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Objective Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as the gold standard to differentiate between Cushing´s disease (CD) and ectopic Cushing's syndrome (ECS). However, published data on the diagnostic value of additional prolactin analysis are controversial. Thus, we evaluated the diagnostic performance of BIPSS with and without prolactin in a multicenter study. Design and methods Retrospective study in five European reference centers. Patients with overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of BIPSS with human corticotropin–releasing hormone stimulation were eligible. Cut-offs for the inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and the normalized ACTH:prolactin IPS:P ratio were calculated via receiver operator characteristic analyses (reference: CD). Results 156 patients with BIPSS were identified. Of these, 120 patients (92 [77%] females; 106 [88%] CD, 14 [12%] ECS) had either histopathologically confirmed tumors or biochemical remission and/or adrenal insufficiency after surgery; only this subgroup was analyzed by ROC analysis. The optimal cut-offs for the ACTH IPS:P ratio were ≥1.9 at baseline (sensitivity 82.1% [95% CI, 73.2-88.6], specificity 85.7% [95% CI, 56.2-97.5], AUC 0.86) and ≥2.1 at 5 minutes post-CRH (sensitivity 91.3% [95% CI, 83.6-95.7], specificity 92.9% [95% CI, 64.1-99.6], AUC 0.96). A subgroup underwent additional prolactin analysis. An optimal cut-off of ≥1.4 was calculated for the normalized ACTH:prolactin IPS:P ratio (sensitivity 96.0% [95% CI, 77.7-99.9], specificity 100% [95% CI, 56.1-100], AUC 0.99). Conclusion Our study confirms the high accuracy of BIPSS in the differential diagnosis of ACTH-dependent Cushing's syndrome and suggests that the simultaneous measurement of prolactin might further improve the diagnostic performance of this test.

Context Osteopathy and morphometric vertebral fractures (VFs) are emerging complications in acromegaly. However, the prediction of VFs in this clinical setting is still a matter of uncertainty, and it is debated whether they are an early event in the natural history of the disease. Objective We aimed to evaluate the prevalence and determinants of morphometric VFs in patients with recently diagnosed acromegaly. Methods We enrolled 92 patients (43 men/49 women) on admission to the neurosurgery unit before transsphenoidal surgery, and compared them with control individuals without secondary forms of osteoporosis and pituitary disorders. We performed a VF assessment on preoperative chest x-ray images and collected biochemical, demographic, and clinical data. Results We detected a significantly higher prevalence of VFs (33.7%) in patients with acromegaly than in controls (P = .001). Among the patients with acromegaly and VFs, 12 (38.7%) showed multiple VFs, and 5 (16.1%) showed moderate/severe VFs. Patients with VFs had higher random serum growth hormone (GH) levels than those with no VFs (P = .03), but there was no difference in insulin-like growth factor-1 (IGF-1) (P = .07) and IGF-1/Upper Normal Limit ratio (P = .08). Free 3,5,3′-triiodothyronine was slightly lower in patients with acromegaly and VFs than in those without VFs (P = .05). In multiple logistic analysis, GH was independently associated with risk for VFs (P = .003). The preoperative serum GH cutoff value that predicted VFs was 12 ng/mL. Conclusion For the first time, high prevalence of radiological VFs is reported in patients with recent diagnosis of acromegaly. Therefore, we can hypothesize that VFs are an early phenomenon of acromegaly and related to GH levels. VF assessment should be included in the workup at the diagnosis of acromegaly.

