Yikes! Are we disgusted by politicians?

In the political domain, disgust is primarily portrayed as an emotion that explains individual differences in pathogen avoidance. We hypothesized that political rhetoric accusing opponents of moral transgressions also elicits disgust responses. In this registered report, we present the results from a laboratory experiment. We find that participants self-report higher disgust and have stronger physiological (Levator labii) responses to pictures of out-party leaders compared with in-party leaders. Participants also report higher disgust in response to moral violations of in-party leaders. There is more suggestive evidence that in-party leaders evoke more labii activity when they commit moral violations than when out-party leaders do. The impact of individual differences in moral disgust and partisanship strength is very limited to absent. Intriguingly, on average, the physiological and self-reported disgust responses to the treatment are similar, but individuals differ in whether their response is physiological or cognitive. This motivates further theorizing regarding the concordance of emotional responses.

Conservatives and liberals have similar physiological responses to threats.

About a decade ago, a study documented that conservatives have stronger physiological responses to threatening stimuli than liberals. This work launched an approach aimed at uncovering the biological roots of ideology. Despite wide-ranging scientific and popular impact, independent laboratories have not replicated the study. We conducted a pre-registered direct replication (n = 202) and conceptual replications in the United States (n = 352) and the Netherlands (n = 81). Our analyses do not support the conclusions of the original study, nor do we find evidence for broader claims regarding the effect of disgust and the existence of a physiological trait. Rather than studying unconscious responses as the real predispositions, alignment between conscious and unconscious responses promises deeper insights into the emotional roots of ideology.

Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis.

Somatostatin analogues (SSA) have demonstrated antiproliferative activity in addition to efficacy for carcinoid symptom control in functional neuroendocrine tumors (NET). A post hoc analysis of the placebo arm of the RAD001 In Advanced Neuroendocrine Tumors-2 (RADIANT-2) study was conducted to assess the efficacy of octreotide long-acting repeatable (LAR) on progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan-Meier method. Out of 213 patients randomized to placebo plus octreotide LAR in RADIANT-2, 196 patients with foregut, midgut, or hindgut NET were considered for present analysis. Of these, 41 patients were SSA-treatment naïve and 155 had received SSA therapy before study entry. For SSA-naïve patients, median PFS by adjudicated central review was 13.6 (95% CI 8.2-22.7) months. For SSA-naïve patients with midgut NET (n=24), median PFS was 22.2 (95% CI 8.3-29.5) months. For patients who had received SSA previously, the median PFS was 11.1 (95% CI 8.4-14.3) months. Among the SSA-pretreated patients who had midgut NET (n=119), the median PFS was 12.0 (95% CI 8.4-19.3) months. Median OS was 35.8 (95% CI 32.5-48.9) months for patients in the placebo plus octreotide LAR arm; 50.6 (36.4 - not reached) months for SSA-naïve patients and 33.5 (95% CI 27.5-44.7) months for those who had received prior SSA. This post hoc analysis of the placebo arm of the large phase 3 RADIANT-2 study provides data on PFS and OS among patients with progressive NET treated with octreotide therapy.

A variant in FTO shows association with melanoma risk not due to BMI.

We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.

Acromegaly: the disease, its impact on patients, and managing the burden of long-term treatment.

Acromegaly is a rare disease most often caused by the prolonged secretion of excess growth hormone from a pituitary adenoma. The disease is associated with multiple significant comorbidities and increased mortality. The delay to diagnosis is often long. This may be because of low disease awareness among health care professionals, the insidious onset of differentiating features, and because patients are likely to present with complaints typical of other conditions more frequently seen in primary care. Early identification of acromegaly facilitates prompt treatment initiation and may minimize the permanent effects of excess growth hormone. The primary treatment for many patients will be pituitary surgery, although not all patients will be eligible for surgery or achieve a surgical cure. If biochemical control is not achieved following surgery, other treatment options include medical therapy and radiation therapy. Improved biochemical control may only alleviate rather than reverse the associated comorbidities. Thus, lifelong monitoring of patient health is needed, with particular attention to the management of cardiovascular risk factors. It is additionally important to consider the impact of both disease and treatment on patients' quality of life and minimize that impact where possible, but particularly for chronic therapies. For the majority of patients, chronic therapy is likely to include somatostatin analog injections. In some circumstances, it may be possible to extend the dosing interval of the analog once good biochemical control is achieved. Additional convenience may be gained from the possibility of self-/partner administration of treatment or administration of treatment by a health care professional at home. Overall, it is clear that the care of patients with acromegaly requires a highly coordinated approach involving numerous specialties (eg, endocrinology, surgery, cardiology). Further, patients' needs must be at the core of management and every effort must be made to improve health care experiences and minimize treatment burdens.

Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy.

OBJECTIVE: Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based. DATA SOURCES: The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected. STUDY SELECTION: 16 studies that provided incidence rates or data from which these rates could be calculated were included. DATA EXTRACTION: We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate. RESULTS: The incidence of clozapine-induced agranulocytosis varies between 3.8‰-8.0‰. The mortality rate is 0.1‰-0.3‰, and the case-fatality rate is 2.2‰-4.2‰. In diabetic ketoacidosis, the incidence was calculated at 1.2‰-3.1‰, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4‰-8‰, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7‰-34‰) and the rest of the world (0.07‰-0.6‰) impairs a general approach of this side effect. CONCLUSIONS: In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia.

A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis.

OBJECTIVES: We evaluated safety and efficacy of recombinant human growth hormone (rhGH) for improving growth, lean body mass (LBM), pulmonary function, and exercise tolerance in children with cystic fibrosis (CF) and growth restriction. STUDY DESIGN: Multicenter, open-label, controlled clinical trial comparing outcomes in prepubertal children <14 years with CF, randomized in a 1:1 ratio to receive daily rhGH (Nutropin AQ) or no treatment (control) for 12 months, followed by a 6-month observation (month 18). Safety was monitored at each visit, including assessments of glucose tolerance. RESULTS: Sixty-eight subjects were randomized (control n = 32; rhGH n = 36). Mean height standard deviation score (SDS) in the rhGH group increased by 0.5 ± 0.4 at 12 months (mean ± SD, P < 0.001); the control group height SDS remained unchanged. Weight increased by 3.8 ± 1.8 versus 2.8 ± 1.5 kg, (mean ± SD, P = 0.0356) and LBM increased by 3.8 ± 1.8 versus 2.1 ± 1.4 kg (P = 0.0002) in the rhGH group versus controls, respectively. Forced vital capacity increased by 325 ± 319 in the rhGH group compared with 178 ± 152 ml in controls (mean ± SD, P = 0.032). Forced expiratory volume in 1 sec improved in both groups with a significant difference between groups after adjustment for baseline severity (LS mean ± SE: rhGH, 224 ± 37, vs. controls, 108 ± 40 ml; P = 0.04). There was no difference between groups in exercise tolerance (6-min walk distance) at 1 year. Changes in glucose tolerance for the two groups were similar over the 12-month study period, with three subjects developing IGT and one CFRD in each group. One rhGH-treated patient developed increased intracranial pressure. CONCLUSIONS: Treatment with rhGH in prepubertal children with CF was effective in promoting growth, weight, LBM, lung volume, and lung flows, and had an acceptable safety profile.

Genome-wide association study identifies three new melanoma susceptibility loci.

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Melanocytic nevi, nevus genes, and melanoma risk in a large case-control study in the United Kingdom.

BACKGROUND: Increased number of melanocytic nevi is a potent melanoma risk factor. We have carried out a large population-based case-control study to explore the environmental and genetic determinants of nevi and the relationship with melanoma risk. METHODS: We report nevus phenotype in relation to differing patterns of sun exposure, inherited variation at loci shown in recent genome-wide association studies to be nevus genes, and risk. RESULTS: Increased numbers of nevi were associated with holiday sun exposure, particularly on intermittently sun-exposed body sites (test for P(trend) < 0.0001). Large nevi were also associated with holiday sun exposure (P = 0.002). Single nucleotide polymorphisms (SNP) on chromosomes 9 and 22 were associated with increased numbers of nevi (P = 0.04 and P = 0.002 respectively) and larger nevi (P = 0.03 and P = 0.002), whereas that on chromosome 6 was associated only with large nevi (P = 0.01). Melanoma risk was associated with increased nevus count, large nevi, and atypical nevi for tumors in all body sites (including rare sites) irrespective of age. The risk persisted when adjusted for inheritance of nevus SNPs. CONCLUSIONS: The at-risk nevus phenotype is associated with behaviors known to increase melanoma risk (holiday sun exposure). Although SNPs on chromosomes 6, 9, and 22 were shown to be nevus genes, they explained only a small proportion of melanoma risk and nevus phenotype; therefore, several nevus genes likely remain to be identified. IMPACT: This article confirms the importance of nevi in melanoma pathogenesis and increases understanding of their genetic determinants.

Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb).

Multiple osteochondromas (MO) is an autosomal dominant skeletal disease characterized by the formation of multiple cartilage-capped bone tumors growing outward from the metaphyses of long tubular bones. MO is genetically heterogeneous, and is associated with mutations in Exostosin-1 (EXT1) or Exostosin-2 (EXT2), both tumor-suppressor genes of the EXT gene family. All members of this multigene family encode glycosyltransferases involved in the adhesion and/or polymerization of heparin sulfate (HS) chains at HS proteoglycans (HSPGs). HSPGs have been shown to play a role in the diffusion of Ihh, thereby regulating chondrocyte proliferation and differentiation. EXT1 is located at 8q24.11-q24.13, and comprises 11 exons, whereas the 16 exon EXT2 is located at 11p12-p11. To date, an EXT1 or EXT2 mutation is detected in 70-95% of affected individuals. EXT1 mutations are detected in +/-65% of cases, versus +/-35% EXT2 mutations in MO patient cohorts. Inactivating mutations (nonsense, frame shift, and splice-site mutations) represent the majority of MO causing mutations (75-80%). In this article, the clinical aspects and molecular genetics of EXT1 and EXT2 are reviewed together with 895 variants in MO patients. An overview of the reported variants is provided by the online Multiple Osteochondromas Mutation Database (http://medgen.ua.ac.be/LOVD).

Genome-wide association study identifies three loci associated with melanoma risk.

We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 x 10(-7). Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 x 10(-27) for rs258322), 11q14-q21 encompassing TYR (P = 2.41 x 10(-14) for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.

Genome-wide linkage scan in Dutch hereditary non-BRCA1/2 breast cancer families identifies 9q21-22 as a putative breast cancer susceptibility locus.

Breast cancer accounts for over 20% of all female cancers. A positive family history remains one of the most important risk factors for the disease, with first-degree relatives of patients having a twofold elevated risk. Known breast cancer susceptibility genes such as BRCA1 and BRCA2 explain only 20-25% of this risk, suggesting the existence of other breast cancer susceptibility genes. Here, we report the results of a genome-wide linkage scan in 55 high-risk Dutch breast cancer families with no mutations in BRCA1 and BRCA2. Twenty-two of these families were also part of a previous linkage study by the Breast Cancer Linkage Consortium. In addition, we performed CGH analyses in 61 tumors of these families and 31 sporadic tumors. Three regions were identified with parametric HLOD scores >1, and three with nonparametric LOD scores >1.5. Upon further marker genotyping for the candidate loci, and the addition of another 30 families to the analysis, only the locus on chromosome 9 (9q21-22, marker D9S167) remained significant, with a nonparametric multipoint LOD score of 3.96 (parametric HLOD 0.56, alpha = 0.18). With CGH analyses we observed preferential copy number loss at BAC RP11-276H19, containing D9S167 in familial tumors as compared to sporadic tumors (P < 0.001). Five candidate genes were selected from the region around D9S167 and their coding regions subjected to direct sequence analysis in 16 probands. No clear pathogenic mutations were found in any of these genes.

Y chromosome detection by Real Time PCR and pyrophosphorolysis-activated polymerisation using free fetal DNA isolated from maternal plasma.

OBJECTIVES: To validate the use of Real Time PCR, a widely used technique that can detect very low levels of Y chromosomal sequence, and to assess the use of a highly sensitive PCR technique, pyrophosphorolysis-activated polymerisation (PAP), for fetal sex determination using free fetal DNA (ffDNA). METHODS: The fetal sex was determined by Real Time PCR in 58 pregnancies using ffDNA isolated from maternal plasma. In parallel with the Real Time PCR experiments, the presence of Y chromosome sequence was also determined using PAP on 54 isolated ffDNA samples. RESULTS: Both techniques detected Y chromosome sequence at very low levels with 98% specificity and 100% sensitivity (Real Time n = 44, PAP n = 54). Furthermore, the PAP technique was shown to be more robust than the Real Time PCR as none of the samples tested failed to meet the acceptance criteria. Combining the two techniques for male fetal sex detection from maternal blood plasma increases the sensitivity and specificity to 100% in this series. CONCLUSIONS: This study shows that both Real Time PCR and PAP can be used for Y chromosome detection on ffDNA. Furthermore, by using PAP in combination with Real Time PCR more reliable early prenatal sexing can be performed using ffDNA.

