In the majority (>95%) of patients with acromegaly, the underlying cause is a somatotroph adenoma. Pituitary-targeted surgery and radiotherapy can achieve long-term disease control but carry a significant adverse risk to the remaining normal gland, especially if undertaken outside a Pituitary Tumor Center of Excellence or when repeat surgery is performed. Maximizing benefits and minimizing the risks of pituitary surgery and radiotherapy is critically dependent on high-quality imaging that allows accurate localization of site(s) of either de novo, residual, or recurrent disease. Macroadenomas continue to predominate among somatotroph tumors (70%), but more widespread use of intracranial imaging leads to earlier detection of smaller adenomas, posing new challenges for imaging diagnostics. Despite several comprehensive guidelines on the management of acromegaly, there is little consensus regarding optimal imaging, and current scanning protocols remain heterogeneous. This serves as a barrier to optimal patient management and constrains comparison between centers, with inevitable consequences for research within the field. Here, based on a comprehensive review of previous studies and focusing on recent advances in magnetic resonance and molecular (functional) imaging techniques, we propose a standardized, tiered approach to pituitary imaging in patients with acromegaly, guided by individual patient features and tailored to the anticipated therapeutic approach. An online tool, which can be adapted to the clinical context, is provided as an aid to decision-making.

Giant pituitary adenomas (GPA) are considered difficult to treat and the operative procedures are associated with more complications. This study aimed to assess treatment strategies of GPAs in a large consecutive and uniformly documented series in a single specialized center. A total of 289 patients with GPA who underwent primary surgery in our department between December 1982 and December 2022 were analyzed in this retrospective study. GPAs were defined by a maximum diameter of ≥ 4 cm in at least one plane. Patients were reviewed for endocrine, radiological and ophthalmological outcomes as well as complication and mortality rates. The mean maximum tumor diameter was 4.6 ± 0.7 cm. 201 patients (69.6

BACKGROUND:Recurrence after successful pituitary surgery remains a challenge in the management of patients with Cushing's disease, with no reliable predictors of long-term outcome. Pathogenic somatic USP8 variants are found in one third of cases and their association with recurrence is unclear. The aim of this study was to determine the association between USP8 status and postoperative outcome. METHODS:This international, retrospective, longitudinal study was done in eight tertiary centres in east Asia, Europe, and North America. We reviewed clinical records and genetic information of patients with clinically diagnosed and pathologically confirmed Cushing's disease who underwent first pituitary surgery in any of the participating centres between Jan 1, 1989, and April 1, 2024. Inclusion criteria were postoperative follow-up of at least 3 months after first pituitary surgery, known postsurgical outcome, and tissue availability or known USP8 status. The primary outcomes were recurrence and time to recurrence after first surgery. We assessed recurrence-free intervals and recurrence risk using survival analysis, multivariate logistic regression, and Cox proportional hazards models. FINDINGS:We retrospectively retrieved and examined clinical records from 558 patients, 123 of whom were excluded. 360 (83%) of 435 patients were female and 75 (17%) were male. We detected USP8 variants in 195 (45%) cases. Recurrence was recorded in 66 (18%) of 371 patients in immediate remission. Risk of recurrence depended on USP8 status and tumour size. Patients with USP8-variant microadenomas and USP8-variant macroadenomas had similar cumulative hazards for recurrence, so they were considered as a single risk group. 10-year recurrence rate was higher for USP8-variant tumours (36·8%, 95% CI 23·7-47·7) than for wildtype microadenomas (15·0%, 4·9-24·0; adjusted p=0·016) but was lower than for wildtype macroadenomas (44·5%, 26·2-58·2; adjusted p=0·025). Patients with USP8-variant tumours (hazard ratio 2·41, 95% CI 1·19-4·87; p=0·014) or wildtype macroadenomas (4·48, 2·11-9·52; p<0·0001) had significantly higher risk of recurrence than patients with wildtype microadenomas, even after adjusting for age, postoperative nadir serum cortisol, tumour invasion, and ethnicity or centre. INTERPRETATION:Combined USP8 genotype-tumour size identified patients at increased risk of recurrence, particularly in largely heterogeneous groups of patients with non-invasive tumours or low postoperative serum cortisol not considered high risk in standard care. Implementing this combined genetic-clinical stratification could provide more accurate risk assessment, indicate those at higher risk of recurrence, and ultimately personalise long-term follow-up in patients with Cushing's disease. FUNDING:Deutsche Forschungsgemeinschaft, National Natural Science Funds of China, and CAMS Innovation Fund for Medical Sciences.

