Epidemiologic research for rare diseases such as acromegaly is challenging due to low prevalence, heterogeneous data sources, and regional variability. Here, we review recent epidemiologic studies and provide a synthesis of the changing landscape of acromegaly and an overview of mortality rates and their determinants.Over the past few decades, the reported incidence and prevalence of acromegaly have increased, likely due to improved diagnostic tools, earlier diagnosis, and more efficient management of the disease, leading to increased life expectancy. Available data suggest that the delay in diagnosis of acromegaly has progressively declined, and there is now a considerable increase in the rate of biochemical control-achieved in up to 90% of patients in some centers. This progress reflects improvements in disease management with the expanding use of multimodal and personalized treatment strategies. Consequently, mortality rates have substantially declined, approaching those of the general population. Despite these advances, most patients continue to be diagnosed only after acromegaly complications have developed. Comorbidities still have an independent and adverse effect on mortality and morbidity. Therefore, improved management of comorbidities is the optimal goal in the overall treatment of patients with acromegaly.

Abstract Background Mutations in the Four-and-a-Half LIM Domains 1 (FHL1) gene are increasingly recognized as a rare cause of inherited cardiomyopathies, often associated with skeletal myopathy and adverse cardiac outcomes. The phenotypic spectrum and clinical implications of FHL1 variants remain poorly defined. Objective To systematically review published cases of FHL1-related cardiomyopathy and characterize the clinical, genetic, and pathological features. Methods We conducted a systematic literature search in PubMed and EMBASE up to July 2025 using predefined criteria to identify studies reporting clinical cases of patients with FHL1 mutations and cardiac involvement. Data on genotype, phenotype, cardiac and neuromuscular features, and clinical outcomes were extracted and synthesized. Results Twenty-two studies were included, comprising 114 patients with pathogenic or likely pathogenic FHL1 mutations. Most patients were male (69%), with a median age of onset of 18 (IQR 10–26) years. Cardiac involvement consisted in left ventricular hypertrophy (56%), followed by arrhythmias (51%), and conduction abnormalities (8%). The incidence of sudden cardiac death was 7%, and heart transplantation was reported in 5% of patients. Skeletal muscle involvement was present in 75%, ranging from mild contractures to more severe myopathic phenotypes with functional impairment. Creatine kinase levels were variably elevated. Truncating variants were reported in several severe cardiac presentations in young males, while isolated cardiac disease occurred with selected variants. Conclusions FHL1-related cardiomyopathy is a rare but important diagnosis. Genetic testing should be considered in patients with cardiac hypertrophy and neuromuscular features. Further research is needed to define prognostic markers and guide management.

Objective Discordance between growth hormone (GH) and insulin-like growth factor-1 (IGF-1), where one hormone is within the age- and sex-adjusted reference and the other is not, can be observed in patients with acromegaly. The discrepancy complicates the interpretation of disease activity, thereby presenting a significant challenge in the clinical management of acromegaly. This study aimed to assess postoperative discordance prevalence and clinical correlates to clarify the implication of discordance. Methods This retrospective study describes a cohort of patients that has undergone pituitary surgery at Sahlgrenska University Hospital between 1994 and 2019 due to acromegaly. Medical records were reviewed and the group with postoperative discordant hormones was compared with the group with concordant hormones. Results In a cohort of 82 patients surgically treated for acromegaly and thereafter examined with an oral glucose tolerance test (OGTT), 16 (19.5%) exhibited biochemical discordance. Fourteen of 16 patients showed elevated IGF-1 but normal GH. The IGF-1 levels at diagnosis were significantly higher in patients with discordance compared with the controlled concordant group. However, no differences were observed between the discordant and the concordant group regarding the baseline variables at diagnosis: age, gender, invasive tumour, micro/macro-adenoma or BMI, nor hypertensive treatment at time of surgery and postoperative radiotherapy or reoperation. Conclusion The prevalence of biochemical discordance in our cohort was 19.5%. The predominant pattern was elevated IGF-1 levels with a normal nadir GH. The discordant group had higher IGF-1 at diagnosis, suggesting that greater preoperative disease activity may predispose to postoperative biochemical discordance.

