P Bult

Maastricht Universitair Medisch Centrum, Maestricht, Limburg, Netherlands

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Publications (59)278.58 Total impact

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    ABSTRACT: The distinction between primary gastric adenocarcinoma and gastric metastatic breast carcinoma can be difficult. Expression of hepatocyte nuclear factor 4A (HNF4A) has been described as being specific to distinguish between neoplastic gastric and breast epithelial cells. The aim of this study was to validate the use of HNF4A with immunohistochemistry in discriminating gastric from breast carcinomas. Immunohistochemical expressions of HNF4A, estrogen receptor (ER), progesterone receptor (PR), and BRST-2 were determined in primary sporadic gastric adenocarcinomas (n = 107) and breast carcinomas (n = 105). The same markers and clinicopathological features were studied in 1 patient with breast metastasis of gastric cancer, 6 patients with gastric metastases of breast cancer, and 13 patients with both primary gastric and breast carcinomas. HNF4A expression was seen in 106 of 107 primary gastric adenocarcinomas and was absent in all 105 primary breast carcinomas (sensitivity 99 %, specificity 100 %). ER, PR, and BRST-2 were 100 % specific for breast carcinomas with sensitivities of 77, 58, and 38 %, respectively. The metastasis of gastric carcinoma to the breast showed strong expression of HNF4A. None of the metastases of breast carcinomas to the stomach showed expression of HNF4A. Tissues of patients with two primary carcinomas showed strong expression of HNF4A in all gastric carcinomas and no expression in breast carcinomas. Our results indicate that HNF4A is a very good marker to discriminate between primary and metastatic gastric and breast carcinomas.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2014; · 2.68 Impact Factor
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    ABSTRACT: Non-SN prediction models are frequently used in clinical decision making to identify patients that may not need axillary treatment, but these models still need to be validated by follow-up data. Our purpose was the validation of non-sentinel node (SN) prediction models in predicting regional recurrences in patients without axillary treatment. We followed a cohort of 486 women with favorable primary tumor characteristics and pN0(i+)(sn) or pN1mi(sn) for median 4.5 years. None of the patients underwent axillary treatment. Based on four published non-SN prediction models, the threshold allowing separation into low versus high-risk on non-SN involvement was set at 10%. Overall 5-year regional recurrence rate was 3.0% (SE, ±0.1%). Using the Tenon scoring system, 438 low-risk patients had a 5-year regional recurrence rate of 2.3% (±0.8%), and 48 high-risk patients a recurrence rate of 10.1% (±0.4%). The MSKCC nomogram identified 300 low-risk patients with a recurrence rate of 2.8% (±1.1%), versus 166 high-risk patients with a rate of 3.4% (±0.5%) (20 patients not assessable). The Stanford nomogram identified 21 high-risk patients without recurrence, and 465 low-risk patients with a 3.2% (±0.9%) recurrence rate. A Dutch model discriminated between 384 low-risk patients with a recurrence rate of 2.2% (±0.8%) and 102 high-risk patients with a rate of 6.3% (±2.9%). The Tenon scoring system outperformed the other models as it identified the largest subgroup of patients with low recurrence rate. In patients resembling our cohort we would recommend axillary treatment if they had a Tenon score above 3.5.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 10/2013; · 2.56 Impact Factor
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    ABSTRACT: Yes Associated Protein (YAP) has been implicated in the control of organ size by regulating cell proliferation and survival. YAP is a transcriptional coactivator that controls cellular responses through interaction with TEAD transcription factors in the nucleus, while its transcriptional functions are inhibited by phosphorylation-dependent translocation to the cytosol. YAP overexpression has been associated with different types of cancer, such as lung, skin, prostate, ovary and liver cancer. Recently, YAP was linked to E-cadherin-dependent regulation of contact inhibition in breast cancer cells. In this study we examined YAP protein expression and cellular localization in 237 cases of human invasive breast cancer by immunohistochemistry and related its expression to clinicopathological features and E-cadherin expression. We observed that invasive lobular carcinoma is characterized by higher expression levels of both nuclear and cytosolic YAP (p < 0.001). Nuclear YAP expression did not associate with other variables such as lymph node involvement, tumor grade, tumor size, mitotic activity or the molecular sub-types of invasive breast cancer. We observed that high nuclear and cytosolic YAP expression are associated with the E-cadherin deficient breast cancer subtype ILC (p < 0.001) and cell lines derived from human breast cancers and conditional mouse models of human lobular breast cancer. Since our data indicate that nuclear YAP localization is more common in breast cancers lacking functional adherens junctions, it suggests that YAP-mediated transcription may be involved in the development and progression of invasive lobular breast cancer.
