Search Results (129)

Gain-of-function gene alterations in rearranged during transfection (RET), a receptor tyrosine kinase, are observed in both sporadic and hereditary medullary thyroid cancers (MTCs) and pheochromocytomas and paragangliomas (PPGLs). Several tyrosine kinase inhibitors (TKIs) that target RET have been proven to be effective on MTCs and PCCs. Recently, TKIs, namely, sunitinib and selpercatinib, which were clinically used to target PPGLs, have been reported to decrease catecholamine levels without reducing tumor size. Our clinical case of metastatic medullary thyroid cancer, which is associated with RET mutations undergoing treatment with vandetanib, also suggests that vandetanib can decrease catecholamine levels. Therefore, we investigated the effect of vandetanib, a representative multi-targeted TKI for RET-related MTC, on cell proliferation and catecholamine synthesis in rat pheochromocytoma PC12 cells. Vandetanib reduced viable cells in a concentration-dependent manner. The dopamine and noradrenaline levels of the cell lysate were reduced in a concentration-dependent manner. They also decreased more prominently at lower concentrations of vandetanib compared to the inhibition of cell proliferation. The RNA knockdown study of Ret revealed that this inhibitory effect on catecholamine synthesis is mainly mediated by the suppression of RET signaling. Next, we focused on two signaling pathways downstream of RET, namely, ERK and AKT signaling. Treatment with vandetanib reduced both ERK and AKT phosphorylation in PC12 cells. Moreover, both an MEK inhibitor U0126 and a PI3K/AKT inhibitor LY294002 suppressed catecholamine synthesis without decreasing viable cells. This study in rat pheochromocytoma PC12 cells reveals the direct inhibitory effects of vandetanib on catecholamine synthesis via the suppression of RET-ERK and RET-AKT signaling. Full article

One of the main issues with paragangliomas and pheochromocytomas is that these tumors have up to a 20% rate of metastatic disease, which cannot be reliably predicted. While machine learning models hold great promise for enhancing predictive accuracy, their often opaque nature limits trust and adoption in critical fields such as healthcare. Understanding the factors driving predictions is essential not only for validating their reliability but also for enabling their integration into clinical decision-making. In this paper, we propose an architecture that combines data mining, machine learning, and explainability techniques to improve predictions of metastatic disease in these types of cancer and enhance trust in the models. A wide variety of algorithms have been applied for the development of predictive models, with a focus on interpreting their outputs to support clinical insights. Our methodology involves a comprehensive preprocessing phase to prepare the data, followed by the application of classification algorithms. Explainability techniques were integrated to provide insights into the key factors driving predictions. Additionally, a feature selection process was performed to identify the most influential variables and explore how their inclusion affects model performance. The best-performing algorithm, Random Forest, achieved an accuracy of 96.3%, precision of 96.5%, and AUC of 0.963, among other metrics, combining strong predictive capability with explainability that fosters trust in clinical applications. Full article

Pheochromocytoma, a rare catecholamine-secreting tumor, poses significant perioperative challenges due to its potential for severe hemodynamic instability. Careful management of patients with pheochromocytoma is critical for patient safety and favorable outcomes. The diagnostic workup focuses on biochemical analysis of plasma or urinary metanephrines, followed by imaging for tumor localization and genetic testing to identify hereditary syndromes. Preoperative management emphasizes adequate alpha-adrenergic blockade followed by beta-blockade to stabilize cardiovascular function. Anesthetic planning requires meticulous attention to volume status, cardiovascular optimization, and intraoperative monitoring to mitigate the risks of hypertensive crises and hypotension. Postoperative care must account for ongoing hemodynamic and metabolic fluctuations. A multidisciplinary, protocol-driven approach is essential to improve outcomes in patients undergoing pheochromocytoma resection. This paper provides a comprehensive overview of the genetic, biochemical, clinical, and anesthetic considerations involved in the diagnosis and perioperative management of pheochromocytoma. Full article