CONTEXT:Secondary diabetes mellitus occurs in 30-50% of patients with acromegaly despite a lean phenotype, whereas type 2 diabetes mellitus (T2DM) is associated with adiposity. OBJECTIVE:We compared mortality, morbidity and treatment patterns between patients with acromegaly-associated diabetes (ACRO-DM) and T2DM. DESIGN:Nationwide, retrospective, matched-cohort study in Sweden. METHODS:The ACRO-DM group included patients with an acromegaly diagnosis in the Patient Register, with diabetes registered in the National Diabetes Register (NDR) or a dispensed glucose-lowering drug in the Prescribed Drug Register. Controls with T2DM from the NDR were matched 10:1 for sex, age, calendar year, diabetes duration. We derived mortality and morbidity outcomes from the Death and Patient Registers. RESULTS:We included 348 patients with ACRO-DM and 3,480 with T2DM. Mean (SD) age was 60.3 (13.2) and 59.5 (15.6) years while diabetes duration was 2.8 (5.8) and 3.0 (7.1) years in ACRO-DM and T2DM, respectively. Baseline cardiovascular morbidity was more common in ACRO-DM than T2DM group (61% vs 43%), including hypertension (48% vs 29%), heart failure (11% vs 5%), arrhythmia (13% vs 9%) and stroke (8% vs 5%).The hazard ratio (HR) for overall mortality was 1.18 (95% CI, 0.96-1.46) in ACRO-DM compared with T2DM group. The ACRO-DM group had a higher risk of cardiovascular morbidity (HR 1.55; 95% CI, 1.24-1.94), with increased hazards for venous thromboembolism, specifically pulmonary, and arrhythmia, whereas cardiovascular mortality was not increased (HR 1.12; 95% CI, 0.78-1.60). CONCLUSIONS:The risk of cardiovascular morbidity was increased in patients with ACRO-DM compared to T2DM.

IntroductionPrimary aldosteronism (PA) can be managed either by unilateral adrenalectomy (ADX) or pharmacologically with mineralocorticoid receptor antagonists (MRA). Several recent meta-analyses have examined how these treatment modalities affect cardiovascular outcomes in patients with PA. However, the impact of treatment on quality of life (QoL) remains largely unexplored.ObjectiveTo synthesize data from previous studies that have investigated QoL in either medically or surgically treated patients with PA.MethodsA literature search was conducted in May 2025 in PubMed, Embase and Web of Science. Studies containing data on QoL before and after ADX or MRA were selected.ResultsFifteen studies evaluated QoL after treatment for PA. Most comparative studies reported greater and faster QoL improvement after ADX than with MRA. QoL consistently improved after ADX, whereas results with MRA were variable and less consistent. Patients treated with MRA were older than patients treated with ADX and frequently received low MRA doses. Five studies (259 ADX-treated and 88 MRA-treated patients) were included in a meta-analysis. Baseline QoL did not differ between treatment groups. At 6 months, QoL improved in both groups, with no statistically significant difference between ADX and MRA.ConclusionTreatment of PA is associated with improved QoL following both ADX and MRA therapy. Although several studies suggest superior outcomes after adrenalectomy, the meta-analysis did not show a significant difference at 6 months of follow-up. The limited number of patients, short follow-up duration, and potential undertreatment with MRA represent important limitations.