    Cellular oncology (Dordrecht). 08/2013;
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    ABSTRACT: OBJECTIVE: To assess the value of breast MRI in size assessment of breast cancers in high risk patients, including those with a BRCA 1 or 2 mutation. Guidelines recommend invariably breast MRI screening for these patients and therapy is thus based on these findings. However, the accuracy of breast MRI for staging purposes is only tested in sporadic cancers. METHODS: We assessed concordance of radiologic staging using MRI with histopathology in 49 tumors in 46 high risk patients (23 BRCA1, 12 BRCA2 and 11 Non-BRCA patients). The size of the total tumor area (TTA) was compared to pathology. In invasive carcinomas (n=45) the size of the largest focus (LF) was also addressed. RESULTS: Correlation of MRI measurements with pathology was 0.862 for TTA and 0.793 for LF. TTA was underestimated in 8(16%), overestimated in 5(10%), and correctly measured in 36(73%) cases. LF was underestimated in 4(9%), overestimated in 5(11%), and correctly measured in 36(80%) cases. Impact of BRCA 1 or 2 mutations on the quality of size estimation was not observed. CONCLUSIONS: Tumor size estimation using breast MRI in high risk patients is comparable to its performance in sporadic cancers. Therefore, breast MRI can safely be used for treatment planning.
    European journal of radiology 04/2013; · 2.65 Impact Factor
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    ABSTRACT: BACKGROUND: Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN) in breast cancer patients. Previously, we reported that ultra-staging led to more axillary lymph node dissections (ALND). The question was, whether ultra-staging is effective in reducing the risk of regional relapse. METHODS: From January 2002 to July 2003, 541 patients from 4 hospitals were prospectively registered when they underwent a SN biopsy. In hospitals A, B, and C, 3 levels of the SN were examined pathologically, whereas in hospital D at least 7 additional levels were examined. Patients with a positive SN, including isolated tumor cells, underwent an ALND. This analysis focuses on the 341 patients with a negative SN. Primary endpoint was 5-year regional recurrence rate. RESULTS: In hospital D 34% of the patients had a negative SN as compared to 71% in hospitals A, B, and C combined (p < 0.001). At 5 years follow-up, 9 (2.6%) patients had developed a regional lymph node relapse. In hospital D none of the patients had a regional recurrence, as compared to 9 (2.9%) cases of recurrence in hospitals A, B, and C. CONCLUSION: The less intensified SN pathology protocol appeared to be associated with a slightly increased risk of regional recurrence. The absolute risk was still less than 3%, and does not seem to justify the intensified SN pathology protocol of hospital D.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 02/2013; · 2.56 Impact Factor
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    ABSTRACT: No published data concerning intraobserver and interobserver variability in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia (DVIN) are available, although it is widely accepted to be a subtle and difficult histopathological diagnosis. In this study, the reproducibility of the histopathological diagnosis of DVIN is evaluated. Furthermore, we investigated the possible improvement of the reproducibility after providing guidelines with histological characteristics and tried to identify histological characteristics that are most important in the recognition of DVIN. A total number of 34 hematoxylin and eosin-stained slides were included in this study and were analyzed by six pathologists each with a different level of education. Slides were reviewed before and after studying a guideline with histological characteristics of DVIN. Kappa statistics were used to compare the interobserver variability. Pathologists with a substantial agreement were asked to rank items by usefulness in the recognition of DVIN. The interobserver agreement during the first session varied between 0.08 and 0.54, which slightly increased during the second session toward an agreement between -0.01 and 0.75. Pathologists specialized in gynecopathology reached a substantial agreement (kappa 0.75). The top five of criteria indicated to be the most useful in the diagnosis of DVIN included: atypical mitosis in the basal layer, basal cellular atypia, dyskeratosis, prominent nucleoli and elongation and anastomosis of rete ridges. In conclusion, the histopathological diagnosis of DVIN is difficult, which is expressed by low interobserver agreement. Only in experienced pathologists with training in gynecopathology, kappa values reached a substantial agreement after providing strict guidelines. Therefore, it should be considered that specimens with an unclear diagnosis and/or clinical suspicion for DVIN should be revised by a pathologist specialized in gynecopathology. When adhering to suggested criteria the diagnosis of DVIN can be made easier.Modern Pathology advance online publication, 1 February 2013; doi:10.1038/modpathol.2012.235.
