Pravastatin improves endothelial function in arteries used in coronary bypass grafting.

Internal mammary artery (IMA) and radial artery (RA) are the 2 main arterial conduits used in coronary artery bypass grafting (CABG). The aim of this study was to analyze in vitro the vasoreactive properties in both vessels and to investigate the effects of pravastatin incubation on vascular function. IMA and RA rings obtained from patients undergoing CABG were studied in organ baths. We examined the contractile responses to phenylephrine and U46619 and the relaxation to acetylcholine (ACh) and sodium nitroprusside. In another series of experiments, the vascular reactivity and the superoxide anion production were studied after incubation with pravastatin. The effect of mevalonic acid on such responses was also assessed. Our results show that RA significantly evoked greater tension in response to vasoconstrictor agents and higher relaxation to ACh than IMA. In contrast, relaxation induced by sodium nitroprusside was not significantly different. Incubation with pravastatin reduced the contractile response to U46619 and improved the endothelium-dependent relaxation to ACh in both arteries. Whereas the effect of pravastatin on response to U46619 was completely abolished by coincubation with mevalonic acid, only a partial inhibition on ACh relaxation was observed. In conclusion, in vitro incubation with pravastatin enhanced endothelial function in IMA and RA. This suggests that postoperative (may include intraoperative) administration of statins could improve the endothelial function of arterial grafts in patients undergoing CABG.

Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction.

Although much is known about environmental factors that predispose individuals to hypertension and cardiovascular disease, little information is available regarding the genetic and signaling events involved. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases, as an essential factor regulating the homeostasis of the cardiovascular system. Vav3-deficient mice exhibited tachycardia, systemic arterial hypertension and extensive cardiovascular remodeling. These mice also showed hyperactivity of sympathetic neurons from the time of birth. The high catecholamine levels associated with this condition led to the activation of the renin-angiotensin system, increased levels of kidney-related hormones and the progressive loss of cardiovascular and renal homeostasis. Pharmacological studies with drugs targeting sympathetic and renin-angiotensin responses confirmed the causative role and hierarchy of these events in the development of the Vav3-null mouse phenotype. These observations uncover the crucial role of Vav3 in the regulation of the sympathetic nervous system (SNS) and cardiovascular physiology, and reveal a signaling pathway that could be involved in the pathophysiology of human disease states involving tachycardia and sympathetic hyperactivity with unknown etiologies.

Using Explainable Artificial Intelligence in the Clock Drawing Test to Reveal the Cognitive Impairment Pattern.

The prevalence of dementia is currently increasing worldwide. This syndrome produces a deterioration in cognitive function that cannot be reverted. However, an early diagnosis can be crucial for slowing its progress. The Clock Drawing Test (CDT) is a widely used paper-and-pencil test for cognitive assessment in which an individual has to manually draw a clock on a paper. There are a lot of scoring systems for this test and most of them depend on the subjective assessment of the expert. This study proposes a computer-aided diagnosis (CAD) system based on artificial intelligence (AI) methods to analyze the CDT and obtain an automatic diagnosis of cognitive impairment (CI). This system employs a preprocessing pipeline in which the clock is detected, centered and binarized to decrease the computational burden. Then, the resulting image is fed into a Convolutional Neural Network (CNN) to identify the informative patterns within the CDT drawings that are relevant for the assessment of the patient's cognitive status. Performance is evaluated in a real context where patients with CI and controls have been classified by clinical experts in a balanced sample size of [Formula: see text] drawings. The proposed method provides an accuracy of [Formula: see text] in the binary case-control classification task, with an AUC of [Formula: see text]. These results are indeed relevant considering the use of the classic version of the CDT. The large size of the sample suggests that the method proposed has a high reliability to be used in clinical contexts and demonstrates the suitability of CAD systems in the CDT assessment process. Explainable artificial intelligence (XAI) methods are applied to identify the most relevant regions during classification. Finding these patterns is extremely helpful to understand the brain damage caused by CI. A validation method using resubstitution with upper bound correction in a machine learning approach is also discussed.

Transcriptional factor aryl hydrocarbon receptor (Ahr) controls cardiovascular and respiratory functions by regulating the expression of the Vav3 proto-oncogene.