The 16th Acromegaly Consensus Conference in September 2024 updated recommendations on diagnosis and treatment of acromegaly comorbidities. Since the 2020 acromegaly comorbidity management guideline was published, new evidence has emerged on novel and known comorbidities and new treatment approaches. Forty-three experts in the management of acromegaly reviewed the current literature and assessed changes in clinical practice standards and management. Current outcome goals were considered and updated, with a focus on the impact of current and emerging treatments of these comorbidities. Participants assessed factors that determine pharmacological choices, as well as use of specific agents in the management of the most relevant acromegaly comorbidities. We present consensus recommendations highlighting optimization of evidence-based acromegaly comorbidities management.

OBJECTIVES:Rathke cleft cysts (RCC) in childhood are rare, often asymptomatic, and thus discovered incidentally. We aimed to summarize clinical features and pituitary function of patients with symptomatic RCC. METHODS:This retrospective study included 14 patients (8 male) from the university hospital's database (period 2005-2023). RESULTS:RCC diagnosis based on magnetic resonance imaging at 12.2 (1.8-17.6) years. Presenting symptoms were headaches (n=8), occurring alone (n=1) or with nausea/fatigue (n=2), polydipsia (n=2), or dizziness (n=3), followed by growth retardation (n=5), occurring alone (n=4) or with polydipsia (n=1). Two patients exhibited visual disturbances. Endocrinological evaluation revealed pituitary insufficiency in 10, including isolated or combined growth hormone (GH) deficiency (n=5), arginine-vasopressin deficiency (AVP-D; n=5), central hypothyroidism (n=2), and hypocortisolism (n=2). Three patients had hyperprolactinemia. Nine patients were monitored by regular imaging; five underwent surgery. In the observation group, cyst size remained unchanged in seven and decreased in two patients, while it increased in four patients treated surgically. At last presentation after 6.4 (0.33-14.8) years of follow-up, the endocrine status of the conservatively followed patients was normal in n=6, and pathological in n=3. Pituitary function did not normalize after surgery. Five patients developed hypogonadotropic hypogonadism, including two children who were followed conservatively. CONCLUSIONS:We found a high incidence of pituitary insufficiency among symptomatic pediatric RCC patients. Pituitary function was not closely related to cyst size or location and did not improve after surgery. Regular clinical and radiological follow-up is mandatory for both conservatively and surgically treated patients.

Background Pituitary metastases are rare, resulting in limited evidence regarding characteristic clinical features, diagnostic indicators, and prognostic factors. This study aimed to describe pre- and postoperative presentations, evaluate the impact of surgical intervention, and identify factors associated with overall survival to support earlier recognition and individualized treatment strategies. Methods From a prospectively maintained database, 56 patients with histologically confirmed pituitary metastases treated in a single center between 1982 and 2022 were retrospectively analyzed. Clinical, ophthalmologic, and endocrinologic findings before and after surgery were assessed, supplemented by follow-up data (mean postoperative follow-up 9.6 months). Descriptive and analytical statistics were used to evaluate symptom patterns, perioperative changes, and survival. Results Sellar metastases occurred equally in men and women. Most patients (> 90%) were symptomatic, predominantly with visual impairment. Endocrinologic abnormalities affected mainly the gonadotropic axis; diabetes insipidus was rare. Surgery significantly reduced prolactin levels but was associated with postoperative insufficiency in several hormonal axes. Primary tumors most frequently originated from breast and kidney cancer. Renal cell carcinoma predominated in male patients. Pituitary metastasis was diagnosed 8.1 years after the primary tumor, and in nearly one quarter of patients it led to first detection of the underlying malignancy. Median postoperative survival was 9.6 months. Fewer additional metastases were associated with longer survival. Conclusion Compared with the literature, this cohort showed a distinct distribution of primary tumors. Surgical intervention may alleviate visual symptoms, but overall prognosis is mainly determined by the primary malignancy and metastatic burden. The potential role of renal cell carcinoma in symptom severity and survival warrants further investigation.

