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Pharmacological Research Oct 2020Neuroplastic alterations are the key processes involved in adaptation and rehabilitation after all neurological injuries and pathologies. Being the central contributor... (Review)
Review
Neuroplastic alterations are the key processes involved in adaptation and rehabilitation after all neurological injuries and pathologies. Being the central contributor to the developmental and adult neuroplasticity, the polysialylated form of Neural Cell Adhesion Molecule (PSA-NCAM) may prove to be a potential target to facilitate repair/regeneration after CNS injury and disease. Over the years, several experimental approaches have been developed to exploit the therapeutic potential of PSA-NCAM. Broadly, the studies focused on cell-transplantation strategies to alter PSA-NCAM properties at the injury site, injection of peptide based as well as synthetic PSA mimetics directly into the injury site or the application of PSA containing hydrogels and scaffolds as biomaterials. A comprehensive understanding of the PSA-based experimental approaches, as well as their pros and cons, is urgently required for successful implementation of this molecule in therapeutics. The current review, therefore, has been designed to give the readers a thorough account of all the diverse roles of PSA in the adult nervous system and the recent progress that has been made in developing PSA-based therapeutic approaches for neuroregeneration.
Topics: Animals; Humans; Nerve Regeneration; Neural Cell Adhesion Molecules; Neurodegenerative Diseases; Neuronal Plasticity; Sialic Acids
PubMed: 32898689
DOI: 10.1016/j.phrs.2020.105186 -
Cardiology in the Young Jul 2022The effects of alpha-blockade on haemodynamics during and following congenital heart surgery are well documented, but data on patient outcomes, mortality, and hospital...
INTRODUCTION
The effects of alpha-blockade on haemodynamics during and following congenital heart surgery are well documented, but data on patient outcomes, mortality, and hospital charges are limited. The purpose of this study was to characterise the use of alpha-blockade during congenital heart surgery admissions and to determine its association with common clinical outcomes.
MATERIALS AND METHODS
A cross-sectional study was conducted using the Pediatric Health Information System database. De-identified data for patients under 18 years of age with a cardiac diagnosis who underwent congenital heart surgery were obtained from 2004 to 2015. Patients were subdivided on the basis of receiving alpha-blockade with either phenoxybenzamine or phentolamine during admission or not. Continuous and categorical variables were analysed using Mann−Whitney U-tests and Fisher exact tests, respectively. Characteristics between subgroups were compared using univariate analysis. Regression analyses were conducted to determine the impact of alpha-blockade on ICU length of stay, hospital length of stay, billed charges, and mortality.
RESULTS
Of the 81,313 admissions, 4309 (5.3%) utilised alpha-blockade. Phentolamine was utilised in 4290 admissions. In univariate analysis, ICU length of stay, total length of stay, inpatient mortality, and billed charges were all significantly higher in the alpha-blockade admissions. However, regression analyses demonstrated that other factors were behind these increased. Alpha-blockade was significantly, independently associated with a 1.5 days reduction in ICU length of stay (p < 0.01) and a 3.5 days reduction in total length of stay (p < 0.01). Alpha-blockade was significantly, independently associated with a reduction in mortality (odds ratio 0.8, 95% confidence interval 0.7−0.9). Alpha-blockade was not independently associated with any significant change in billed charges.
CONCLUSIONS
Alpha-blockade is used in a subset of paediatric cardiac surgeries and is independently associated with significant reductions in ICU length of stay, hospital length of stay, and mortality without significantly altering billed charges.
Topics: Adolescent; Child; Cross-Sectional Studies; Heart Defects, Congenital; Hospital Mortality; Hospitalization; Humans; Length of Stay; Phentolamine; Retrospective Studies
PubMed: 34530952
DOI: 10.1017/S1047951121003875 -
Hypertension in Pheochromocytoma and Paraganglioma: Evaluation and Management in Pediatric Patients.Current Hypertension Reports May 2021The rare catecholamine-secreting tumors, pheochromocytomas and paragangliomas (PPGL), account for a minority of cases of secondary hypertension in pediatrics. As such,... (Review)
Review
PURPOSE OF REVIEW
The rare catecholamine-secreting tumors, pheochromocytomas and paragangliomas (PPGL), account for a minority of cases of secondary hypertension in pediatrics. As such, perioperative blood pressure (BP) management in pediatric patients presents a distinct challenge. This review will expand the practitioner's knowledge of antihypertensive treatment options for the pediatric patient with PPGL with a focus on literature in the past several years.
