-
Veterinary and Comparative Oncology Dec 2023Adrenalectomies for canine adrenal tumours are associated with peri-operative morbidity and mortality. Objectives of this study included assessing the prognostic value...
Adrenalectomies for canine adrenal tumours are associated with peri-operative morbidity and mortality. Objectives of this study included assessing the prognostic value of tumour- or surgery-related variables in predicting peri-operative mortality and overall survival in dogs undergoing adrenalectomies for primary adrenal tumours as well as pre-treatment with phenoxybenzamine on survival to discharge with pheochromocytomas specifically. A multi-institutional retrospective cohort study was performed across nine institutions. Electronic medical record searches identified 302 dogs which met the inclusion criteria. Data collected included dog-related, tumour-related, treatment-related, surgery-related, and outcome variables. Univariate and multivariable logistic regression and cox proportional hazards models were used to identify variables associated with death prior to discharge and tumour-related survival. Overall, 87% of dogs survived to discharge with a tumour-related survival time of 3.96 years. Post-operative complications were reported in 25%. Increased surgical time (p = 0.002) and pre-surgical medical treatment other than phenoxybenzamine (p = 0.024) were significantly associated with increased peri-operative mortality while ureteronephrectomy (p = 0.021), post-operative pancreatitis (p = 0.025), and post-operative aspiration pneumonia (p < 0.001) were significantly associated with decreased overall survival. Phenoxybenzamine pretreatment had no effect on peri-operative mortality. Thirty-seven of 45 (82%) dogs with pheochromocytomas not pretreated survived to discharge, and 50 of 59 (85%) dogs with pheochromocytomas pretreated with phenoxybenzamine survived to discharge (p = 0.730). This study provides information on risk factors for death prior to discharge and tumour-related survival that may help guide clinical management and owner expectations. In addition, the study findings challenge the previously reported benefit of phenoxybenzamine for pretreatment of dogs undergoing adrenalectomies for pheochromocytomas.
Topics: Animals; Dogs; Adrenal Gland Neoplasms; Adrenalectomy; Dog Diseases; Patient Discharge; Phenoxybenzamine; Pheochromocytoma; Retrospective Studies; Risk Factors
PubMed: 37652746
DOI: 10.1111/vco.12931 -
Endocrine Practice : Official Journal... Sep 2022Phenoxybenzamine (nonselective, noncompetitive alpha-blocker) is the preferred drug for preoperative treatment of pheochromocytoma, but doxazosin (selective, competitive...
OBJECTIVE
Phenoxybenzamine (nonselective, noncompetitive alpha-blocker) is the preferred drug for preoperative treatment of pheochromocytoma, but doxazosin (selective, competitive alpha-blocker) may be equally effective. We compared the efficacy of doxazosin vs phenoxybenzamine.
METHODS
We conducted a prospective study of patients undergoing pheochromocytoma or paraganglioma resection by randomizing pretreatment with phenoxybenzamine or doxazosin at a single tertiary referral center. The high cost of phenoxybenzamine led to high crossover to doxazosin. Randomization was halted, and a consecutive historical cohort of phenoxybenzamine patients was included for a case-control study design. The efficacy of alpha-blockade was assessed with preinduction infusion of incremental doses of phenylephrine. The primary outcomes were mortality, cardiovascular complications, and intensive care unit admission. The secondary outcomes were hemodynamic instability index (proportion of operation outside of hemodynamic goals), adequacy of blockade by the phenylephrine titration test, and drug costs.
RESULTS
Twenty-four patients were prospectively enrolled (doxazosin, n = 20; phenoxybenzamine, n = 4), and 15 historical patients treated with phenoxybenzamine were added (total phenoxybenzamine, n = 19). No major cardiovascular complications occurred in either group. The phenylephrine dose-response curves showed less blood pressure rise in the phenoxybenzamine than in the doxazosin group (linear regression coefficient = 0.008 vs 0.018, P = .01), suggesting better alpha-blockade in the phenoxybenzamine group. The median hemodynamic instability index was 14% vs 13% in the phenoxybenzamine and doxazosin groups, respectively (P = .56). The median highest daily cost of phenoxybenzamine was $442.20 compared to $5.06 for doxazosin.
CONCLUSION
Phenoxybenzamine may blunt intraoperative hypertension better than doxazosin, but this difference did not translate to fewer cardiovascular complications and is offset by a considerably increased cost.
Topics: Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Case-Control Studies; Doxazosin; Humans; Phenoxybenzamine; Phenylephrine; Pheochromocytoma; Prospective Studies
PubMed: 35809774
DOI: 10.1016/j.eprac.2022.06.013 -
Scientific Reports May 2022Screening of mRNAs and lncRNAs associated with prognosis and immunity of lung adenocarcinoma (LUAD) and used to construct a prognostic risk scoring model (PRS-model) for...