This study evaluates the clinical presentation, endocrine dysfunction, surgical outcome, and long-term prognosis in patients with histologically confirmed posterior pituitary tumors (PPTs). A retrospective cohort study was conducted on 19 patients treated for PPTs at a single center between 2000 and 2023. Data on clinical, endocrine, and surgical outcomes were collected and analyzed. The cohort included 3 pituicytomas (PCs), 8 granular cell tumors (GCTs), and 8 spindle cell oncocytomas (SCOs) patients, with a female predominance (58

The 15th Acromegaly Consensus Conference in September 2023 updated recommendations on therapeutic outcomes for acromegaly. Since the publication of medical management guidelines in 2018, new pharmacological agents and new treatment approaches have been developed. Fifty-two experts in the management of acromegaly reviewed the current literature and assessed changes in drug approvals, clinical practice standards and management. Current outcome goals were considered, with a focus on the effect of current and emerging somatostatin receptor ligands, the growth hormone receptor antagonist pegvisomant and the dopamine agonist cabergoline on biochemical control, clinical control, adenoma mass and surgical outcomes. Participants assessed factors that determine pharmacological choices, as well as the proposed use of each agent. Here, we present consensus recommendations highlighting how an evidence-based acromegaly management algorithm could be optimized in clinical practice. In this Consensus Statement, an international group of experts provide updated recommendations on the treatment of acromegaly, including discussion of treatment outcomes.

Tinnitus is the subjective perception of a sound without corresponding external acoustic stimuli. Research highlights the influence of the sensorimotor system on tinnitus perception. Associated neuronal processes, however, are insufficiently understood, and it remains unclear how and at which hierarchical level the sensorimotor system interacts with the tinnitus-processing auditory system. We therefore asked 23 patients suffering from chronic tinnitus (11 males) to perform specific exercises, aimed at relaxing or tensing the jaw area, which temporarily modulated tinnitus perception. Associated neuronal processes were assessed using magnetencephalography. Results show that chronic tinnitus patients experienced their tinnitus as weaker and less annoying after completion of relaxing compared with tensing exercises. Furthermore, (1) sensorimotor alpha power and alpha-band connectivity directed from the somatosensory to the auditory cortex increased and (2) gamma power in the auditory cortex reduced, which (3) related to reduced tinnitus annoyance perception on a trial-by-trial basis in the relaxed state. No effects were revealed for 23 control participants without tinnitus (six males) performing the same experiment. We conclude that the increase in directed alpha-band connectivity from the somatosensory to the auditory cortex most likely reflects the transmission of inhibition from the somatosensory to the auditory cortex during relaxation, where concurrently tinnitus-related gamma power reduces. We suggest that revealed neuronal processes are transferable to other tinnitus-modulating systems beyond the sensorimotor one that is involved in attentional or emotional tinnitus modulation and provides deeper mechanistic insights into how and through which channels phantom sound perception might be modulated on a neuronal level.

