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Frontiers in Endocrinology 2020Metastatic pheochromocytoma/paraganglioma (MPP) therapy mainly involves radionuclide therapy, chemotherapy, and targeted therapy. In recent years, temozolomide (TMZ)... (Review)
Review
Metastatic pheochromocytoma/paraganglioma (MPP) therapy mainly involves radionuclide therapy, chemotherapy, and targeted therapy. In recent years, temozolomide (TMZ) showed great promise in some MMP patients, especially those with germline mutation. We reported a patient with MPP who did not have any known germline genetic change and responded remarkably well to TMZ monotherapy. The patient was a 41-year-old woman with local and distant recurrence (soft tissues and bone metastases) of retroperitoneal paraganglioma. She suffered from dizziness, palpitation, sweating, weight loss and constipation, with the blood pressure fluctuating substantially from 130/100 mmHg to 190/120 mmHg, although she was on phenoxybenzamine and metoprolol medication. The patient showed clinical and radiological response after 3-cycle TMZ therapy. Upon 15 cycles of TMZ therapy, her symptoms were dramatically alleviated, urinary norepinephrine excretion decreased from 1,840 μg/24 h to 206 μg/24 h, and CT showed that the lesions further shrank. Molecular profiling of the tumor tissue of the patient revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase () promoter and a negative immunostaining for MGMT. Globally, only 26 cases of MPP treated with TMZ have been described so far. TMZ is effective, especially in patients with mutation, which can be explained by the silencing of MGMT expression as a consequence of promoter hypermethylation in -mutated tumors. Although, in general, patients with mutation or MGMT promoter hypermethylation have better response to TMZ, there are also exceptions. Severe side effects are uncommon, with only 17.4% patients experiencing Grade 3 toxicities, including lymphopenia, and hypertension. TMZ is effective and safe in MPP patients, and, it may work better on patients with -related MPP. Measurement of MGMT expression might help assess the tumor sensitivity to TMZ but this needs further systematic investigation.
Topics: Adrenal Gland Neoplasms; Adult; Antineoplastic Agents, Alkylating; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Humans; Mutation; Paraganglioma; Pheochromocytoma; Prognosis; Promoter Regions, Genetic; Succinate Dehydrogenase; Temozolomide; Tumor Suppressor Proteins
PubMed: 32132978
DOI: 10.3389/fendo.2020.00061 -
British Journal of Anaesthesia Feb 2017Mortality associated with surgery for phaeochromocytoma has dramatically decreased over the last decades. Many factors contributed to the dramatic decline of the... (Observational Study)
Observational Study
BACKGROUND
Mortality associated with surgery for phaeochromocytoma has dramatically decreased over the last decades. Many factors contributed to the dramatic decline of the mortality rate, and the influence of an α-receptor blockade is unclear and has never been tested in a randomized trial. We evaluated intraoperative haemodynamic conditions and the incidence of complications in patients with and without α-receptor blockade undergoing surgery for catecholamine producing tumours.
METHODS
Haemodynamic conditions and perioperative complications were assessed in 110 patients with (B) and 166 without (N) α-receptor blockade. Data were analysed as a consecutive case series of 303 cases and subsequently via propensity score matching, and presented as mean and confidence interval (CI).
RESULTS
No difference in maximal intraoperative systolic arterial pressures (B = 178 mm Hg (CI 169-187) vs N = 185 mm Hg (CI 177-193; P = 0.2542) and hypertensive episodes above 250 mm Hg were found (P = 0.7474) for the closed case series. No major complications occurred. Propensity score matching (75 pairs) revealed a significant difference of 17 mm Hg in maximal intraoperative systolic bp for these selected pairs (P = 0.024).
CONCLUSIONS
Only a slight difference in mean maximal systolic arterial pressure was detected between patients with or without an α-receptor blockade. There was no difference in the incidence of excessive hypertensive episodes between groups and no major complications occurred. The basis for the general recommendation of perioperative α- receptor blockade for phaeochromocytoma surgery demands further study.