Changes in height, weight, and body mass index in children with craniopharyngioma after three years of growth hormone therapy: analysis of KIGS (Pfizer International Growth Database).

Extreme degrees of obesity may occur in association with hypothalamic tumors, usually after surgical intervention. This phenomenon has been reported to occur in as many as 25-75% of children undergoing extensive surgical extirpation of craniopharyngiomas (Cranio). Because less is known about the auxology of children with Cranio with milder alterations in growth, we undertook a 3-yr longitudinal analysis, using the KIGS database (Pfizer International Growth Database), to study their growth patterns and evolution of weight. We compared the effect of GH therapy on height, weight, and body mass index (BMI) in 199 prepubertal children with diagnosed Cranio treated by surgery and/or radiotherapy to two other groups of children with other causes of organic GH deficiency (OGHD): one with postsurgical and/or postirradiated OGHD (OGHD + S/I; n = 92) and the other with OGHD not due to Cranio and not having undergone either surgery or irradiation (OGHD - S/I; n = 85). At the start of GH therapy, 1) mean chronological (P < 0.0001) and bone (P = 0.0002) ages were youngest in OGHD - S/I and oldest in OGHD + S/I; 2) the mean height sd score (SDS) was lowest in OGHD - S/I and comparably higher in the other two groups (P < 0.0001); 3) mean weight and BMI SDS were greatest in Cranio and least in OGHD - S/I (both P < 0.0001); and 4) the mean initial GH dose prescribed was highest in OGHD - S/I and comparable in the other two groups (P < 0.0001). After 3 yr of GH therapy, 1) mean bone age remained youngest in OGHD - S/I and oldest in OGHD + S/I (P < 0.0001); 2) mean height SDS was highest in Cranio and comparably lower in the other two groups (P = 0.0159); 3) mean weight and BMI SDS remained greatest in Cranio and least in OGHD - S/I (P < 0.0001 and P = 0.0003, respectively); and 4) the mean GH dose remained highest in the OGHD - S/I group and least in the Cranio group (P = 0.0082). There were statistically significant increases within each group between the start of treatment and after 3 yr of GH therapy in height and weight, but not in BMI SDS. Lastly, after 3 yr of GH treatment, children in the Cranio group continued to have disproportionately heavier weight and higher BMI (with the greatest values in those with lower stimulated peak GH concentrations) compared with members of the other two groups, with no salutary effect of GH treatment on weight SDS and a mild improvement in BMI SDS. After S/I treatment, children with Cranio are disproportionately prone to varying degrees of weight gain compared with children with other forms of OGHD. In the present cohort of prepubertal children with Cranio, GH therapy induced excellent linear growth, but failed to have an ameliorative effect on weight gain and had only a slight beneficial effect on BMI gain. Because affected children may have resultant significant long-term medical morbidity and diminished quality of life, it is critical that the mechanism of this phenomenon be determined to devise helpful preventive or therapeutic interventions.

Two-color multiplex ligation-dependent probe amplification: detecting genomic rearrangements in hereditary multiple exostoses.

Genomic deletions and duplications play an important role in the etiology of human disease. Versatile tests are required to detect these rearrangements, both in research and diagnostic settings. Multiplex ligation-dependent probe amplification (MLPA) is such a technique, allowing the rapid and precise quantification of up to 40 sequences within a nucleic acid sample using a one-tube assay. Current MLPA probe design, however, involves time-consuming and costly steps for probe generation. To bypass these limitations we set out to use chemically synthesized oligonucleotide probes only. The inherent limitations of this approach are related to oligonucleotide length, and thus the number of probes that can be combined in one assay is also limited. This problem was tackled by designing a two-color assay, combining two sets of probes, each amplified by primers labeled with a different fluorophore. In this way we successfully combined 28 probes in a single reaction. The assay designed was used to screen for the presence of deletions and duplications in patients with hereditary multiple exostoses (HME). Screening 18 patients without detectable point mutations in the EXT1 and EXT2 genes revealed five cases with deletions of one or more exons: four in EXT1 and one in EXT2. Our results show that a two-color MLPA assay using only synthetic oligonucleotides provides an attractive alternative for probe design. The approach is especially suited for cases in which the number of patients to be tested is limited, making it financially unattractive to invest in cloning.

Growth hormone treatment in Aarskog syndrome: analysis of the KIGS (Pharmacia International Growth Database) data.

