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Journal of Zhejiang University.... Mar 2024Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs...
Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.
Topics: Pheochromocytoma; Humans; Adrenal Gland Neoplasms; Pyrimidines; Methionine; Tyrosine; Cysteine; Male; Metabolomics; Female; Middle Aged; Adult; Metabolic Networks and Pathways
PubMed: 38725340
DOI: 10.1631/jzus.B2300579 -
Frontiers in Endocrinology 2023We seek a simple and reliable tool to predict malignant behavior of pheochromocytoma and paraganglioma (PPGL).
AIM
We seek a simple and reliable tool to predict malignant behavior of pheochromocytoma and paraganglioma (PPGL).
METHODS
This single-center prospective cohort study assessed size of primary PPGLs on preoperative cross-sectional imaging and prospectively scored specimens using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS). Multiplication of PASS points with maximum lesion diameter (in mm) yielded the SIZEPASS criterion. Local recurrence, metastasis or death from disease were surrogates defining malignancy.
RESULTS
76 consecutive PPGL patients, whereof 58 with pheochromocytoma and 51 female, were diagnosed at a mean age of 52.0 ± 15.2 years. 11 lesions (14.5%) exhibited malignant features at a median follow-up (FU) of 49 months (range 4-172 mo). Median FU of the remaining cohort was 139 months (range 120-226 mo). SIZEPASS classified malignancy with an area under the curve (AUC) of 0.97 (95%CI 0.93-1.01; p<0.0001). Across PPGL, SIZEPASS >1000 outperformed all known predictors of malignancy, with sensitivity 91%, specificity 94%, and accuracy 93%, and an odds ratio of 72 fold (95%CI 9-571; P<0.001). It retained an accuracy >90% in cohorts defined by location (adrenal, extra-adrenal) or mutation status.
CONCLUSIONS
The SIZEPASS>1000 criterion is a lesion-based, clinically available, simple and effective tool to predict malignant behavior of PPGLs independently of age, sex, location or mutation status.
Topics: Humans; Female; Adult; Middle Aged; Aged; Pheochromocytoma; Prospective Studies; Paraganglioma; Adrenal Gland Neoplasms; Adrenal Glands
PubMed: 37600698
DOI: 10.3389/fendo.2023.1235243 -
Journal of Diabetes Jan 2024Iron homeostasis is critical for functional respiratory chain complex of mitochondrial, thus potentially contributing to fat biology and energy homeostasis. Transferrin...
AIM
Iron homeostasis is critical for functional respiratory chain complex of mitochondrial, thus potentially contributing to fat biology and energy homeostasis. Transferrin receptor (Tfrc) binds to transferrin for extracellular iron uptake and is recently reported to be involved in brown fat development and functionality. However, whether TFRC levels and variants are associated with human obesity is unknown.
METHODS
To investigate the association of TFRC levels and variants with human obesity, fat biopsies were obtained from surgery. Exon-sequencing and genetic assessments were conducted of a case-control study. For TFRC levels assessment in fat biopsy, 9 overweight and 12 lean subjects were involved. For genetic study, obese (n = 1271) and lean subjects (n = 1455) were involved. TFRC levels were compared in abdominal mesenteric fat of pheochromocytoma patients versus control subjects, and overweight versus lean subjects. For genetic study, whole-exome sequencing of obese and matched control subjects were conducted and analyzed. In addition, the possible disruption in protein stability of TFRC variant was assessed by structural and molecular analysis.
RESULTS
TFRC levels are increased in human browning adipose tissue and decreased in fat of overweight patients. Besides, TFRC levels are negatively correlated with body mass index and positively correlated with uncoupling protein 1 levels. Furthermore, a rare heterozygous missense variant p.I337V in TFRC shows a tendency to enrich in obese subjects. Structural and functional study reveals impaired protein stability of the TFRC variant compared to wild-type.
CONCLUSIONS
Reduced TFRC levels and its rare variant p.I337V with protein instability are associated with human obesity.