Aryl hydrocarbon receptor (Ahr) is a transcriptional factor involved in detoxification responses to pollutants and in intrinsic biological processes of multicellular organisms. We recently described that Vav3, an activator of Rho/Rac GTPases, is an Ahr transcriptional target in embryonic fibroblasts. These results prompted us to compare the Ahr(-/-) and Vav3(-/-) mouse phenotypes to investigate the implications of this functional interaction in vivo. Here, we show that Ahr is important for Vav3 expression in kidney, lung, heart, liver, and brainstem regions. This process is not affected by the administration of potent Ahr ligands such as benzo[a]pyrene. We also report that Ahr- and Vav3-deficient mice display hypertension, tachypnea, and sympathoexcitation. The Ahr gene deficiency also induces the GABAergic transmission defects present in the Vav3(-/-) ventrolateral medulla, a main cardiorespiratory brainstem center. However, Ahr(-/-) mice, unlike Vav3-deficient animals, display additional defects in fertility, perinatal growth, liver size and function, closure, spleen size, and peripheral lymphocytes. These results demonstrate that Vav3 is a bona fide Ahr target that is in charge of a limited subset of the developmental and physiological functions controlled by this transcriptional factor. Our data also reveal the presence of sympathoexcitation and new cardiorespiratory defects in Ahr(-/-) mice.

Functional Alterations Involved in Increased Bleeding in Hereditary Hemorrhagic Telangiectasia Mouse Models.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal-dominant genetic disorder involving defects in two predominant genes known as endoglin (ENG; HHT-1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT-2). It is characterized by mucocutaneous telangiectases that, due to their fragility, frequently break causing recurrent epistaxis and gastrointestinal bleeding. Because of the severity of hemorrhages, the study of the hemostasis involved in these vascular ruptures is critical to find therapies for this disease. Our results demonstrate that HHT patients with high bleeding, as determined by a high Epistaxis Severity Score (ESS), do not have prolonged clotting times or alterations in clotting factors. Considering that coagulation is only one of the processes involved in hemostasis, the main objective of this study was to investigate the overall mechanisms of hemostasis in HHT-1 (Eng +/-) and HHT-2 (Alk1 +/-) mouse models, which do not show HHT vascular phenotypes in the meaning of spontaneous bleeding. In Eng +/- mice, the results of in vivo and in vitro assays suggest deficient platelet-endothelium interactions that impair a robust and stable thrombus formation. Consequently, the thrombus could be torn off and dragged by the mechanical force exerted by the bloodstream, leading to the reappearance of hemorrhages. In Alk1 +/- mice, an overactivation of the fibrinolysis system was observed. These results support the idea that endoglin and Alk1 haploinsufficiency leads to a common phenotype of impaired hemostasis, but through different mechanisms. This contribution opens new therapeutic approaches to HHT patients' epistaxis.

Chromosomal changes in sporadic and familial head and neck paragangliomas.

OBJECTIVE: Paragangliomas (PGLs) of the head and neck are benign neoplasms derived from the autonomic nervous system. Familial PGLs have been associated with germline mutations in succinate dehydrogenase (SDH) genes, and occasionally in Von Hippel-Lindau (VHL) and RET. The aim of this study was to compare somatic DNA copy number changes in tumors of familial and sporadic origin. MATERIAL AND METHODS: Eight familial and 16 sporadic patients were analyzed for germline mutations and exon deletions in SDHB, SDHC, SDHD, VHL, and RET by direct sequencing and MLPA. Microarray CGH analysis was applied to map genome-wide somatic copy number changes. RESULTS: Fifteen cases carried a germline mutation in SDHB or SDHD, four of which not described before. Microarray CGH detected abnormalities in 10 of 18 cases, most frequently concerning deletions at 1p, 1q, and 11q, the sites where SDH are located. However, these deletions occurred in both SDH mutation-positive and SDH mutation-negative cases. CONCLUSIONS: These data suggest that inactivating germline SDH mutations and somatic deletions of SDH genes as a "second hit" are involved in a subset, but not in all PGLs. Additional genes and mechanisms may need to be studied, especially in the group of sporadic PGL showing no chromosomal aberrations.

Vagal afferents contribute to sympathoexcitation-driven metabolic dysfunctions.

