Summary
Background
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 be achieved in about 37% of patients and a partial response on catecholamine excess in about 40% of patients. However, in the included studies, the protocol when to initiate treatment was not well described. Therefore, it cannot be excluded that the reported effect of chemotherapy on tumour volume reflects the natural course of the disease, at least partially.
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.
The overall penetrance of succinate dehydrogenase B (SDHB) mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers. The maximum likelihood estimate of the age‐related penetrance of SDHB mutations for paraganglioma and/or pheochromocytoma (continuous line) and 95% confidence interval (dashed line).
(131)I-MIBG therapy can be used for palliative treatment of malignant paraganglioma and phaeochromocytoma. The main objective of this study was to perform a systematic review and meta-analysis ...assessing the effect of (131)I-MIBG therapy on tumour volume in patients with malignant paraganglioma/phaeochromocytoma.
A literature search was performed in December 2012 to identify potentially relevant studies. Main outcomes were the pooled proportions of complete response, partial response and stable disease after radionuclide therapy. A meta-analysis was performed with an exact likelihood approach using a logistic regression with a random effect at the study level. Pooled proportions with 95% confidence intervals (CI) were reported.
Seventeen studies concerning a total of 243 patients with malignant paraganglioma/phaeochromocytoma were treated with (131)I-MIBG therapy. The mean follow-up ranged from 24 to 62 months. A meta-analysis of the effect of (131)I-MIBG therapy on tumour volume showed pooled proportions of complete response, partial response and stable disease of, respectively, 0·03 (95% CI: 0·06-0·15), 0·27 (95% CI: 0·19-0·37) and 0·52 (95% CI: 0·41-0·62) and for hormonal response 0·11 (95% CI: 0·05-0·22), 0·40 (95% CI: 0·28-0·53) and 0·21 (95% CI: 0·10-0·40), respectively. Separate analyses resulted in better results in hormonal response for patients with paraganglioma than for patients with phaeochromocytoma.
Data on the effects of (131)I-MIBG therapy on malignant paraganglioma/phaeochromocytoma suggest that stable disease concerning tumour volume and a partial hormonal response can be achieved in over 50% and 40% of patients, respectively, treated with (131)I-MIBG therapy. It cannot be ruled out that stable disease reflects not only the effect of MIBG therapy, but also (partly) the natural course of the disease.
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.
Although sudden cardiac death (SCD) is relatively common, contemporary data on its incidence are lacking.
The purpose of this study was to investigate the current incidence of SCD and its trend over ...the past 2 decades in a general middle-aged and elderly population.
This study was performed within the Rotterdam Study, a prospective population-based cohort study of persons aged 45 years and older. Age-standardized incidence rates of SCD were calculated. To study trends in incidence, we compared 2 subcohorts within the total study population, 1 followed from 1990-2000 and the other from 2001-2010.
From 1990-2010, 5512 of 14,628 participants died, of whom 583 (4.0%) were classified as SCD. The overall incidence was 4.2 per 1000 person-years. The incidence was higher in men (5.2 per 1000 person-years) than in women (3.6 per 1000 person-years). Age-adjusted hazard ratio (HR) 1.84 (95% confidence CI 1.56-2.17) and risk of SCD increased with age (HR 1.10 per year; 95% CI 1.09-1.11). The incidence rate from 1990-2000 was 4.7 per 1000 person-years vs 2.1 per 1000 person-years from 2001-2010 (age- and sex-adjusted HR of SCD 0.60, 95% CI 0.44-0.80). To check for cohort effects, we also analyzed the incidence of total mortality and found an age- and sex-adjusted HR of total mortality of 0.82 (95% CI 0.75-0.90) for the second compared to the first subcohort, which was significantly higher than the decline in SCD incidence.
We found an incidence of SCD of 4.2 per 1000 person-years. The incidence decreased from 1990-2010, a period during which the diagnosis and treatment of heart disease greatly improved.