Background/Objectives: Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of neural crest origin that secrete varying levels of catecholamines. [¹⁸F]Fluorodeoxyglucose-positron emission tomography (FDG-PET) is a valuable tool for the detection of metastases and the prediction of prognoses. However, varying FDG avidities in PPGLs raise concerns regarding cost-effectiveness and unnecessary radiation exposure. Catecholamine secretion patterns are associated with metastasis and clinical outcomes. This study aimed to explore the relationships among FDG avidity, catecholamine levels, and clinical factors in patients with PPGLs. Methods: This retrospective study included 25 patients with unresectable or metastatic PPGLs scheduled for [¹³¹I]metaiodobenzylguanidine therapy with FDG-PET data available within 40 days of urine catecholamine measurements. FDG avidity was assessed using semiquantitative parameters such as the maximum standardized uptake value (SUVmax), total metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Urine catecholamine levels were quantified. Logistic regression and Spearman’s correlation were performed to evaluate the relationship between FDG parameters and urinary catecholamine levels. Results: Urinary noradrenaline levels were significantly higher in patients with FDG-avid lesions than in those without (726.25 μg/day vs. 166.3 μg/day, p = 0.001). Noradrenaline levels showed significant positive correlations with SUVmax, MTV, and TLG (ρ = 0.527, 0.541, and 0.557, respectively; all p < 0.01). Urinary noradrenaline levels predicted FDG avidity with an AUC of 0.849; a cutoff value of 647.5 μg/day achieved 55.6% sensitivity and 100% specificity. Conclusions: Urinary noradrenaline levels were significantly associated with FDG avidity in PPGLs, suggesting their potential utility in predicting FDG-PET outcomes. Therefore, FDG-PET may be unnecessary in PPGL patients with low urinary noradrenaline levels. These findings may help optimize imaging strategies for patients with PPGLs. Full article

Pheochromocytomas and paragangliomas (PPGLs) are infrequent neuroendocrine hypervascular neoplasms arising within different sites of the paraganglion system. They are divided into sympathetic (including pheochromocytomas and extraadrenal paragangliomas) and parasympathetic extraadrenal tumors. These tumors are usually not malignant and grow slowly; about 90% of them are found in the adrenal paraganglia (pheochromocytomas). Extraadrenal tumors are most frequently located in the abdominal cavity (85%), followed by the thoracic cavity (12%), and head and neck (3%). About 25% of PPGLs are related to germline mutations, which are risk factors for multifocal and metastatic disease. In PPGL diagnostics, laboratory, biochemical, and imaging (anatomical and functional) examinations are used. Surgery is the standard management choice for locoregional disease. For patients who are not candidates for surgery and who have stable, not-growing, or slow-growing tumors, active observation or other less invasive techniques (i.e., stereotactic surgery, hypofractionated stereotactic radiotherapy) are considered. In metastatic disease, systemic therapies (tyrosine kinase inhibitors [TKIs], mTORC1 inhibitor everolimus, immunotherapy, cold somatostatin analogs [biotherapy], and radioligand therapy) are used. The prognosis for PPGLs is quite good, and the 5-year survival rate is >90%. The goal of this paper is to review knowledge on the etiopathogenesis, current diagnostics, and therapy for PPGL patients. Our paper is particularly focused on the current management of PPGLs. Full article

