SummaryBackground 131 I-MIBG therapy can be used for palliative treat-

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SummaryBackground Chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD) can be used for palliative treatment of malignant pheochromocytoma and paraganglioma. However, the precise effect of this chemotherapeutic regimen on tumour volume is unclear. The main objective of this study was to perform a systematic review and meta-analysis assessing the effect of chemotherapy with CVD on tumour volume in patients with malignant paraganglioma/pheochromocytoma. Methods A literature search was performed in October 2013 to identify potentially relevant studies. Main outcomes were the pooled percentages of complete response, partial response and stable disease after chemotherapy with CVD. A meta-analysis was performed with an exact likelihood approach using a logistic regression. Pooled percentages with 95% confidence intervals (CI) were reported. Results Four studies concerning a total of 50 patients with malignant paraganglioma/pheochromocytoma reported on treatment with a combination of CVD chemotherapy. A meta-analysis of the effect of chemotherapy on tumour volume showed pooled percentages of complete response, partial response and stable disease of, respectively, 4% (95% CI: 1%-15%), 37%(95% CI: 25%-51%) and 14% (95% CI: 7%-27%). Only two studies concerning a total of 35 patients assessed the response on catecholamine excess; pooled percentages for complete, partial and stable hormonal response were 14% (95% CI: 6%-30%), 40% (95% CI: 25%-57%) and 20% (95% CI: 10%-36%), respectively. Duration of response was also reported in only two studies with a median duration of response of 20 months and 40 months. Conclusions Data on the effects of a combination of CVD chemotherapy on malignant paraganglioma/pheochromocytoma suggest that a partial response concerning tumour volume can

This focus group study demonstrated that important disease-specific aspects of QoL are neglected in current pituitary disease-specific questionnaires and elucidated potential factors that contribute to a decreased QoL. Information provided in this study can (and will) be used for developing additional items for disease-specific QoL questionnaires and for the development of a self-management intervention aiming to improve QoL in patients treated for pituitary diseases.

This study strengthens the etiological association of SDH genes with pituitary neoplasia, renal tumorigenesis, and gastric gastrointestinal stromal tumors. Furthermore, our results indicate that pancreatic neuroendocrine tumor also falls within the SDH-related tumor spectrum.

In this nationwide study of disease-affected and unaffected mutation carriers, we observed a lower rate of metastatic disease and a relatively high number of head and neck paragangliomas compared with previously reported referral-based cohorts.

Germline mutations in succinate dehydrogenase B (SDHB) predispose to hereditary paraganglioma (PGL) syndrome type 4. The risk of developing PGL or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. A total of 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers).One hundred and twelve carriers (57%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (28%), 4 patients had a PHEO (2%), 26 patients an extra-adrenal PGL (13%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers. K E Y W O R D Sparaganglioma, penetrance, pheochromocytoma, SDHB

In the Netherlands, the majority of hereditary paragangliomas (PGL) is caused by SDHD, SDHB and SDHAF2 mutations. Founder mutations in SDHD are particularly prevalent, but several SDHB founder mutations have also been described. Here, we describe an extended PGL family with a Dutch founder mutation in SDHB, c.201-4429_287-933del. The proband presented with apparently sporadic head and neck paraganglioma at advanced age. Subsequently, evaluation of the family identified several unaffected mutation carriers, asymptomatic and symptomatic PGL patients, and patients presenting with early-onset malignant pheochromocytoma. The calculated penetrance of the SDHB mutation in this kindred is lower than the risk suggested for SDHB mutations in the literature. This may represent a characteristic of this particular SDHB mutation, but may also be a reflection of the inclusion of relatively large numbers of asymptomatic mutation carriers in this family and adequate statistical correction for ascertainment bias. The low penetrance of SDHB mutations may obscure the hereditary nature of SDHB-linked disease and is important in the counseling of SDHB-linked patients. Risk estimates should preferably be based on the specific mutation involved.