RECENT FINDINGS
There continue to be only small case series and single-center experiences to provide guidelines regarding BP management. While phenoxybenzamine has been more routinely used, selective α-blockers, such as doxazosin, as well as calcium channel blockers, have also been utilized with success in pediatric patients. While the concept of obligatory α-adrenergic blockade for adult patients has been recently challenged, international guidelines and current practice patterns among pediatric clinicians continue to support preoperative α-adrenergic blockade to ensure the best possible patient outcomes. Selective α-blockers and calcium channel blockers are becoming more commonly used given the high cost, limited availability, and undesirable side effect profile of phenoxybenzamine.
Topics: Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Adult; Child; Humans; Hypertension; Paraganglioma; Pediatrics; Pheochromocytoma
PubMed: 34041599
DOI: 10.1007/s11906-021-01150-9 -
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 4.3cm (3-6cm); 27.7% of the patients had tumors ≥6cm. Incidental PCCs were significantly smaller than symptomatic PCCs (3.4cm [2.4-5.0cm] vs. 5.6cm [4.0-7.0cm], p<.001). Scintigraphy by I-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.
PubMed: 32646754
DOI: 10.1016/j.rce.2019.12.016 -
Surgery Jan 2023Phenoxybenzamine has been the standard agent for blockade before adrenalectomy for pheochromocytoma. However, high cost and limited availability have hampered its use....
BACKGROUND
Phenoxybenzamine has been the standard agent for blockade before adrenalectomy for pheochromocytoma. However, high cost and limited availability have hampered its use. This study investigated whether other agents have supplanted the use of phenoxybenzamine as the first-line agent for alpha blockade in pheochromocytoma.
METHODS
We performed a retrospective analysis of patients in the IBM MarketScan Database who underwent adrenalectomy for pheochromocytoma (2008-2019). Patients were categorized as having been blocked with phenoxybenzamine, selective alpha blockers, calcium channel blockers and/or beta blockers, or none of the above. The outcomes included prescription costs, perioperative costs, and length of stay.
RESULTS
A total of 552 patients were identified; 58.7% were female, and the median age was 49 (interquartile range 40-57) years. In total, 291 (52.7%) patients were blocked with phenoxybenzamine, 114 (20.7%) with selective alpha blockers, 42 (7.6%) with only calcium channel blockers and/or beta blockers, and 76 (13.8%) with none. The proportion of patients blocked with phenoxybenzamine decreased from 71.0% in 2008 to 21.2% in 2019. The proportion of patients blocked with selective alpha blockers increased from 6.5% in 2008 to 42.4% and in 2019. The median cost of phenoxybenzamine increased from $722 (interquartile range $441-$1,514) in 2008 to $9,616 (interquartile range $5,049-$16,373) in 2019 (P < .001). Length of stay (2 [interquartile range 1-4] days vs 2 [interquartile range 0-3] days) and total perioperative costs ($24,250 [interquartile range $17,462-$33,849] vs $22,098 [interquartile range $16,341-$29,178] between phenoxybenzamine and selective alpha blocker groups were similar.
CONCLUSION
There has been a significant shift away from phenoxybenzamine for preoperative blockade before resection of pheochromocytoma. Selective alpha blockers and calcium channel blockers are increasingly used, likely due to reduced costs, without compromised length of stay or intensive care unit admission.
Topics: Humans; Female; Adult; Middle Aged; Male; Phenoxybenzamine; Retrospective Studies; Calcium Channel Blockers; Pheochromocytoma; Adrenal Gland Neoplasms; Adrenalectomy; Adrenergic alpha-Antagonists
PubMed: 36167697
DOI: 10.1016/j.surg.2022.05.039 -
Omics : a Journal of Integrative Biology Jul 2023Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease that affects the pulmonary arteries, resulting in increased pulmonary vascular resistance and...
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease that affects the pulmonary arteries, resulting in increased pulmonary vascular resistance and right ventricular dysfunction, which can ultimately lead to heart failure and death. The molecular substrates of IPAH are poorly understood while diagnostics and therapeutics innovation remain as unmet needs for this debilitating disease. In this study, a network-based methodology was used to uncover the salient molecular mechanisms of IPAH to inform drug and diagnostic discovery, and personalized medicine. Expression profiling datasets associated with IPAH were obtained from the Gene Expression Omnibus database: GSE15197, GSE113439, GSE53408, and GSE67597. The comparative analysis of mRNA and miRNA expression data and the modular analysis of a transcriptome-based weighted gene coexpression network unraveled disease-specific gene and miRNA signatures. DEAD-box helicase 52 (), ESF1 nucleolar pre-RNA processing protein (), heterogeneous nuclear ribonuclearprotein A3 (), Myosin VA (), replication factor C subunit 1 (), and arginine and serine rich coiled coil 1 () were detected as the salient genes for IPAH. In addition, the salient gene-based drug repositioning analysis identified alvespimycin, tanespimycin, geldanamycin, LY294002, cephaeline, digoxigenin, lanatoside C, helveticoside, trichostatin A, phenoxybenzamine, genistein, pioglitazone, and rosiglitazone as potential drug candidates for IPAH. In conclusion, this study provides new molecular signatures in relation to IPAH and attendant potential drug candidates for further experimental and translational clinical research for patients with IPAH.