Topics: Adolescent; Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Adult; Aged; Aged, 80 and over; Female; Hemodynamics; Humans; Male; Middle Aged; Pheochromocytoma; Propensity Score; Young Adult
PubMed: 28100521
DOI: 10.1093/bja/aew392 -
Oncology Letters Nov 2020Primary liver cancer is a rapidly progressing neoplasm with high morbidity and mortality rates. The present study aimed to identify potential diagnostic and prognostic...
Identification of diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus-associated early stage hepatocellular carcinoma based on RNA-sequencing data.
Primary liver cancer is a rapidly progressing neoplasm with high morbidity and mortality rates. The present study aimed to identify potential diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus (HBV)-associated early stage hepatocellular carcinoma (HCC). The gene expression profiles were extracted from the Gene Expression Omnibus database. Differentially expressed genes (DEGs), hub genes and the enrichment of signaling pathways were filtered out via a high-throughput sequencing method. The association between hub genes and the effects of the abnormal expression of hub genes on the rate of genetic variation, overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS) and disease-free survival (DSS) of patients with HCC, as well as pathological stage and grade, were analyzed using different databases. A total of 1,582 DEGs were identified. Gene Ontology analysis revealed that the DEGs were mainly involved in the 'oxidation-reduction process', 'steroid metabolic process', 'metabolic process' and 'fatty acid beta-oxidation'. Enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways revealed that the DEGs were mainly associated with 'metabolic pathways', 'PPAR signaling pathway', 'fatty acid degradation' and the 'cell cycle'. A total of 8 hub genes were extracted. Additionally, the abnormal expression levels of hub genes were closely associated with the OS, RFS, PFS and DSS of patients, the pathological stage and the grade. Furthermore, abnormal expression levels of the 8 hub genes were found in >30% of all samples. Several small molecular compounds that may reverse the altered DEGs were identified based on Connectivity Map analysis, including phenoxybenzamine, GW-8510, resveratrol, 0175029-0000 and daunorubicin. In conclusion, the dysfunction of fat metabolic pathways, the cell cycle, oxidation-reduction processes and viral carcinogenesis may serve critical roles in the occurrence of HBV-associated early stage HCC. The identified 8 hub genes may act as robust biomarkers for diagnosis and prognosis. Some small molecular compounds may be promising targeted agents against HBV-associated early stage HCC.
PubMed: 32968453
DOI: 10.3892/ol.2020.12094 -
The Journal of Maternal-fetal &... Dec 2014To investigate the diagnosis and treatment of pheochromocytoma during pregnancy.
OBJECTIVE
To investigate the diagnosis and treatment of pheochromocytoma during pregnancy.
MATERIALS AND METHODS
The data of four cases of pheochromocytoma was analyzed retrospectively. Their ages were 41, 28, 32 and 30 years old, and the four patients were at 32nd week, 12th week, 14th week and 13th week of gestation. All patients had hypertension during pregnancy, accompanied with headache, dizziness, palpitation and sweating. The 24-h urinary catecholamines (24 h UCA) increased significantly. Ultrasound and MRI confirmed the diagnosis of pheochromocytoma.
RESULTS
One case had Cesarean section at 32 weeks of gestation, and a healthy baby girl was delivered smoothly. Laparoscopic resection of the right adrenal pheochromocytoma was performed at the same time, and an adrenal tumor of 7.0 cm was resected successfully. Two cases chose abortion and laparoscopic resection of pheochromocytoma was performed. One case chose abortion and refused further treatment. Histopathology confirmed the diagnosis of pheochromocytoma.