    Modern Pathology 02/2013; · 5.25 Impact Factor
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    ABSTRACT: Many attempts have been made to combine the high diagnostic accuracy and conclusive rate of core needle biopsy (CNB) with the speed of fine needle aspiration cytology in evaluation of solid breast lesions. Multiple hybrid techniques have been developed to achieve this. We describe a cohort of patients for whom we used a relatively new, accelerated method of CNB processing, allowing for a definitive diagnosis the same day. All patients visiting the Radboud University Nijmegen Medical Centre breast clinic during a 4-year period were reviewed to identify all CNBs in this period performed in a same-day diagnosis track. CNB result was compared to post-operative pathology reports when available, and to follow-up when patients were not surgically treated. 1,060 patients underwent CNB of 1,383 lesions, 898 of which in a same-day diagnosis track with a sensitivity of 96.9 % and a specificity of 99.4 %. The inconclusive rate was 9.2 %. For a same-day diagnosis for solid breast lesions, we could give a conclusive diagnosis with accelerated CNB processing in 65 % of our patients requiring CNB. This technique can be used reliably in a same-day diagnosis breast clinic with a very high sensitivity, specificity, and conclusive rate.
    Breast Cancer Research and Treatment 12/2012; · 4.47 Impact Factor
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    ABSTRACT: BACKGROUND: NOTCH signaling is involved in every step of metazoan development and maintenance of adult tissue homeostasis. It is frequently deregulated by mutations and overexpression in different cancer types including solid tumors such as breast cancer. Another common feature of solid tumors is hypoxia, which occurs due to defective or insufficient vascularization. Hypoxia-inducible factors (HIFs) are key regulators of the homeostatic response to low oxygen levels. HIF-1α is overexpressed in many solid tumors, including breast cancer. Hypoxia-induced stabilization of HIF transcription factors has been shown to lead to NOTCH activation in vitro in different contexts and tissues, causing differentiation arrest and induction of proliferation and migration. METHODS: Since the link between HIF-1α and NOTCH signalling has hardly been studied, we set out to closely investigate associations between the expression of HIF-1α and NOTCH pathway members in primary and metastatic human breast cancer specimens and their prognostic value. RESULTS: Co-expression of NOTCH1 intracellular domain (N1ICD) and HIF-1α was associated with a high grade and a high proliferation rate in invasive breast cancer. HIF-1α expression was low in classic, but high in pleomorphic lobular cancers, which also frequently showed stromal HIF-1α expression. NOTCH1 pathway activation was prognostically unfavorable. CONCLUSION: In breast cancer, NOTCH pathway activation appears to be associated with a poor prognosis, but NOTCH and HIF signaling do not seem to be functionally associated.
    Cellular oncology (Dordrecht). 09/2012;
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    ABSTRACT: Poly(ADP-ribose) polymerase 1 (PARP) is a key element of the single-base excision pathway for repair of DNA single-strand breaks. To compare the cytoplasmic and nuclear poly(ADP-ribose) expression between familial (BRCA1, BRCA2, or non BRCA1/2) and sporadic breast cancer, we investigated 39 sporadic and 39 familial breast cancer cases. The two groups were matched for hormone receptor status and human epidermal growth factor receptor 2 status. Additionally, they were matched by grading with a maximum difference of ±1 degree (e.g., G2 instead of G3). Cytoplasmic PARP (cPARP) expression was significantly higher in familial compared to sporadic breast cancer (P = 0.008, chi-squared test for trends) and a high nuclear PARP expression (nPARP) was significantly more frequently observed in familial breast cancer (64 %) compared with sporadic breast cancer (36 %) (P = 0.005, chi-squared test). The overall PARP expression was significantly higher in familial breast cancer (P = 0.042, chi-squared test). In familial breast cancer, a combination of high cPARP and high nPARP expression is the most common (33 %), whereas in sporadic breast cancer, a combination of low cPARP and intermediate nPARP expression is the most common (39 %). Our results show that the overall PARP expression in familial breast cancer is higher than in sporadic breast cancer which might suggest they might respond better to treatment with PARP inhibitors.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 09/2012; 461(4):425-31. · 2.68 Impact Factor
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    ABSTRACT: TRPM7 encodes a Ca2+-permeable nonselective cation channel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer progression has not been established. Here we report that high levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that it is functionally required for metastasis formation in a mouse xenograft model of human breast cancer. Mechanistic investigation revealed that TRPM7 regulated myosin II-based cellular tension, thereby modifying focal adhesion number, cell-cell adhesion and polarized cell movement. Our findings therefore suggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasis formation.
