Pharma, Novartis Pharma, and Crinetics Pharmaceuticals. RP has received grants to his institution from Novartis, Pfizer, Ipsen, Shire, IBSA Farmaceutici, HRA Pharma, Cortendo AB, Corcept Therapeutics, and Merck Serono, and personal honoraria for consulting, lectures, support for meeting attendance, and advisory boards from Novartis, Shire, HRA Pharma, Cortendo AB, Pfizer, Recordati, IBSA Farmaceutici, and Crinetics Pharmaceuticals. HR has received personal honoraria for consulting from Cerium and non-financial support from Corcept. MR has received personal honoraria for consulting, lectures, and advisory boards from Novartis, Recordati, HRA Pharma, and Ipsen. RS has received grants to his institution from Corcept and Crinetics, and personal honoraria for consulting from Strongbridge, Corcept, HRA Pharma, and Sterotherapeutics. CS has received grants and personal honoraria for lectures from Pfizer, Novartis, Recordati Rare Diseases, and HRA Pharma. IS has received personal honoraria for consulting from Medison Pharma. CAS has received grants from Pfizer; personal honoraria for consulting and support for meeting attendance from Lundbeck Pharma and the NIH; holds patents on the genetics of PRKAR1A, PDE11A, and GPR101; and has served as a Board member or advisor for Society for Pediatric Research, Children's Inn at NIH, and Cushing's Foundation. AT has received grants to his institution from HRA Pharma, and personal honoraria for consulting, lectures, and support for meeting attendance from HRA Pharma, Recordati Rare Diseases, and Ipsen. YT has received personal honoraria for consulting and lectures from Novo Nordisk, Recordati Rare Diseases, Bohringer Ingelheim, and Sumitomo Dainippon Pharma. MT has served as an advisor to European Society of Endocrinology. ST has received grants to his institution from Strongbridge, Crinetics, and Novartis, and personal honoraria for lectures, advisory boards, and support for meeting attendance from Recordati, Pfizer, and Ipsen. EV has received grants through the European Society of Endocrinology from HRA Pharma, Novartis, Recordati, and Corcept, and received personal honoraria for consulting, lectures, and advisory boards from HRA Pharma, HRA Pharma Spain, and Recordati Rare Diseases. GV has received grants to her institution from Novartis, Recordati, and Corcept; personal honoraria and honoraria to the institution for consulting and lectures from HRA Pharma and Recordati; and served as an advisor for Cushing's Hub. SMW has received grants through the European Society of Endocrinology from HRA Pharma, Novartis, Recordati, and Corcept, and received personal honoraria for consulting and lectures from HRA Pharma and Recordati Rare Diseases. MCZ has served as a Board member for European Neuroendocrine Association. BMKB has received grants to her institution from Novartis, Opko, Strongbridge, and Millendo; personal honoraria for consulting from Aeterna Zentaris, Ascendis, Crinetics, Merck Serono, Novartis, Novo Nordisk, Recordati, Strongbridge, and Sparrow; and served as an advisor for Endocrine Society. MB, KH, PM, BS, EVV, and JW have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

