The Value of Textbook Outcome in Benchmarking Pancreatoduodenectomy for Nonfunctioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Textbook outcome (TO) is a composite variable that can define the quality of pancreatic surgery. The aim of this study is to evaluate TO after pancreatoduodenectomy (PD) for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). PATIENTS AND METHODS: All patients who underwent PD for NF-PanNETs (2007-2016) in different centers were included in this retrospective study. TO was defined as the absence of severe postoperative complications and mortality, length of hospital stay ≤ 19 days, R0 resection, and at least 12 lymph nodes harvested. RESULTS: Overall, 477 patients were included. The TO rate was 32%. Tumor size [odds ratio (OR) 1.696; p = 0.013], a minimally invasive approach (OR 12.896; p = 0.001), and surgical volume (OR 2.062; p = 0.023) were independent predictors of TO. The annual frequency of PDs increased over time as well as the overall rate of TO. At a median follow-up of 44 months, patients who achieved TO had similar disease-free (p = 0.487) and overall survival (p = 0.433) rates compared with patients who did not achieve TO. TO rate in patients with NF-PanNET > 2 cm was 35% versus 27% in patients with NF-PanNET ≤ 2 cm (p = 0.044). Considering only NF-PanNETs > 2 cm, patients with TO and those without TO had comparable 5-year overall survival rates (p = 0.766) CONCLUSIONS: TO is achieved in one-third of patients after PD for NF-PanNETs and is not associated with a benefit in terms of long-term survival.

Enucleation for Sporadic Nonfunctioning Pancreatic Neuroendocrine Tumors Larger than 2 Centimeters Is Associated with Equivalent Morbidity and Survival Compared to Smaller Tumors: A Multi-Institutional Study.

INTRODUCTION: Nonfunctioning pancreatic neuroendocrine tumor (NF-PanNET) ≤2 cm can be observed or resected. Surgery remains recommended for NF-PanNET >2 cm but its extent, enucleation (EN) versus formal resection, remains controversial. METHODS: Multicentric retrospective cohort of sporadic NF-PanNET patients treated with EN. Short- and long-term outcomes were compared according to tumor size on imaging ≤2 cm versus >2 cm. RESULTS: 131 patients underwent EN for NF-PanNET, including 103 (79.0%) ≤2 cm and 28 (21.0%) >2 cm (extremes, 4-55 mm). Patients' characteristics were comparable, and tumor characteristics only differed in their diameter. Clavien III-IV complications were similar (18.4% vs. 17.9%, p = 1.00) with one death in NF-PanNET ≤2 cm. Grade B/C pancreatic fistula were comparable (16.5% vs. 10.7%, p = 0.850). In NF-PanNET >2 cm there were more pT2/3 stage tumors (85.7% vs. 21.4%, p < 0.001), similar rates of grade G2/3 tumors (25% vs. 16.5%, p = 0.408) with a median Ki67 of 2 (interquartile range: 1-3), and of lymphovascular and perineural invasions. Lymph node picking was done in 46 (35.1%) patients, with a higher median number of harvested lymph nodes in NF-PanNET >2 cm (4 vs. 3, p = 0.01). All were pN0. R0 resection rate (78.6% vs. 82.5%, respectively; p = 0.670) was equivalent. Five-year overall (100% vs. 99%, p = 0.602) and 10-year disease-free (96% vs. 92%, respectively; p = 0.532) survivals were comparable. CONCLUSIONS: EN for selected NF-PanNET >2 cm carries equivalent morbidity, overall and disease-free survivals compared to those observed with NF-PanNET ≤2 cm.

Cabergoline treatment for surgery-naïve non-functioning pituitary macroadenomas.