Adult growth hormone (GH) deficiency is associated with increased body fat mass, abdominal obesity, dyslipidaemia, reduced exercise capacity, impaired cardiac function, reduced self-reported well-being, impaired quality of life, as well as increased morbidity. Randomised controlled trials and cohort studies, together with meta-analyses, have shown improved outcome in adult patients with hypopituitarism receiving GH, with a reassuring safety profile. Women with GH deficiency and hypopituitarism have greater morbidity and mortality than men, particularly in relation to metabolic and cardiovascular outcome. The response to GH replacement is also less favourable in women than in men. The reason for these differences in women and men with hypopituitarism is not entirely clear, but is likely related to the interaction between sex steroid and the somatotroph axis. In this narrative review we summarize the burden of GH deficiency in adults with hypopituitarism, and the impact of GH replacement, with focus on differences among women and men.

L’asse GH/IGF-1 è regolato a livello centrale dall’ipotalamo tramite la secrezione di GHRH e somatostatina; tuttavia, un numero crescente di studi dimostra l’influenza esercitata su questo asse da parte dei differenti macronutrienti, direttamente o tramite la mediazione di altri ormoni quali insulina, ghrelina e adipochine. Nella popolazione generale, i carboidrati causano un aumento dell’insulinemia e sopprimono la secrezione di GH in condizioni di iperglicemia, mentre le proteine e gli amminoacidi stimolano la produzione di GH e IGF-1, con una risposta particolarmente evidente dopo l’assunzione di proteine animali. I lipidi tendono a ridurre i livelli di entrambi gli ormoni, probabilmente a causa della minore risposta insulinemica e della modulazione degli ormoni regolatori del tessuto adiposo. I pazienti con acromegalia presentano un’eccessiva secrezione di GH che causa insulino-resistenza e alterazioni della composizione corporea che possono influenza la produzione di adipochine. I dati presentati in questa rassegna supportano l’ipotesi che interventi nutrizionali mirati alla modulazione della composizione dei macronutrienti nella dieta possano influenzare l’asse GH/IGF-1, configurandosi come un possibile complemento alle terapie convenzionali nell’acromegalia. Sono tuttavia necessari ulteriori studi per definire con precisione le indicazioni nutrizionali ottimali per il paziente con acromegalia e chiarire il ruolo di queste strategie nella pratica clinica

Background Non-small cell lung cancer (NSCLC) is a significant global health challenge, with 2% of cases fuelled by RET rearrangements. RET inhibitors (RETi) have revolutionized treatment for these patients, but resistance remains an important clinical challenge limiting therapy effectiveness. This study investigated the mechanisms underlying resistance to RETi. Methods NSCLC cells were exposed to increasing doses of RETi (pralsetinib/BLU-667 and selpercatinib/LOXO-292) to generate resistant cells. RNA-Sequencing analysis identified differentially expressed genes in resistant versus sensitive cells, followed by in vitro and in vivo functional assays to explore novel therapeutic strategies. Additionally, tumor biopsies from RET -rearranged NSCLC patients who exhibited cancer progression on RET inhibitor therapy were analyzed. Results RNA-sequencing analysis revealed the upregulation of the EGFR signaling pathway and hyperactivation of AP1 complex members in resistant cells compared to sensitive cells. Silencing of EGFR and AP1 complex members significantly reversed drug resistance, whereas EGFR overexpression reduced the sensitivity of parental Lc2/AD cells to RET inhibitors. Furthermore, the combination of RET and EGFR inhibitors showed synergistic antitumor activity in vitro and hindered tumor growth in mouse models with resistant cell xenografts. Notably, we observed a significant increase in EGFR expression in tumor biopsies from NSCLC patients treated with RET inhibitors who experienced disease progression, further validating the clinical relevance of our findings. Conclusions This study elucidates EGFR's role in mediating resistance to RET inhibitors in NSCLC patients. These findings offer insights into therapeutic adaptation and explore personalized combinations of RET and EGFR inhibitors for improved clinical outcomes.