CD4 + T cells expressing choline acetyltransferase (ChAT) have recently been shown to cause a drop in systemic blood pressure when infused into mice. The aim of this study was to determine if ChAT-expressing T cells could regulate coronary vascular reactivity. Preconstricted segments of epicardial and intramyocardial porcine coronary arteries relaxed in response to Jurkat T cells (JT) that overexpressed ChAT (JT ChAT cells). The efficacy of the JT ChAT cells was similar in epicardial and intramyocardial vessels with a maximum dilator response to 3 × 10 5 cells/mL of 38.0 ± 6.7% and 38.7 ± 7.25%, respectively. In contrast, nontransfected JT cells elicited a weak dilator response, followed by a weak contraction. The response of JT ChAT cells was dependent on the presence of the endothelial cells. In addition, the response could be significantly reduced by N ω -nitro-l-arginine methyl ester (l-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) in the presence of indomethacin. JT ChAT cells, but not JT cells, increased the expression of phosphorylated endothelial nitric oxide synthase (eNOS). JT ChAT cells contained significantly greater levels of acetylcholine compared with JT cells; however, the nonselective muscarinic antagonist atropine and the M 1 receptor antagonist pirenzepine both failed to block the dilator effect of JT ChAT cells. Exogenously added acetylcholine induced only a weak relaxation (∼10%) at low concentrations, which became a contractile response at higher concentrations. These data illustrate the capacity for cells that express ChAT to regulate coronary vascular reactivity, via mechanisms that are dependent on interaction with the endothelium and in part mediated by the release of nitric oxide. NEW & NOTEWORTHY This study shows ChAT-expressing T cells can induce vasodilation of the blood vessel in the coronary circulation and that this effect relies on a direct interaction between T cells and the coronary vascular endothelium. The study establishes a potential immunomodulatory role for T cells in the coronary circulation. The present findings offer an additional possibility that a deficiency of ChAT-expressing T cells could contribute to reduced coronary blood flow and ischemic events in the myocardium.

A significant amount of knowledge has been gained with the use of cell-based assays to elucidate the mechanisms that mediate heart valve calcification. However, cells used in these studies lack their association with the extra-cellular matrix or the influence of other cellular components of valve leaflets. We have developed a model of calcification using intact porcine valve leaflets, that relies upon a biological stimulus to drive the formation of calcified nodules within the valve leaflets. Alizarin Red positive regions were formed in response to lipopolysaccharide and inorganic phosphate, which could be quantified when viewed under polarized light. Point analysis and elemental mapping analysis of electron microscope images confirmed the presence of nodules containing calcium and phosphorus. Immunohistochemical staining showed that the development of these calcified regions corresponded with the expression of RUNX2, osteocalcin, NF-kB and the apoptosis marker caspase 3. The formation of calcified nodules and the expression of bone markers were both inhibited by adenosine in a concentration-dependent manner, illustrating that the model is amenable to pharmacological manipulation. This organ culture model offers an increased level of tissue complexity in which to study the mechanisms that are involved in heart valve calcification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chester, Sarathchandra, McCormack and Yacoub.)

Objective: Clinically non-functioning pituitary tumours (NFPT) are a heterogenous group of neoplasms with diverse outcomes. The purpose of this narrative review was to summarize available data on predictive factors, both in routine practice and research settings., Design: A literature review was conducted for papers published in peer-reviewed journals, investigating clinical, radiological, pathological and genetic predictive factors in NFPT., Results: Several clinical and radiological factors have been associated with NFPT recurrence and/or aggressiveness, including larger size and pre-/post-operative growth rates. Application of transcription factor immunohistochemistry has given rise to improved subtype identification, including 'higher-risk' subtypes, in routine clinical practice. Numerous other pathological and genetic biomarkers have demonstrated promise for prognostication in the research setting., Conclusion: NFPT are a heterogenous group of tumours, characterized by diverse presentation, pathogenesis and outcomes. Ongoing refinements in understanding of tumour biology are likely to pave the way to improved integrative prognostication and precision medicine for NFPT., (© 2021 John Wiley & Sons Ltd.)

