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Endocrine Connections May 2022Patients with pheochromocytoma and paraganglioma (PPGL) are treated with α-adrenoceptor antagonists to improve peroperative hemodynamics. However, preoperative blood...
Patients with pheochromocytoma and paraganglioma (PPGL) are treated with α-adrenoceptor antagonists to improve peroperative hemodynamics. However, preoperative blood pressure targets differ between institutions. We retrospectively compared per- and postoperative hemodynamics in 30 patients with PPGL that were pretreated with phenoxybenzamine aiming at different blood pressure targets at two separate endocrine departments. All patients were subsequently undergoing laparoscopic surgery at Department of Urology, Herlev University hospital. Fourteen patients were treated targeting to symptomatic and significant orthostatic hypotension and 16 patients to a seated blood pressure below 130/80 mmHg. As a control group, we included 34 patients undergoing laparoscopic adrenalectomy for other reasons. The group titrated to orthostatic hypotension required a higher dose of phenoxybenzamine to achieve the blood pressure target. This group had less intraoperative systolic and diastolic blood pressure fluctuation (Mann-Whitney U test; P < 0.05) and less periods with heart rate above 100 b.p.m. (Mann-Whitney U test; P = 0.04) as compared to the group with a preoperative blood pressure target below 130/80 mmHg. Peroperative use of intravenous fluids were similar between the two groups, but postoperatively more intravenous fluids were administered in the group with a target of ortostatism. Overall, the control group was more hemodynamic stable as compared to either group treated for PPGL. We conclude that phenoxybenzamine pretreatment targeting ortostatic hypotension may improve peroperative hemodynamic stability but causes a higher postoperative requirement for intravenous fluids. Overall, PPGL surgery is related to greater hemodynamic instability compared to adrenalectomy for other reasons.
PubMed: 35358058
DOI: 10.1530/EC-21-0539 -
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 -
Behavioural Brain Research Mar 2015The action of PACAP-38 was studied by measuring the anxiogenic-anxiolytic behavior of rats in an elevated plus maze. PACAP-38 was administered into the lateral brain...
The action of PACAP-38 was studied by measuring the anxiogenic-anxiolytic behavior of rats in an elevated plus maze. PACAP-38 was administered into the lateral brain ventricle and the behavior of the animals was measured 3h later. The possible involvement of transmitters was measured by pretreating the animals with receptor blockers which alone did not influence the task, but in the doses used were effective with other neuropeptides. The receptor antagonist PACAP 6-38 (a PAC 1/VPAC2 receptor antagonist of PACAP-38 receptor), haloperidol (a non-selective dopamine receptor antagonist), phenoxybenzamine (an α1/α2β-adrenergic receptor antagonist), propranolol(a β-adrenergic receptor antagonist), bicuculline (a gamma-aminobutyric acid subunit A receptor antagonist), methysergide (a nonselective 5-HT2 serotonergic receptor antagonist), atropine (a nonselective muscarinic acetylcholine receptor antagonist), naloxone (a nonselective opioid receptor antagonist) and nitro-l-arginine which acts by blocking the enzyme nitric oxide synthase, thereby blocking the nitric oxide synthesis, were tested. The following parameters were measured: the time spent in open arms/the time spent in total entries. PACAP-38 decreased the ratio of time spent in open arms to the time spent in total entries, indicating anxiogenic action. The total number of entries was not altered significantly either by PACAP-38 or by the receptor blockers. The following receptor blockers diminished the action of PACAP-38: PACAP 6-38,haloperidol, methysergide, naloxone and nitro-l-arginine. Pretreatment with atropine, phenoxybenzamine, propranolol and bicuculline did not influence the action of PACAP-38 on the time spent in open arms. The results demonstrate that PACAP-38 administered into the lateral brain ventricle exerted anxiogenic action at 3 h following treatment. Pretreatment of the animals with various receptor blockers indicated that a nonselective dopaminergic receptor antagonist, 5HT2 serotonergic and opioid receptors, nitric oxide and PAC1 receptors are involved in the anxiogenic action induced by PACAP-38.
Topics: Adrenergic Antagonists; Adrenergic beta-Antagonists; Animals; Anxiety; Arginine; Atropine; Bicuculline; Dopamine Antagonists; Exploratory Behavior; Haloperidol; Male; Maze Learning; Methysergide; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Neurotransmitter Agents; Nitroso Compounds; Peptide Fragments; Phenoxybenzamine; Pituitary Adenylate Cyclase-Activating Polypeptide; Propranolol; Rats; Rats, Wistar; Receptors, GABA; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Serotonin 5-HT2 Receptor Antagonists
PubMed: 25543171
DOI: 10.1016/j.bbr.2014.12.039 -
Frontiers in Physiology 2017Octopamine and tyramine, both biogenic amines, are bioactive chemicals important in diverse physiological processes in invertebrates. In insects, octopamine and tyramine...