Aarskog syndrome is an X-linked disorder characterized by faciogenital dysplasia and short stature. The present study set out to determine the effect of growth hormone (GH) therapy in patients with Aarskog syndrome enrolled in KIGS--the Pharmacia International Growth Database. Twenty-one patients (20 males) were evaluated. Median age at start of treatment was 8.3 years (10-90th percentiles, 5.1-14.1 years) and median height SDS was -2.8 (10-90th percentiles, -2.1 to -3.7). The median dose of GH was 0.22 mg/kg/week (10-90th percentiles, 0.15-0.30 mg/kg/week) given at a median frequency of six (4-7) times per week. Prepubertal patients were followed longitudinally for 1 year (n = 13) or 3 years (n = 7). After 1 year, the median height SDS had improved from -2.8 to -2.3 in 13 patients. After 3 years, height SDS had improved significantly (p <0.05) to -1.8 (10-90th percentiles, -2.1 to -1.1) in the seven patients. No adverse events were noted. Although final height data for these patients are still awaited, the present results support the use of GH to promote growth in children with Aarskog syndrome.

The KIGS experience with the addition of gonadotropin-releasing hormone agonists to growth hormone (GH) treatment of children with idiopathic GH deficiency.

Although recombinant techniques have enabled the production of limitless amounts of human growth hormone (GH), and clinical methods for diagnosis and treatment have been greatly enhanced, the mean final heights of children with idiopathic GH deficiency (IGHD) treated with GH remain in the range of -1.3 standard deviation scores (SDS) below normal height. One of the methods used to increase height outcomes is to delay the onset and progression of puberty to allow for a longer 'pre-pubertal' growth phase. We reviewed the KIGS (Pharmacia International Growth Database) data of patients with IGHD who had been treated with gonadotropin-releasing hormone agonists (GnRHa) in order to see if a greater gain in height could be achieved by altering the tempo of pubertal maturation. Near-final height data were analysed in 39 adolescents (out of a total of 249) who had received GH + GnRHa therapy and were compared with similar data from 1,893 patients with IGHD treated with GH alone. The total change in height SDS in boys who received GH alone was +1.6, in contrast to +1.1 in GH + GnRHa-treated boys; the total change in height SDS in girls who received GH alone was +1.4 in contrast to +1.1 in girls treated with GH + GnRHa. The near final height SDS in girls treated with GH + GnRHa was 1.0 below the mid-parental target height (MPH), whereas there was only a -0.5 SDS difference in girls treated with GH. Approximation to the MPH did not differ in boys between the two treatment groups. These data suggest that the attainment of a substantial height SDS by manipulating the tempo of puberty is limited, but that optimizing growth during the pre-pubertal phase is a more important factor.

Combined vascular endothelial growth factor and TP53 status predicts poor response to tamoxifen therapy in estrogen receptor-positive advanced breast cancer.

PURPOSE: In recent studies, we showed that TP53 gene mutation or high levels of cytosolic vascular endothelial growth factor (VEGF) in estrogen receptor (ER)-alpha-positive primary breast tumors predict a poor disease outcome for patients treated with first-line tamoxifen for advanced disease. Mutant TP53 may up-regulate VEGF, whereas, on the other hand, wild-type TP53 may decrease VEGF production. EXPERIMENTAL DESIGN: In the present study, we aimed to assess the combined predictive value of TP53 gene mutation and VEGF status of 160 advanced breast cancer patients with ER-positive tumors who were treated with tamoxifen (median follow-up from start of tamoxifen treatment, 64 months). To assess TP53 gene mutation status, the entire open reading frame was sequenced; for VEGF status, an ELISA was used. RESULTS: In univariate analysis, both TP53 gene mutation (28% of the tumors) and a VEGF level above the median value were significantly associated with a short progression-free survival, post-relapse overall survival, and a poor rate of response to tamoxifen. In Cox multivariate regression analysis including the traditional predictive factors, the addition of TP53 gene mutation and VEGF status, alone or in combination, significantly predicted a poor efficacy of tamoxifen treatment. When the two factors were combined, a significantly decreased odds ratio was seen for the rate of response (odds ratio, 0.27). Similarly, an increased hazard ratio (HR) was seen for progression-free survival (HR, 2.32) and post-relapse overall survival (HR, 1.68) in the group with mutant TP53 and high VEGF compared with the group with both risk factors absent. CONCLUSIONS: Combined TP53 gene mutation status and high VEGF levels of ER-positive primary breast tumors independently predict a poor course of the disease of patients with advanced breast cancer treated with tamoxifen. These patients, having unfavorable tumor characteristics, might benefit more from other types of (individualized) treatment protocols.