Acromegaly is a rare disease that can be challenging to treat due to residual pituitary adenoma after surgery or variable response to medical treatments. The primary aim of the study was to evaluate the path of treatment and long-term outcome of acromegaly after pituitary surgery. Patients with acromegaly who had undergone surgery for a growth hormone-producing pituitary neuroendocrine tumor also known as a pituitary adenoma, at Sahlgrenska University Hospital between 1994 and 2019 were included in the study. Medical records from diagnosis to the end of study (November 2022) were reviewed for surgical outcome and treatment patterns related to acromegaly. In the cohort of 103 patients, 111 surgeries were performed. Mean follow-up duration was 12.7 (range: 0–37) years. Lesions were identified as a macroadenoma in 76 (76.8

Acromegaly is a rare endocrine disorder caused by excessive growth hormone (GH) production, due, in the vast majority of cases, to the presence of a GH-secreting pituitary tumour. The chronic elevation of GH and the resulting high circulating levels of insulin-like growth factor-1 (IGF-1) cause the characteristic tissue overgrowth and a number of associated comorbidities, including several metabolic changes, such as glucose intolerance and overt diabetes mellitus (DM). Elevated GH concentrations directly attenuate insulin signalling and stimulate lipolysis, decreasing glucose uptake in peripheral tissues, thus leading to the development of impaired glucose tolerance and DM. Acromegaly treatment aims to normalize plasma GH and IGF-1 levels using surgery, medical treatment, or radiotherapy. The effect of the different medical therapies on glucose homeostasis varies. This literature review explores the impact of the currently available pharmacological therapies for acromegaly (first- and second-generation somatostatin receptor ligands, a GH receptor antagonist, and dopamine agonists) on glucose homeostasis. We also discuss the underlying biological mechanisms through which they impact glucose metabolism.

OBJECTIVE:Despite important advances in the management of primary adrenal insufficiency (PAI), prognosis in these patients remains poor. Data on mortality in PAI has not been entirely consistent, and to date, no systematic synthesis has been performed. The aim of this study was to conduct a systematic review and a meta-analysis to synthesize available evidence on mortality in adult patients with PAI including congenital adrenal hyperplasia (CAH). DESIGN:This is a systematic review and meta-analysis. METHODS:Medline, Cochrane CENTRAL, Web of Science, and Embase databases were searched for studies on mortality in PAI. The results were screened by 2 reviewers by titles and abstracts, and selected articles were subsequently reviewed in full text. Observational studies on mortality compared to a reference population were included. RESULTS:Out of the 6238 reports identified, 9 reports were included in the systematic review, with a total population of 13 969 patients. Two of the 9 studies included overlapping population; therefore, only 7 studies were included in the meta-analysis (9876 patients). Four studies assessed mortality utilizing hazard ratio (HR) with a pooled HR of 2.51 (95% confidence interval [CI] 1.47-4.31, I2 = 86.1%); 3 studies used standardized mortality ratio (SMR) with a pooled SMR of 2.49 (95% CI 0.99-6.28, I2 = 97.9%). The main cause of death was cardiovascular disease. A sub-analysis of patients with CAH showed a pooled HR of 2.88 (95% CI 1.38-6.01, I2 = 90.3%), with the main cause of death being adrenal crisis. CONCLUSIONS:Mortality in patients with PAI was increased 2.5-fold compared to the reference population.

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.

Diet composition and energy intake directly modulate the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) axis, and indirectly through endogenous regulators such as insulin, ghrelin, and adipokines. Moreover, diet has a well-established role in the prevention and management of various metabolic and cardiovascular comorbidities in the general population. Acromegaly, caused by an endogenous overproduction of GH, is an endocrine disorder associated with increased risk of metabolic and cardiovascular comorbidities and excess mortality. The treatment of acromegaly aims to normalize GH and IGF-1 levels, manage complications, and reduce mortality. There is a considerable gap in research regarding the specific influence of diet on biochemical control and complications in acromegaly; therefore, consensus guidelines for managing metabolic and cardiovascular complications in acromegaly generally recommend the same nutritional interventions as those for the general population, even though the underlying pathogenic mechanisms often differ. This narrative review aims to provide an overview of how nutrition modulates the GH/IGF-1 axis and to summarize current evidence on the effect of various macronutrients and dietary patterns on biochemical control and comorbidity management in patients with acromegaly. Evidence in healthy individuals suggests that diets low in animal-derived proteins, combined with moderate fat and carbohydrate intake, may lower GH/IGF-1 activity. Nevertheless, further research is needed in patients with acromegaly to determine whether dietary interventions, such as those found effective in the general population, can help achieve biochemical control and effectively manage metabolic and cardiovascular comorbidities in this specific group.