    Cancer Research 08/2012; 72(16):4250-61. · 8.65 Impact Factor
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    ABSTRACT: Mammographic population screening in The Netherlands has increased the number of breast cancer patients with small and non-palpable breast tumors. Nevertheless, mammography is not ultimately sensitive and specific for distinct subtypes. Molecular imaging with targeted tracers might increase specificity and sensitivity of detection. Because development of new tracers is labor-intensive and costly, we searched for the smallest panel of tumor membrane markers that would allow detection of the wide spectrum of invasive breast cancers. Tissue microarrays containing 483 invasive breast cancers were stained by immunohistochemistry for a selected set of membrane proteins known to be expressed in breast cancer. The combination of highly tumor-specific markers glucose transporter 1 (GLUT1), epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF1-R), human epidermal growth factor receptor 2 (HER2), hepatocyte growth factor receptor (MET), and carbonic anhydrase 9 (CAIX) 'detected' 45.5% of tumors, especially basal/triple negative and HER2-driven ductal cancers. Addition of markers with a 2-fold tumor-to-normal ratio increased the detection rate to 98%. Including only markers with >3 fold tumor-to-normal ratio (CD44v6) resulted in an 80% detection rate. The detection rate of the panel containing both tumor-specific and less tumor-specific markers was not dependent on age, tumor grade, tumor size, or lymph node status. In search of the minimal panel of targeted probes needed for the highest possible detection rate, we showed that 80% of all breast cancers express at least one of a panel of membrane markers (CD44v6, GLUT1, EGFR, HER2, and IGF1-R) that may therefore be suitable for molecular imaging strategies. This study thereby serves as a starting point for further development of a set of antibody-based optical tracers with a high breast cancer detection rate.
    BMC Cancer 06/2012; 12:240. · 3.33 Impact Factor
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    ABSTRACT: Background In the MIRROR study, pN0(i + ) and pN1mi were associated with reduced 5-year disease-free survival (DFS) compared with pN0. Nodal status (N-status) was assessed after central pathology review and restaging according to the sixth AJCC classification. We addressed the impact of pathology review. Patients and methods Early favorable primary breast cancer patients, classified pN0, pN0(i + ), or pN1(mi) by local pathologists after sentinel node procedure, were included. We assessed the impact of pathology review on N-status (n = 2842) and 5-year DFS for those without adjuvant therapy (n = 1712). Results In all, 22% of the 1082 original pN0 patients was upstaged. Of the 623 original pN0(i + ) patients, 1% was downstaged, 26% was upstaged. Of 1137 patients staged pN1mi, 15% was downstaged, 11% upstaged. Originally, 5-year DFS was 85% for pN0, 74% for pN0(i + ), and 73% for pN1mi; HR 1.70 [95% confidence interval (CI) 1.27-2.27] and HR 1.57 (95% CI 1.16-2.13), respectively, compared with pN0. By review staging, 5-year DFS was 86% for pN0, 77% for pN0(i + ), 77% for pN1mi, and 74% for pN1 + . Conclusion Pathology review changed the N-classification in 24%, mainly upstaging, with potentially clinical relevance for individual patients. The association of isolated tumor cells and micrometastases with outcome remained unchanged. Quality control should include nodal breast cancer staging.