Disclosure: H. Külper: None. Y. Zhao: None. A. Mattson: None. M. Buchfelder: None. Introduction: Hormone secretion from functioning pituitary adenomas depends on several factors, such as the secretory potential of the neoplasm and regressive changes within the adenoma. Also, a dependency on tumor size has been suggested. In this study, we compared tumor size and oversecretion of respective hormones in a large, prospectively documented series of all types of secreting pituitary adenomas treated between 1988 and 2022. Patients and Methods: All 3496 patients were operated in our institution. Tumour size was determined by analysis of preoperative imaging and intraoperative comparison with surgical instruments. Hormones were measured with commercially available RIA or ELISA methods. The tumors were classified based on immunohistochemistry and hormonal laboratory results. The final classification were prolactinomas (n=848), acromegaly and gigantism (n=1492), Cushing’s disease (n=950), Nelson’s syndrome (n=65), TSHomas (n=60) and gonadotropinomas (n=81). Results were expressed as mean levels ± SD. Tumour size was classified into microadenomas (estimated diameter < 10 mm), macroadenomas (≥10 mm and <40 mm) whereas giant adenomas required an estimated tumour diameter of 40 mm at least in one plane. Results: A positive size-oversecretion relationship was found in prolactinomas (r=0.436) and acromegaly (r=0.0496). The mean prolactin level in prolactinomas was significantly lower in microadenomas (2997±2677 µU/ml) than in macroadenomas (34818±86634 µU/ml) and giant adenomas (237328±521030 µU/ml). Invasive tumours had higher levels (100328±292224 µU/ml) than enclosed ones (17723±68706 µU/ml). Likewise, growth hormone levels in acromegaly were significantly lower in microadenomas (13.7±36.7 ng/ml) than in macroadenomas (87.3±1627.4 ng/ml) and giant adenomas (137.9±319.7 ng/ml). Moreover, growth hormone was higher in invasive (165.8±2409 ng/ml) than in enclosed ones (26.3±44.5 ng/ml). In Cushing’s disease, ACTH plasma levels were 72.7±66.7 pg/ml in microadenomas, 104.5±111.8 pg/ml in macroadenomas and 148.9±93.5 pg/ml in giant adenomas with an r=0.21 for all tumors. However, no significant differences in tumor types were encountered in TSHomas (r=-0.006) and gonadotropinomas (LH: r=-0.26; FSH: r=-0.07). Discussion: Hormone secretion shows a extremely variable pattern as expressed by the enormous standard variations. Nevertheless, we can confirm with our accurrately determined high numbers of investigated tumours, that there is a reliable size-secretion correlation in prolactinomas, growth hormone secreting adenomas and also for ACTH secretion in Cushing‘s disease. This can be clinically useful to distinguish other causes of e.g. hyperprolactinaemia from secreting adenomas. However, we showed that also other factors than just the mere tumor diameter influence the magnitude of hormonal oversecretion. Presentation: Sunday, July 13, 2025

PURPOSE:This study aimed to develop a core outcome set (COS) for pituitary surgery to enhance the quality, efficiency and effectiveness of future pituitary adenoma surgery research. METHODS:Thirty-three outcomes were identified through a systematic review of pituitary adenoma surgery outcomes and a study on patient-reported measures. These were presented in an online survey to healthcare professionals (HCPs), patients and caregivers. In the first round, participants scored each outcome's importance on a 5-point scale (1-strongly disagree; 5-strongly agree) and could also suggest additional outcomes, which were reviewed and, if appropriate, added to existing domains. In the second round, participants re-scored the updated the list, considering group median and interquartile range scores from the previous round. Outcomes with a median score of 5 were included in the COS. A final live online consensus meeting discussed and voted on borderline outcomes (median scores 3-4). RESULTS:The first round received 95 responses (52% HCPs, 48% patients/caregivers). Of the 33 outcomes, 16 received a median score of 5 (strongly agree), three received 4.5 and 14 received 4 (agree). Round two received 87 responses (52% HCPs, 48% patients and caregivers). Of the 33 outcomes, 14 received a median ranking of 5, two received 4.5, 15 received 4 and two received 3 (neutral). The live meeting (attended by 12 participants: 5 HCPs, 6 patients, 1 caregiver), reached consensus on the final COS, which includes 7 domains: short-term surgical outcomes; nasal outcomes; ophthalmic outcomes; endocrine outcomes; quality of life and psychological outcomes; other short-term outcomes; and disease control outcomes. CONCLUSION:We advocate for use of the COS in future pituitary surgery research.