PURPOSE: The treatment strategy of non-functioning pituitary adenomas (NFPAs) includes surgery, radiotherapy, medical therapy, or observation without intervention. Cabergoline, a dopaminergic agonist, was suggested for the treatment of NFPA remnants after trans-sphenoidal surgery. This study investigates the efficacy of cabergoline in surgery-naive patients with NFPA. METHODS: Retrospective cohort study including surgery-naive patients with NFPA ≥ 10 mm, treated with cabergoline at a dose of ≥ 1 mg/week for at least 24 months. Patients with chiasmal damage were excluded. Data collected included symptoms, in particular visual disturbances, hormonal levels, tumor characteristics and size evaluated by MRI. Tumor growth was defined as an increase in maximal diameter of ≥ 2 mm, and shrinkage as reduction of ≥ 2 mm. RESULTS: Our cohort included 25 patients treated with cabergoline as primary therapy. Mean age was 63.3 ± 17.3 years, 56% (14/25) were males. Mean tumor size at diagnosis was 18.6 ± 6.3 mm (median 17 mm, range 10-36), and the average follow-up period with cabergoline was 4.6 ± 3.4 years. Out of the 25 tumors, five tumors (20%) decreased in size (mean decrease of 5.0 ± 3.0 mm), 12 tumors (48%) remained stable, and eight (32%) increased in size (mean growth of 5.0 ± 3.3 mm) with cabergoline treatment. During the first two years of cabergoline treatment, the median tumor size exhibited a reduction of 0.5 mm. Patients with an increase in tumor size had larger adenomas at diagnosis and a longer follow-up. Two patients (8%) underwent surgery due to tumor enlargement. CONCLUSION: Primary treatment with cabergoline is a reasonable approach for selected patients with NFPAs without visual threat.

Pituitary apoplexy: a comprehensive analysis of 93 cases across functioning and non-functioning pituitary adenomas from a single-center.

INTRODUCTION: Pituitary apoplexy (PA) is a rare clinical syndrome due to acute/subacute pituitary hemorrhage and/or infarction; data on PA in functioning pituitary adenoma (FPA) is scarce. METHODS: A retrospective record-review of details of PA in non-functioning (NFPA) and FPA managed at tertiary endocrine center. RESULTS: 93 patients [56 males; 33.3% FPA: 5 acromegaly, 14 prolactinoma, and 12 Cushing's Disease (CD)] diagnosed with PA were included. Median age was 40 years, with younger age of presentation in FPA. Type A (acute) [49.5%] and headache (78.5%) were the commonest presentations, with PA being the initial manifestation in 98.4% of NFPA. Median (range) Pituitary Apoplexy Score (PAS) was 2 (0-8). Median tumor diameter was 2.5 cm, with larger tumors in FPA (3.2 cm vs. 2.3 cm). 29 (46.7%) NFPA-PA and 14 (45.2%) FPA-PA patients [71% prolactinoma, 33% in CD, and none in acromegaly] were conservatively managed. In the NFPA cohort, those managed surgically had significantly higher PAS (4 vs. 1) and larger tumor size (2.6 vs. 1.8 cm); however, both arms had comparable recovery of neuro-visual, radiological, and hormonal outcomes. In FPA cohort, CD and acromegaly required definitive treatment, whereas prolactinomas were effectively managed (clinical and biochemical recovery) with oral cabergoline and glucocorticoids. Matching PAS cohorts (to overcome allocation bias for management approach) in macroadenomas (excluding prolactinoma) showed comparable neuro-deficit and hormonal recovery between surgical and conservative approaches. CONCLUSION: PA in FPA has distinct features and management issues. Carefully selected patients (PAS guided) in NFPA with PA for conservative management have comparable outcomes to surgery.

Headache in patients with non-functioning pituitary adenoma before and after transsphenoidal surgery - a prospective study.

PURPOSE: To study the long-term effect of transsphenoidal surgery (TSS) on headache in patients with non-functioning pituitary adenoma (NFPA) and identify factors predicting headache relief following TSS. METHODS: We evaluated headache in 101 consecutive patients with NFPA who underwent TSS from September 2015 to December 2021, preoperatively and 12-months post-surgery, by using the Migraine Disability Assessment (MIDAS) questionnaire. Health-related quality of life (QoL) was assessed using the EQ-5D visual analogue scale (EQ-VAS). RESULTS: Of 101 patients, 27 (27%) experienced disabling preoperative headache. Among these, the median total MIDAS score improved from 60 (interquartile range (IQR): 19-140) to 10 (IQR: 0-49) (P = 0.004). Additionally, headache frequency over a 90-day period decreased from 45 (IQR: 25-83) to 6 (IQR: 3-36) days (P = 0.002), and headache intensity decreased from 5 (IQR: 4-7) to 4 (IQR: 2-7) (P = 0.016) at 12-months post-surgery. At 12 months post-surgery, 18 (67%) of 27 patients with preoperatively disabling headache showed clinically relevant improvement of their headache, 4 (15%) showed deterioration, and 5 (19%) remained unchanged. In patients with clinically relevant improvement of their headache, the EQ-VAS score improved from 50 (IQR: 30 - 7) to 80 (IQR: 65-86) (P < 0.001). Of the 74 patients with no preoperative headache, 11 (15%) developed postoperative headache. We identified no clinical factors predicting postoperative headache relief. CONCLUSION: The study supports that clinically significant and long-lasting improvements of disabling headache and QoL can be achieved with TSS in a substantial number of patients with NFPA.