    Annals of Oncology 04/2012; 23(10):2561-6. · 7.38 Impact Factor
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    ABSTRACT: Background The cost-effectiveness of adjuvant systemic therapy in patients with low-risk breast cancer and nodal isolated tumor cells or micrometastases is unknown. Patients and methods A cost-effectiveness analysis of adjuvant systemic therapy was carried out using the costs per 1% event prevented after 5 years of follow-up as incremental cost-effectiveness ratio (ICER). Secondary objective was to establish when adjuvant systemic therapy becomes cost saving. Patients included in the MIRROR study with isolated tumor cells or micrometastases who had a complete 5-year follow-up and who either did or did not receive systemic therapy were eligible. Sensitivity analyses were carried out. Results In the no adjuvant therapy cohort (N = 366), 24.9% of patients had an event within 5 years versus 16.8% of patients in the adjuvant therapy cohort (N = 483) (P < 0.01). The ICER was €363 per 1% event prevented. Beyond 18 years after diagnosis, the extrapolated mean cumulative costs per patient in the no adjuvant therapy cohort exceeded those of the adjuvant therapy cohort. Conclusions In this population of breast cancer patients with isolated tumor cells or micrometastases, €36 300 had to be invested to prevent one event in 5 years of follow-up. Adjuvant systemic therapy was cost saving beyond 18 years after diagnosis.
    Annals of Oncology 03/2012; 23(10):2585-91. · 7.38 Impact Factor
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    ABSTRACT: p53 is a tumor suppressor that is frequently mutated in human cancers. Although alterations in p53 are common in breast cancer, few studies have specifically investigated TP53 mutations in the breast cancer subtype invasive lobular carcinoma (ILC). Recently reported conditional mouse models have indicated that functional p53 inactivation may play a role in ILC development and progression. Since reports on the detection of TP53 mutations in the relatively favorable classic and more aggressive pleomorphic variants of ILC (PILC) are rare and ambiguous, we performed a comprehensive analysis to determine the mutation status of TP53 in these breast cancer subtypes. To increase our understanding of p53-mediated pathways and the roles they may play in the etiology of classic ILC and PILC, we investigated TP53 mutations and p53 accumulation in a cohort of 22 cases of classic and 19 cases of PILC by direct DNA sequencing and immunohistochemistry. We observed 11 potentially pathogenic TP53 mutations, of which three were detected in classic ILC (13.6%) and 8 in PILC (42.1%; p = 0.04). While p53 protein accumulation was not significantly different between classic and pleomorphic ILC, mutations that affected structure and protein function were significantly associated with p53 protein levels. TP53 mutations occur more frequently in PILC than classic ILC.
    Cellular oncology (Dordrecht). 02/2012; 35(2):111-8.
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    ABSTRACT: The impact of axillary treatment in daily practice on 5-year regional recurrence rate in breast cancer patients with isolated tumor cells or micrometastases in the sentinel node (SLN). Axillary dissection is recommended in patients with tumor-positive SLNs. But, in recent studies, regional recurrence rates seemed low if dissection was omitted. We identified all patients in The Netherlands with invasive breast cancer who had an SLN biopsy before 2006, favorable primary tumor characteristics, and node-negative disease, isolated tumor cells or micrometastases as final nodal status. The primary endpoint was regional recurrence rate. To investigate differences in recurrence rates between patients with and without axillary treatment, a proportional hazard regression was carried out correcting for potential confounders. In total, 857 patients with node-negative disease, 795 patients with isolated tumor cells, and 1028 patients with micrometastases in the SLN were included. Without axillary treatment, the 5-year regional recurrence rates were 2.3%, 2.0%, and 5.6%, respectively. Compared with patients who underwent axillary treatment, the adjusted hazard ratio for regional recurrence in patients who underwent an SLN procedure only was 1.08 (95% CI, 0.23-4.98) for node-negative disease, 2.39 (95% CI, 0.67-8.48) for isolated tumor cells, and 4.39 (95% CI, 1.46-13.24) for micrometastases. Doubling of tumor size, grade 3 and negative hormone receptor status were also significantly associated with recurrence. Not performing axillary treatment in patients with SLN micrometastases is associated with an increased 5-year regional recurrence rate. Axillary treatment is recommended in patients with SLN micrometastases and unfavorable tumor characteristics.