Octopamine and tyramine, both biogenic amines, are bioactive chemicals important in diverse physiological processes in invertebrates. In insects, octopamine and tyramine operate analogously to epinephrine and norepinephrine in the vertebrates. Octopamine and tyramine bind to G-protein coupled receptors (GPCRs) leading to changes in second messenger levels and thereby modifying the function in target tissues and insect behavior. In this paper, we report the cDNA sequences of two GPCRs, RhoprOctβ2-R, and RhoprTyr1-R, have been cloned and functionally characterized from . Octopamine and tyramine each activate RhoprOctβ2-R and RhoprTyr1-R in a dose-dependent manner. Octopamine is one order of magnitude more potent than tyramine in activating RhoprOctβ2-R. Tyramine is two orders of magnitude more potent than octopamine in activating RhoprTyr1-R. Phentolamine and gramine significantly antagonize RhoprOctβ2-R, whereas yohimbine and phenoxybenzamine are effective blockers of RhoprTyr1-R. The transcripts of both receptors are enriched in the central nervous system (CNS) and are expressed throughout the adult female reproductive system. It has been shown in other insects that Octβ2-R is essential for processes such as ovulation and fertilization. We previously reported that octopamine and tyramine modulate oviducts and bursa contractions in . Our data confirm the importance of octopamine and tyramine signaling in the reproductive system of .
PubMed: 29018364
DOI: 10.3389/fphys.2017.00744 -
Endocrine May 2024Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial... (Observational Study)
Observational Study
PURPOSE
Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study.
METHODS
This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared.
RESULTS
No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group.
CONCLUSION
The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.
Topics: Humans; Doxazosin; Female; Male; Pheochromocytoma; Middle Aged; Adrenal Gland Neoplasms; Retrospective Studies; Paraganglioma; Adult; Aged; alpha-Methyltyrosine; Adrenergic alpha-1 Receptor Antagonists; Drug Therapy, Combination; Preoperative Care; Treatment Outcome
PubMed: 38206436
DOI: 10.1007/s12020-023-03681-4 -
Annals of Surgical Oncology Jan 2017The optimal preoperative α-blockade strategy is debated for patients undergoing laparoscopic adrenalectomy for pheochromocytomas. We evaluated the impact of selective...
BACKGROUND
The optimal preoperative α-blockade strategy is debated for patients undergoing laparoscopic adrenalectomy for pheochromocytomas. We evaluated the impact of selective versus non-selective α-blockade on intraoperative hemodynamics and postoperative outcomes.
METHODS
We identified patients having laparoscopic adrenalectomy for pheochromocytomas from 2001 to 2015. As a marker of overall intraoperative hemodynamics, we combined systolic blood pressure (SBP) > 200, SBP < 80, SBP < 80 and >200, pulse > 120, vasopressor infusion, and vasodilator infusion into a single variable. Similarly, the combination of vasopressor infusion in the post-anesthesia care unit (PACU) and the need for intensive care unit (ICU) admission provided an overview of postoperative support.
RESULTS
We identified 52 patients undergoing unilateral laparoscopic adrenalectomy for pheochromocytoma. Selective α-blockade (i.e. doxazosin) was performed in 35 % (n = 18) of patients, and non-selective blockade with phenoxybenzamine was performed in 65 % (n = 34) of patients. Demographics and tumor characteristics were similar between groups. Patients blocked selectively were more likely to have an SBP < 80 (67 %) than those blocked with phenoxybenzamine (35 %) (p = 0.03), but we found no significant difference in overall intraoperative hemodynamics between patients blocked selectively and non-selectively (p = 0.09). However, postoperatively, patients blocked selectively were more likely to require additional support with vasopressor infusions in the PACU or ICU admission (p = 0.02). Hospital stay and complication rates were similar.
CONCLUSION
Laparoscopic adrenalectomy for pheochromocytoma is safe regardless of the preoperative α-blockade strategy employed, but patients blocked selectively may have a higher incidence of transient hypotension during surgery and a greater need for postoperative support. These differences did not result in longer hospital stay or increased complications.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adrenergic alpha-1 Receptor Antagonists; Doxazosin; Female; Hemodynamics; Humans; Laparoscopy; Male; Middle Aged; Phenoxybenzamine; Pheochromocytoma; Treatment Outcome
PubMed: 27561909
DOI: 10.1245/s10434-016-5514-7 -
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