Best practice & research. Clinical endocrinology & metabolism最新文献

Adolescent primary hyperparathyroidism (PHPT) is a rare endocrine disorder bearing distinctions from the adult form. This review examines its unique aspects, focusing on clinical presentation, genetic etiologies, genotype-phenotype correlations, and therapeutic management. Adolescent PHPT often has a genetic basis, whether familial, syndromic, or apparently sporadic, and identifying the underlying genetic cause is important for patient care. The clinical presentation is predominantly symptomatic worldwide. Unique manifestations in this age group include rickets, short stature, and slipped capital femoral epiphysis. Genotype-specific differences are evident in the adolescent PHPT characteristics. Diagnostic evaluation requires careful interpretation of biochemical and dual-energy X-ray absorptiometry findings using age and gender-specific reference ranges, with targeted screening for syndrome-associated neoplasms. Surgery remains the cornerstone of management. Current knowledge gaps in their management include treatment protocols for multiple endocrine neoplasia type 1-associated PHPT, the efficacy and safety of nonsurgical options, and long-term post-surgical outcomes.

Primary hyperparathyroidism is the main cause of hypercalcemia, resulting predominantly from parathyroid adenomas followed by hyperplasia. Diagnosis relies on clinical and biochemical parameters. Accurate pre-operative localization is mandatory for better surgical outcome. Various non-invasive imaging modalities includes cervical ultrasound, radionuclide scintigraphy with ^99mTc-Methoxyisobutyl isonitrile combined with SPECT/CT, 4DCT, MRI and ¹⁸F-Choline PET/CT. Functional imaging has shown higher accuracy in localization especially in ectopic parathyroid adenomas and persistent or recurrent hyperparathyroidism. Combined ultrasound and ^99mTc-MIBI has shown high sensitivity and specificity than individual imaging modality. ¹⁸F-Choline PET/CT has better diagnostic performance in identifying parathyroid hyperplasia and multiple adenomas. In patients with equivocal findings and concurrent thyroid nodular diseases, ¹⁸F-Choline PET/MRI and 4DCT helps in better characterization of lesion. Intraoperative probe guided surgery facilitates targeted and minimally invasive surgery resulting in better surgical outcome. More specific radiopharmaceuticals for parathyroid imaging need to be developed to reduce false positive results.

Parathyroid carcinoma (PC) is a rare malignancy, comprising 1 % of all cases of primary hyperparathyroidism (PHPT). This narrative review explores recent advances in PC management, with a focus on molecular insights, diagnostic advancements, surgical innovations, and emerging targeted therapies. Manuscripts published between 2023 and 2024 were obtained from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). The review highlights advances in biochemical markers, such as circulating tumour cells (CTCs), and imaging modalities such as ¹⁸F-FDG PET/CT and 4D-CT, which are improving diagnostic accuracy. Surgical resection remains central to localised and metastatic disease management. For patients with widespread metastatic or unresectable disease, newer targeted approaches such as tyrosine kinase inhibitors (TKIs), temozolomide, and immune checkpoint inhibitors (ICIs) may offer clinical benefit to specific patient cohorts. This review identifies future research areas to improve outcomes and recommends that patients with advanced PC continue to be managed in centres of excellence.

Abdominal pheochromocytomas and paragangliomas (PPGLs) are characterized by the overproduction of catecholamines, which are associated with hemodynamic instability (HDI) during surgery. Therefore, perioperative management to prevent intraoperative HDI is imperative for the surgical treatment of PPGLs. Owing to the rarity and heterogeneous nature of these tumors, pre-surgical prediction of HDI is a clinical dilemma. The reported risk factors for HDI include perioperative preparation, genetic background, tumor conditions, body composition, catecholamine levels, and surgical approach. Additionally, several personalized algorithms or models including these factors have been developed. The first part of this review outlines the prediction models that include clinical features such as tumor size and location, body mass index (BMI), blood glucose level, catecholamine levels, and preoperative management with α-adrenoceptor blockade and crystal/colloid fluid. We then summarize recently reported models that consider additional factors such as genetic background, radiomics, robotic-assisted surgical approach, three-dimensional visualization, and machine-learning models. These findings suggest that a comprehensive model including risk factors is the most likely approach for achieving effective perioperative management.

Pheochromocytomas and paragangliomas (PPGLs) represent the highest degree of heritability of any known tumor types in humans. Previous studies have characterized a dramatic difference between Chinese and European Caucasians with regards to both genetics and clinical features of PPGLs. The proportion of PGLs in Chinese patients was higher than in Caucasians, and the prevalence of metastasis was much lower in Chinese patients. Compared with Caucasians, there were more pathogenic variants (PVs) found in HRAS and FGFR1, but less in NF1 and SDHB. There were less germline PVs found in Chinese patients. Importantly, in Chinese patients, there was a large proportion of PGLs with PVs found in HRAS and FGFR1, mostly with epinephrine-producing capacity. This finding provided solid evidence that genetics (cluster 1 vs. 2), rather than location (PCC vs. PGL), determines the catecholamine-producing phenotype. Besides, the lower prevalence of SDHB partially explained lower occurrence of metastatic lesions in Chinese patients. These findings underscore the importance of considering ethnic differences when evaluating PPGLs and patient outcomes.

