[Genetics of pheochromocytoma]. / Genetik der Phäochromozytome.

About one third of all patients with a pheochromocytoma are carriers of germ line mutations of 1 of the 10 susceptibility genes. Thus, these patients can be diagnosed and classified with specific tumor syndromes. This group is composed of the entities of multiple endocrine neoplasia type 2 (MEN2) due to mutations in the RET gene, von Hippel-Lindau disease (VHL, VHL gene), the paraganglioma syndromes types 1-4 (PGL1-4) due to mutations of the genes SDHD, SDHAF2, SDHC, SDHB, neurofibromatosis type 1 (NF1) due to mutations of the NF1 gene and familial pheochromocytoma syndromes due to mutations of the SDHA, TMEM127 and MAX genes. Patients with hereditary pheochromocytomas run a lifelong risk of relapse of pheochromocytoma. In addition extraparaganglial tumors are frequent and include medullary thyroid carcinoma in MEN2 or renal cancer or neuroendocrine pancreatic cancer as well as hemangioblastomas of the retina and the central nervous system in VHL. Furthermore, renal cancer may be associated with PGL4 and PGL3. In conclusion, molecular genetic screening is essential for the diagnosis of pheochromocytoma-associated cancer syndromes and is thus the cornerstone for successful lifelong preventive medicine of such patients and their relatives.

Quality of randomised trials in COPD.

Randomised trials can provide high-level evidence to inform treatment decisions. Since their quality in respiratory medicine is largely unknown, we assessed the quality of a large set of chronic obstructive pulmonary disease (COPD) trials. As a marker of trial quality, we assessed the procedure and concealment of random allocation, and the conduct of an intention-to-treat-analysis in 344 randomised trials published between 1957 and 2006. We used ordered logistic regression to assess the association between trial quality and type of intervention, type of journal, journal impact factor and year of publication. 257 (75%) trials assessed pharmacological and 87 (25%) assessed nonpharmacological interventions. The generation of appropriate randomisation was reported in 27.0% of the trials, concealment of random allocation in 11.6% and an intention-to-treat analysis in 21.8% of trials. Significantly higher quality was found in trials on nonpharmacological interventions (OR 2.49, 95% CI 1.56-3.99), and in trials published in general medical journals (versus specialised journals; OR 2.25, 95% CI 1.30-3.90) and after 2000 (versus 1957-2000; OR 2.28, 95% CI 1.45-3.58). The association of quality with a high impact factor was of borderline significance (p = 0.06). The quality of many COPD trials is low but tends to become better since the adoption of the CONSORT (Consolidated Standards of Reporting Trials) statement.

Smoking cessation interventions in COPD: a network meta-analysis of randomised trials.

The aim of this study was to rank order the effectiveness of smoking cessation interventions for chronic obstructive pulmonary disease (COPD) patients. We searched 10 databases to identify randomised trials of smoking cessation counselling (SCC) with or without pharmacotherapy or nicotine replacement therapy (NRT). We conducted a network meta-analysis using logistic regression analyses to assess the comparative effectiveness of smoking cessation interventions while preserving randomisation of each trial. The analysis of 7,372 COPD patients from six out of eight identified trials showed that SCC in combination with NRT had the greatest effect on prolonged abstinence rates versus usual care (OR 5.08, p<0.0001) versus SCC alone (2.80, p = 0.001) and versus SCC combined with an antidepressant (1.53, p = 0.28). The second most effective intervention was SCC combined with an antidepressant (3.32, p = 0.002) versus SCC alone (1.83, p = 0.007), with no difference between antidepressants. SCC alone was of borderline superiority compared with usual care (1.81, p = 0.07). A small body of evidence suggests that SCC combined with NRT is more effective than other combinations and single smoking cessation treatments in COPD, but substantially more research is needed for this most important COPD treatment.

The malignant potential of a succinate dehydrogenase subunit B germline mutation.

Familial catecholamine secreting tumors have been associated with multiple endocrine neoplasia type 2, Von Hippel-Lindau disease and neurofibromatosis type 1. In the last years, mutations of genes encoding subunits B, C and D of the succinate dehydrogenase have been discovered as other causes of pheochromocytomas and paragangliomas. We diagnosed a malignant retroperitoneal paraganglioma in a 64-yr-old man with bone metastasis in 2001. Two years later a retroperitoneal benign paraganglioma was found and resected in his 32-yr-old daughter. Thus we diagnosed in this family a paraganglioma syndrome. We performed molecular genetic analyses of the genes SDHB, SDHC, and SDHD. We detected in the SDHB gene the mutation SDHB c. 558-3 C> G affecting the splice site of exon 5. In a second daughter the mutation was also detected, thorough clinical investigation revealed normal results. We conclude that the SDHB mutation predisposes to abdominal extra-adrenal and potential malignant pheochromocytoma with incomplete penetrance.

Genetic testing for pheochromocytoma-associated syndromes.

Pheochromocytoma and paraganglioma are tumors of the autonomic nervous system. Various syndromes have been found to be associated with the development of pheochromocytomas and paragangliomas: multiple endocrine neoplasia type 2 (MEN 2, susceptibility gene: RET), von Hippel-Lindau disease (VHL, susceptibility gene: VHL), neurofibromatosis 1 (NF 1), and paraganglioma syndromes type 1, 3, and 4 (susceptibility genes: succinate dehydrogenase gene, SDH, subunits D, C and B, respectively). Prevalence and clinical features of pheochromocytomas and paragangliomas are different for each of these syndromes. Mutational analysis of the susceptibility genes of these syndromes in patients presenting with pheochromocytoma or paraganglioma may help to judge the risks of multifocality of the tumor as well as development of malignant pheochromocytoma or of other malignant tumors. Here we review the recent progress in clinical characterization and genetic testing for these syndromes. Based on tumor characteristics and prevalence data we give recommendations for an efficient genetic testing procedure in patients presenting with pheochromocytomas and paragangliomas.