Screening of mRNAs and lncRNAs associated with prognosis and immunity of lung adenocarcinoma (LUAD) and used to construct a prognostic risk scoring model (PRS-model) for LUAD. To analyze the differences in tumor immune microenvironment between distinct risk groups of LUAD based on the model classification. The CMap database was also used to screen potential therapeutic compounds for LUAD based on the differential genes between distinct risk groups. he data from the Cancer Genome Atlas (TCGA) database. We divided the transcriptome data into a mRNA subset and a lncRNA subset, and use multiple methods to extract mRNAs and lncRNAs associated with immunity and prognosis. We further integrated the mRNA and lncRNA subsets and the corresponding clinical information, randomly divided them into training and test set according to the ratio of 5:5. Then, we performed the Cox risk proportional analysis and cross-validation on the training set to construct a LUAD risk scoring model. Based on the risk scoring model, patients were divided into distinct risk group. Moreover, we evaluate the prognostic performance of the model from the aspects of Area Under Curve (AUC) analysis, survival difference analysis, and independent prognostic analysis. We analyzed the differences in the expression of immune cells between the distinct risk groups, and also discuss the connection between immune cells and patient survival. Finally, we screened the potential therapeutic compounds of LUAD in the Connectivity Map (CMap) database based on differential gene expression profiles, and verified the compound activity by cytostatic assays. We extracted 26 mRNAs and 74 lncRNAs related to prognosis and immunity by using different screening methods. Two mRNAs (i.e., KLRC3 and RAET1E) and two lncRNAs (i.e., AL590226.1 and LINC00941) and their risk coefficients were finally used to construct the PRS-model. The risk score positions of the training and test set were 1.01056590 and 1.00925190, respectively. The expression of mRNAs involved in model construction differed significantly between the distinct risk population. The one-year ROC areas on the training and test sets were 0.735 and 0.681. There was a significant difference in the survival rate of the two groups of patients. The PRS-model had independent predictive capabilities in both training and test sets. Among them, in the group with low expression of M1 macrophages and resting NK cells, LUAD patients survived longer. In contrast, the monocyte expression up-regulated group survived longer. In the CMap drug screening, three LUAD therapeutic compounds, such as resveratrol, methotrexate, and phenoxybenzamine, scored the highest. In addition, these compounds had significant inhibitory effects on the LUAD A549 cell lines. The LUAD risk score model constructed using the expression of KLRC3, RAET1E, AL590226.1, LINC00941 and their risk coefficients had a good independent prognostic power. The optimal LUAD therapeutic compounds screened in the CMap database: resveratrol, methotrexate and phenoxybenzamine, all showed significant inhibitory effects on LUAD A549 cell lines.
Topics: Adenocarcinoma; Carrier Proteins; Histocompatibility Antigens Class I; Humans; Lung; Lung Neoplasms; Male; Membrane Proteins; Methotrexate; Phenoxybenzamine; RNA, Long Noncoding; RNA, Messenger; Resveratrol; Tumor Microenvironment
PubMed: 35504892
DOI: 10.1038/s41598-022-11052-8 -
PloS One 2018The principal finding from this study was the recognition that the α-adrenergic antagonist, phenoxybenzamine, possesses histone deacetylase inhibitory activity....
The principal finding from this study was the recognition that the α-adrenergic antagonist, phenoxybenzamine, possesses histone deacetylase inhibitory activity. Phenoxybenzamine is approved by the United States Food and Drug Administration for the treatment of hypertensive crises associated with tumors of the adrenal medulla, pheochromocytomas. It has several "off label" indications relative to its capacity to relax vascular smooth muscle and smooth muscle of the urogenital tract. The drug also has a long history of apparent efficacy in ameliorating, and perhaps reversing, the severe symptoms of neuropathic pain syndromes. Our interest in this feature of the drug relates to the fact that certain types of neuropathic pain, in particular complex regional pain syndrome, demonstrate a proliferative nature, with the capacity to spread from an injured limb, for example, to a non-injured limb and perhaps to essentially the entire body. Sensory neuronal sprouting in the spinal cord has been observed under conditions where there is a high sensory input from painful stimuli. Searches of gene expression signatures in the BroadBuild02 Molecular Signature Database using their connectivity map software suggested that phenoxybenzamine may have histone deacetylase inhibitory activity. Studies by others have reported inhibitory effects of phenoxybenzamine on growth, invasion and migration of human tumor cell cultures and, in one study, inhibition of tumor expansion in animal experiments. Inhibitory effects on human tumor cell cultures are also reported in the present study. Phenoxybenzamine was also found to have histone deacetylase inhibitory activity; histone deacetylase isoforms 5, 6, and 9 were the most sensitive to inhibition by phenoxybenzamine. The importance of elevated levels of these isoforms as biomarkers of poor prognosis in human malignant disease, and the recognized suppression of tumor growth that may accrue from their inhibition, opens consideration of possible translation of phenoxybenzamine to new clinical applications. This might be facilitated by the fact that phenoxybenzamine is already an approved drug entity. There appears to be no previous report of the activity of phenoxybenzamine as a histone deacetylase inhibitor.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Databases, Factual; Histone Deacetylases; Humans; Inhibitory Concentration 50; Isoenzymes; Neoplasms; Phenoxybenzamine