Background: Pheochromocytoma and paraganglioma are catecholamine-secreting tumors, rarely presenting with pheochromocytoma multisystem crisis (PMC), a life-threatening endocrine emergency. The severity of the condition includes a refractory cardiogenic shock and may therefore require the use of temporary mechanical circulatory support. The aim of this review is to describe the incidence of pheochromocytoma and paraganglioma crises associated with refractory cardiogenic shock, the physiopathological impact of this condition on the myocardial function, the role of temporary mechanical circulatory support (tMCS) in its management, and the outcomes of this specific population. Methods: For the purpose of this narrative review, a literature search of PubMed was conducted as of 16 November 2024. Medical Subject Headings (MeSH) terms used included extracorporeal circulation”, “Impella”, “pheochromocytoma”, “paraganglioma”, and “cardiogenic shock”, combined with Boolean “OR” and “AND”. Data from case series, retrospective studies, and systematic reviews were considered. Seven studies reporting on 45 patients who developed PMC with cardiogenic shock requiring tMCS were included. Patients were young, with a median age of 43 years (range 25–65) at presentation. Most cases presented with severe hemodynamic instability, blood pressure lability, and rapid progression to severe left ventricular dysfunction. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was the most common tMCS used to stabilize patients, initiate specific pheochromocytoma treatments, and, in some cases, provide circulatory support during emergent surgery. The median duration of VA-ECMO support was 4 days (range 1–7) and the reported mean in-hospital survival rate was 93.5%. Following VA-ECMO weaning, survivors showed full recovery of the left ventricular ejection fraction (LVEF). Conclusions: The cardiac dysfunction observed in PMC-associated cardiogenic shock may be severe and life-threatening but appears reversible. tMCS should therefore be considered in eligible cases, as a bridge to recovery, treatment, or surgery. The reported survival rates are impressively high, suggesting possibly a substantial risk of publication bias. Full article

Background: Pheochromocytoma and paragangliomas (PPGLs) caused refractory hypertension in clinics. The sustained risk of local or metastatic recurrences or new tumor development prompted more research on diagnosis, prognosis prediction, and immunotherapy. Method: The tumor stemness is closely related to the heterogeneous growth of tumor, metastasis, and drug-resistance, and mRNA expression-based stemness indices (mRNAsi) could reflect tumor stemness. This was calculated based on OCLR machine learning algorithm and PPGLs patients’ TCGA RNAseq data. The relationship between clinical, molecular, and tumor microenvironment (TME) features and tumor stemness was analyzed through the hub genes that best captured the stem cell characteristics of PPGLs using weighted gene co-expression network analysis (WGCNA), Cox, and LASSO regression analysis. Results: Our study found that metastatic PPGLs had higher mRNAsi scores, suggesting the degree of tumor stemness could affect metastasis and progression. HRAS, CSDE1, NF1, RET, and VHL-mutant subtypes displayed significant difference in stemness expression. Patients were divided into stemness high-score and low-score subtypes. High-score PPGLs displayed the more unfavorable prognosis compared with low-score, associated with their immune-suppressive features, manifested as low macrophages M1 infiltration and downregulated expression of immune checkpoints. Furthermore, from the viewpoint of stemness features, we established a reliable prognostic for PPGLs, which has the highest AUC value (0.908) in the field so far. And this could stratify PPGLs patients into high-risk and low-risk subtypes, showing the significant differences in prognosis, underlying mechanisms correlated with specific molecular alterations, biological processes activation, and TME. Notably, high immune infiltration and tumor neoantigen in low-risk patients and further resulted in more responsive to immunotherapy. Conclusion: We indicated that tumor stemness could act as the potential biomarker for metastasis or prognosis of PPGLs, and integrated multi-data sources, analyzed valuable stemness-related genes, developed and verified a novel stemness scoring system to predict prognosis and guide the choice of treatment strategies. Full article