CONCLUSIONS
For hypertension in pregnant women during pregnancy, typical paroxysmal hypertension accompanied by triad of headache, palpitation and sweating, pheochromocytoma should be considered. Early diagnosis can reduce the maternal and fetal mortality significantly. Second trimester of pregnancy is the ideal time for surgical treatment. Laparoscopic resection of pheochromocytoma during pregnancy is safe and effective.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adult; Blood Pressure; Female; Humans; Laparoscopy; Phenoxybenzamine; Pheochromocytoma; Piperazines; Pregnancy; Pregnancy Complications, Neoplastic
PubMed: 24397547
DOI: 10.3109/14767058.2014.880883 -
Tumour Biology : the Journal of the... Mar 2016Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to...
Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function of PHEN in glioma. Cell proliferation assay was used to assess glioma cell growth. Migration and invasion capacity of glioma cells was monitored by wound-healing and transwell assay, respectively. Neurosphere formation test was adopted for the tumorigenesis of glioma cells, which was also confirmed by soft agar cloning formation test in vitro and a nude mouse model in vivo. Finally, we explored the potential pathway utilized by PHEN using Western blot and immunofluoresce staining. PHEN exhibited a significant inhibitory effect on the proliferation of both U251 and U87MG glioma cell lines in a positive dose-dependent manner. PHEN apparently attenuated the malignancy of glioma in terms of migration and invasion and also suppressed the tumorigenic capacity both in vitro and in vivo. Mechanism study showed that PHEN promoted tumor suppression by inhibiting the TrkB-Akt pathway. The results of the present study demonstrated that PHEN suppressed the proliferation, migration, invasion, and tumorigenesis of glioma cells, induced LINGO-1 expression, and inhibited the TrkB-Akt pathway, which may prove to be the mechanisms underlying the anti-tumor effect of PHEN on glioma cells.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Glioma; Humans; Membrane Proteins; Mice; Neoplasm Invasiveness; Nerve Tissue Proteins; Phenoxybenzamine
PubMed: 26409450
DOI: 10.1007/s13277-015-4102-y -
Journal of Receptor and Signal... Apr 2019Drugs such as positive allosteric modulators (PAMs) produce complex behaviors when acting on tissues in different physiological contexts . This study describes the use...
Drugs such as positive allosteric modulators (PAMs) produce complex behaviors when acting on tissues in different physiological contexts . This study describes the use of functional assays of varying receptor sensitivity to unveil the various behaviors of PAMs and thus quantify allosteric effect through system independent scales. Muscarinic receptor activation with acetylcholine (ACh) was used to the demonstrate activity of the PAM agonist 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, Benzyl quinolone carboxylic acid (BQCA) in terms of direct agonism, potentiation of ACh affinity, and ACh efficacy. Concentration-response curves were fit to the functional allosteric model to yield indices of agonism (τ), effects on affinity (α cooperativity), and efficacy (β cooperativity). It is shown that a highly sensitive functional assay revealed the direct efficacy of BQCA as an agonist and relatively insensitive cells (produced by chemical alkylation of muscarinic receptor with phenoxybenzamine) revealed a positive allosteric effect of BQCA on ACh efficacy. A wide range of functional assay sensitivities produced a complex pattern of behavior for BQCA all of which was accurately quantified through the system-independent parameters of the functional allosteric model. The study of complex allosteric molecules in a range of functional assays of varying sensitivity allows the measurement of the complete array of activities of these molecules on receptors and also better predicts which will be seen with these where a range of tissue sensitivities is encountered.
Topics: Acetylcholine; Allosteric Regulation; Animals; CHO Cells; Cricetinae; Cricetulus; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Muscarinic Agonists; Phenoxybenzamine; Quinolines; Receptor, Muscarinic M1; Structure-Activity Relationship
PubMed: 31322035
DOI: 10.1080/10799893.2019.1634101 -
BMJ Case Reports Jan 2021A 55-year-old man presented with severe right upper quadrant abdominal pain and hypertension up to 231/171 mm Hg on a background of a known adrenal mass, intravenous...