PubMed: 29897996
DOI: 10.1371/journal.pone.0198514 -
Advances in Clinical and Experimental... 2015Compared to efficient and secure female contraception, a vasectomy and condoms are the only options for men. The choice of male contraceptive methods is limited, so... (Review)
Review
Compared to efficient and secure female contraception, a vasectomy and condoms are the only options for men. The choice of male contraceptive methods is limited, so contraception mainly rests on the shoulders of women. Several concepts are considered: testosterone administration--inhibiting pituitary secretion of lutropin (LH) and follicle stimulating hormone (FSH), progestogen--affecting the secretion of gonadotropin and gonadoliberin (GnRH) antagonists. New potential targets for non-hormonal male contraception were discovered: glyceraldehyde-3-phosphate-dehydrogenase (GAPDHS)--specific to male germ cells and voltage-gated cation channel (CatSper). Both are responsible for sperm motility. Drugs such as thioridazine used in schizophrenia treatment and phenoxybenzamine (antihypertensive activity) exhibit a contraceptive effect. Similar action exhibits an analogue of lonidamine--adjudin and an antagonist of retinoic acid receptors (BMS-189453). Researchers are working on a contraceptive vaccine, whose active ingredient is epididymal protease inhibitor (Eppin). Another promising method acts by blocking Bromodomain testis-specific proteins (Brdt) involved in the process of spermatogenesis. JQ1-the Brdt inhibitor causes reversible infertility without affecting the endocrine signaling pathways. A recent discovery of Juno as the binding partner for Izumo1 identifies these proteins as the cell-surface receptor pair, essential for gamete recognition and this interaction can be inhibited by an anti-Juno monoclonal antibody. Our review shows that the situation of men can change and investigators are close to the optimal solution. In the near future men will be able to choose the best contraceptive suited to their needs.
Topics: Animals; Condoms; Female; Fertility; Humans; Male; Nuclear Proteins; Pregnancy; Pregnancy, Unplanned; Pregnancy, Unwanted; Spermatogenesis; Spermatogenesis-Blocking Agents; Testis; Vasectomy
PubMed: 26469117
DOI: 10.17219/acem/33827 -
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 -
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 -
Journal of Endourology Nov 2014Paraganglioma (PG) is a rare neuroendocrine entity. Surgical resection is recommended as the mainstay of treatment due to the uncontrolled hypertension, close proximity... (Review)
Review
BACKGROUND AND PURPOSE
Paraganglioma (PG) is a rare neuroendocrine entity. Surgical resection is recommended as the mainstay of treatment due to the uncontrolled hypertension, close proximity to major vessels, variable location, and higher potential malignancy. With rapid development of minimally invasive techniques during the past decade, laparoscopic resection of retroperitoneal PG has been reported with successful results. There are only a few publications describing retroperitoneal access, however. In the present study, we proposed to summarize our experience on retroperitoneal laparoscopic resection in 10 patients and systematically review relevant publications to evaluate its safety and efficacy.
PATIENTS AND METHODS
From June 2009 to October 2013, 10 patients with PG who were treated with retroperitoneoscopy were included in the study. Minimal effective dosage α-blockade with phenoxybenzamine was routinely used. Preoperative, intraoperative, and postoperative baseline data were collected and analyzed. Meanwhile, two reviewers independently searched and identified 8 retrospective studies and 23 case reports in the Medline, Embase, and Science Citation Index between 1998 and 2013.
RESULTS
Operations in 9 of 10 patients were successfully completed without conversion; one case was converted to open surgery because of left accessory renal artery injury. Mean operative time, blood loss, and postoperative hospital stay were 97.8±20.6 minutes, 44.4±8.2 mL, and 4.8±3.5 days, respectively. There were three complications in this series, including accessory renal artery injury, renal vein injury, and chylorrhea.
CONCLUSIONS
Retroperitoneoscopic resection is feasible, effective, and safe in the treatment of patients with PG according to our preliminary clinical experience and has distinct advantages including direct access to the tumor, less intraperitoneal interference, precise dissection, and minimal invasiveness.
Topics: Blood Loss, Surgical; Female; Humans; Laparoscopy; Length of Stay; Male; Middle Aged; Minimally Invasive Surgical Procedures; Operative Time; Paraganglioma; Postoperative Complications; Retroperitoneal Neoplasms; Retrospective Studies
PubMed: 24955712
DOI: 10.1089/end.2014.0345 -
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