Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

• MeSH
• dítě MeSH
• dospělí MeSH
• feochromocytom * genetika   terapie   diagnóza   MeSH
• lidé MeSH
• nádory nadledvin * genetika   terapie   diagnóza   MeSH
• paragangliom * genetika   terapie   MeSH
• sukcinátdehydrogenasa genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• SDHB protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH

INTRODUCTION: Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors, which are mostly benign in nature. Amongst all genes, Succinate Dehydrogenase Subunit D (SDHD) is the most commonly mutated in familial HNPGLs. In about 30% of HNPGLs, germline mutations in SDHD can also occur in the absence of positive family history, thus giving rise to "occult familial" cases. Our aim was to evaluate the pattern of SDHD germline mutations in Czech patients with HNPGLs. MATERIALS AND METHODS: We analyzed a total of 105 patients with HNPGLs from the Otorhinolaryngology departments of 2 tertiary centers between 2006 - 2021. All underwent complex diagnostic work-up and were also consented for genetic analysis. RESULTS: Eighty patients aged 13-76 years were included; around 60% with multiple PGLs were males. Carotid body tumor was the most frequently diagnosed tumor. Germline SDHD mutation was found in only 12% of the Czech patients; approximately 78% of those harboring the mutation had negative family history. The mutation traits had higher affiliation for multiple tumors with nearly 70% patients of ≤ 40 years of age. CONCLUSION: An SDHD mutation variant was shared amongst unrelated patients but no founder-effect was established. Our findings confirmed that the pattern of SDHD mutation distribution amongst HNPGLs in Czech Republic differs from most studies worldwide.

• Klíčová slova
• CBPGL, HNPGL, SDHD gene, germline mutation, paraganglioma syndrome,
• MeSH
• dospělí MeSH
• incidence MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace MeSH
• nechromafinní paragangliom * MeSH
• paragangliom * epidemiologie   genetika   diagnóza   MeSH
• senioři MeSH
• sukcinátdehydrogenasa genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• SDHD protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.

• MeSH
• feochromocytom * diagnóza   genetika   terapie   MeSH
• lidé MeSH
• nádory nadledvin * diagnóza   genetika   terapie   MeSH
• paragangliom * diagnóza   genetika   terapie   MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• sukcinátdehydrogenasa genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• SDHD protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors, comprising only 3% of all head and neck tumors. Early diagnosis forms an integral part of the management of these tumors. The two main aims of any treatment approach are long-term tumor control and minimal cranial nerve morbidity. The scope of this article is to present our case series of HNPGLs to stress most important clinical aspects of their presentation as well as critical issues of their complex management. Thirty patients with suspected HNPGLs were referred to our otorhinolaryngology clinic for surgical consultation between 2016-2020. We assessed the demographical pattern, clinicoradiological correlation, as well as type and outcome of treatment. A total of 42 non-secretory tumors were diagnosed-16.7% were incidental findings and 97% patients had benign tumors. Six patients had multiple tumors. Jugular paragangliomas were the most commonly treated tumors. Tumor control was achieved in nearly 96% of operated patients with minimal cranial nerve morbidity. Surgery is curative in most cases and should be considered as frontline treatment modality in experienced hands for younger patients, hereditary and secretory tumors. Cranial nerve dysfunction associated with tumor encasement is a negative prognostic factor for both surgery and radiotherapy. Multifocal tumors and metastasis are difficult to treat, even with early detection using genetic analysis. Detecting malignancy in HNPGLs is challenging due to the lack of histomorphological criteria; therefore, limited lymph node dissection should be considered, even in the absence of clinical and radiological signs of metastasis in carotid body, vagal, and jugular paragangliomas.

• Klíčová slova
• Fisch’s classification, HNPGLs, Shamblin’s classification, cranial nerve dysfunction, facial nerve palsy, incidentaloma, jugular paragangliomas, otorhinolaryngology,
• Publikační typ
• časopisecké články MeSH

Multiple head and neck paragangliomas (HNPGLs) are neuroendocrine tumors of a mostly benign nature that can be associated with a syndrome, precipitated by the presence of a germline mutation. Familial forms of the disease are usually seen with mutations of SDHx genes, especially the SDHD gene. SDHB mutations are predisposed to malignant tumors. We found 6 patients with multiple tumors amongst 30 patients with HNPGLs during the period of 2016 to 2021. We discuss the phenotypic and genetic patterns in our patients with multiple HNPGLs and explore the management possibilities related to the disease. Fifty percent of our patients had incidental findings of HNPGLs. Twenty-one biochemically silent tumors were found. Four patients had germline mutations, and only one had a positive family history. Three out of five underwent surgery without permanent complications. Preventative measures (genetic counselling and tumor surveillance) represent the gold standard in effectively controlling the disease in index patients and their relatives. In terms of treatment, apart from surgical and radiotherapeutic interventions, new therapeutic measures such as gene targeted therapy have contributed very sparsely. With the lack of standardized protocols, management of patients with multiple HNPGLs still remains very challenging, especially in those with sporadic or malignant forms of the disease.