Cavernous sinus invasion (CSI) by pituitary tumors is associated with subtotal resection and persistent endocrinopathy. The Knosp classification is a magnetic resonance imaging (MRI) tool used to define CSI in the 2017 World Health Organization Classification. However, alternative criteria may have superior diagnostic performance. This study aimed to assess the diagnostic performance of four MRI criteria, using a combination of endoscopy and day 1 MRI as the reference standard for CSI. A cross-sectional study was conducted including patients treated with endoscopic endonasal transsphenoidal surgery for pituitary macroadenomas, recruited from a tertiary pituitary multidisciplinary center in Sydney, Australia between September 2013, and February 2021. The diagnostic performances of four MRI criteria were assessed: the Knosp criteria, percentage encasement of the internal carotid (PEICA), venous compartment obliteration (VCO), and the Fernandez-Miranda classification. Reference CSI was defined using a combination of intraoperative endoscopy and day 1 MRI. A total of 210 cavernous sinuses (105 patients), were analyzed, (51.7 ± 16.3yrs, 43% female), of which 18% had CSI. CSI was best diagnosed by Knosp ≥ 2 (63% sensitivity and 89% specificity), PEICA ≥ 28% (84% sensitivity and 77% specificity) and VCO of ≥ 3 compartments (65% sensitivity and 89% specificity). CSI was unlikely if any of the following signs were present: Knosp < 1, PEICA < 28%, preservation of the medial or superior compartments or sparing of the superior Fernandez-Miranda compartment (negative predictive value 95%, 95%, 94%, 91% and 92% respectively). In conclusion, alternatives to the Knops criteria including PEICA and VCO can aid CSI diagnosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumours have not been assessed. This study aimed to (1) determine the clinical utility of transcription factor analysis for classification of pituitary tumours and (2) determine the prognostic value of improved lineage-based classification of pituitary tumours., Methods: This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumours at St Vincent's Public and Private Hospitals, Sydney, Australia between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the 'histological cohort'. Patients with at least 12 months of post-surgical follow-up were included in the subgroup 'clinical cohort'. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying 'higher-risk' histological subtypes was assessed., Results: There were 171 patient tumour samples analyzed in the histological cohort. Of these, there were 95 patients forming the clinical cohort. Subtype diagnosis was changed in 20/171 (12%) of tumours. Within the clinical cohort, there were 21/95 (22%) patients identified with higher-risk histological subtype tumours. These were associated with tumour invasiveness (P = 0.050), early recurrence (12-24 months, P = 0.013), shorter median time to recurrence (49 (IQR: 22.5-73.0) vs 15 (IQR: 12.0-25.0) months, P = 0.005) and reduced recurrence-free survival (P = 0.031)., Conclusions: Application of transcription factor analysis, in addition to hormone immunohistochemistry, allows for refined pituitary tumour classification and may facilitate an improved approach to prognostication.

Purpose: Transsphenoidal surgery (TSS) is the first-line treatment for Cushing's disease (CD). This review aimed to synthesize the remission and recurrence rates following TSS for CD and identify predictors of these outcomes., Methods: Medline (1946-) and Embase (1947-) were searched until 23rd January 2019 for original studies. A meta-analysis was performed of remission and recurrence rates. Studies were excluded if patients had prior radiosurgery/radiotherapy, mixed pathologies or interventions without separated data, follow-up not reported or population size < 20. For recurrence rate syntheses, studies with follow-up < 6 months were excluded., Results: The search produced 2663 studies, of which n = 68 were included, involving 5664 patients. Remission rates after primary and revision TSS were 80% [77-82] and 58% [50-66] at last follow-up. After primary TSS, predictors of remission were micro- v macroadenomas (83% v 68%, p < 0.01), imaging-visible adenomas (81% v 69%, p < 0.01), adenomas confirmed on histopathology (87% v 45%, p < 0.01), absence of cavernous sinus invasion (80% v 30%, p < 0.01), postoperative serum cortisol (MSeC) nadir < 2 μg/dL (< 55 nmol/L; 95% v 46%, p < 0.01) and lower preoperative 24-h urine free cortisol (1250 nmol v 1726 nmol, p < 0.01). For revision TSS, predictors of remission were postoperative MSeC nadir < 2 μg/dL (< 55 nmol/L; 100% v 38%, p < 0.01) and operations for recurrence v persistence (80% v 54%, p < 0.01). Recurrence rates after primary and revision TSS were 18% [14-22] and 28% [16-42]., Conclusions: TSS is most effective in primary microadenomas, visible on preoperative imaging and without CS invasion, lower preoperative 24-h urine free cortisol and postoperative MSeC nadir < 2 μg/dL (< 55 nmol/L).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral strain that has caused the coronavirus disease 2019 (COVID-19) pandemic, has presented healthcare systems around the world with an unprecedented challenge. In locations with significant rates of viral transmission, social distancing measures and enforced 'lockdowns' are the new 'norm' as governments try to prevent healthcare services from being overwhelmed. However, with these measures have come important challenges for the delivery of existing services for other diseases and conditions. The clinical care of patients with pituitary disorders typically involves a multidisciplinary team, working in concert to deliver timely, often complex, disease investigation and management, including pituitary surgery. COVID-19 has brought about major disruption to such services, limiting access to care and opportunities for testing (both laboratory and radiological), and dramatically reducing the ability to safely undertake transsphenoidal surgery. In the absence of clinical trials to guide management of patients with pituitary disease during the COVID-19 pandemic, herein the Professional Education Committee of the Pituitary Society proposes guidance for continued safe management and care of this population.