While the establishment of human phaeochromocytoma and paraganglioma (PPGL) cell lines has proven to be particularly difficult over several decades of research, there are other reliable pre-clinical PPGL models currently available. This review provides a summary of these models, together with our recently established personalised drug screening platform using patient-derived PPGL primary cultures. Such currently available PPGL models include murine and rat PPGL cell lines, of which only one cell line (PC12) is publicly accessible through a cell repository, and PPGL animal models, of which the patient-derived xenograft models are promising but complex to establish. We have developed next-generation implementation of human PPGL primary cultures, enabling reliable and personalised drug screening and an individualised analysis of tumour drug responsivity based on the tumour's unique genetic, biochemical, immunohistochemical and clinical profile. Overall, reliable PPGL models, including patient-derived primary culture models, are essential to advance pre-clinical research in the field of PPGLs.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours. Around 20-25 % of patients develop metastases, for which there is an urgent need of prognostic markers and therapeutic stratification strategies. The presence of a MAML3-fusion is associated with increased metastatic risk, but neither the processes underlying disease progression, nor targetable vulnerabilities have been addressed. We have compiled a cohort of 850 patients, which has shown a 3.65 % fusion prevalence and represents the largest MAML3-positive series reported to date. While MAML3-fusions mainly cause single pheochromocytomas, we also observed somatic post-zygotic events, resulting in multiple tumours in the same patient. MAML3-tumours show increased expression of neuroendocrine-to-mesenchymal transition markers, MYC-targets, and angiogenesis-related genes, leading to a distinct tumour microenvironment with unique vascular and immune profiles. Importantly, our findings have identified MAML3-tumours specific vulnerabilities beyond Wnt-pathway dysregulation, such as a rich vascular network, and overexpression of PD-L1 and CD40, suggesting potential therapeutic targets.

Head and neck paragangliomas (HNPGLs), rare neuroendocrine tumors that mainly arise from parasympathetic ganglia along the cranial nerves, are challenging due to anatomic origin, tendency to aggressive neurovascular and skull base infiltration, unpredictable metastatic potential, radio-chemoresistance, and risk of multiplicity. Symptoms range from mild to life threatening depending on location/size, but rarely relate to catecholamine excess. Risk factors include female sex and pathogenic germline variants in genes affecting hypoxia signaling (foremost succinate dehydrogenase genes). Diagnostic work-up relies on imaging, measurements of plasma free metanephrines/methoxytyramine, genetic testing, and pathology/immunohistochemistry. Management is tailored to patient/tumor characteristics and encompasses wait-scan, upfront surgery, debulking surgery, and radiotherapy. Presurgical embolization is recommended, except for small tympanic and tympanomastoid tumors. Presurgical stenting is required for internal carotid artery involvement, and two-stage surgery for intradural extension. Current treatments for metastatic/inoperable HNPGL are non-curative, and long-term follow-up should be recommended for all patients to monitor local recurrence and new tumors.

Pheochromocytomas and sympathetic paragangliomas (PPGL) are rare neuroendocrine tumors originating from chromaffin tissue of the adrenal medulla and extra-adrenal sympathetic paraganglia. Historically, many of these tumors were diagnosed postmortem, earning pheochromocytomas the moniker "great mimic" due to their diverse clinical manifestations that can resemble various other conditions. Over time, the clinical presentation of PPGL has evolved, with a shift from symptomatic or postmortem diagnoses to more frequent incidental discoveries or diagnoses through screening, with postmortem identification now being rare. The development of a clinical scoring system has improved the identification of patients at increased risk for PPGL. Notably, the proportion of PPGL patients with normal blood pressure ranges from 15 % to 40 %, varying based on the clinical context. Despite the tumor's reputation, PPGL is an exceedingly rare cause of resistant hypertension. Management of a pheochromocytoma crisis has advanced, with several classes of drugs available for treatment. However, PPGL during pregnancy remains a significant concern, associated with substantial maternal and fetal mortality rates. Additionally, PPGL can present as rare disorders, including catecholamine-induced cardiomyopathy, Cushing syndrome, and urinary bladder PGL. Given these varied presentations, heightened awareness and prompt recognition of PPGL are crucial for timely diagnosis and treatment, ultimately improving patient outcomes. In this article, we offer an in-depth analysis of the diverse clinical presentations of PPGL, highlighting their complexity and the associated diagnostic and treatment strategies.