• Klíčová slova
• HNPGL, SDHB gene, SDHD gene, carotid body tumors, genetic counselling, germline mutation, incidentalomas, malignant paragangliomas,
• Publikační typ
• časopisecké články MeSH

: Phaeochromocytoma and paraganglioma (PPGL) are chromaffin cell tumours that require timely diagnosis because of their potentially serious cardiovascular and sometimes life- threatening sequelae. Tremendous progress in biochemical testing, imaging, genetics and pathophysiological understanding of the tumours has far-reaching implications for physicians dealing with hypertension and more importantly affected patients. Because hypertension is a classical clinical clue for PPGL, physicians involved in hypertension care are those who are often the first to consider this diagnosis. However, there have been profound changes in how PPGLs are discovered; this is often now based on incidental findings of adrenal or other masses during imaging and increasingly during surveillance based on rapidly emerging new hereditary causes of PPGL. We therefore address the relevant genetic causes of PPGLs and outline how genetic testing can be incorporated within clinical care. In addition to conventional imaging (computed tomography, MRI), new functional imaging approaches are evaluated. The novel knowledge of genotype-phenotype relationships, linking distinct genetic causes of disease to clinical behaviour and biochemical phenotype, provides the rationale for patient-tailored strategies for diagnosis, follow-up and surveillance. Most appropriate preoperative evaluation and preparation of patients are reviewed, as is minimally invasive surgery. Finally, we discuss risk factors for developing metastatic disease and how they may facilitate personalised follow-up. Experts from the European Society of Hypertension have prepared this position document that summarizes the current knowledge in epidemiology, genetics, diagnosis, treatment and surveillance of PPGL.

• MeSH
• biomedicínský výzkum MeSH
• feochromocytom * diagnóza   genetika   terapie   MeSH
• hypertenze * MeSH
• konsensus MeSH
• lidé MeSH
• nádory nadledvin * diagnóza   genetika   terapie   MeSH
• paragangliom * diagnóza   genetika   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Intramural MeSH
• Geografické názvy
• Evropa MeSH

Metastatic pheochromocytoma continues to be an incurable disease, and treatment with conventional cytotoxic chemotherapy offers limited efficacy. In the present study, we evaluated a novel topoisomerase I inhibitor, LMP-400, as a potential treatment for this devastating disease. We found a high expression of topoisomerase I in human metastatic pheochromocytoma, providing a basis for the evaluation of a topoisomerase 1 inhibitor as a therapeutic strategy. LMP-400 inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. In a study performed in athymic female mice, LMP-400 demonstrated a significant inhibitory effect on tumor growth with two drug administration regimens. Furthermore, low doses of LMP-400 decreased the protein levels of hypoxia-inducible factor 1 (HIF-1α), one of a family of factors studied as potential metastatic drivers in these tumors. The HIF-1α decrease resulted in changes in the mRNA levels of HIF-1 transcriptional targets. In vitro, LMP-400 showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. We conclude that LMP-400 has promising antitumor activity in preclinical models of metastatic pheochromocytoma and its use should be considered in future clinical trials.

• MeSH
• benzodioxoly aplikace a dávkování   farmakologie   MeSH
• buňky PC12 MeSH
• DNA-topoisomerasy I metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   metabolismus   MeSH
• feochromocytom farmakoterapie   enzymologie   patologie   MeSH
• hypoxie buňky MeSH
• inhibitory topoisomerasy I aplikace a dávkování   farmakologie   MeSH
• isochinoliny aplikace a dávkování   farmakologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nádorové buňky kultivované MeSH
• nádory jater farmakoterapie   enzymologie   sekundární   MeSH
• nádory nadledvin farmakoterapie   enzymologie   patologie   MeSH
• nádory plic farmakoterapie   enzymologie   sekundární   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• synergismus léků MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• benzodioxoly MeSH
• DNA-topoisomerasy I MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• HIF1A protein, human MeSH Prohlížeč
• inhibitory topoisomerasy I MeSH
• isochinoliny MeSH
• NSC 724998 MeSH Prohlížeč
• protinádorové látky MeSH