Background/Objectives: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that produce catecholamines. Unresectable or metastatic PPGLs are treated with [¹³¹I]metaiodobenzylguanidine (MIBG), but MIBG avidity is often heterogeneous. Identifying predictive factors for non-avid lesions on scintigraphy is clinically important. The primary objective of this study was to investigate the relationship between MIBG avidity and catecholamine secretion patterns in patients with unresectable or metastatic PPGLs. Methods: This retrospective study included 27 patients treated with [¹³¹I]MIBG for unresectable/metastatic PPGLs between 2001 and 2024. Patients received a single intravenous dose of [¹³¹I]MIBG (5.5–7.4 GBq), with post-therapy scintigraphy performed 3–7 days later. Non-avid lesions were assessed by imaging and confirmed using CT, MRI, and FDG-PET. Clinical factors, including age, sex, prior treatments, metastasis sites, and urine catecholamines, were evaluated using univariate logistic analysis. Predictive factors were assessed via receiver operating characteristic curves. Results: Non-avid lesions were found in nine patients (33.3%). These patients were younger (median age 38 vs. 62.5 years) and had higher urine dopamine levels (median 1510 vs. 779 μg/day) than those without non-avid lesions. Younger age (odds ratio: 0.892, p < 0.01) and higher urinary dopamine levels (odds ratio: 1.003, p < 0.01) were significantly associated with non-avid lesions. All patients > 45 years with urinary dopamine < 1190 μg/day had no non-avid lesions, whereas patients < 45 years with urinary dopamine > 1190 μg/day had non-avid lesions. Conclusions: Age and urinary dopamine levels may predict non-avid lesions in unresectable/metastatic PPGLs, aiding treatment decisions for [¹³¹I]MIBG therapy. This article is a revised and expanded version of a paper entitled “Urine dopamine level and age can predict non-avid lesion on scintigraphy after I-131 MIBG treatment for unresectable/metastatic PPGL”, which was presented at SNMMI 2024, Toronto, from 8 June to 11 June 2024. Full article

Background: Quantifying urinary catecholamines and metanephrines is essential for the clinical screening and diagnosis of neuroendocrine tumours. HPLC with electrochemical detection (HPLC-ECD) is commonly used for this type of analysis but requires extensive sample cleanup. Simple and rapid dilute-and-shoot LC–multiple-reaction monitoring (MRM)-MS assays have been developed for quantitating these analytes in urine but have not yet been validated according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Methods: A simple dilute-and-shoot sample preparation without derivatization was used. C18 RP-UPLC-MRM-MS and positive-ion ESI were used, usually with two transitions per analyte being monitored. Certified deuterated internal standards were used for each analyte. Results: This assay was validated according to the CLSI C62-A guidelines, including accuracy/trueness, imprecision, sensitivity, specificity, carryover, stability, and linearity. The final MRM-MS method was compared to the established HPLC-ECD clinical chemistry reference method. The run time was reduced from 25 min to 5 min. Conclusions: A simple, robust, rapid, and cost-effective LC-MRM-MS assay for measuring urinary catecholamines and metanephrines was developed and validated according to the CLSI guidelines. This validated method requires minimal sample manipulation before analysis and provides sensitivity, specificity, and improved precision. The implementation of this assay in clinical laboratories will facilitate early and accurate diagnosis. Full article

Head and neck paragangliomas (HNPGLs) are rare neoplasms that, along with pheochromocytomas and extra-adrenal paragangliomas, are associated with inherited mutations in at least 12 susceptibility genes in approximately 40% of cases. However, due to the rarity of HNPGLs, only a series of small-scale studies and individual cases have reported mutations in additional genes that may be involved in tumorigenesis. Consequently, numerous disease-causing mutations and genes responsible for the pathogenesis of HNPGLs remain poorly investigated. The aim of this study was to gain a deeper understanding of the genetic basis of HNPGLs by focusing on variants in genes that were not previously identified as well-known drivers. A whole-exome data analysis was conducted on a representative set of 152 HNPGLs. In 30% of the tumors examined, 53 potentially deleterious variants were identified in 36 different genes. The analysis identified pathogenic or likely pathogenic variants in the ARNT, IDH2, L2HGDH, MYH3, PIK3CA, and TERT genes. A functional network analysis of the mutated genes revealed numerous associations and a list of metabolic pathways (e.g., the TCA cycle, carbon metabolism, pyruvate metabolism, etc.) and signaling pathways (e.g., HIF1, PI3K-Akt, FoxO, AMPK, MAPK, etc.) that may play an important role in the development of HNPGLs. The identified range of genetic alterations affecting multiple genes and, potentially, influencing diverse cellular pathways provides an enhanced molecular genetic characterization of HNPGLs. Full article