Functional high risk multiple myeloma (FHRMM) remains a challenging entity with poor outcomes and limited survival, and there is no international consensus on optimal second-line therapeutic strategies in relapsed/refractory patients. In this multicenter real-world retrospective study, we investigated clinical characteristics and outcomes of a total of 62 FHRMM patients previously treated with a first-line daratumumab-based quadruplet regimen or who relapsed within 12 months after frontline autologous stem cell transplantation (ASCT). In our cohort, the overall response rate was 61

227 Background: Metastatic hormone-sensitive prostate cancers (mHSPC) are generally sensitive to androgen deprivation therapy (ADT). However, resistance often occurs, leading to disease progression. Understanding the transcriptomic changes underpinning the shift to antiandrogen resistance is crucial for identification of novel therapeutic vulnerabilities. Methods: Sixty patients with mHSPC undergoing ADT plus androgen receptor pathway inhibitors (ARPI) were enrolled. We defined non-responder (NR) patients (13/60) with biochemical/ radiological progression within 6 months of treatment and responder (R) (47/60) as those with stable disease or partial/complete response and eventually disease progression after 6 months. Total RNA was extracted from archived Formalin-Fixed Paraffin-Embedded (FFPE) basal prostate biopsies tissue samples using Maxwell RSC RNA FFPE Kit, and RNA was profiled using NanoString Tumor Signaling 360 Panel. Results: To identify gene signatures associated with response to ADT + ARPI, we analyzed differentially expressed genes between NR and R patients, through Rosalind platform Gene Set Analysis. Notably, NR patients exhibited significant upregulation of genes linked to cell cycle progression and DNA replication. The mitotic kinases AURKB and PLK1 were the most markedly upregulated genes in NR versus R samples (p=0.02 and p=0.01, respectively), suggesting enhanced cell cycle progression despite antiandrogen therapy. Coherent with these results, hyper-expression of KIF23 and CDC20 in NR vs R samples further confirmed aberrant cell cycle progression. Importantly, NR biopsies also exhibited increased expression of metastasis-promoting genes, such as HGF (p= 6.53 e-3 ), which may influence therapy response. Kaplan-Meier survival analysis reinforced the clinical significance of these findings, revealing that patients with hyper-expression of AURKB, KIF23, or CDC20, had shorter progression-free survival (PFS) compared to those with lower expression levels (p=0.0037, p=0.0007 and p=0.0289, respectively). These results underscore the potential of these molecular markers as predictive tools for resistance to ADT + ARPI and as potential targets for future therapeutic interventions. Conclusions: This study provides new insights into the transcriptomic landscape of mHSPC and identifies key gene signatures responsible for resistance to standard-of-care. Validation in larger cohorts is essential to confirm the predictive value of these genes and to identify patients eligible for novel combinatory treatments aimed at delaying this critical phenomenon.