Rapamycin and its analogues have significant antiproliferative action against a variety of tumors. However, sensitivity to rapamycin is reduced by Akt activation that results from the ablative effects of rapamycin on a p70 S6K–induced negative feedback loop that blunts phosphoinositide 3-kinase (PI3K)–mediated support for Akt activity. Thus, sensitivity to rapamycin might be increased by imposing an upstream blockade to the PI3K/Akt pathway. Here, we investigated this model using the somatostatin analogue octreotide as a tool to decrease levels of activated Ser473-phosphorylated Akt (pAkt-Ser473) in pituitary tumor cells that express somatostatin receptors. Octreotide increased levels of phosphorylated insulin receptor substrate-1 that were suppressed by rapamycin, subsequently decreasing levels of pAkt-Ser473 through effects on phosphotyrosine phosphatase SHP-1. Octreotide potentiated the antiproliferative effects of rapamycin in immortalized pituitary tumor cells or human nonfunctioning pituitary adenoma cells in primary cell culture, sensitizing tumor cells even to low rapamycin concentrations. Combined treatment of octreotide and rapamycin triggered G1 cell cycle arrest, decreasing E2F transcriptional activity and cyclin E levels by increasing levels of p27/Kip1. These findings show that adjuvant treatment with a somatostatin analogue can sensitize pituitary tumor cells to the antiproliferative effects of rapamycin. Cancer Res; 70(2); 666–74

Supplementary Figures 1-6 from The Somatostatin Analogue Octreotide Confers Sensitivity to Rapamycin Treatment on Pituitary Tumor Cells

Supplementary Figure Legends 1-6 from The Somatostatin Analogue Octreotide Confers Sensitivity to Rapamycin Treatment on Pituitary Tumor Cells

Introduction. The glucocorticoid receptor is pivotal to control corticotrophin (ACTH) secretion and its function is closely linked to the heat shock protein 90 (HSP90) chaperone complex. Impaired sensitivity to glucocorticoid feedback is a hallmark of human corticotroph adenomas, i.e., Cushing’s disease, a disorder with few medical treatment options. Silibinin, a HSP90 inhibitor, has been studied in tumoral corticotroph cells and its use proposed in Cushing’s disease. Aim of the present study was to further investigate the effect of silibinin on human corticotroph adenomas in vitro. Methods. Seven human ACTH-secreting pituitary adenomas were established in culture and treated with 10 – 50 µM silibinin with/without dexamethasone for up to 72 hours. ACTH medium levels were measured and POMC and glucocorticoid receptor, i.e., NR3C1, gene expression assessed. Results. Silibinin reduced spontaneous ACTH secretion and restored sensitivity to steroid negative feedback to a different extent in individual adenomas. POMC expression was decreased both in control and dexamethasone-treated wells in specimens sensitive to silibinin. Interestingly, silibinin reduced constitutive NR3C1 expression and reversed the dexamethasone-induced inhibition. Conclusions. Our findings indicate that silibinin can inhibit ACTH synthesis and secretion in individual human corticotroph adenomas and directly affects NR3C1 gene expression. These results reveal promising effects of this HSP90 inhibitor on human corticotroph adenomas and support an innovative target treatment for patients with Cushing’s disease.

Funder: Ono PharmaceuticalsTheodo Ida Herzog-Egli Stiftung, Funder: Stavros Niarchos Foundation (SNF); doi: https://doi.org/10.13039/501100004343, Funder: RCUK | Biotechnology and Biological Sciences Research Council (BBSRC); doi: https://doi.org/10.13039/501100000268, Funder: EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council); doi: https://doi.org/10.13039/100010663, Funder: Frances and Augustus Newman Foundation; doi: https://doi.org/10.13039/100007898, Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): H2020-WIDESPREAD-2018-2020-6; NCBio; 951923, Funder: FWO (Grant 1513616N), Funder: Lions Club Monteceneri, Funder: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation); doi: https://doi.org/10.13039/501100001711, Funder: Gelu Foundation, Swiss Initiative in Systems Biology, SystemsX.ch (PrionX, SynucleiX), Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond ('H-latch'), altering the flexibility of the α2-α3 and β2-α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity.

Gli adenomi ipofisari rappresentano un problema clinico di frequente presentazione nella pratica endocrinologica. Nella maggior parte dei casi si comportano come lesioni a bassa velocita di crescita, non invasive, con buona risposta alla terapia convenzionale e scarsa tendenza alla recidiva. Una quota di tali adenomi esibiscono pero un comportamento aggressivo e rappresentano una sfida nella pratica clinica quotidiana. Numerosi tentativi di classificazione sono stati effettuati nel tempo con lo scopo di semplificare l’approccio al paziente con adenoma ipofisario e permettere una corretta stratificazione e un piu precoce inquadramento delle lesioni. Scopo della Rassegna e quello di rivedere le principali innovazioni introdotte negli anni circa la definizione dell’adenoma ipofisario aggressivo, riprendendo le proposte di differenti gruppi associativi e soffermandosi sulle linee guida della WHO del 2017 e della European Society of Endocrinology del 2018, evidenziando quelli che, a nostro avviso, sono i potenziali vantaggi apportati da tali classificazioni e gli eventuali limiti applicativi individuabili.