Surveillance Imaging Strategies for Pituitary Adenomas: When, How Frequent, and When to Stop.

OBJECTIVE: To describe a practical approach of when and how often to perform imaging, and when to stop imaging pituitary adenomas (PAs). METHODS: A literature review was carried out and recommendations provided are derived largely from personal experience. RESULTS: Magnetic resonance imaging is the mainstay imaging modality of choice in the assessment, treatment planning, and follow-up of PAs. These adenomas are discovered incidentally during imaging for a variety of unrelated conditions, because of clinical symptoms related to mass effects on the adjacent structures, or during workup for functional alterations of the adenoma. Imaging is also used in the preoperative and postoperative phases of assessment of PAs, for surgical and radiotherapy planning, for postoperative surveillance to assess for adenoma stability and detection of adenoma recurrence, and for surveillance to monitor for adenoma growth in unoperated PAs. Currently, because there are no evidence-based consensus recommendations, the optimal strategy for surveillance imaging of PAs is not clearly established. Younger age, initial adenoma size, extrasellar extension, mass effect, cavernous sinus invasion, functional status, histopathologic characteristics, cost considerations, imaging accessibility, patient preference, and patient contraindications (eg, implanted metallic devices and patient claustrophobia) are all important factors that influence the strategy for surveillance imaging. CONCLUSIONS: This review provides a practical approach of performing surveillance imaging strategies for PAs that should be individualized based on clinical presentation, history, adenoma morphology on imaging, and histopathologic characteristics.

Excess mortality in patients with non-functioning pituitary adenoma: a systematic review and meta-analysis.

BACKGROUND: Patients with non-functioning pituitary adenoma (NFPA) often present with a variety of clinical manifestations and comorbidities, mainly determined by the local mass effect of the tumor and by hypopituitarism. Whether this has an impact on overall mortality, however, is still unclear. METHODS: PubMed/Medline, EMBASE, and Cochrane Library databases were systematically searched until May 2023 for studies reporting data either about standardized mortality ratios (SMRs) or about predictors of mortality in patients with NFPA. Effect sizes were pooled through a random-effect model. This systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO, #CRD42023417782). RESULTS: Eleven studies were eligible for inclusion in the systematic review; among these, five studies reported data on SMRs, with a total follow-up time of approximately 130,000 person-years. Patients with NFPA showed an increased mortality risk compared to the general population (SMR = 1.57 [95%CI: 1.20-1.99], p < 0.01). Age and sex appeared to act as effect modifiers, with a trend towards higher SMRs in females (SMR = 1.57 [95%CI: 0.91-2.41], p = 0.10) than in males (SMR = 1.00 [95%CI: 0.89-1.11], p = 0.97), and in patients diagnosed at age 40 years or younger (SMR = 3.19 [95%CI: 2.50-3.97], p < 0.01) compared to those with later onset of the disease (SMR = 1.26 [95%CI: 0.93-1.65], p = 0.13). The trend towards excess mortality was similar in patients with normal (SMR = 1.22 [95%CI: 0.94-1.53], p = 0.13) or deficient (SMR = 1.26 [95%CI: 0.82-1.79], p = 0.27) pituitary function. CONCLUSIONS: Excess mortality is observed in patients with NFPA, regardless of pituitary function, especially in women and in patients with a younger age at diagnosis.

Different tumor growth pattern of clinically nonfunctioning pituitary neuroendocrine tumor according to sex and age: a longitudinal study.

PURPOSE: Asymptomatic patients with clinically non-functional pituitary neuroendocrine tumors (CNF-PitNETs) are usually followed up. However, the natural course of CNF-PitNETs according to sex and age remains unclear. Therefore, this study assessed growth patterns of CNF-PitNETs according to sex and age. METHODS: In this longitudinal study, we enrolled 431 consecutive patients with CNF-PitNETs who were treated at Seoul National University Hospital from 1997 to 2021. The patients underwent hormone function testing and visual field testing, and were subsequently followed up with imaging over a median duration of 66 months. RESULTS: The median age of the patients was 53.0 years, and 37.1% (n = 160) were men. Men were older and harbored more macroadenomas than women. The annual tumor volume change was higher in men than in women (0.21 vs. 0.04 cm3/year, P < 0.001). The estimated cutoff value of age for significant tumor growth was 51 years. In men, the annual tumor volume change was similar across all age groups. In women, those aged ≤ 50 years showed significantly lower annual tumor volume change than those aged > 50 years (0.01, 0.11, and 0.17 cm3/year, P = 0.001). When comparing sexes within the same age group, the annual tumor volume changes was significantly lower for women than for men, only in patients aged ≤ 50 years (0.01 vs. 0.15 cm3/year, P < 0.001). CONCLUSIONS: Among patients with CNF-PitNET, tumor growth was slower in women aged ≤ 50 years than in men and women aged > 50. These findings may guide the customization of surveillance strategies for CNF-PitNETs according to sex and age.