A 55-year-old man presented with severe right upper quadrant abdominal pain and hypertension up to 231/171 mm Hg on a background of a known adrenal mass, intravenous drug use and recurrent anxiety attacks. CT showed heterogenous lesion of the right adrenal gland but the sudden severe pain remained unexplained. After correction of the blood pressure with analgesia and antihypertensives, the patient developed a type 2 non-ST-elevation myocardial infarction that was treated with aspirin and therapeutic enoxaparin. This resulted in worsening pain and a repeat CT angiogram showed a haemoretroperitoneum around the right adrenal lesion. On review, an occult intra-adrenal haemorrhage was identified on the initial CT scan. Presumably this concealed haemorrhage caused the initial pain crisis and later decompressed into the retroperitoneal space. Raised metanephrine levels confirmed the diagnosis of pheochromocytoma and after preoperative optimisation with phenoxybenzamine, an open right adrenalectomy was performed.
Topics: Abdominal Pain; Adrenal Gland Neoplasms; Adrenal Glands; Adrenalectomy; Antihypertensive Agents; Computed Tomography Angiography; Electrocardiography; Hemorrhage; Humans; Hypertension; Male; Metanephrine; Middle Aged; Myocardial Infarction; Pain Measurement; Pheochromocytoma; Retroperitoneal Space; Tomography, X-Ray Computed
PubMed: 33431458
DOI: 10.1136/bcr-2020-237975 -
Journal of Fish Diseases Apr 2019In this study, we evaluated the impact of the catecholamines on growth, swimming motility, biofilm formation and some virulence factors activities of pathogenic Yersinia...
Effect of catecholamine stress hormones (dopamine and norepinephrine) on growth, swimming motility, biofilm formation and virulence factors of Yersinia ruckeri in vitro and an in vivo evaluation in rainbow trout.
In this study, we evaluated the impact of the catecholamines on growth, swimming motility, biofilm formation and some virulence factors activities of pathogenic Yersinia ruckeri. Norepinephrine and dopamine (at 100 µM) significantly increased the growth of Y. ruckeri in culture media containing serum. An increase in swimming motility of the pathogen was found following the exposure to the hormones; however, no effect was seen on caseinase, phospholipase and haemolysin productions. Further, antagonists for the catecholamine receptors were observed to block some of the influences of the catecholamines. Indeed, the effects of catecholamines were inhibited by chlorpromazine (the dopaminergic receptor antagonist) for dopamine, labetalol (α-and β-adrenergic receptor antagonist) and phenoxybenzamine (the α-adrenergic receptor antagonist) for norepinephrine, but propranolol (the β-adrenergic receptor antagonist) showed no effect. Pretreatment of Y. ruckeri with the catecholamines resulted in a significant enhancement of its virulence towards rainbow trout and the antagonists could neutralize the effect of the stress hormones in vivo. In summary, our results show that the catecholamines increase the virulence of Y. ruckeri which is pathogenic to trout through increasing the motility, biofilm formation and growth.
Topics: Animals; Biofilms; Catecholamines; Dopamine; Fish Diseases; Locomotion; Norepinephrine; Oncorhynchus mykiss; Virulence; Virulence Factors; Yersinia ruckeri
PubMed: 30694560
DOI: 10.1111/jfd.12934 -
Annals of Surgical Oncology Nov 2014Resection of pheochromocytoma is often associated with hemodynamic instability (HDI). We examined patient and tumor factors that may influence HDI. The effect of...
BACKGROUND
Resection of pheochromocytoma is often associated with hemodynamic instability (HDI). We examined patient and tumor factors that may influence HDI. The effect of pretreatment with nonselective α blockade phenoxybenzamine (PXB) versus selective α blockade on HDI and outcomes was also evaluated.
METHODS
The records of 91 patients who underwent adrenalectomy between 2002 and 2013 were retrospectively reviewed. HDI was determined by number of intraoperative episodes of systolic blood pressure (SBP) > 200 mmHg, those greater than or less than 30 % of baseline, heart rate > 110 bpm, and the need for postoperative vasopressors. Fishers exact, t test and regressions were performed.