Multiple crosstalk between peripheral organs and the nervous system are required to maintain physiological and metabolic homeostasis. Using Vav3-deficient mice as a model for chronic sympathoexcitation-associated disorders, we report here that afferent fibers of the hepatic branch of the vagus nerve are needed for the development of the peripheral sympathoexcitation, tachycardia, tachypnea, insulin resistance, liver steatosis and adipose tissue thermogenesis present in those mice. This neuronal pathway contributes to proper activity of the rostral ventrolateral medulla, a sympathoregulatory brainstem center hyperactive in Vav3-/- mice. Vagal afferent inputs are also required for the development of additional pathophysiological conditions associated with deregulated rostral ventrolateral medulla activity. By contrast, they are dispensable for other peripheral sympathoexcitation-associated disorders sparing metabolic alterations in liver.

Vav proteins maintain epithelial traits in breast cancer cells using miR-200c-dependent and independent mechanisms.

The bidirectional regulation of epithelial-mesenchymal transitions (EMT) is key in tumorigenesis. Rho GTPases regulate this process via canonical pathways that impinge on the stability of cell-to-cell contacts, cytoskeletal dynamics, and cell invasiveness. Here, we report that the Rho GTPase activators Vav2 and Vav3 utilize a new Rac1-dependent and miR-200c-dependent mechanism that maintains the epithelial state by limiting the abundance of the Zeb2 transcriptional repressor in breast cancer cells. In parallel, Vav proteins engage a mir-200c-independent expression prometastatic program that maintains epithelial cell traits only under 3D culture conditions. Consistent with this, the depletion of endogenous Vav proteins triggers mesenchymal features in epithelioid breast cancer cells. Conversely, the ectopic expression of an active version of Vav2 promotes mesenchymal-epithelial transitions using E-cadherin-dependent and independent mechanisms depending on the mesenchymal breast cancer cell line used. In silico analyses suggest that the negative Vav anti-EMT pathway is operative in luminal breast tumors. Gene signatures from the Vav-associated proepithelial and prometastatic programs have prognostic value in breast cancer patients.

[Complications and sequelae in acoustic neuroma surgery]. / Complicaciones y secuelas en la cirugía de los neurinomas del acústico.

OBJECTIVE: To evaluate the complications and sequelae of acoustic neuroma surgery, according to tumour size. PATIENTS AND METHOD: A retrospective analysis of 120 patients who underwent microsurgical resection of vestibular schwannomas between November 1994 and September 2006 was undertaken. Tumour size, extent of removal, preservation of facial and cochlear nerves, complications, and sequelae were considered. The degree of hearing preservation after surgery was determined by the Gardner-Robertson classification. RESULTS: There were 39 small (<1.5 cm), 59 medium (1.5-3 cm), and 22 large tumours (>3 cm). Gross total resection was accomplished in 106 cases (88.3 %). The facial nerve was anatomically and functionally preserved in 103 cases on long-term follow-up (85.4 %). The cochlear nerve was functionally preserved (Gardner-Robertson class 1 and 2) in 54.4 % of the small tumours with useful preoperative hearing. Two patients died due to postoperative complications (mortality rate, 1.6 %), and 15 (12.5 %) developed a CSF leak. CONCLUSIONS: Despite the progress in the surgical treatment of acoustic neuromas, a considerable rate of complications and sequelae still remains. Therefore, there is a need to balance pros and cons of surgery in each patient according to the concurrent circumstances, as well as to consider other therapeutic strategies such as radiosurgery or a wait-and-see policy.

Cardiovascular effects of nebivolol in spontaneously hypertensive rats persist after treatment withdrawal.