Stereotactic radiosurgery for recurrent/residual nonfunctioning pituitary adenoma: a single-arm systematic review and meta-analysis.

BACKGROUND: Nonfunctioning pituitary adenomas (NFPAs) are a significant subtype of pituitary tumors, accounting for 30% of all pituitary tumors and 10-20% of intracranial tumors. The primary treatment for NFPAs is resection, but complete resection is often challenging due to the tumor's proximity to critical structures, leading to frequent recurrences. Stereotactic radiosurgery (SRS) has emerged as a viable treatment option for recurrent or residual NFPAs, but its long-term efficacy and safety profile require further investigation. METHODS: This systematic review followed PRISMA guidelines and included studies published up to February 2024. We searched MEDLINE, Embase, and Cochrane databases for studies evaluating SRS for recurrent/residual NFPAs. Inclusion criteria focused on studies reporting outcomes and complications of SRS, while exclusion criteria omitted case reports, case series, and non-English studies. Data extracted included demographic details, dosimetry parameters, and follow-up durations. The risk of bias was assessed using the ROBINS-I tool, and statistical analyses were performed using single-arm meta-analyses. RESULTS: A total of 24 studies involving 3,781 patients were included. The mean follow-up duration was 60 months. Tumor control was achieved in approximately 92.3% of patients. The risk of developing hypopituitarism post-SRS was 13.62%, while the risk for panhypopituitarism was 2.55%. New visual field deficits occurred in 3.94% of patients. Cranial nerve deficits were rare, with event rates below 1% for CN III, CN V, and CN VI. CONCLUSION: SRS is effective in managing recurrent or residual NFPAs, achieving high tumor control rates. However, the risk of hypopituitarism remains a significant concern, necessitating regular endocrinological monitoring. While generally safe, the potential for new visual field deficits and other cranial nerve deficits must be considered. SRS remains a valuable treatment option, but clinicians should be aware of its potential complications.

Is radiomics a useful addition to magnetic resonance imaging in the preoperative classification of PitNETs?

BACKGROUND: The WHO 2021 introduced the term pituitary neuroendocrine tumours (PitNETs) for pituitary adenomas and incorporated transcription factors for subtyping, prompting the need for fresh diagnostic methods. Current biomarkers struggle to distinguish between high- and low-risk non-functioning PitNETs. We explored if radiomics can enhance preoperative decision-making. METHODS: Pre-treatment magnetic resonance (MR) images of patients who underwent surgery between 2015 and 2019 with available WHO 2021 classification were used. The tumours were manually segmented on the T1w, T1-contrast enhanced, and T2w images using 3D Slicer. One hundred Pyradiomic features were extracted from each MR sequence. Models were built to classify (1) somatotroph and gonadotroph PitNETs and (2) high- and low-risk subtypes of non-functioning PitNETs. Feature were selected independently from the MR sequences and multi-sequence (combining data from more than one MR sequence) using Boruta and Pearson correlation. Support vector machine (SVM), logistic regression (LR), random forest (RF), and multi-layer perceptron (MLP) were the classifiers used. Data imbalance was addressed using the Synthetic Minority Oversampling TEchnique (SMOTE). Performance of the models were evaluated using area under the receiver operating curve (AUC), accuracy, sensitivity, and specificity. RESULTS: A total of 222 PitNET patients (train, n = 149; test, n = 73) were enrolled in this retrospective study. Multi-sequence-based LR model discriminated best between somatotroph and gonadotroph PitNETs, with a test AUC of 0.84, accuracy of 0.74, specificity of 0.81, and sensitivity of 0.70. Multi-sequence-based MLP model perfomed best for the high- and low-risk non-functioning PitNETs, achieving a test AUC of 0.76, accuracy of 0.67, specificity of 0.72, and sensitivity of 0.66. CONCLUSIONS: Utilizing pre-treatment MRI and radiomics holds promise for distinguishing high-risk from low-risk non-functioning PitNETs based on the latest WHO classification. This could assist neurosurgeons in making critical decisions regarding surgery or alternative management strategies for PitNETs after further clinical validation.