Purpose: Nelson’s syndrome (NS) is a long-term complication of bilateral adrenalectomy in patients with Cushing’s disease. The best therapeutic strategy in NS has not been well defined. Gamma knife radiosurgery (GKRS) is very effective to stop the growth of the pituitary adenoma, which is the main goal of the treatment of patients with NS. We report the largest series of patients with NS treated by GKRS at a single center. Methods: The study was an observational, retrospective analysis of 28 consecutive patients with NS treated by GKRS in our department between 1995 and 2019. All patients had a growing ACTH-secreting pituitary adenoma. The main outcome of the study was to assess by the Kaplan–Meier method the risk of tumor progression after GKRS. Results: The median follow-up after GKRS treatment was 98months (IQR 61–155months, range 7–250months). Two patients (7.1%) had a recurrence of disease during follow-up. The 10-year progression-free survival was 91.7% (95% CI 80.5–100%). No patient had deterioration of visual function or oculomotor function after GKRS. New onset of hypogonadism and hypothyroidism occurred in 18.8% and 14.3% of the patients at risk. Conclusion: Our study confirms that GKRS may stop the tumor growth in the majority of patients with NS, even though very aggressive adenomas may ultimately escape this treatment. Safety of GKRS was good in our experience, but due attention must be paid to planning the distribution of radiation to critical structures, especially in patients previously treated by radiation.

Genome-wide CRISPR phenotypic screens are clarifying many fundamental biological phenomena. While pooled screens can be used to study selectable features, arrayed CRISPR libraries extend the screening territory to cell-nonautonomous, biochemical and morphological phenotypes. Using a novel high-fidelity liquid-phase plasmid cloning technology, we generated two human genome-wide arrayed libraries termed T.spiezzo (gene ablation, 19,936 plasmids) and T.gonfio (gene activation and epigenetic silencing, 22,442 plasmids). Each plasmid encodes four non-overlapping single-guide RNAs (sgRNAs), each driven by a unique housekeeping promoter, as well as lentiviral and transposable vector sequences. The sgRNAs were designed to tolerate most DNA polymorphisms identified in 10,000 human genomes, thereby maximizing their versatility. Sequencing confirmed that ∼90% of each plasmid population contained ≥3 intact sgRNAs. Deletion, activation and epigenetic silencing experiments showed efficacy of 75-99%, up to 10,000x and 76-92%, respectively; lentiviral titers were ∼107/ml. As a proof of concept, we investigated the effect of individual activation of each human transcription factor (n=1,634) on the expression of the cellular prion protein PrPC. We identified 24 upregulators and 12 downregulators of PrPC expression. Hence, the T.spiezzo and T.gonfio libraries represent a powerful resource for the individual perturbation of human protein-coding genes.

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.