OBJECTIVES: We observed previously that nebivolol treatment for 2 months reduced cardiovascular lesions in spontaneously hypertensive rats (SHR). Therefore, we investigated whether this beneficial effect is increased with a longer treatment, and its persistence after withdrawal. METHODS: Male SHR were treated with 8 mg/kg per day of nebivolol (N-SHR) for 6 months. A separate group was also given identical treatment but they were then monitored for a further 3 months after drug withdrawal. SHR and Wistar-Kyoto rats (WKY) receiving vehicle were used as controls. Systolic blood pressure and heart rate were measured using the tail-cuff method. Left ventricular weight/body weight ratio was calculated as the hypertrophy index. Cardiac and vascular fibrosis was evaluated on sections stained with sirious red. Vascular reactivity was evaluated on aortic rings through acetylcholine and sodium nitroprusside responses. The effect of treatment on vascular structure was assessed by lumen diameter, wall thickness and medial cross-sectional area determination. RESULTS: Blood pressure was reduced in N-SHR. After withdrawal it increased progressively, without reaching the values of the hypertensive controls. Cardiac hypertrophy and collagen content both in heart and aorta were significantly reduced, and these changes persisted after nebivolol suppression. Acetylcholine-induced relaxant response was improved by nebivolol and maintained after withdrawal. Medial thickness and cross-sectional area were significantly reduced in both conductance and resistance arteries, and these effects persisted after withdrawal. CONCLUSION: The nebivolol antihypertensive effect was accompanied by an important reduction of hypertrophy and collagen deposition in both vascular and left ventricle tissue, which was maintained after a long period of therapy withdrawal.

Zofenopril exerts a cardiovascular protective effect on rats infused with angiotensin II beyond angiotensin-converting enzyme inhibition.

OBJECTIVES: Elevated levels of angiotensin II are implicated in the hypertensive pathophysiological process. Zofenopril has a sulphydryl group which gives it antioxidant properties. The aim of this study was to investigate its beneficial effects beyond angiotensin-converting enzyme (ACE) inhibition using angiotensin II-infused rats as hypertension model. METHODS: Zofenopril was added in drinking water. Systolic blood pressure was assessed by the tail-cuff method. Left ventricular weight/body weight ratio was calculated as cardiac hypertrophy index. An estimate of the cardiac collagen was performed by measuring the content of hydroxyproline. Vascular reactivity was evaluated on aortic rings and isolated perfused kidney, and vascular structure in thoracic aorta was studied. Superoxide anion generation was quantified in aorta by lucigenin-enhanced chemiluminescence. KEY FINDINGS: Zofenopril partially prevented the increase in systolic blood pressure and cardiac hypertrophy induced by angiotensin II and avoided the increase in collagen deposition. The treatment improved vasorelaxing responses, reversed the vascular remodelling and abolished the effects of angiotensin II on the production of ·O2-. It is worth to mention that all these results are observed even with high levels of plasma angiotensin. CONCLUSION: Zofenopril could exert additional beneficial effects beyond ACE inhibition that would justify the improvement of pathophysiological processes triggered by angiotensin II.

Immunosuppression-Independent Role of Regulatory T Cells against Hypertension-Driven Renal Dysfunctions.

Hypertension-associated cardiorenal diseases represent one of the heaviest burdens for current health systems. In addition to hemodynamic damage, recent results have revealed that hematopoietic cells contribute to the development of these diseases by generating proinflammatory and profibrotic environments in the heart and kidney. However, the cell subtypes involved remain poorly characterized. Here we report that CD39(+) regulatory T (TREG) cells utilize an immunosuppression-independent mechanism to counteract renal and possibly cardiac damage during angiotensin II (AngII)-dependent hypertension. This mechanism relies on the direct apoptosis of tissue-resident neutrophils by the ecto-ATP diphosphohydrolase activity of CD39. In agreement with this, experimental and genetic alterations in TREG/TH cell ratios have a direct impact on tissue-resident neutrophil numbers, cardiomyocyte hypertrophy, cardiorenal fibrosis, and, to a lesser extent, arterial pressure elevation during AngII-driven hypertension. These results indicate that TREG cells constitute a first protective barrier against hypertension-driven tissue fibrosis and, in addition, suggest new therapeutic avenues to prevent hypertension-linked cardiorenal diseases.

Sub-nephrotoxic cisplatin sensitizes rats to acute renal failure and increases urinary excretion of fumarylacetoacetase.

