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PeerJ 2020Lung adenocarcinoma (ACA) is the most common subtype of non-small-cell lung cancer. About 70%-80% patients are diagnosed at an advanced stage; therefore, the survival...
BACKGROUND
Lung adenocarcinoma (ACA) is the most common subtype of non-small-cell lung cancer. About 70%-80% patients are diagnosed at an advanced stage; therefore, the survival rate is poor. It is urgent to discover accurate markers that can differentiate the late stages of lung ACA from the early stages. With the development of biochips, researchers are able to efficiently screen large amounts of biological analytes for multiple purposes.
METHODS
Our team downloaded GSE75037 and GSE32863 from the Gene Expression Omnibus (GEO) database. Next, we utilized GEO's online tool, GEO2R, to analyze the differentially expressed genes (DEGs) between stage I and stage II-IV lung ACA. The using the Cytoscape software was used to analyze the DEGs and the protein-protein interaction (PPI) network was further constructed. The function of the DEGs were further analyzed by cBioPortal and Gene Expression Profiling Interactive Analysis (GEPIA) online tools. We validated these results in 72 pairs human samples.
RESULTS
We identified 109 co-DEGs, most of which were involved in either proliferation, S phase of mitotic cell cycle, regulation of exit from mitosis, DNA replication initiation, DNA replication, and chromosome segregation. Utilizing cBioPortal and University of California Santa Cruz databases, we further confirmed 35 hub genes. Two of these genes, encoding CDC28 protein kinase regulatory subunit 2 (CKS2) and RecQ-mediated genome instability 2 (RMI2), were upregulated in lung ACA compared with adjacent normal tissues. The Kaplan-Meier curves revealed upregulation of CKS2 and RMI2 are associated with worse survival. Using CMap analysis, we discovered 10 small molecular compounds that reversed the altered DEGs, the top five are phenoxybenzamine, adiphenine, resveratrol, and trifluoperazine. We also evaluated 72 pairs resected samples, results revealed that upregulation of CKS2 and RMI2 in lung ACA were associated with larger tumor size. Our results allow the deeper recognizing of the mechanisms of the progression of lung ACA, and may indicate potential therapeutic strategies for the therapy of lung ACA.
PubMed: 33083148
DOI: 10.7717/peerj.10126 -
The Journal of Clinical Endocrinology... Jul 2021Preoperative blockade with α-blockers is recommended in patients with pheochromocytoma/paraganglioma (PPGL). The data on calcium channel blockade (CCB) in PPGL are... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Preoperative blockade with α-blockers is recommended in patients with pheochromocytoma/paraganglioma (PPGL). The data on calcium channel blockade (CCB) in PPGL are scarce.
OBJECTIVE
We aimed to compare the efficacy of CCB and α-blockers on intraoperative hemodynamic instability (HDI) in PPGL.
METHODS
In the interim analysis of this monocentric, pilot, open-label, randomized controlled trial, patients with solitary, secretory, and nonmetastatic PPGL were randomized to oral prazosin gastrointestinal therapeutic system (GITS) (maximum 30 mg, n = 9) or amlodipine (maximum 20 mg, n = 11). The primary outcomes were the episodes and duration of hypertension (systolic blood pressure ≥ 160 mmHg) and hypotension (mean arterial pressure < 60 mmHg) and duration of HDI (hypertension and/or hypotension) as a percentage of total surgical time (from induction of anesthesia to skin closure).
RESULTS
The median (IQR) episodes (2 [1-3] vs 0 [0-1]; P = 0.002) and duration of hypertension (19 [14-42] vs 0 [0-3] minutes; P = 0.001) and intraoperative HDI duration (22.85 ± 18.4% vs 2.44 ± 2.4%; CI, 8.68-32.14%; P 0.002) were significantly higher in the prazosin GITS arm than the amlodipine arm, whereas episodes and duration of hypotension did not differ between the 2 groups. There was no perioperative mortality. One patient had intraoperative ST depression on the electrocardiogram. The drug-related adverse effects were pedal edema (1 in amlodipine), dizziness (1 in prazosin GITS), and tachycardia (6 in prazosin GITS and 3 in amlodipine).