How effective is nephrectomy in curing hypertension in children with unilateral poorly functioning kidney? A systematic review.

PURPOSE: Some children with hypertension (HTN) have unilateral poorly functional kidney (PFK). This provides an opportunity for the clinician to cure the HTN by removal of the PFK, thereby avoiding the problems of long-term medication. However, there is sparse data in children regarding the effect of PFK nephrectomy on curing HTN. In this review, we analysed the etiology of PFK causing HTN and the effectiveness of nephrectomy in curing HTN in children. METHODS: We searched the databases to identify papers between January 2000 to December 2020 pertaining to children with PFK and HTN who underwent nephrectomy. Outcome analyzed was the resolution of HTN following nephrectomy. Duplicate publications, review articles and incomplete articles were excluded. Meta-analysis of heterogeneity was reported with I2statistics. Forest plot was constructed to compare the pooled prevalence of HTN resolution. RESULTS: Five articles with 88 patients were included. Majority (43%) of PFK were due to the unilateral atrophic kidney with or without vesicoureteral reflux (VUR); ureteropelvic junction obstruction and multicystic dysplastic kidney together accounted for 35% of cases and renovascular pathology for 22% of cases. With a follow-up of 1.5 to 3.3 years, nephrectomy was effective to cure HTN in 65.9% (95% CI 55-75%) children. CONCLUSIONS: In children with HTN and a unilateral PFK, nephrectomy cured the HTN in two-thirds of children. Unilateral atrophic kidney due to VUR was the most common cause of PFK. An increase in the utilisation of laparoscopy was observed in recent publications, hence laparoscopic nephrectomy may be considered a first choice of treatment in these children.

Induction of apoptosis by oridonin in nonfunctioning pituitary adenoma cells.

Nonfunctioning pituitary adenoma (NFPA) is one of the major subtypes of pituitary adenomas (PA) and its primary treatment is surgical resection. However, normal surgery fails to remove lesions completely and there remains in lack of frontline treatment, so the development of new drugs for NFPA is no doubt urgent. Oridonin (ORI) has been reported to have antitumor effects on a variety of tumors, but whether it could exhibit the same effect on NFPA requires to be further investigated. The effects of ORI on pituitary-derived folliculostellate cell line (PDFS) cell viability, colony formation, proliferation ability, migration, and invasion were examined by Cell Counting Kit-8, colony formation assay, 5­Ethynyl­2'­deoxyuridine proliferation assay, wound-healing assay, and Transwell assay. The differentially expressed genes in the control and ORI-treated groups were screened by transcriptome sequencing analysis and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Cell cycle analysis was performed to detect changes in cell cycle. Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to detect apoptosis in ORI-treated cells. Western blot assay was performed to detect Bax, Bcl-2, and cleaved Caspase-3 protein expression. ORI inhibited PDFS cell viability and significantly suppressed cell proliferation, migration, and invasion. GO and KEGG results showed that ORI was associated with signaling pathways such as cell cycle and apoptosis in PDFS cells. In addition, ORI blocked cells in G2/M phase and induced apoptosis in PDFS cells. ORI can trigger cell cycle disruption and apoptosis collaboratively in PDFS cells, making it a promising and effective agent for NFPA therapy.

Magnetic Resonance Imaging Features of the Sphenoid Sinus in Patients with Non-Functioning Pituitary Adenoma.

Background and Objectives: A magnetic resonance imaging (MRI) scan is part of the diagnostic protocol in pituitary adenoma patients. The goal of the present study is to present and analyse the MRI appearances of the sphenoid sinus (SS) in patients with non-functioning pituitary adenoma (NFPA). Materials and Methods: This is a retrospective case-control study conducted between January 2015 and December 2023 in a tertiary referral hospital. Forty NFPA patients were included in the study group, while the control group consisted of 30 age- and gender-matched cases. Results: The sellar type of SS pneumatization was the most frequently encountered pattern among both groups. The presence of the lateral recess of the SS, mucosal cysts, and sphenoethmoidal cells was similar in both patient groups. The proportion of patients with SS mucosal thickness greater than 3 mm was 42.5% in NFPA group and 3% in the control group, and this difference was statistically significant (p < 0.001). The space between the two optic nerves was significantly larger in the NFPA group as compared to the control group (p < 0.001). Conclusions: Our study was able to establish a statistically significant association between the presence of NFPA and both the thickening of the SS mucosa and increased space between optic nerves.