Simple Summary Pituitary tumors represent approximately 10–15% of all brain neoplasms. Gamma Knife, the most commonly used stereotactic radiosurgery technique worldwide, plays an important role in the treatment of several pituitary neoplasm. It is currently used in cases of residual or recurrent tumors after surgery or as primary treatment when surgery is contraindicated. Its goals are long-term tumor control, preservation of visual function, and, for secreting pituitary adenomas, endocrine remission. Several retrospective case-series (level of evidence IV) on Gamma Knife for pituitary tumors have been published describing encouraging outcomes; only one systematic review and meta-analysis on non-functioning pituitary adenoma has been recently reported. We provide a systematic review of the literature and meta-analysis from the last two decades on Gamma Knife radiosurgery for several pituitary tumors with the aim of describing and confirming safety and effectiveness of this technique. Abstract To describe and evaluate outcomes of Gamma Knife radiosurgery (GK) for the treatment of pituitary tumors over the past twenty years, a systematic review and meta-analysis according to PRISMA statement was performed. Articles counting more than 30 patients were included. A weighted random effects models was used to calculate pooled outcome estimates. From 459 abstract reviews, 52 retrospective studies were included. Among them, 18 reported on non-functioning pituitary adenomas (NFPA), 13 on growth hormone (GH)-secreting adenomas, six on adrenocorticotropic hormone (ACTH)-secreting adenomas, four on prolactin hormone (PRL)-secreting adenomas, and 11 on craniopharyngiomas. Overall tumor control and five-year progression free survival (PFS) estimate after one GK procedure for NFPA was 93% (95% CI 89–97%) and 95% (95% CI 91–99%), respectively. In case of secreting pituitary adenomas, overall remission (cure without need for medication) estimates were 45% (95% CI 35–54%) for GH-secreting adenomas, 64% (95% CI 0.52–0.75%) for ACTH-secreting adenomas and 34% (95% CI: 19–48%) for PRL-secreting adenomas. The pooled analysis for overall tumor control and five-year PFS estimate after GK for craniopharyngioma was 74% (95% CI 67–81%) and 70% (95% CI: 64–76%), respectively. This meta-analysis confirms and quantifies safety and effectiveness of GK for pituitary tumors.

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more “typical” corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

Purpose: The increased life expectancy in the general population is causing rapid growth of the number of elderly patients. Pituitary adenomas (PAs) are one of those tumors whose incidence increases with age. Pituitary surgery in elderly has usually been considered riskier than in the younger population. The aim of this study was to evaluate the surgical outcome of a large series of patients who underwent transsphenoidal surgery for PAs. Methods: We retrospectively reviewed a series of patients who underwent transsphenoidal surgery for PAs in our institution. Inclusion criteria were: 65 years of age or more, and no previous pituitary surgery. Surgical outcomes of patients aged

Benchmarks are important to measure and aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery are not available. Therefore, we aimed to establish robust, standardized outcome benchmarks for transsphenoidal surgery of pituitary adenomas. A total of 2862 transsphenoidal tumor resections from 12 high-volume centers in 4 continents were analyzed. Patients were risk stratified and the median values of each center’s outcomes were established. The outcome benchmark was defined as the 75th percentile of all median values for a particular outcome as defined by Staiger et al. Out of 2862 patients, 1201 (41.9%) defined the benchmark cohort. The proportion of benchmark cases contributing to the final cohort ranged across centers between 22.1% to 59.7%. Within the benchmark cases, 928 (73.3%) patients underwent microscopic (MTS) and 263 (21.9%) patients endoscopic endonasal resection (EES). The overall postoperative complication rate was 18.9% with an in-hospital mortality between 0.0-0.8%. Benchmark cutoffs were ≤ 3.3% for reoperation rate, ≤ 4.6% for cerebrospinal fluid leak requiring intervention, and ≤ 15.3% for transient diabetes insipidus. At 6 months follow-up, benchmark cutoffs were calculated as follows: readmission rate: ≤ 7.1%, new hypopituitarism ≤ 15.5%, new neurological deficit ≤ 1.2%, tumor remnant ≤ 25.5%. This analysis defines benchmark values for transsphenoidal resection of pituitary adenomas targeting morbidity, mortality, surgical and tumor-related outcomes. The benchmark cutoffs can be used to assess different centers, patients’ populations, and novel surgical techniques.