Background: Hemodynamic instability is common during adrenalectomy for pheochromocytoma and paraganglioma (PPGL). Most analyses focus on the risk factors for intraoperative hypertension, but hypotension is a frequent and undesirable phenomenon during PPGL surgery. This study aimed to analyze the risk factors for hypotensive episodes during the removal of PPGL, and whether these episodes are always associated with concomitant intraoperative hypertensive events. Methods: A consecutive series of 121 patients (91.7% receiving preoperative alpha-blockade) treated with transperitoneal endoscopic adrenalectomy at a university hospital were analyzed, and pre- and intraoperative risk factors for intraoperative hypotension with or without intraoperative hypertension were analyzed using univariable and multivariable logistic regression analyses. Results: In total, 58 (56.2%) patients presented with intraoperative hypotension. Of these, 25 (20.7%) patients showed only hypotensive episodes but no hypertensive episodes (group 1), and 43 (35.5%) patients had both intraoperative hypotension and hypertension (group 2). The remaining 53 patients did not present with hypotension at all (group 3). When comparing group 1 (hypotension only) to all other patients with incidental diagnosis, higher age and lower preoperative diastolic arterial blood pressure (ABP) were significant risk factors for intraoperative hypotension; only the latter two were still significant in multivariate analysis. The significant risk factors for hypotension independent of hypertension (group 1 + 2 vs. group 3) were age and incidental diagnosis, pre-existing diabetes mellitus, and intraoperative use of remifentanil. Incidental diagnosis and use of remifentanil reached the level of significance in multivariate analysis. Conclusions: Since older age, incidental diagnosis of PPGL, lower preoperative ABP, and diabetes mellitus are risk factors for intraoperative hypotension, preoperative alpha-blocker treatment should be individualized for those at risk for hypotension. In addition, remifentanil should be used cautiously in the risk group. Full article

Pheochromocytomas (PCCs) and paragangliomas (PGLs), denoted PPGLs, are rare neuroendocrine tumours and are highly heterogeneous. The phenotype–genotype correlation is poor; therefore, additional studies are needed to understand their pathogenesis. We describe the clinical characteristics of 63 patients with PPGLs and perform a genetic study. Genetic screening was performed via a targeted gene panel, and clinical variables were compared among patients with a positive molecular diagnosis and negative ones in both PCC and PGL cohorts. The mean age of patients with PCC was 50.0, and the mean age of those with PGL was 54.0. Disease-causing germline variants were identified in 16 individuals (25.4%), twelve and five patients with PCC and PGL, respectively. Genetically positive patients were younger at diagnosis in both cohorts. Variants in genes associated with either isolated PPGLs or syndromic forms of the disease were detected in a cohort of PPGLs. We have identified novel variants in known genes and set the importance of genetic screening to every patient with PPGLs, with a special focus on the young. A longer follow up of patients with variants in genes associated with syndromic forms is of clinical value. Full article

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially malignant behavior require in-depth knowledge of the pathology and multidisciplinary management. Nowadays, diagnostic ability has certainly improved and guidelines and consensus documents for treatment and follow-up are available. A major impulse to the development of this knowledge has come from the new findings on the genetic and molecular characteristics of PPGLs. Germline mutation in susceptibility genes is detected in 40% of subjects, with a mutation frequency of 10–12% also in patients with sporadic presentation and genetic testing should be incorporated within clinical care. PPGL susceptibility genes include “old genes” associated with Neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and Multiple Endocrine Neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), and genes less frequently involved such as TMEM, MAX, and FH. Each gene has a different risk of relapse, malignancy, and other organ involvement; for mutation carriers, affected or asymptomatic, it is possible to define a tailored long-life surveillance program according to the gene involved. In addition, molecular characterization of the tumor has allowed the identification of somatic mutations in other driver genes, bringing to 70% the PPGLs for which we know the mechanisms of tumorigenesis. This has expanded the catalog of tumor driver genes, which are identifiable in up to 70% of patients Integrated genomic and transcriptomic data over the last 10 years have revealed three distinct major molecular signatures, triggered by pathogenic variants in susceptibility genes and characterized by the activation of a specific oncogenic signaling: the pseudo hypoxic, the kinase, and the Wnt signaling pathways. These molecular clusters show a different biochemical phenotype and clinical behavior; they may also represent the prerequisite for implementing customized therapy and follow-up. Full article