The use of temozolomide (TMZ) for the management of aggressive pituitary tumours (APT) has revolutionised clinical practice in this field with significantly improved clinical outcomes and long-term survival. Its use is now well established however a large number of patients do not respond to treatment and recurrence after cessation of TMZ is common. A number of challenges remain for clinicians such as appropriate patient selection, treatment duration and the role of combination therapy. This review will examine the use of TMZ to treat APT including mechanism of action, treatment regimen and duration; biomarkers predicting response to treatment and patient selection; and current evidence for administration of TMZ in combination with other agents.

Pituitary adenohypophyseal tumors are considered as benign and termed "adenomas". However, many tumors are invasive and a proportion of these exhibit an "aggressive behavior" with premature death due to progressive growth. Only very rare (0.2%) tumors with metastases are considered malignant and termed "carcinomas". Taking into account this variability in behavior and the oncological definition, pathologists have proposed changing the term adenoma to tumor. Here we explain why use the term tumor instead of adenoma and identify tumor characteristics, associated with a high risk for poor prognosis. In a cohort of 125 tumors with aggressive behavior (APT) and 40 carcinomas with metastases (PC), clinical and pathological features were very similar. The comparison of this cohort (APT+PC) with a reference surgical cohort of 374 unselected patients clearly shows that the two cohorts differ greatly, especially the percentage of tumors with Ki67 ≥ 10% (35%vs3%; p < 0.001). A five-tiered prognostic classification, associating invasion and proliferation, identified grade 2b tumors (invasive and proliferative), with a high risk of recurrence/progression. Because half of the APT+ PC tumors have a Ki67 index ≥10%, and 80% of them show 2 or 3 positive markers of proliferation, we suggest that tumors that are clinically aggressive, invasive and highly proliferative with a Ki67 ≥ 10%, represent tumors with malignant potential. The percentage of grade 2b tumors, suspected of malignancy, which will become aggressive tumors or carcinomas is unknown. It is probably very low, but higher than 0.2% in surgical series. Early identification and active treatment of these aggressive tumors is needed to decrease morbidity and prolong survival.

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour's molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.

Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 years using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2 , TP53 , RB1 , and PTEN , resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression; however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses., (© 2019 McCabe et al.; Published by Cold Spring Harbor Laboratory Press.)