Pasireotide long-acting release (PasiLAR), a somatostatin multireceptor ligand, is effective in achieving biochemical control but can increase the risk of hyperglycemia in acromegaly. However, the impact of PasiLAR on lipid and glucose metabolism in patients with acromegaly has not been systematically studied. This systematic review aimed at synthesizing evidence on PasiLAR effects (as monotherapy or combination therapy with pegvisomant) on lipid and glucose metabolism in patients with acromegaly. MEDLINE, Embase, Cochrane Library, and Web of Science were searched for studies published between 2000 and 2024. Prospective and retrospective studies reporting metabolic outcomes before and under PasiLAR treatment for a minimum follow-up of 6 months. Two reviewers screened eligible publications (3441), extracted outcomes, and assessed risk of bias. Nineteen studies (896 patients) were included in the meta-analysis. PasiLAR was associated with increased fasting plasma glucose (FPG) (mean difference [MD] 23.4 mg/dL, 95

The liquid biopsy (LB) represents a minimally invasive method for cancer screening that has been introduced in clinical practice for over a decade and that can accelerate treatment response assessment. LB allows the analysis of tumor cells or tumor-derived products (e.g. cell-free circulating nucleic acids, extracellular vesicles, and proteins) released from primary or metastatic tumor lesions into blood or other body fluids. In the era of immune-oncology, recent evidence indicates that tumor-specific immune responses can be detected in peripheral immune cells. The improvement of knowledge and the standardization of the isolation methods of these techniques will allow the detection and characterization of circulating tumor and immune biomarkers at an early stage as innovative tools to predict response to therapies. Nowadays, the analysis of peripheral blood mononuclear cells (PBMCs), circulating tumor cells (CTCs), peripheral blood-derived extracellular vesicles (EVs) and circulating tumor RNA (ctRNA) remains under-developed even if these non-invasive techniques can provide the complete genetic landscape of tumors and allow systematic tracking of cancer evolution. In addition, the evaluation of blood circulating cytokines, and early dynamics changes in the PBMCs of patients with solid tumors represent a promising area of research. Here, we present a comprehensive methodological framework for the evaluation of innovative peripheral blood-derived biomarkers. We also address the current challenges in isolation methods and analysis of PBMC, CTC, EVs and TEPs which are crucial for structuring the large amount of comprehensive information obtained from such samples, with the aim of advancing the translational cancer field.

PurposeAnti-programmed cell death 1 (PD1) is the first-choice treatment in patients with advanced cutaneous squamous cell carcinoma (cSCC), when curative options are unavailable. However, reliable biomarkers for patient selection are still lacking.Experimental designIn this translational study, clinical annotations, tissue and liquid biopsies were acquired to investigate the association between sustained objective responses and transcriptional profiles, immune cell dynamics in tumor tissue and peripheral blood samples, as well as circulating cytokine levels.ResultsFirst, we investigated the baseline characteristics of the immune landscape of cSCC biopsies. Gene Set Enrichment Analysis showed upregulation of interleukin (IL)2/STAT5 pathways and downregulation of Interferon signatures in non-responder patients compared with responders. Next, we studied the early changes induced by cemiplimab in tissue biopsies. Notably, after only three weeks, cemiplimab treatment induced an increase in B cells and CD8+ T cells in responders, whereas their abundance decreased in non-responder patients. Moreover, analyzing differentially expressed genes modulated early during treatment, compared with baseline biopsies, we found that IL1β and IL8 exhibited early downregulation in responder patients’ tumor specimens. We assessed whether changes in the local tumor microenvironment were mirrored in peripheral blood. Similar to tissue findings, no changes were observed in the whole T regulatory (Treg) population, although PD1+ Tregs, which were downregulated in responder patients (vs T0), showed a rebound enrichment in non-responders after three cycles of cemiplimab. Finally, IL8 mirrored the tissue results, unlike IL1β, with early (T1) and then sustained (T3) downregulation of its levels in responder patients, while increased in non-responders.ConclusionsTaken together, these findings shed light on the significance of early transcriptomic and immune cell modulation in predicting responses to cemiplimab therapy. Additionally, our data suggest that IL8 levels in peripheral blood offer promising avenues for personalized treatment selection and response assessment in patients with cSCC receiving cemiplimab, while PD1+Tregs can be followed longitudinally to monitor response to therapy.