Nephrotoxicity limits the therapeutic efficacy of the antineoplastic drug cisplatin. Due to dosage adjustment and appropriate monitoring, most therapeutic courses with cisplatin produce no or minimal kidney damage. However, we studied whether even sub-nephrotoxic dosage of cisplatin poses a potential risk for the kidneys by predisposing to acute kidney injury (AKI), specifically by lowering the toxicity threshold for a second nephrotoxin. With this purpose rats were treated with a single sub-nephrotoxic dosage of cisplatin (3mg/kg, i.p.) and after two days, with a sub-nephrotoxic regime of gentamicin (50mg/kg/day, during 6 days, i.p.). Control groups received only one of the drugs or the vehicle. Renal function and renal histology were monitored throughout the experiment. Cisplatin treatment did not cause any relevant functional or histological alterations in the kidneys. Rats treated with cisplatin and gentamicin, but not those under single treatments, developed an overt renal failure characterized by both renal dysfunction and massive tubular necrosis. In addition, the urinary excretion of fumarylacetoacetase was increased in cisplatin-treated animals at subtoxic doses, which might be exploited as a cisplatin-induced predisposition marker. In fact, the urinary level of fumarylacetoacetase prior to the second nephrotoxin correlated with the level of AKI triggered by gentamicin in predisposed animals.

Amlodipine decreases fibrosis and cardiac hypertrophy in spontaneously hypertensive rats: persistent effects after withdrawal.

Our objective was to examine the effect of chronic treatment with amlodipine on blood pressure, left ventricular hypertrophy, and fibrosis in spontaneously hypertensive rats and the persistence of such an effect after drug withdrawal. We investigated the effects of treatment with 2, 8 and 20 mg/kg/day of amlodipine given orally for six months and at three months after drug withdrawal. Systolic blood pressure was measured using the tail-cuff method. At the end of the study period, the heart was excised, the left ventricle was isolated, and the left ventricle weight/body weight ratio was calculated as a left ventricular hypertrophy index. Fibrosis, expressed as collagen volume fraction, was evaluated using an automated image-analysis system on sections stained with Sirius red. Age-matched untreated Wistar-Kyoto and SHR were used as normotensive and hypertensive controls, respectively. Systolic blood pressure was reduced in the treated SHR in a dose-dependent way and after amlodipine withdrawal it increased progressively, without reaching the values of the hypertensive controls. Cardiac hypertrophy was reduced by 8 and 20 mg/kg/day amlodipine, but when treatment was withdrawn only the group treated with 8 mg/kg/day maintained significant differences versus the hypertensive controls. All three doses of amlodipine reduced cardiac fibrosis and this regression persisted with the two highest doses after three months without treatment. We concluded that antihypertensive treatment with amlodipine is accompanied by a reduction in left ventricular hypertrophy and regression in collagen deposition. Treatment was more effective in preventing fibrosis than in preventing ventricular hypertrophy after drug withdrawal.

Genetic dissection of the vav2-rac1 signaling axis in vascular smooth muscle cells.

Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them.

High phosphate diet increases arterial blood pressure via a parathyroid hormone mediated increase of renin.

BACKGROUND: There is growing evidence suggesting that phosphate intake is associated with blood pressure levels. However, data from epidemiological studies show inconsistent results. METHOD AND RESULTS: The present study was designed to evaluate the effect of high circulating phosphorus on arterial blood pressure of healthy rats and to elucidate the potential mechanism that stands behind this effect. Animals fed a high phosphate diet for 4 weeks showed an increase in blood pressure, which returned to normal values after the addition of a phosphate binder (lanthanum carbonate) to the diet. The expression of renin in the kidney was higher, alongside an increase in plasma renin activity, angiotensin II (Ang II) levels and left ventricular hypertrophy. The addition of the phosphate binder blunted the increase in renin and Ang II levels. The levels of parathyroid hormone (PTH) were also higher in animals fed a high phosphate diet, and decreased when the phosphate binder was present in the diet. However, blood P levels remained elevated. A second group of rats underwent parathyroidectomy and received a continuous infusion of physiological levels of PTH through an implanted mini-osmotic pump. Animals fed a high phosphate diet with continuous infusion of PTH did not show an increase in blood pressure, although blood P levels were elevated. Finally, unlike with verapamil, the addition of losartan to the drinking water reverted the increase in blood pressure in rats fed a high phosphate diet. CONCLUSION: The results of this study suggest that a high phosphate diet increases arterial blood pressure through an increase in renin mediated by PTH.

The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells.