Non-functioning pituitary carcinomas (NFPC) are defined as tumours of adenophyseal origin with craniospinal or systemic dissemination, with the absence of a hormonal hypersecretion syndrome. These are a histologically heterogenous group of tumours, comprising gonadotroph, null cell, "silent" tumours of corticotroph, somatotroph or lactotroph cell lineages as well as plurihormonal Pit-1 tumours. NFPC are exceedingly rare, and hence few cases have been described. This review has identified 38 patients with NFPC reported in the literature. Recurrent invasive non-functioning pituitary adenomas (NFPA) were observed in a majority of patients. Various factors have been identified as markers of the potential for aggressive behaviour, including rapid tumour growth, growth after radiotherapy, gain or shift of hormone secretion and raised proliferative markers. Typically, there is a latency of several years from the original presentation with an NFPA to identification of metastases and only 5 cases reported with rapidly progressive malignant disease within 1 month of presentation. Therapeutic options include debulking surgery, radiation therapy and chemotherapy with temozolomide recommended as first line systemic treatment. Although long-term survivors are described, prognosis remains generally very poor (median survival 8 months). Improvements in molecular tumour profiling may assist in predicting tumour behaviour, guide therapeutic choices and identify novel therapies.

Objective: Petrosal venous prolactin concentrations have been promoted to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS), beyond that achieved with ACTH measurement alone, in diagnosing a pituitary ACTH source and determining corticotrophinoma side (L/R). Our objective was to assess the effect of using prolactin to confirm adequacy of petrosal cannulation in a cohort of patients with ACTH-dependent Cushing's syndrome., Design: Retrospective cohort study., Patients: Thirteen patients with clinical and biochemical Cushing's syndrome who underwent IPSS., Measurements: Serum prolactin and ACTH in peripheral and inferior petrosal sinus blood before and after corticotrophin-releasing hormone (CRH) injection., Results: Thirteen consecutive patients were diagnosed with Cushing's disease using uncorrected ACTH ratios. The side of PRL excess was the same as the side of ACTH excess in all cases. Use of various published prolactin-related equations suggested that the ACTH non-dominant side was not cannulated in four, six or seven patients depending on the equation used. The equations generally decreased the central-to-peripheral gradient on the uncorrected ACTH dominant side, increased the central-to-peripheral gradient on the contralateral side and diminished or even reversed the ACTH intersinus gradient., Conclusions: Consistent co-lateralisation of prolactin and ACTH in IPSS strongly suggests that prolactin cannot act as an independent guide to the diagnosis and lateralisation of Cushing's disease. All patients with Cushing's disease had a prolactin intersinus gradient towards the tumourous side of the pituitary, for likely biological reasons. PRL-corrected ACTH concentrations may threaten the sensitivity and specificity of IPSS in diagnosing Cushing's disease and conceal lateralisation., (© 2017 John Wiley & Sons Ltd.)

Background: Normal and calcified human valve cusps, coronary arteries, and aortae harbor spherical calcium phosphate microparticles of identical composition and crystallinity, and their role remains unknown., Objective: The objective was to examine the direct effects of isolated calcified particles on human valvular cells., Method and Results: Calcified particles were isolated from healthy and diseased aortae, characterized, quantitated, and applied to valvular endothelial cells (VECs) and interstitial cells (VICs). Cell differentiation, viability, and proliferation were analyzed. Particles were heterogeneous, differing in size and shape, and were crystallized as calcium phosphate. Diseased donors had significantly more calcified particles compared to healthy donors (P<.05), but there were no differences between the composition of the particles from healthy and diseased donors. VECs treated with calcified particles showed a significant decrease in CD31 and VE-cadherin and an increase in von Willebrand factor expression, P<.05. There were significantly increased α-SMA and osteopontin in treated VICs (P<.05), significantly decreased VEC and VIC viability (P<.05), and significantly increased number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive VECs (P<.05) indicating apoptosis when treated with the calcified particles., Conclusions: Isolated calcified particles from human aortae are not innocent bystanders but induce a phenotypical and pathological change of VECs and VICs characteristic of activated and pathological cells. Therapy tailored to reduce these calcified particles should be investigated., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Over the past half decade, temozolomide, an oral akylating chemotherapeutic agent, has been shown to have significant activity in the management of aggressive pituitary tumours. The expression of 06-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is an important predictor of response to therapy. Low MGMT expression has been reported with a higher frequency amongst more aggressive pituitary tumours, suggesting MGMT may play a role in pituitary tumour progression. In this study, we performed a microarray analysis to determine whether there was a distinct gene expression profile between tumours with low MGMT and high MGMT expression. Overall, 1,403 differentially expressed genes were identified with raw p values less than 0.05. Gene set enrichment analysis (GSEA) revealed significant differences in the gene expression profile between high and low MGMT expressing pituitary tumours. High MGMT expressing pituitary tumours were found to have upregulation of components of the FGFR family and downstream signaling cascades such as PI3 K/Akt and MAPK pathways. Activation of genes involved in the DNA damage response and DNA repair pathways, as well as genes involved in transcription, were identified in pituitary tumours with low MGMT expression. These results form the basis of our proposed model to describe the role of MGMT in pituitary tumorigenesis.