CONCLUSION
Preoperative blockade with amlodipine is an efficacious alternative to prazosin GITS in preventing intraoperative HDI in PPGL. Larger studies that compare preoperative blockade by amlodipine with other α-blockers like phenoxybenzamine and/or doxazosin in PPGL patients are warranted.
Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Aged; Amlodipine; Blood Pressure; Calcium Channel Blockers; Female; Hemodynamics; Humans; Male; Middle Aged; Monitoring, Intraoperative; Pheochromocytoma; Treatment Outcome; Young Adult
PubMed: 33839787
DOI: 10.1210/clinem/dgab231 -
Revista Clinica Espanola Jan 2021To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC).
OBJECTIVE
To analyze the clinical and analytical features, diagnostic tests, therapies, and outcomes of pheochromocytoma (PCC).
DESIGN AND METHODS
A multicenter retrospective study in surgically treated patients with PCC followed in 3 Spanish tertiary referral hospitals.
RESULTS
A total of 106 patients (61 [57.5%] women, mean age 52.3 ± 14.8 years) were evaluated. At diagnosis, PCC was symptomatic in 62% and sporadic in 83%. Patients with familial PCC were significantly younger than those with sporadic disease (40.8 ± 14.2 years vs 54.5 ± 13.9 years, p < .001). Familial PCCs were more frequently associated with MEN2A (n = 8). Levels of 24-h urinary fractionated metanephrines were positively related to tumor size. The maximum tumor diameter was 4.3 cm (3-6 cm); 27.7% of the patients had tumors ≥6 cm. Incidental PCCs were significantly smaller than symptomatic PCCs (3.4 cm [2.4-5.0 cm] vs 5.6 cm [4.0-7.0 cm], p < .001). Scintigraphy by ¹²³I-metaiodobenzylguanidine showed a high sensitivity (81.9%). Preoperative alpha blockade with phenoxybenzamine was used in 93.6% and doxazosin in the rest. Laparoscopic surgery was used in 2/3 of the patients, with a low conversion (1.9%) to open surgery. Perioperative complications appeared in approximately 20% of patients, mainly hypertensive crisis (9.4%). Recurrent disease appeared in 10%, and malignant PCC was uncommon (6.3%).
CONCLUSIONS
PCCs surgically treated in Spain are usually large, symptomatic, and sporadic tumors diagnosed around the sixth decade of life. Hereditary PCC is usually associated with MEN2A. The main type of surgical technique used is laparoscopic surgery, and the prevalence of metastatic PCC is low.
Topics: 3-Iodobenzylguanidine; Adolescent; Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Adult; Aged; Aged, 80 and over; Catecholamines; Conversion to Open Surgery; Doxazosin; Female; Humans; Hypertension; Male; Metanephrine; Middle Aged; Multiple Endocrine Neoplasia Type 2a; Pancreatic Neoplasms; Phenoxybenzamine; Pheochromocytoma; Postoperative Complications; Retrospective Studies; Time Factors; Tumor Burden; Young Adult
PubMed: 33998473
DOI: 10.1016/j.rceng.2019.12.011 -
Frontiers in Oncology 2022Progressive multiple organ failures still occur in some patients with pheochromocytoma multisystem crisis (PMC) despite α- and β-blockade being used, and emergency...
BACKGROUND
Progressive multiple organ failures still occur in some patients with pheochromocytoma multisystem crisis (PMC) despite α- and β-blockade being used, and emergency adrenalectomy may lead to rapid hemodynamic stabilization and recovery. Therefore, the optimal timing and surgical approach under PMC remain controversial.
CASE PRESENTATION
A 50-year-old man presented with persistent chest pain accompanied by vomiting and headache. CT showed a right adrenal mass, and plasma catecholamine levels were significantly elevated. Phenoxybenzamine was used, but his symptoms were aggravated. He progressed to acute respiratory distress syndrome (ARDS) and received mechanical ventilation. Reexamination of CT showed pheochromocytoma rupture. Emergency pheochromocytoma resection was performed on the 5th day, and he was discharged on the 21st day. A 46-year-old woman was admitted for intrauterine device removal and received hysteroscopy under intravenous anesthesia. She presented with dyspnea, fluctuating blood pressure, and loss of consciousness 9 h after hysteroscopy surgery. CT showed a left adrenal mass, and plasma catecholamine levels were significantly elevated. Her condition fluctuated and could not meet the preoperative preparation criteria for pheochromocytoma despite adequate doses of α-blockade and β-blockade were taken. Furthermore, her lung condition worsened due to recurrent crises and pulmonary edema. After multidisciplinary discussions, laparoscopic left adrenalectomy with venoarterial extracorporeal membrane oxygenation (VA-ECMO) support was performed on the 28th day, and she was discharged on the 69th day.