RESULTS
Among 91 patients, 78 % received PXB, 18 % selective α blockade and 4 % no adrenergic blockade. Patient demographics, tumor factors and surgical approach were similar among the blockade groups. On multivariate analysis, increasing tumor size was associated with a significant rise in the number of episodes of SBP > 30 % [rate ratio (RR) 1.40] and an increased postoperative vasopressor requirement [odds ratio (OR) 1.23]. Open adrenalectomy and use of selective blockade were associated with an increased number of episodes of SBP > 200 mmHg (RR 27.8 and RR 20.9, respectively). Open adrenalectomy was also associated with increased readmissions (OR 12.3), complications (OR 5.6), use of postoperative vasopressors (OR 4.4) and hospital stay (4.6 days longer). There were no differences in other HDI measurements or postoperative outcomes among the blockade groups.
CONCLUSIONS
Tumor size, open adrenalectomy, and type of α blockade were associated with intraoperative HDI during pheochromocytoma resection. Selective blockade was associated with significantly more episodes of intraoperative hypertension but no perioperative adverse outcomes.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adult; Blood Pressure; Combined Modality Therapy; Female; Follow-Up Studies; Hemodynamics; Humans; Intraoperative Complications; Male; Middle Aged; Phenoxybenzamine; Pheochromocytoma; Postoperative Complications; Preoperative Care; Prognosis; Retrospective Studies; Risk Factors; Vasodilator Agents
PubMed: 24939623
DOI: 10.1245/s10434-014-3847-7 -
Pharmacological Reports : PR Apr 2020Kynurenic acid (KYNA) is an L-tryptophan metabolite with neuromodulatory activities, regulating the release of neurotransmitters such as glutamate, dopamine (DA), and...
BACKGROUND
Kynurenic acid (KYNA) is an L-tryptophan metabolite with neuromodulatory activities, regulating the release of neurotransmitters such as glutamate, dopamine (DA), and acetylcholine (Ach). Dysregulation of the kynurenine pathway has been associated with neurodegenerative, neurological, and psychological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, major depressive disorder, and schizophrenia.
METHODS
The antidepressant-like effects of KYNA were studied with a modified mouse forced swimming test (FST), and the potential involvement of the serotonin (SER), norepinephrine, DA, Ach, N-methyl-D-aspartate, or gamma-aminobutyric acid subunit A (GABA) receptors in its antidepressant-like effect was assayed by modified combination mouse FST. In combination studies, the mice were pretreated with the respective receptor antagonist, cyproheptadine (CPH), phenoxybenzamine, yohimbine, propranolol, haloperidol (HPD), atropine, MK-801, or bicuculline (BCL).
RESULTS
The FST revealed that KYNA reversed immobility, climbing, and swimming times, suggesting the antidepressant-like effects of KYNA. Furthermore, the combination studies showed that CPH prevented the antidepressant-like effects of KYNA on immobility, climbing, and swimming times, whereas HPD reduced climbing time and BCL influenced immobility and climbing times and prevented the effects of KYNA on swimming time.
CONCLUSIONS
The results demonstrated, for the first time, the presence of antidepressant-like effects of KYNA in a modified mouse FST. Furthermore, modified combination FST showed that the antidepressant-like actions of KYNA strongly interacted with 5-hydroxytryptamine type 2 SER-ergic receptors, weakly interacted with D, D, D DA-ergic receptors, and interacted moderately with GABA receptors.
Topics: Animals; Antidepressive Agents; Behavior, Animal; Depression; Disease Models, Animal; Kynurenic Acid; Male; Mice, Inbred Strains; Motor Activity; Receptors, Dopamine; Receptors, GABA-A; Receptors, Serotonin, 5-HT2; Swimming
PubMed: 32162182
DOI: 10.1007/s43440-020-00067-5