Background: Aggressive pituitary tumours are associated with substantial morbidity and mortality. Treatment options are often limited, and chemotherapy has been reserved as salvage therapy although historically results have often been disappointing. However, temozolomide, an oral alkylating agent, has recently demonstrated significant activity against these tumours. A DNA repair protein, 06-methylguanine-DNA methyltransferase (MGMT) has been suggested as a biomarker to predict response to temozolomide in pituitary tumours., Materials and Methods: This paper will review the current literature on temozolomide and pituitary tumours and discuss the recent controversy surrounding the value of determining the MGMT status in this tumour group. A PubMed search was performed to retrieve articles, using the terms 'pituitary tumour' and 'temozolomide'., Results: Overall, 24/40 (60%) of the published cases demonstrated a response to temozolomide therapy. The highest response rates were seen amongst prolactinomas (73%) and ACTH-secreting tumours (60%), whilst nonfunctioning pituitary tumours exhibit lower response rates (40%). Responsivity is typically evident in the first 3 months of therapy and may be dramatic and sustained. Low MGMT expression, as determined by immunohistochemistry, is associated with a high response rate (76%), whilst high MGMT expression has not been associated with responses. MGMT promoter methylation does not correlate with temozolomide response., Conclusions: Temozolomide is the first chemotherapeutic agent to show substantial response rates in aggressive pituitary tumours. MGMT immunohistochemistry, but not MGMT methylation analysis, shows promise as a predictive tool. Prospective clinical trials are now necessary to more accurately determine the efficacy of this agent in this patient group., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

In humans the majority of endothelial cells (EC) constitutively express MHC class II Ags. We know that in vitro ECs can activate CD45RO(+) B7-independent CD4(+) T cells to proliferate and produce IL-2. The in vivo correlate of this T cell response is not known, and here we have explored whether endothelial expression of MHC class II Ags affects the transendothelial migration of alloreactive CD4(+) CD45RO(+) B7-independent T cells. Alloreactive CD4(+) T cell clones and lines were generated against HLA-DR11, DR13, DR4, and DR1 MHC Ags, and their rates of migration across untreated EC line Eahy.926 (MHC class II negative) or Eahy.926 transfected with CIITA (EahyCIITA) to express DR11 and DR13 were investigated. The migrations of EahyCIITA-specific T cell clones and lines were retarded in a DR-specific manner, and retardation was reversed in the presence of mAb to DR Ag. When investigating the ability of T cells to proliferate in response to EahyCIITA before and after transmigration, migrated cells were still able to proliferate, but the frequency of EahyCIITA-specific cells was much reduced compared with that of nonmigrated cells. The use of fluorescently labeled T cells revealed that specific cells become trapped within the endothelial monolayer. Pretreatment of EahyCIITA with IFN-gamma restored the ability of DR11- or DR13-specific T cells to transmigrate and proliferate, thus abrogating DR-specific retardation. We conclude that cognate interaction between T cells and endothelial MHC class II initiates a stop signal possibly similar to an immunological synapse, but this is overcome in an inflammatory milieu.