CONCLUSION
Elective surgical resection is the essential therapy for PMC with adequate preoperative medical management. Emergency surgery is recommended for patients who fail to achieve medical stabilization or progressive organ dysfunction within 1 week, especially those with tumor rupture and uncontrolled bleeding. The laparoscopic approach may represent an option even under PMC.
PubMed: 35795034
DOI: 10.3389/fonc.2022.908039 -
Endocrine Dec 2021To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery.
PURPOSE
To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery.
METHODS
A retrospective study of pheochromocytomas submitted to surgery in ten Spanish hospitals between 2011 and 2021. Postoperative complications were classified according to Clavien-Dindo scale.
RESULTS
One hundred and sixty-two surgeries (159 patients) were included. Preoperative antihypertensive blockade was performed in 95.1% of the patients, being doxazosin in monotherapy (43.8%) the most frequent regimen. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more frequently (49.4% vs 25.0%, P = 0.003) than patients treated with phenoxybenzamine, but no differences in the rate of intraoperative and postsurgical complications were observed. However, patients treated with phenoxybenzamine had a longer hospital stay (12.2 ± 11.16 vs 6.2 ± 6.82, P < 0.001) than those treated with doxazosin. Hypertension resolution was observed in 78.7% and biochemical cure in 96.6% of the patients. Thirty-one patients (19.1%) had postsurgical complications. Prolonged hypotension was the most common, in 9.9% (n = 16), followed by hypoglycaemia in six patients and acute renal failure in four patients. 13.0% of complications had a score ≥3 in the Clavien-Dindo scale. Postsurgical complications were more common in patients with diabetes, cerebrovascular disease, higher plasma glucose levels, higher urinary free metanephrine and norepinephrine, and with pheochromocytomas larger than 5 cm.
CONCLUSION
Preoperative medical treatment and postsurgical monitoring of pheochromocytoma should be especially careful in patients with diabetes, cerebrovascular disease, higher levels of plasma glucose and urine free metanephrine and norepinephrine, and with pheochromocytomas >5 cm, due to the higher risk of postsurgical complications.
Topics: Adrenal Gland Neoplasms; Humans; Phenoxybenzamine; Pheochromocytoma; Retrospective Studies; Treatment Outcome
PubMed: 34373995
DOI: 10.1007/s12020-021-02843-6 -
Frontiers in Endocrinology 2021Surgery is the major treatment option for pheochromocytoma but carries potential risks, including hemorrhage and hemodynamic instability. Even with laparoscopic...
PURPOSE
Surgery is the major treatment option for pheochromocytoma but carries potential risks, including hemorrhage and hemodynamic instability. Even with laparoscopic adrenalectomy, intraoperative blood transfusion happens from time to time, but few studies have investigated risk factors. For the first time we develop and validate a nomogram for prediction of red blood cell transfusion in pheochromocytoma surgery.
METHODS
There were 246 patients in our center and 56 patients in Peking Union Medical College Hospital, who underwent pheochromocytoma surgery, enrolled in the study. We incorporated clinical and radiological risk factors, and presented this with a nomogram. Lasso regression model was used for feature selection. Logistic regression analysis was performed to identify the odd ratios. The performance of the nomogram was assessed with respect to its discrimination, calibration and clinical usefulness.