PURPOSE: To analyse the efficacy and safety of the transsphenoidal microsurgical approach with open sella technique (OST) for the treatment of pituitary adenoma (PA) with suprasellar extension. METHODS: We retrospectively reviewed 2305 consecutive patients with PA who underwent their first surgery through the transsphenoidal microsurgical approach at our department between 1990 and 2018. Focusing on tumours with suprasellar extension, in particular, grade B, C and D adenomas according to Wilson-Hardy's classification, 376 patients who received the OST surgery were identified. Outcomes and complications were evaluated and compared with those obtained in patients who underwent a standard transsphenoidal approach (TSM). RESULTS: Two-hundred and sixty-four of 376 patients (70.2%) were found to be suffering from a non-functioning pituitary adenoma, whereas 112 of 376 patients (29.8%) from a hormone-secreting PA. The mean craniocaudal diameter of the tumor was 30.6 ± 0.3 mm (range, 21-75 mm) and 151 patients (40.1%) had a cavernous sinus invasion too. An overall surgical remission rate of 50.3% was achieved in the OST group, whereas the recurrence rate was 10.5%. Patients were followed for a mean period of 68 ± 1.4 months (range, 6-96 months). Less postoperative intrasellar haemorrhages have been recorded in the OST group than the TSM one (1.1% vs. 4.6%, p = 0.02). CONCLUSIONS: In experienced hands, OST represents an effective and safe treatment strategy for PA with suprasellar extension.

ASC-containing inflammasomes form specks, extracellular aggregates which enhance the aggregation of Aβ amyloid in Alzheimer’s disease. This raises the question whether ASC participates to additional aggregation proteinopathies. Here we show that ASC controls the extent of inflammation-related AA amyloidosis, a systemic disease caused by the aggregation of the acute-phase reactant serum amyloid A (SAA). Using superresolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Purified recombinant ASC specks accelerated SAA fibril formationin vitro. Mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain. In a murine model of inflammation-related AA amyloidosis, splenic AA amyloid load was conspicuously decreased inPycardtm1Vmd/tm1Vmdmice which lack ASC. This reduction was not a consequence of enhanced amyloid phagocytosis, as SAA stimulation increased phagocytic activity inAsc+/+, but not inAsc-/-macrophages. Treatment with anti-ASC antibodies decreased the amyloid loads and attenuated the body-weight loss of wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC50≥ 2) in 19,334 hospital patients was

BACKGROUND Little is known about possible underlying psychological abnormalities and physiology of reflux hypersensitivity (RH) as defined in the recent Rome IV classification. We aimed to assess markers of psychological comorbidity as well as gastro-esophageal reflux measurements in RH patients compared to controls and also in patients with functional heartburn (FH) and non-erosive reflux disease (NERD) versus controls. METHODS Data of 304 patients visiting our Functional Diagnostics Centre from 2016 to 2018 were analyzed. We focused on a psychological assessment using validated questionnaires (visceral sensitivity index; VSI, hospital anxiety and depression score; HADS) as well as multichannel intraluminal impedance (MII) and pH-metry data from the diagnostic work-up. KEY RESULTS We found a decreased VSI of 57.8 ± 15.4 points (pts) among RH patients (n = 45) indicating higher visceral sensitivity compared to 85.7 ± 2.0 pts in the control group (n = 31, P

Colorectal cancers (CRCs) remain one of the most common and challenging neoplasia in the Western world. The response rate of immunotherapeutic treatment approaches in a subset of advanced CRCs is remarkable and has sustainably changed treatment regimens. Unfortunately, currently available immunotherapeutics only displayed significant antitumoral activity – in terms of progression free survival (PFS) and objective response rate (ORR) – in microsatellite instability-high (MSI-H)/DNA mismatch repair deficient (dMMR) CRCs. Subsequently, these remarkable results had led to the US Food and Drug Administration’s approval of both immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab in the treatment of advanced MSI-H/dMMR CRCs. However, in microsatellite stable (MSS)/DNA mismatch repair proficient (pMMR) CRCs, ICIs have clearly failed to meet their expectations and are therefore not considered effective. As the vast majority of CRCs display a molecular MSS/pMMR profile, current treatment approaches endeavor to improve tumor immunogenicity that consecutively leads to increased proinflammatory cytokine levels as well as tumor infiltrating T-cells, which in turn may be targeted by various immunotherapeutic agents. Therefore, ongoing studies are investigating novel synergistic therapy modalities and approaches to overcome a “cold” to “hot” tumor conversion in MSS/pMMR CRCs. In this review, we summarize the efficacy and possible immune-related adverse events as well as novel therapeutic approaches of ICIs in the treatment of MSI-H/dMMR and MSS/pMMR CRCs.