Clinical, radiological, and surgical outcomes of 431 patients with adrenal incidentalomas: retrospective study of a 10-year single-center experience.

Background/aim: The incidence of adrenal tumors is increasing due to the widespread utilization of radiographic imaging techniques. Factors such as tumor size, radiological characteristics, and functionality of adrenal adenomas play crucial roles in diagnosis and subsequent management. In this retrospective study, we investigated the clinical, radiological, and surgical features of patients with adrenal incidentalomas (AIs) and evaluated their follow-up results. Materials and methods: We analyzed data from 431 patients diagnosed with AIs (130 males, 301 females) who underwent adrenal hormone evaluation at our center. We compared nonfunctioning and functioning AIs in terms of radiological features. We also compared baseline and follow-up characteristics in nonfunctioning AIs. Results: The mean age of the patients was 55.4 ± 11.5 years, with a mean tumor size of 25.9 ± 14.3 mm. Mean follow-up duration was 3.17 ± 2.07 years. Adenoma localization revealed 165 (38.3%) right-sided, 185 (42.9%) left-sided, and 81 (18.8%) bilateral cases. Most patients (76.6%) had nonfunctioning AIs. During follow-up, nonfunctioning AIs exhibited increased fasting blood glucose, fasting insulin and HOMA-IR values (p = 0.002, <0.001 and 0.004, respectively). Among the functioning AIs cases (23.4%), autonomous cortisol secretion, Cushing's syndrome, pheochromocytoma, and primary aldosteronism were observed in 10.4%, 5.1%, 3.9%, and 3.9% of cases, respectively. Receiver operating characteristic curve analysis determined an adrenal adenoma size of 26.5 mm as the optimal cut-off for distinguishing between functioning and nonfunctioning AIs, with a sensitivity and specificity of 61.4% and 70.0%, respectively. Conclusion: Although the majority of AIs are nonfunctioning, the prevalence of functioning adrenal adenomas is not rare. Our findings suggest that adenoma size emerges as a valuable predictor for early detection of functioning adenomas. In addition, smaller masses appear to carry a lower risk of malignancy.

Expression of cAMP and oxidative phosphorylation-related lncRNAs in non-functioning pituitary adenomas.

Non-functioning pituitary adenomas (NFPAs) are benign lesions in the pituitary gland with important morbidities. In this study, based on a bioinformatics analysis to identify the genes and pathways that display significant differences between tumour tissues of NFPA patients and normal pituitary tissues, we selected lncRNAs related to cAMP and oxidative phosphorylation pathways, namely DNAH17-AS1, LINC00706 and SLC25A5-AS1. Then, we aimed to investigate by means of RT-qPCR, the expression of these lncRNAs along with two other lncRNAs, namely CADM3-AS1 and MIR7-3HG in NFPA samples compared to that in healthy tissues adjacent to the tumours. Transcripts of DNAH17-AS1, LINC00706 and MIR7-3HG were lower in NFPA samples compared with controls (Expression ratios (95% CI) = 0.43 (0.23-0.78), 0.58 (0.35-0.96) and 0.58 (0.35-0.96); p-values = 0.009, 0.025 and 0.036, respectively). AUC values of ROC curves of DNAH17-AS1, LINC00706 and MIR7-3HG were 0.62, 0.61 and 0.62, respectively. Expression of CADM3-AS1 was associated with the gender of patients in a way that it was lower in female patients (p-value = 0.04). The level of SLC25A5-AS1 was lower in subjects with disease duration lower than 1 year (p-value = 0.048). We showed dysregulation of three lncRNAs in NFPA tissues and potentiates these lncRNAs as important regulators of pathogenic events in these tumours.

Upregulation of MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 lncRNAs in non-functioning pituitary adenoma.

Long non-coding RNAs (lncRNAs) have been shown to be dysregulated in a variety of malignant and non-malignant lesions including non-functioning pituitary adenomas (NFPAs). In the current experimental study, we have selected six lncRNAs, namely MAPKAPK5-AS1, NUTM2B-AS1, ST7-AS1, LIFR-AS1, PXN-AS1 and URB1-AS1 to assess their expression in a cohort of Iranian patients with NFPA. MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 were shown to be over-expressed in NFPA tissues compared with control samples (Expression ratios (95% CI) = 10 (3.94-25.36), 11.22 (4.3-28.8) and 9.33 (4.12-21.12); p values < 0.0001, respectively). The depicted ROC curves showed the AUC values of 0.73, 0.80 and 0.73 for MAPKAPK5-AS1, PXN-AS1 and URB1-AS1, respectively. Relative expression level of PXN-AS1 was associated with tumour subtype (p value = 0.49). Besides, relative expression levels of MAPKAPK5-AS1 and LIFR-AS1 were associated with gender of patients (p values = 0.043 and 0.01, respectively). Cumulatively, the current study indicates the possible role of MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 lncRNAs in the pathogenesis of NFPAs.