Objective Currently, there is no consensus on the definition of hyperemesis gravidarum (HG; protracted vomiting in pregnancy) and no single widely used set of diagnostic criteria for HG. The various ...definitions rely on symptoms, sometimes in combination with laboratory tests. Through a systematic review, we aimed to summarize available evidence on the diagnostic value of biomarkers for HG. This could assist diagnosis and may shed light on the, as yet, not understood cause of the disorder. Study Design We searched Medline and Embase for articles about diagnostic biomarkers for either the presence or severity of HG or nausea and vomiting of pregnancy. We defined HG as any combination of nausea, vomiting, dehydration, weight loss, or hospitalization for nausea and/or vomiting in pregnancy, in the absence of any other obvious cause for these complaints. Results We found 81 articles on 9 biomarkers. Although 65% of all studies included only HG cases with ketonuria, we did not find an association between ketonuria and presence or severity of HG in 5 studies reporting on this association. Metaanalysis, with the use of the hierarchical summary receiver operating characteristics model, yielded an odds ratio of 3.2 (95% confidence interval, 2.0–5.1) of Heliobacter pylori for HG, as compared with asymptomatic control subjects (sensitivity, 73%; specificity, 55%). Studies on human chorionic gonadotropin and thyroid hormones, leptin, estradiol, progesterone, and white blood count showed inconsistent associations with HG; lymphocytes tended to be higher in women with HG. Conclusion We did not find support for the use of ketonuria in the diagnosis of HG. H pylori serology might be useful in specific patients.
PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small ...biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions.
A prolonged heart rate-corrected QT (QTc) interval is a well-known risk indicator for sudden cardiac death (SCD) and a contraindication for drugs with potentially arrhythmogenic adverse effects.
We ...aimed to study the consistency of QTc interval prolongation and whether a consistent QTc interval prolongation correlates differently with SCD than does an inconsistently prolonged QTc interval.
We used a population-based cohort study of persons 55 years and older. We excluded participants using QTc-prolonging drugs or with bundle branch block. The QT interval was corrected for heart rate using Bazett and Fridericia formulas. Using a Cox regression model, we assessed the association between QTc interval prolongation consistency and the occurrence of SCD.
A total of 3484 participants had electrocardiograms (ECGs) recorded on 2 consecutive visits. In 96%-98% of participants with a normal QTc interval on the first ECG, the QTc interval remained normal, but only in 27%-35% of those with a prolonged QTc interval, the QTc interval was prolonged on the second ECG after a median of 1.8 years. A consistently prolonged QTc interval was associated with an increased risk of SCD as compared with a consistently normal QTc interval (Bazett: hazard ratio 2.23; 95% confidence interval 1.17-4.24, Fridericia: hazard ratio 6.67; 95% confidence interval 2.96-15.06). A prolonged QTc interval preceded or followed by a normal QTc interval was not significantly associated with an increased risk of SCD.
Persons with an inconsistently prolonged QTc interval did not have a higher risk of SCD than those with a consistently normal QTc interval. Persons with a consistently prolonged QTc interval did have a higher risk of SCD. Our results suggest that repeated measurements of the QTc interval could enhance risk stratification.
Germline mutations in the succinate dehydrogenase B (SDHB) gene predispose to hereditary paraganglioma (PGL) syndrome type 4. The aim of this study was to evaluate the clinical characteristics and ...outcome of treatment strategies for patients with head and neck paraganglioma (HNPGL) carrying SDHB germline mutations.
This was a retrospective evaluation of patients with HNPGL carrying SDHB germline mutations in the Netherlands.
In a Dutch nationwide cohort study of SDHB germline mutation carriers, 54 patients with a total of 62 HNPGLs were identified. Forty-one of 54 patients (76 per cent) visited the outpatient clinic because of associated complaints. Eight patients (15 per cent) had multiple PGLs. One patient (2 per cent) developed a phaeochromocytoma and three (6 per cent) developed a malignant PGL. Twenty-seven patients (50 per cent) had an operation for their HNPGL and 15 (28 per cent) received radiotherapy. Three patients with HNPGL (6 per cent) were diagnosed with additional non-paraganglionic tumours.
If an SDHB germline mutation is identified in a patient with HNPGL, the clinician should be aware of the variable manifestations of the SDHB-linked tumour syndrome, the risk of catecholamine excess, concurrent phaeochromocytoma, and association with non-paraganglionic tumours.
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