Topics: Humans; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Multiomics; Pulmonary Artery; MicroRNAs
PubMed: 37410515
DOI: 10.1089/omi.2023.0066 -
Endocrinology, Diabetes & Metabolism... Mar 2020Ectopic adrenocorticotropic hormone (ACTH) production is an uncommon cause of Cushing's syndrome and, rarely, the source can be a phaeochromocytoma. A 55-year-old man...
SUMMARY
Ectopic adrenocorticotropic hormone (ACTH) production is an uncommon cause of Cushing's syndrome and, rarely, the source can be a phaeochromocytoma. A 55-year-old man presented following an episode of presumed gastroenteritis with vomiting and general malaise. Further episodes of diarrhoea, joint pains and palpitations followed. On examination, he was hypertensive with no clinical features to suggest hypercortisolaemia. He was subsequently found to have raised plasma normetanephrines of 3.98 nmol/L (NR <0.71) and metanephrines of 0.69 nmol/L (NR <0.36). An adrenal CT showed a 3.8 cm right adrenal nodule, which was not MIBG-avid but was clinically and biochemically consistent with a phaeochromocytoma. He was started on alpha blockade and referred for right adrenalectomy. Four weeks later, on the day of admission for adrenalectomy, profound hypokalaemia was noted (serum potassium 2.0 mmol/L) with non-specific ST-segment ECG changes. He was also diagnosed with new-onset diabetes mellitus (capillary blood glucose of 28 mmol/L). He reported to have gained weight and his skin had become darker over the course of the last 4 weeks. Given these findings, he underwent overnight dexamethasone suppression testing, which showed a non-suppressed serum cortisol of 1099 nmol/L. Baseline serum ACTH was 273 ng/L. A preliminary diagnosis of ectopic ACTH secretion from the known right-sided phaeochromocytoma was made and he was started on metyrapone and insulin. Surgery was postponed for 4 weeks. Following uncomplicated laparoscopic adrenalectomy, the patient recovered with full resolution of symptoms.
LEARNING POINTS
Phaeochromocytomas are a rare source of ectopic ACTH secretion. A high clinical index of suspicion is therefore required to make the diagnosis. Ectopic ACTH secretion from a phaeochromocytoma can rapidly progress to severe Cushing's syndrome, thus complicating tumour removal. Removal of the primary tumour often leads to full recovery. The limited literature suggests that the presence of ectopic Cushing's syndrome does not appear to have any long-term prognostic implications.
PubMed: 32168466
DOI: 10.1530/EDM-20-0011 -
Experimental and Therapeutic Medicine Nov 2021This review provides a brief clinically relevant review of pheochromocytoma in pregnancy, to raise awareness among doctors in obstetrics and the aim is to serve as the... (Review)
Review
This review provides a brief clinically relevant review of pheochromocytoma in pregnancy, to raise awareness among doctors in obstetrics and the aim is to serve as the first point of reference when confronted by their presence. Pheochromocytomas are neuroendocrine, catecholamine-secreting tumours. Despite having the highest incidence rate among other hormone-secreting adrenal tumours, they remain rare especially when associated with pregnancy. The non-specific presentation of pheochromocytomas, the difficulties in their diagnosis during pregnancy as well as the high maternal and fetal mortality rates associated with them, present a challenge. Clinical suspicion and meticulous patient history-taking remain the primary lines of defense, while biochemical proof of catecholamine excess (or their metabolites) and imaging-based localisation of the tumour are required for diagnosis. Antenatal diagnosis and complete localisation of the tumour increase the likelihood of successful outcomes for both mother and newborn. Magnetic resonance imaging (MRI) remains the method of choice during pregnancy without excluding the use of ultrasound. Treatment goals should include the avoidance of hypertensive crises while maintaining adequate uteroplacental circulation. The target blood pressure is not strictly defined but is in line with the general guideline addressing chronic hypertension during pregnancy. Antihypertensive medications remain the cornerstone in managing pheochromocytoma. As a first-line, the α-adrenergic, nonselective antagonist phenoxybenzamine is the most frequently used agent, while α1-selective adrenergic antagonists with or without the addition of β- or β1-blockers are also prescribed in certain cases, rendering calcium channel blockers as 'second-choice'. Blood-pressure control of the mother and the well-being of the fetus are determining factors in deciding the time of delivery, which is preferably conducted by Caesarean section. Excision of the tumour(s) remains the final treatment goal. Lifelong biochemical testing is required with or without medical treatment, to address mineralocorticoid or glucocorticoid deficits. Despite ever-improving positive outcome rates, pheochromocytoma associated with pregnancy remains a pathology with high mortality and morbidity rates.