Characterisation of the urinary steroid profile of patients with nonfunctioning adrenal incidentalomas: A matched controlled cross-sectional study.

AIM: To identify alterations in steroid metabolism in patients with nonfunctioning adrenal incidentalomas (NFAIs) through the analysis of their urinary steroid profile (USP). METHODS: Cross-sectional study with one study group (NFAIs, cortisol post dexamethasone suppression test [DST] ≤ 1.8 µg/dl [49.7 nmol/L]) and 2 control groups: patients with autonomous cortisol secretion (ACS group, cortisol post-DST > 1.8 µg/dl (49.7 nmol/L) and patients without adrenal tumours (healthy-adrenal group). Twenty-four-hour urine collections for USP measurement (total and free fraction of 51 24 h-urine specimens) were obtained from 73 participants (24 with NFAIs, 24 without AIs, and 25 with ACS). USP was determined by gas chromatography coupled to mass spectrometry. Patients of the three groups were matched according to sex, age (±5 years-old) and body mass index (±5 kg/m2 ). RESULTS: Compared to healthy-adrenal controls, patients with NFAIs had a lower excretion of androgen metabolites (230.5 ± 190.12 vs. 388.7 ± 328.58 µg/24 h, p = .046) and a higher excretion of urinary free cortisol (UFC) (54.3 ± 66.07 vs. 25.4 ± 11.16 µg/24 h, p = .038). UFC was above the reference range in 20.8% of patients in the NFAI, compared to 0% in the healthy-adrenal group (p = .018). Patients with ACS had a higher prevalence of hypertension, dyslipidemia, and diabetes than patients with NFAIs or the control group. A lower excretion of androgen metabolites (218.4 ± 204.24 vs. 231 ± 190 µg/24 h, p = .041) and a nonsignificant higher excretion of glucocorticoid metabolites (2129.6 ± 1195.96 vs. 1550.8 ± 810.03 µg/24 h, p = .180) was found in patients with ACS compared to patients with NFAIs. CONCLUSION: NFAIs seem to secrete a subtle, yet clinically relevant, excess of glucocorticoids. Future studies are needed to confirm our findings; and to identify metabolic alterations associated with an increased cardiometabolic risk.

Natural history of nonfunctioning pituitary macroadenomas followed without intervention: A retrospective cohort study.

OBJECTIVE: The treatment strategy for nonfunctioning pituitary adenomas (NFPA) includes surgery, radiotherapy, medical treatment, or follow-up. Prior series of patients with NFPAs followed without intervention include small numbers of patients with macroadenomas. This study investigated the natural history of patients with macroadenomas followed without treatment. DESIGN AND PATIENTS: Retrospective cohort study included patients>18 years, with a diagnosis of NFPA ≥ 10 mm who were naïve to surgery or medical treatment and followed more than 12 months after diagnosis. Patients with chiasmal threat were excluded. Follow-up terminated if the patient underwent surgery, received cabergoline or was lost to follow-up. MEASUREMENTS: Data collected included evaluation of tumour characteristics and size by MRI, symptoms including visual disturbances, and hormonal levels. Tumour growth was defined as maximal diameter increase of ≥2 mm. RESULTS: The cohort included 49 patients (30 males, mean age 68.0 ± 12.0 years). At diagnosis, the average tumour size was 17.8 ± 5.9 mm. Mean follow-up time was 4.9 ± 4.9 years. Increase in tumour size occurred in 16 patients (33%), with an average growth of 5.1 ± 4.4 mm. Reduction in tumour size occurred in 10 patients (20%), with a mean decrease of 3.5 ± 1.3 mm. Twenty-three patients remained with stable tumours. Overall, 33 patients (67%) were observed without any intervention; 3 patients were operated and 13 were treated with cabergoline. None of the parameters including age, gender, baseline tumour size, invasiveness, visual disturbances, or hypopituitarism at diagnosis, predicted tumour growth. CONCLUSION: Observation of NFPAs without surgery or medical therapy is a reasonable approach in selected patients. In our study, no parameter predicted tumour growth.

The degree of cortisol secretion is associated with diabetes mellitus and hypertension in patients with nonfunctioning adrenal tumors.