RESULTS
Thirty-two features were reduced to five, which were phenoxybenzamine use, phenoxybenzamine treatment duration, preinduction heart rate, tumor diameter and surgical procedure. The model showed good discrimination (C-index, 0.857; 95% CI, 0.781-0.836) and application in the validation sets also gave good discrimination (internal validation: C-index, 0.831; 95% CI, 0.750-0.822; external validation: C-index, 0.924; 95% CI, 0.766-1.000). Calibration tested with the Hosmer-Lemeshow test yielded a good agreement between prediction and observation (training P=0.358; internal validation P=0.205; external validation P=0.395). Odd ratios of phenoxybenzamine use, phenoxybenzamine treatment duration, preinduction HR, tumor diameter and open surgery were 13.32 (95% CI, 1.48-197.38; P = 0.034), 1.04 (95% CI, 0.99-1.08; P = 0.092), 1.04 (95% CI, 1.01-1.08; P=0.006), 1.03 (95% CI, 1.02-1.06; P<0.001), 17.13 (95% CI, 5.18-78.79; P<0.001), respectively. Decision curve analysis demonstrated the clinical usefulness of the nomogram.
CONCLUSIONS
This study presents a nomogram that may be used to facilitate the prediction of red blood cell transfusion in pheochromocytoma surgery and help to do the preoperative management more efficiently.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adult; Blood Transfusion; Endocrinology; Erythrocyte Transfusion; Female; Humans; Laparoscopy; Male; Middle Aged; Multivariate Analysis; Nomograms; Phenoxybenzamine; Pheochromocytoma; Preoperative Period; ROC Curve; Regression Analysis; Reproducibility of Results; Retrospective Studies; Risk Factors; Treatment Outcome
PubMed: 33790869
DOI: 10.3389/fendo.2021.647610 -
Endocrinology, Diabetes & Metabolism... Aug 2020We report the case of a 76-year-old male with a remote history of papillary thyroid cancer who developed severe paroxysmal headaches in the setting of episodic...
SUMMARY
We report the case of a 76-year-old male with a remote history of papillary thyroid cancer who developed severe paroxysmal headaches in the setting of episodic hypertension. Brain imaging revealed multiple lesions, initially of inconclusive etiology, but suspicious for metastatic foci. A search for the primary malignancy revealed an adrenal tumor, and biochemical testing confirmed the diagnosis of a norepinephrine-secreting pheochromocytoma. Serial imaging demonstrated multiple cerebral infarctions of varying ages, evidence of vessel narrowing and irregularities in the anterior and posterior circulations, and hypoperfusion in watershed areas. An exhaustive work-up for other etiologies of stroke including thromboembolic causes or vasculitis was unremarkable. There was resolution of symptoms, absence of new infarctions, and improvement in vessel caliber after adequate alpha-adrenergic receptor blockade for the management of pheochromocytoma. This clinicoradiologic constellation of findings suggested that the etiology of the multiple infarctions was reversible cerebral vasoconstriction syndrome (RCVS). Pheochromocytoma remains a poorly recognized cause of RCVS. Unexplained multifocal cerebral infarctions in the setting of severe hypertension should prompt the consideration of a vasoactive tumor as the driver of cerebrovascular dysfunction. A missed or delayed diagnosis has the potential for serious neurologic morbidity for an otherwise treatable condition.
LEARNING POINTS
The constellation of multifocal watershed cerebral infarctions of uncertain etiology in a patient with malignant hypertension should trigger the consideration of undiagnosed catecholamine secreting tumors, such as pheochromocytomas and paragangliomas. Reversible cerebral vasoconstriction syndrome is a serious but reversible cerebrovascular manifestation of pheochromocytomas that may lead to strokes (ischemic and hemorrhagic), seizures, and cerebral edema. Alpha-adrenergic receptor blockade can reverse cerebral vasoconstriction and prevent further cerebral ischemia and infarctions. Early diagnosis of catecholamine secreting tumors has the potential for reducing neurologic morbidity and mortality in patients presenting with cerebrovascular complications.
PubMed: 32820130
DOI: 10.1530/EDM-20-0078 -
ACS Chemical Neuroscience Nov 2021Dysfunction of the cardiac sympathetic nervous system contributes to the development of cardiovascular diseases including ischemia, heart failure, and arrhythmias....