Disclosure: E. Lefevre: None. F. Chasseloup: None. A. Dormoy: None. S. Deng: None. N. Ladurelle: None. C. Janot: None. M. Hage: None. M. Hage: None. K. Chappel: None. A. Larabi: None. J. Alvarez: None. P. Zizzari: None. J. Bouligand: None. J. Young: None. P. Chanson: None. S. Viengchareun: None. M. Buchfelder: None. P. Kamenicky: None. Context: Cavernous sinus invasion by pituitary adenomas remains challenging in clinical practice. In this study we aimed to identify the molecular actors involved their invasive phenotype and test novel therapeutic approaches. Methods: Using RNA-seq, we compared the gene expression profiles of human intrasellar non-invasive portions and intracavernous invasive portions of the same pituitary adenoma samples. Among the up-regulated genes in the invasive portions, we selected those involved in tumorigenesis and invasiveness that exhibited consistent overexpression in the intracavernous samples. In vitro functional studies of selected genes were performed in murine lactostomatotroph GH3 cells and gonadotroph LbT2 cells using the Transwell Assay. Further, in vivo experiments were conducted using an original orthotopic model of invasive somatotroph pituitary tumors generated via stereotaxic GC cell injection into the pituitary lobes of immunocompetent rats. After surgery, rats were monitored weekly, and tumor progression was assessed fortnightly by 3 successive 7 Tesla MRIs. Half of the rats received experimental treatment. Treatment’s efficacy was evaluated by tumor progression and survival outcomes. Results: RNA-seq of 52 samples from 26 patients with somatotroph or gonadotroph invasive pituitary adenomas identified 32 upregulated genes in the invasive portions of the adenomas. Among these, di-peptydyl-peptidase-4 (DPP4) was homogeneously upregulated in 21 out of 26 (81%) invasive portions and is known for its role in extracellular matrix degradation in cancer, warranting further investigations. In vitro, pharmacological inhibition of the DPP4 with sitagliptin reduced cell migration and invasion in GH3 cells (p=0.0205 and p=0.0038) and LbT2 cells (p=0.0345 and p=0.0131) in Transwell assays. In vivo, 24 out of 28 injected rats (86%) developed invasive pituitary tumors. Tumor growth was rapid, leading to obstructive hydrocephalus-related death in 92.3 % of control animals versus 63.6% of animals receiving sitagliptin by day 49. Sitagliptin treatment increased overall survival (p = 0.0389) and slowed tumor growth, as shown by volumetric 7 Tesla MRI studies (tumor volume = 45.4 vs 131.2 mm3 on day 28; p = 0.036). In conclusion, we identified DPP4 as a key molecular driver promoting the invasive behavior of pituitary adenomas. Pharmacologic inhibition of DPP4 with sitagliptin, that has been largely used for treatment of diabetes, could be a promising therapeutic approach in invasive pituitary tumors. Presentation: Sunday, July 13, 2025