Purpose: The effects of growth hormone (GH) replacement on bone mass and body composition in adult with GH deficiency (AGHD) are still debated with regard to their persistence in the long term. Moreover, the impact of gender on the response to GH is controversial. Aim of this study was to evaluate the long-term effects of rhGH replacement on bone mass and body composition in a monocentric cohort of patients with AGHD.Methods: Data from 138 patients with AGHD (34.3 ± 14.3 years, 48 women and 90 men) treated with rhGH for a period of at least 3 years up to a maximum of 10 were retrospectively collected. Bone mineral density (BMD) at the lumbar spine, femur, and radius, and total and truncular body composition were evaluated by dual energy X-ray absorption (DXA) before and during treatment. Clinical and laboratory evaluations were performed before and during the treatment period on an annual basis.Results: Lumbar spine BMD consistently increased in males, while in females decreased after a transient improvement observed during the first 4 years of therapy. There were no significant changes in femoral BMD in either sexes, while a progressive increase at radius was observed only in males. Lean mass significantly increased in both sexes, while fat mass decreased only in males.Conclusions: In AGHD patients long-term rhGH replacement therapy induces a positive effect with regard to bone mass and body composition. A sexual dimorphism in the response to treatment is evident, with males displaying more favorable outcome.

Background Corticotroph tumor progression (CTP) leading to Nelson’s syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing’s disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. Methods A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. Results Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). Conclusions We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2–4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension

Brain‐matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion‐mimetic antibodies deplete the phosphoinositide kinase PIKfyve—which controls endolysosomal maturation—from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt‐Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB‐dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion‐infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2 suppressed prion‐induced vacuolation and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases., The phosphoinositide kinase PIKfyve is identified as the driver of brain vacuolation (spongiosis) in prion diseases. A hierarchy of events, starting the delocalization of PIKfyve‐specific acyltransferases and culminating in the enlargement of endolysosomes underlying spongiosis, is established.

Radiation therapy plays a crucial role as an adjuvant treatment in patients with residual or recurrent pituitary adenomas following surgery. Stereotactic radiosurgery permits a more precise dose delivery to the biological target and sparing of the normal surrounding structures. The Leksell Gamma Knife equipment is the most widespread technology to deliver stereotactic radiosurgery. Starting from the early 1990s, data on the efficacy and safety of Gamma Knife radiosurgery (GKRS) in pituitary adenoma have become increasingly available. The results of several studies confirm that GKRS has a good efficacy to reverse hormone hypersecretion and control tumor growth in most cases of pituitary adenomas. The safety profile of GKRS has been well demonstrated. Severe adverse events are rare, while the risk of hypopituitarism in cases with favorable morphological features may be relatively low.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP‐binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage‐derived antibodies. When expressed recombinantly, these antibodies exhibited anti‐PrP reactivity. Furthermore, we surveyed 48,718 samples from 37,894 hospital patients for the presence of anti‐PrP IgGs and found 21 high‐titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti‐PrP autoimmunity is innocuous. The existence of anti‐prion antibodies in unbiased human immunological repertoires suggests that they might clear nascent prions early in life. Combined with the reported lack of such antibodies in carriers of disease‐associated PRNP mutations, this suggests a link to the low incidence of spontaneous prion diseases in human populations., This study assessed the anti‐prion protein (PrP) immunoreactivity in human immunoglobulin repertoires and patient samples. Anti‐PrP autoimmunity can exist in human communities, appears to be innocuous, and may protect against prion infections.