BACKGROUND: Similarly to cortisol-secreting adrenal tumors, also non-functioning adrenal tumors (NFAT) may be associated with an increased cardiovascular risk. We assessed in NFAT patients: (i) the association between hypertension (HT), diabetes mellitus (DM), obesity (OB), dyslipidemia (DL) and cardiovascular events (CVE) and cortisol secretion; (ii) the cut-off of the cortisol secretion parameters for identifying NFAT patients with a worse cardiometabolic profile. PATIENTS AND METHODS: In 615 NFAT patients (with cortisol levels after 1 mg overnight dexamethasone suppression test, F-1mgDST < 1.8 µg/dL [50 nmol/L]) F-1mgDST and adrenocorticotroph hormone (ACTH) levels and data on HT, DM, OB, DL and CVEs prevalence were retrospectively collected. RESULTS: HT, DM and HT plus DM were associated with F-1mgDST levels (area under the ROC curve: 0.588 ± 0.023, 0.610 ± 0.028, 0.611 ± 0.033, respectively, p < 0.001 for all comparisons) but not with ACTH. The cut-off for identifying patients with either HT or DM or HT plus DM was set at ≥ 1.2 µg/dL (33 nmol/L). As compared with patients with F-1mgDST < 1.2 µg/dL (n = 289), patients with F-1mgDST 1.2-1.79 µg/dL (33-49.4 nmol/L) (n = 326) had lower ACTH levels (17.7 ± 11.9 vs 15.3 ± 10.1 pg/mL, respectively, p = 0.008), older age (57.5 ± 12.3 vs 62.5 ± 10.9 years, respectively, p < 0.001), and higher prevalence of HT (38.1% vs 52.5% respectively p < 0.001), DM (13.1% vs 23.3%, respectively, p = 0.001), HT plus DM (8.3% vs 16.9%, respectively, p < 0.002) and CVE (3.2% vs 7.3%, respectively, p = 0.028). F-1mgDST 1.2-1.79 µg/dL was associated with either HT (odd ratio, OR, 1.55, 95% confidence interval, 95% CI 1.08-2.23, p = 0.018) or DM (OR 1.60, 95% CI 1.01-2.57, p = 0.045) after adjusting for age, gender, OB, DL, and DM (for HT) or HT (for DM), and with the presence of HT plus DM (OR 1.96, 95% CI 1.12-3.41, p = 0.018) after adjusting for age, gender, OB and DL. CONCLUSIONS: In NFAT patients, F-1mgDST 1.2-1.79 µg/dL seems to be associated with a higher prevalence of HT and DM and a worse cardiometabolic profile, even if the poor accuracy of these associations suggests caution in interpreting these results.

UK practice on incidentally detected non-functioning pituitary microadenomas: analysis of two national surveys during a 12-year interval.

PURPOSE: The optimal management approach for presumed non-functioning pituitary microadenomas (microNFPAs) remains unclear. Our aim was to capture current UK practice and identify changes with time. METHODS: Two online surveys investigating clinicians' approaches were performed in 2009-2010 and 2021-2022 (advertised through Society for Endocrinology UK). RESULTS: 150 and 214 clinicians participated in the 2021 and 2009 survey, respectively (response rates 31.2% and 35.4%, respectively). At baseline, 2021 survey respondents were more likely to measure IGF-1 (96.0% vs 74.1%, p < 0.001) and morning cortisol (87.9% vs 62.6%, p < 0.001), and less likely GH (26.2% vs 42.6% p = 0.002), 24 h urine free cortisol (3.4% vs 23.2%, p < 0.0001) or dynamically assess adrenal reserve (11.4% vs 30.4%, p < 0.001). 47.2% of clinicians in 2021 would reassess pituitary function annually until discharge (in absence of tumour growth/symptoms). The 2021 survey respondents were more likely to stop imaging at or before 3 years (81.7% vs 44.3%, p < 0.001) and at or before 5 years (86.6.% vs 72.9%, p = 0.002), whilst 2009 survey respondents were more likely to continue imaging beyond 5 years (24% vs 7%, p < 0.001). Responses on imaging frequency/intervals showed notable variability in both surveys. CONCLUSIONS: Diagnostic and management approaches for microNFPAs have evolved in the UK. Biochemical investigations are performed in accord with consensus guidelines, though many clinicians perform annual biochemical surveillance without tumour growth/symptoms. A small number of clinicians request imaging beyond 5 years, but the frequency of imaging intervals until discharge remains variable. Robust evidence on the long-term natural history of microNFPAs is necessary to unify clinician approach.