PubMed: 34630699
DOI: 10.3892/etm.2021.10780 -
Endocrine Dec 2022Pheochromocytomas are rare tumors and biochemically silent ones with normal catecholamine levels are even rarer. Up to date, biochemically inactive pheochromocytomas are...
PURPOSE
Pheochromocytomas are rare tumors and biochemically silent ones with normal catecholamine levels are even rarer. Up to date, biochemically inactive pheochromocytomas are poorly investigated. We aimed to systematically assess the pre- and peri-operative characteristics and the outcomes of patients with these tumors who had been treated and followed-up in 2 tertiary centers.
METHODS
Clinical, laboratory and imaging data, treatment outcomes and follow-up of biochemically silent pheochromocytoma patients were recorded.
RESULTS
Ten patients (5 men) [median age at diagnosis 52.5 years (24-72)] were included. Adrenal masses were incidentally discovered in all patients except from one who presented with pheochromocytoma-related manifestations. Twenty-four-hour urine metanephrine and normetanephrine levels were in the low-normal, normal and high-normal range in 4, 4 and 2 patients and in 1, 6 and 3 patients, respectively. Tumors were unilateral [median size 46 mm (17-125)] and high density on pre-contrast CT imaging or high signal intensity on T2-weighted MRI scans were found in all cases. Pre-operatively, 5 patients were treated with phenoxybenzamine [median total daily dose 70 mg (20-100)]. Intra-operatively, 4 patients developed hypertension requiring vasodilator administration and 8 developed hypotension; vasoconstrictors were required in 5 cases. One patient, not pre-operatively treated with phenoxybenzamine, developed Takotsubo cardiomyopathy. During a median 24-month (12-88) follow-up period, one patient had disease progression.
CONCLUSIONS
The majority (90%) of patients with biochemically silent pheochromocytomas developed hemodynamic instability during adrenal surgery. In patients with biochemically silent adrenal lesions and a high suspicion index for pheochromocytoma based on tumor imaging characteristics, pre-operative alpha-blockade treatment may be advisable.
Topics: Male; Humans; Young Adult; Adult; Middle Aged; Aged; Pheochromocytoma; Phenoxybenzamine; Adrenal Gland Neoplasms; Normetanephrine; Hypertension
PubMed: 36074243
DOI: 10.1007/s12020-022-03182-w -
BMC Surgery Aug 2021Retroperitoneal vascular leiomyosarcoma (RVLMS) is an extremely rare disease in clinical practice, and it has poor prognosis. This article is to explore the diagnosis...
BACKGROUND
Retroperitoneal vascular leiomyosarcoma (RVLMS) is an extremely rare disease in clinical practice, and it has poor prognosis. This article is to explore the diagnosis and treatment of RVLMS and present our experience.
METHODS
Data of RVLMS patients were continuously collected in our hospital from August 2018 to February 2020: two males and two females with a median age of 56 (min-max = 33-61) years were included. Patients in whom paraganglioma could not be excluded were asked to take phenoxybenzamine before surgery. A multi-disciplinary team (MDT) meeting had been held and surgery was recommended. The operation procedures varied based on the tumor location, shape, and stage, and the core steps were "exposure of the retroperitoneum and tumor, identification of vital blood vessels, blocking the bloodstream, complete removal of the tumor and tumor thrombus, and release of blood flow". A Satinsky clamp was used to partially block the blood vessels. Follow-up was conveyed by revisits and phone calls.
RESULTS
One patient underwent open surgery, and three patients underwent laparoscopic surgery, one of whom underwent conversion to open surgery. The procedures were finished successfully, with a median operative time of 314.5 (min-max = 224-467) mins. The median amount of intraoperative bleeding was 550 (min-max = 200-1500) ml, and three patients had transfusion during the operation. The mass was irregular in shape, with a median maximum size of 7.45 (min-max = 4.2-10.7) cm, and the pathological examination confirmed RVLMS, which has spindle-shape, high mitotic activity and atypia. One week after the operation, the median serum creatinine level was 85 (min-max = 70-99) µmol/L. The median follow-up time was 16 (min-max = 13-21) months, and 1 case reported asymptomatic recurrence.
CONCLUSION
Uncharacteristic manifestations and imaging features contribute to the problematic diagnosis of RVLMS. Comprehensive preoperative evaluation and careful surgical planning are essential. Multicenter research is needed in the future to reach a dominant consensus.
Topics: Adult; Female; Humans; Laparoscopy; Leiomyosarcoma; Male; Middle Aged; Neoplasm Recurrence, Local; Retroperitoneal Neoplasms; Retroperitoneal Space; Retrospective Studies
PubMed: 34392834
DOI: 10.1186/s12893-021-01322-z