The regulation of arterial contractility is essential for blood pressure control. The GTPase RhoA promotes vasoconstriction by modulating the cytoskeleton of vascular smooth muscle cells. Whether other Rho/Rac pathways contribute to blood pressure regulation remains unknown. By studying a hypertensive knockout mouse lacking the Rho/Rac activator Vav2, we have discovered a new signaling pathway involving Vav2, the GTPase Rac1, and the serine/threonine kinase Pak that contributes to nitric oxide-triggered blood vessel relaxation and normotensia. This pathway mediated the Pak-dependent inhibition of phosphodiesterase type 5, a process that favored RhoA inactivation and the subsequent depolymerization of the F-actin cytoskeleton in vascular smooth muscle cells. The inhibition of phosphodiesterase type 5 required its physical interaction with autophosphorylated Pak1 but, unexpectedly, occurred without detectable transphosphorylation events between those 2 proteins. The administration of phosphodiesterase type 5 inhibitors prevented the development of hypertension and cardiovascular disease in Vav2-deficient animals, demonstrating the involvement of this new pathway in blood pressure regulation. Taken together, these results unveil one cause of the cardiovascular phenotype of Vav2-knockout mice, identify a new Rac1/Pak1 signaling pathway, and provide a mechanistic framework for better understanding blood pressure control in physiological and pathological states.

Baroreceptor failure after bilateral resection of carotid artery parangliomas.

Multiple head and neck parangliomas are unusual pathologies. We report a case of a 24-year-old patient operated on at our centre for bilateral carotid artery parangliomas who developed baroreceptor failure after their resection. Albeit an infrequent complication, it is important to be aware of it in order to ensure is speedy diagnosis and treatment so as to avoid major post-surgical complications.

Vav3 is involved in GABAergic axon guidance events important for the proper function of brainstem neurons controlling cardiovascular, respiratory, and renal parameters.

Vav3 is a phosphorylation-dependent activator of Rho/Rac GTPases that has been implicated in hematopoietic, bone, cerebellar, and cardiovascular roles. Consistent with the latter function, Vav3-deficient mice develop hypertension, tachycardia, and renocardiovascular dysfunctions. The cause of those defects remains unknown as yet. Here, we show that Vav3 is expressed in GABAegic neurons of the ventrolateral medulla (VLM), a brainstem area that modulates respiratory rates and, via sympathetic efferents, a large number of physiological circuits controlling blood pressure. On Vav3 loss, GABAergic cells of the caudal VLM cannot innervate properly their postsynaptic targets in the rostral VLM, leading to reduced GABAergic transmission between these two areas. This results in an abnormal regulation of catecholamine blood levels and in improper control of blood pressure and respiration rates to GABAergic signals. By contrast, the reaction of the rostral VLM to excitatory signals is not impaired. Consistent with those observations, we also demonstrate that Vav3 plays important roles in axon branching and growth cone morphology in primary GABAergic cells. Our study discloses an essential and nonredundant role for this Vav family member in axon guidance events in brainstem neurons that control blood pressure and respiratory rates.

Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management.

BACKGROUND: Head and neck paraganglioma (PGL) are benign tumors that can cause important direct or surgery induced morbidity. Almost all familial and 11-29% of sporadic PGL are caused by inactivating germline mutations in succinate dehydrogenase (SDH) genes. Our aim was to screen for such mutations and to evaluate clinical parameters as predictors of germline mutation. METHODS: Seventy-four PGL patients were analyzed for germline mutations and large deletions in SDH genes, VHL and RET. Results were correlated to clinical characteristics including gender, age, tumor localization and multifocality. The surgical approach was evaluated in terms of tumor origin, sequelae and subsequent evolution. RESULTS: Mutations in SDHB and SDHD were identified in equal proportion in 13/13 (100%) of familial and in 15/61 (25%) of sporadic cases. Familiarity, age < or =50 years and male gender were predictors of any germline mutation, while multifocality and carotid/vagal localization were indicative of SDHD mutation in particular. CONCLUSION: In contrast to other series, this cohort of Spanish patients showed many SDHB mutations. Sporadic cases with germline mutation are frequent and underline the importance of mutational screening of all PGL patients, allowing the identification of relatives at risk and the early diagnosis of the disease, reducing or avoiding morbidity.