Topics: Humans; Adipose Tissue, Brown; Case-Control Studies; Iron; Obesity; Overweight; Receptors, Transferrin
PubMed: 37646182
DOI: 10.1111/1753-0407.13467 -
Medicina (Kaunas, Lithuania) Oct 2023Paragangliomas are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, i.e., small organs consisting mainly of neuroendocrine cells that... (Review)
Review
Paragangliomas are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, i.e., small organs consisting mainly of neuroendocrine cells that are derived from the embryonic neural crest and have the ability to secrete catecholamines. Paragangliomas can derive from either parasympathetic or sympathetic paraganglia. Most of the parasympathetic ganglia-derived paragangliomas are nonfunctional, and symptoms result from mass effect. Conversely, the sympathetic paragangliomas are functional and produce catecholamine. Although such patients could have symptoms similar to pheochromocytoma, mass effect symptoms, or non-specific symptoms, being benign tumors, they can also present with anemia, specifically iron-deficiency anemia. Considering that neoplastic pathology is chronically accompanied by moderate, normochromic, normocytic anemia, association between paragangliomas that are mostly benign but with a potential degree of malignancy and anemia is not as frequent as expected, with only 12 cases reported in the literature. We report a case of a 54-year-old female patient diagnosed with a paraganglioma of the carotid glomus accompanied by severe normochromic, normocytic anemia, which reached normal limits after excision of the paraganglioma.
Topics: Female; Humans; Middle Aged; Paraganglioma; Pheochromocytoma; Catecholamines; Adrenal Gland Neoplasms; Anemia
PubMed: 38003974
DOI: 10.3390/medicina59111925 -
Theranostics 2024Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [I]MIBG and [Lu]Lu-DOTA-TATE are routinely... (Review)
Review
Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [I]MIBG and [Lu]Lu-DOTA-TATE are routinely used for the treatment of a subset of NENs, including pheochromocytomas, paragangliomas and gastroenteropancreatic tumors. Some patients suffering from other forms of NENs, such as medullary thyroid carcinoma or neuroblastoma, were shown to respond to radionuclide therapy; however, no general recommendations exist. Although [I]MIBG and [Lu]Lu-DOTA-TATE can delay disease progression and improve quality of life, complete remissions are achieved rarely. Hence, better individually tailored combination regimes are required. This review summarizes currently applied radionuclide therapies in the context of NENs and informs about recent advances in the development of theranostic agents that might enable targeting subgroups of NENs that previously did not respond to [I]MIBG or [Lu]Lu-DOTA-TATE. Moreover, molecular pathways involved in NEN tumorigenesis and progression that mediate features of radioresistance and are particularly related to the stemness of cancer cells are discussed. Pharmacological inhibition of such pathways might result in radiosensitization or general complementary antitumor effects in patients with certain genetic, transcriptomic, or metabolic characteristics. Finally, we provide an overview of approved targeted agents that might be beneficial in combination with radionuclide therapies in the context of a personalized molecular profiling approach.
Topics: Humans; Neuroendocrine Tumors; 3-Iodobenzylguanidine; Quality of Life; Octreotide; Carcinoma, Neuroendocrine; Radioisotopes
PubMed: 38164150
DOI: 10.7150/thno.87345 -
International Journal of Surgery Case... Aug 2023Adrenal adenomas are benign neoplasms of the adrenal cortex which can be functional or non-functional. The functional tumors manifest as Cushing syndrome. Rarely, they...
INTRODUCTION AND IMPORTANCE
Adrenal adenomas are benign neoplasms of the adrenal cortex which can be functional or non-functional. The functional tumors manifest as Cushing syndrome. Rarely, they are associated with high levels of metanephrine due to pheochromocytoma. Here, we report an extremely rare case of adrenal adenoma associated with raised metanephrine, but no histopathological evidence of medullary changes.
CASE PRESENTATION
A 30-year female with diabetes, hypothyroidism, and hypertension was admitted for resistant hypertension, severe refractory hypokalemia, decreased sleep, fearfulness, anxiety, and palpitation. Facial puffiness, ecchymoses on upper and lower limbs, and bilateral pedal edema were present. Laboratory investigation revealed raised 24-hour-urine cortisol (52.5 μmol/dL) and metanephrine (56.00 μmol/24 h), very low ACTH (<5.0 pg/mL), and negative dexamethasone suppression test. MRI brain findings were normal. CT scan of the abdomen revealed a well-defined soft tissue lesion in the right adrenal gland and diffuse osteopenia vertebrae. Hence, diagnosis of Cushing Syndrome secondary to adrenal adenoma, and pheochromocytoma was made, and laparoscopic adrenalectomy was done under pheochromocytoma protocol. The patient improved dramatically, thereafter. Histopathological findings showed adrenocortical adenoma only; no evidence of pheochromocytoma was found.