Pituitary surgery is the mainstay treatment for most pituitary adenomas, but many questions remain about perioperative and long-term management and outcomes. This study aimed to identify the most pressing research priorities in pituitary surgery with input from patients, caregivers, and healthcare professionals. An initial survey of patients, caregivers, and healthcare professionals assembled priorities related to preoperative care, surgical techniques, and postoperative management in pituitary surgery. Priorities were thematically grouped into summary priorities, and those answered by existing evidence were omitted following a literature review. An interim survey asked patients, caregivers, and healthcare professionals to select their top 10 priorities from the remaining list. The highest-ranked priorities advanced to a consensus meeting, where the top 10 questions were prioritized. In the initial survey, 147 participants-60.5% of whom were patients, caregivers, or patient support group representatives-submitted 785 priorities, which were then condensed into 52 summary priorities. After a literature review, 33 unanswered priorities were included in the interim survey, completed by 155 respondents, of whom 54.2% were patients, caregivers, or patient support group representatives. The top-ranked priorities were discussed by 14 participants (7 patients and 7 healthcare professionals) during a consensus meeting. The top 10 priorities covered a variety of themes including enhancing diagnosis and management of pituitary adenomas, advancing surgical techniques and technologies, optimizing the prediction of outcomes and complications, and improving patient support and follow-up. The top 10 research priorities in pituitary surgery aim to align researchers and direct funding in order to maximize impact and champion patient representation.

Disclosure: Q. Zhang: None. Y. Cai: None. A. Abreu: None. M. Buchfelder: None. B. Yao: None. F. Hanzu: None. Y. Liu: None. J. Thorsteinsdottir: None. Z. Ma: None. J. Flitsch: None. S. Zhang: None. H. Ye: None. J. Honegger: None. R.S. Carroll: None. Z. Zhang: None. U.B. Kaiser: None. M. Reincke: None. M. Theodoropoulou: None. Y. Zhao: None. L. Gustavo Perez-Rivas: None. Background: The recurrence rate of Cushing’s disease (CD) after surgery varies between 5-50%. About 30-60% of CD tumors carry somatic USP8 variants. Prior studies on small cohorts have reported opposite associations between USP8 variants and recurrence. Here, we analyzed USP8 genotype and recurrence risk in a large, international cohort of patients with postoperative remission and long follow-up. Methods: Retrospective analysis across seven neuroendocrine centers from China, Europe, and USA. All patients had USP8 genotype, demographic, clinical, biochemical, and follow-up data. Patients with prior pituitary intervention or bilateral adrenalectomy were excluded. We estimated the recurrence risk with Kaplan-Meier curve, log-rank test, and Cox regression. Results: Among 435 patients (82.8% female; median follow-up 5.61 years), USP8 variants were identified in 195 (44.8%) tumors. Variants were more prevalent in younger (p<0.001) and female (p<0.001) patients and were associated with a lower incidence of cavernous sinus invasion (p=0.021) and reduced post-operative cortisol levels (p=0.004). Of these, 371 initially reached post-op remission, but 71 recurred during follow-up. USP8 variants significantly increased recurrence risk in microadenomas (HR 2.36, p=0.025), while in macroadenomas, no significant association was observed (HR 0.58, p=0.126). Stratification by USP8 genotype and tumor size produced four subgroups. However, due to similar recurrence risks (HR 1.08, p=0.824) and comparable clinical characteristics between USP8 variant microadenomas and macroadenomas, these two variant subgroups were merged into a single category, resulting in three distinct categories: wild-type microadenomas, USP8 variant adenomas, and wild-type macroadenomas, with 5-year cumulative recurrence rates of 6.45%, 12.53%, and 31.16%, respectively. The log-rank test revealed significant differences in recurrence risk among these 3 categories (p<0.001). Further evaluation of postoperative 1-week nadir cortisol levels showed category-specific recurrence risks. For wildtype microadenomas, cortisol levels ≥ 2 µg/dL were associated with increased recurrence risk (HR 7.26, p=0.016). In USP8 variant adenomas, recurrence risk was elevated only at cortisol levels ≥ 5 µg/dL (HR 6.11, p<0.001). Postoperative cortisol levels were not significantly associated with recurrence in wildtype macroadenomas. We further identified additional, varied factors associated with recurrence risk across the three categories. Conclusions:USP8 genotype, combined with tumor size, is associated with different risk of recurrence in CD. This study highlights the heterogeneity of CD recurrence patterns and underscores the importance of considering both tumor size and somatic USP8 genotype to guide follow-up strategies. Presentation: Sunday, July 13, 2025

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