Pheochromocytomas (PCCs) are tumors arising from chromaffin cells in the adrenal medulla, and paragangliomas (PGLs) are tumors derived from extra-adrenal sympathetic or parasympathetic paraganglia; these tumors are collectively referred to as PPGL cancer. Treatment for PPGL primarily involves surgical removal of the tumor, and only limited options are available for treatment of the disease once it becomes metastatic. Human carriers of the heterozygous mutations in the succinate dehydrogenase subunit B (SDHB) gene are susceptible to the development of PPGL. A physiologically relevant PCC patient-derived cell line hPheo1 was developed, and SDHB_KD cells carrying a stable short hairpin knockdown of SDHB were derived from it. An untargeted metabolomic approach uncovered an overactive polyamine pathway in the SDHB_KD cells that was subsequently fully validated in a large set of human SDHB-mutant PPGL tumor samples. We previously reported that treatment with the polyamine metabolism inhibitor N¹,N¹¹-diethylnorspermine (DENSPM) drastically inhibited growth of these PCC-derived cells in culture as well as in xenograft mouse models. Here we explored the mechanisms underlying DENSPM action in hPheo1 and SDHB_KD cells. Specifically, by performing an RNAseq analysis, we have identified gene expression changes associated with DENSPM treatment that broadly interfere with all aspects of lipid metabolism, including fatty acid (FA) synthesis, desaturation, and import/uptake. Furthermore, by performing an untargeted lipidomic liquid chromatography–mass spectrometry (LC/MS)-based analysis we uncovered specific groups of lipids that are dramatically reduced as a result of DENSPM treatment. Specifically, the bulk of plasmanyl ether lipid species that have been recently reported as the major determinants of cancer cell fate are notably decreased. In summary, this work suggests an intersection between active polyamine and lipid pathways in PCC cells. Full article

Head and neck paragangliomas (HNPGLs) are rare neoplasms arising from paraganglia of the parasympathetic nervous system. HNPGLs are characterized by high vascularity and are located in proximity to major vessels and nerves, which may be potential sources of microbial invasion in these tumors. There have been no studies in the literature on the microbiota in HNPGLs. Investigation of the microbiome associated with paragangliomas is important for understanding tumor pathogenesis. In this study, we investigated the microbiome composition in two sets of HNPGLs. First, 29 fresh frozen (FF) tissues were subjected to 16S rRNA gene sequencing; concurrently, a panel of candidate laboratory-derived contaminants was investigated. Second, we analyzed microbial reads from whole transcriptome sequencing data obtained for 82 formalin-fixed paraffin-embedded (FFPE) HNPGLs. The bacterial diversity in FF tumors was found to be significantly lower than that observed in FFPE HNPGLs. Based on 16S rRNA gene sequencing, only seven bacterial families were identified as potential tumor inhabitants: Bryobacteraceae, Enterococcaceae, Neisseriaceae, Legionellaceae, Vibrionaceae, Obscuribacteraceae, and Mycobacteriaceae. However, RNA-Seq demonstrated higher sensitivity for identifying microbiome composition and revealed abundant bacterial families that partially correlated with those previously described in pheochromocytomas and extra-adrenal paragangliomas. No viruses were found in HNPGLs. In summary, our findings indicated the presence of a microbiome in HNPGLs, comprising a number of bacterial families that overlap with those observed in pheochromocytomas/paragangliomas and glioblastomas. Full article