Silibinin, a milk thistle extract with known hepatoprotective effects, has recently been shown to act upon tumoral corticotropes and revert the Cushingoid phenotype in an allograft mouse model (Riebold et al 2015). Silbinin is known to inhibit HSP90 -a chaperone to the glucocorticoid receptor- thereby restoring sensitivity to glucocorticoid negative feedback in tumoral corticotropes. Aim of the present study was to assess the effect of silibinin on ACTH synthesis and secretion by human corticotrope adenomas in vitro. Methods: Eight human ACTH-secreting pituitary adenomas were collected during surgery and established in culture as per our protocol (Pecori Giraldi et al 2011). Specimens were treated with 10 - 50 µM silibinin for up to 72 hours. ACTH medium levels were measured by Elisa; POMC expression was assessed by RT-PCR (Cassarino et al 2017). Results. Silibinin reduced spontaneous ACTH secretion to a variable extent in individual adenomas: from 32 to 79% of baseline at 4h, and 54 - 85 % of baseline at 48 and 72h. Silibinin was also effective in reinstating or enhancing sensitivity to steroid negative feedback: ACTH decreases during 10–50 µM silibinin incubation ranged from 10 to 63% of dexamethasone-treated wells at 4 hours, 70 -80% at 48 hours and 36 to 80% at 72 hours, indicating long-lasting effect on glucocorticoid sensitivity. Silibinin induced a variable decrease in POMC expression, both as regards expression in control and dexamethasone-treated wells; some specimens exhibited a marked sensitivity to the inhibitory effect, with POMC expression decreasing to less than 50% of control. Conclusions:, this data suggests that silibinin can inhibit ACTH secretion and POMC synthesis and restore sensitivity to negative glucocorticoid feedback. References: Cassarino et al (2017) Endocrine55: 853–860. Pecori Giraldi et al (2011) Journal of Neuroendocrinology23:1214–21. Riebold et al (2015) Nature Medicine21:276–280.

Introduction: somatostatin receptor ligands (SRL) represent the first-line medical therapy in acromegaly patients who were not cured by surgery and in those where surgical remission is unlikely. It is well known that SRL may negatively act on insulin secretion, with consequent hyperglycemia and diabetes mellitus (DM). Purpose: To evaluate whether the degree of response to surgical pre-treatment with SRL predicts alterations in blood glucose levels.Patients and Methods: We retrospectively studied 181 patients attending the Unit of Neurosurgery of our Hospital prior to transsphenoidal surgery. All patients had a biochemical and radiological diagnosis of acromegaly (nadir GH during OGTT >0.4 ng/mL; IGF-I above age-standardized UNL and pituitary adenoma at MRI scans); diagnosis of DM and impaired fasting glucose (IFG) was performed on fasting blood glucose (FBG) according to the American Diabetes Association guidelines; all parameters of the pituitary axes were determined. The response to SRL treatment was determined as percent change of GH levels. Data are presented as mean±SD; Continuous data normally distributed were analyzed using a two-tailed Student’s t-test to compare two groups, and one-way ANOVA to compare several groups, followed by the Bonferroni post-hoc procedure for pairwise comparison of groups after the null hypothesis was rejected (p

Context Treatment with somatostatin receptor ligands (SRLs) is often given before pituitary surgery to patients with acromegaly. Objective To study whether the response to treatment with SRLs is predictive of surgical outcome. Design Retrospective, observational study. Setting Tertiary care center. Patients We investigated 272 patients with acromegaly who had been treated with an SRL between 1990 and 2018. Intervention All patients underwent pituitary surgery performed by a skilled neurosurgeon. Main outcome measure Outcome of pituitary surgery in patients who had normalization of insulin-like growth factor 1 (IGF-1) levels during SRL therapy in comparison with patients who did not normalize IGF-1 levels. Results Normalization of IGF-1 levels during SRL treatment occurred in 62 patients (22.8%) and was similar for the 3 different types of SRL (P = .88). Surgical remission occurred in 59.6% of the patients. Patients who normalized IGF-1 levels during SRL treatment had a higher probability of surgical cure than patients without IGF-1 normalization (83.9% vs 52.4%, respectively; P < .001). Multivariate analysis confirmed that lack of cavernous sinus invasion, small maximum tumor diameter, and IGF-1 normalization during SRL therapy were the only factors independently associated with a favorable surgical outcome. Conclusions Our study demonstrates that the normalization of IGF-1 levels during treatment with SRLs is an independent predictive factor of a favorable surgical outcome. The underlying mechanisms remain unclear, but an optimal response to medical therapy may be a characteristic of less aggressive tumors that are more likely to be entirely removed at surgery.