Dysfunction of the cardiac sympathetic nervous system contributes to the development of cardiovascular diseases including ischemia, heart failure, and arrhythmias. Molecular imaging probes such as -[I]iodobenzylguanidine have demonstrated the utility of assessing neuronal integrity by targeting norepinephrine transporter (NET, uptake-1). However, current radiotracers can report only on innervation due to suboptimal kinetics and lack sensitivity to NET in rodents, precluding mechanistic studies in these species. The objective of this work was to characterize myocardial sympathetic neuronal uptake mechanisms and kinetics of the positron emission tomography (PET) radiotracer -[F]fluorobenzylguanidine ([F]mFBG) in rats. Automated synthesis using spirocyclic iodonium(III) ylide radiofluorination produces [F]mFBG in 24 ± 1% isolated radiochemical yield and 30-95 GBq/μmol molar activity. PET imaging in healthy rats delineated the left ventricle, with monoexponential washout kinetics ( = 0.027 ± 0.0026 min, = 3.08 ± 0.33 SUV). Ex vivo biodistribution studies revealed tracer retention in the myocardium, while pharmacological treatment with selective NET inhibitor desipramine, nonselective neuronal and extraneuronal uptake-2 inhibitor phenoxybenzamine, and neuronal ablation with neurotoxin 6-hydroxydopamine reduced myocardial retention by 33, 76, and 36%, respectively. Clearance of [F]mFBG from the myocardium was unaffected by treatment with uptake-1 and uptake-2 inhibitors following peak myocardial activity. These results suggest that myocardial distribution of [F]mFBG in rats is dependent on both NET and extraneuronal transporters and that limited reuptake to the myocardium occurs. [F]mFBG may therefore prove useful for imaging intraneuronal dysfunction in small animals.
Topics: Animals; Fluorobenzenes; Guanidines; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Tissue Distribution
PubMed: 34714061
DOI: 10.1021/acschemneuro.1c00575 -
JCEM Case Reports May 2023Pheochromocytomas are neuroendocrine tumors that arise from chromaffin cells in the adrenal medulla. Giant pheochromocytomas commonly measure greater than 7 to 10 cm,...
Pheochromocytomas are neuroendocrine tumors that arise from chromaffin cells in the adrenal medulla. Giant pheochromocytomas commonly measure greater than 7 to 10 cm, and their incidence and presentation is not well known. We present a case of a 62-year-old female with a giant 15.9 cm cystic pheochromocytoma. The patient was medically managed with oral phenoxybenzamine solution dose 4 times greater than average and was treated with a radical left nephrectomy and adrenalectomy. This case offers insight into the clinical presentation of giant pheochromocytomas and the unique challenges they present both medically and surgically.
PubMed: 37908578
DOI: 10.1210/jcemcr/luad065 -
Viruses Jun 2024Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable...
BACKGROUND
Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable feature of coronavirus disease 2019 (COVID-19) is impaired lipid metabolism. The function of lipophagy-related genes in COVID-19 is unknown. The present study aimed to investigate biomarkers and drug targets associated with lipophagy and lipophagy-based therapeutic agents for COVID-19 through bioinformatics analysis.
METHODS
Lipophagy-related biomarkers for COVID-19 were identified using machine learning algorithms such as random forest, Support Vector Machine-Recursive Feature Elimination, Generalized Linear Model, and Extreme Gradient Boosting in three COVID-19-associated GEO datasets: scRNA-seq (GSE145926) and bulk RNA-seq (GSE183533 and GSE190496). The cMAP database was searched for potential COVID-19 medications.
RESULTS
The lipophagy pathway was downregulated, and the lipid droplet formation pathway was upregulated, resulting in impaired lipid metabolism. Seven lipophagy-related genes, including , , , , , , and , were used as biomarkers and drug targets for COVID-19. Moreover, lipophagy may play a role in COVID-19 pathogenesis. As prospective drugs for treating COVID-19, seven potential downregulators (phenoxybenzamine, helveticoside, lanatoside C, geldanamycin, loperamide, pioglitazone, and trichostatin A) were discovered. These medication candidates showed remarkable binding energies against the seven biomarkers.
CONCLUSIONS
The lipophagy-related genes , , , , , , and can be used as biomarkers and drug targets for COVID-19. Seven potential downregulators of these seven biomarkers may have therapeutic effects for treating COVID-19.
Topics: Humans; SARS-CoV-2; COVID-19 Drug Treatment; Biomarkers; COVID-19; Lipid Metabolism; Antiviral Agents; Computational Biology; Machine Learning; Lactams, Macrocyclic; Hydroxamic Acids; Benzoquinones
PubMed: 38932215
DOI: 10.3390/v16060923