CLINICAL DISCUSSION
We came across many articles reporting adrenal adenoma associated with high levels of metanephrine due to co-existing pheochromocytomas either in the ipsilateral or contralateral adrenal gland. But, in our case, the adrenal adenoma was associated with high metanephrine levels with no histopathologic features of pheochromocytoma.
CONCLUSION
Cushing syndrome due to Cortisol secreting Adrenal adenoma can be associated with biochemical and clinical features suggestive of Pheochromocytoma which could resolve after adrenalectomy.
PubMed: 37453323
DOI: 10.1016/j.ijscr.2023.108498 -
Journal of Clinical Hypertension... Apr 2024This study aimed to elucidate the clinical diagnostic value of plasma catecholamines and their metabolites for pheochromocytoma and paraganglioma (PPGL)-induced...
This study aimed to elucidate the clinical diagnostic value of plasma catecholamines and their metabolites for pheochromocytoma and paraganglioma (PPGL)-induced secondary hypertension using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS). The study population included 155 patients with PPGL that were divided into the PPGL with hypertension (n = 79) and a PPGL without hypertension (n = 76) groups, and 90 healthy volunteers and 90 patients with primary hypertension as the control groups. UPLC-MS/MS was performed to detect plasma levels of catecholamines and their metabolites, including dopamine, vanillylmandelic acid (VMA), norepinephrine, metanephrine, and normetanephrine. Receiver operating characteristic curves were generated to analyze the diagnostic value of the plasma levels of catecholamines and their metabolites in PPGL-induced secondary hypertension. Patients in the primary hypertension and PPGL without hypertension groups had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal group (all p < .05). On the other hand, patients in the PPGL with hypertension group had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal, primary hypertension, and PPGL without hypertension groups (all p < .05). Collectively, our findings showed that dopamine, VMA, norepinephrine, metanephrine, and normetanephrine are all effective biomarkers for the diagnosis of PPGL and PPGL-induced secondary hypertension.
Topics: Humans; Catecholamines; Pheochromocytoma; Metanephrine; Normetanephrine; Dopamine; Chromatography, Liquid; Liquid Chromatography-Mass Spectrometry; Hypertension; Tandem Mass Spectrometry; Paraganglioma; Norepinephrine; Adrenal Gland Neoplasms; Essential Hypertension; Mandelic Acids
PubMed: 38459755
DOI: 10.1111/jch.14779 -
Hereditary Cancer in Clinical Practice Mar 2024Adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PPGL) are two rare types of adrenal gland malignancies. Regarding hereditary tumors, some patients... (Review)
Review
Adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PPGL) are two rare types of adrenal gland malignancies. Regarding hereditary tumors, some patients with ACC are associated with with Li-Fraumeni syndrome (LFS), and those with PPGL with multiple endocrine neoplasia type 2. Recent studies have expanded this spectrum to include other types of hereditary tumors, such as Lynch syndrome or familial adenomatous polyposis. Individuals harboring germline TP53 pathogenic variants that cause LFS have heterogeneous phenotypes depending on the respective variant type. As an example, R337H variant found in Brazilian is known as low penetrant. While 50-80% of pediatric ACC patients harbored a LFS, such a strong causal relationship is not observed in adult patients, which suggests different pathophysiologies between the two populations. As for PPGL, because multiple driver genes, such as succinate dehydrogenase (SDH)-related genes, RET, NF1, and VHL have been identified, universal multi-gene germline panel testing is warranted as a comprehensive and cost-effective approach. PPGL pathogenesis is divided into three molecular pathways (pseudohypoxia, Wnt signaling, and kinase signaling), and this classification is expected to result in personalized medicine based on genomic profiles. It remains unknown whether clinical characteristics differ between cases derived from genetic predisposition syndromes and sporadic cases, or whether the surveillance strategy should be changed depending on the genetic background or whether it should be uniform. Close cooperation among medical genomics experts, endocrinologists, oncologists, and early investigators is indispensable for improving the clinical management for multifaceted ACC and PPGL.
PubMed: 38532453
DOI: 10.1186/s13053-024-00276-6