    Annals of surgery 01/2012; 255(1):116-21. · 7.90 Impact Factor
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    ABSTRACT: Kaiso is a BTB/POZ transcription factor that is ubiquitously expressed in multiple cell types and functions as a transcriptional repressor and activator. Little is known about Kaiso expression and localization in breast cancer. Here, we have related pathological features and molecular subtypes to Kaiso expression in 477 cases of human invasive breast cancer. Nuclear Kaiso was predominantly found in invasive ductal carcinoma (IDC) (p = 0.007), while cytoplasmic Kaiso expression was linked to invasive lobular carcinoma (ILC) (p = 0.006). Although cytoplasmic Kaiso did not correlate to clinicopathological features, we found a significant correlation between nuclear Kaiso, high histological grade (p = 0.023), ERα negativity (p = 0.001), and the HER2-driven and basal/triple-negative breast cancers (p = 0.018). Interestingly, nuclear Kaiso was also abundant in BRCA1-associated breast cancer (p<0.001) and invasive breast cancer overexpressing EGFR (p = 0.019). We observed a correlation between nuclear Kaiso and membrane-localized E-cadherin and p120-catenin (p120) (p<0.01). In contrast, cytoplasmic p120 strongly correlated with loss of E-cadherin and low nuclear Kaiso (p = 0.005). We could confirm these findings in human ILC cells and cell lines derived from conditional mouse models of ILC. Moreover, we present functional data that substantiate a mechanism whereby E-cadherin controls p120-mediated relief of Kaiso-dependent gene repression. In conclusion, our data indicate that nuclear Kaiso is common in clinically aggressive ductal breast cancer, while cytoplasmic Kaiso and a p120-mediated relief of Kaiso-dependent transcriptional repression characterize ILC.
    PLoS ONE 01/2012; 7(5):e37864. · 3.73 Impact Factor
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    ABSTRACT: In breast cancer, it has been shown that pN0(i+) and pN1mi have a comparable negative impact on disease-free survival, compared with pN0. However, pN0(i+) is considered to be a heterogeneous group. We determined the effect of metastatic size and microanatomic location within the pN0(i+) group on breast cancer recurrence. We included all Dutch breast cancer patients diagnosed in 1998-2005 with favorable primary tumor characteristics and a final nodal status of pN0(i+). For this analysis, only patients without adjuvant systemic therapy were eligible (n = 513). Presence of single tumor cells versus cell clusters, metastatic size and microanatomic location were recorded. Primary endpoint was disease-free survival. Analyses were adjusted for age at diagnosis, tumor size, tumor grade, axillary treatment and hormone receptor status. The 5-year disease-free survival of patients with single tumor cell(s) (n = 93) was 78.6% and with tumor cell cluster(s) (n = 404) 77.1%. The hazard ratio for disease events was 1.05 (95% CI 0.63-1.76) for cell cluster(s) compared with single cell(s). In a Cox regression model, doubling of metastatic tumor size corresponded to a hazard ratio of 1.21 (95% CI 1.02-1.43). The adjusted hazard ratio was 0.90 (95% CI 0.54-1.50) for parenchymal (n = 112) versus sinusoidal location (n = 395). Single tumor cells bear similar prognostic information as small tumor cell clusters, even though results do suggest that within the pN0(i+) group, increasing size of nodal involvement is associated with reduced survival. Microanatomic location does not seem to have prognostic relevance.
    Breast Cancer Research and Treatment 09/2011; 131(2):645-51. · 4.47 Impact Factor
  • Acta oncologica (Stockholm, Sweden) 04/2011; 50(3):462-5. · 2.27 Impact Factor
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    ABSTRACT: The Immunodeficiency, Centromeric region instability, and Facial anomalies (ICF) syndrome (OMIM #242860) is a rare autosomal recessive disorder caused by defective DNA methylation. Hematological disease and malignancy (macrophage activation syndrome, myelodysplastic syndrome, and Hodgkin lymphoma) have been reported in three patients. To date, there have been no reports of either epithelial or mesenchymal malignancies. We present a patient with all clinical and laboratory findings of the ICF syndrome who died of a metastatic angiosarcoma of the liver. This is the first report of a non-hematological malignancy in the ICF syndrome. The young age at which our patient developed an angiosarcoma suggests an effect of the defective DNA methylation observed in the ICF syndrome. Therefore, with improvement of recognition and treatment of the ICF syndrome, malignancy could become more common in this condition.
    American Journal of Medical Genetics Part A 02/2011; 155A(3):622-5. · 2.30 Impact Factor
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    ABSTRACT: The prognostic relevance of isolated tumor cells and micrometastases in lymph nodes from patients with breast cancer has become a major issue since the introduction of the sentinel lymph node procedure. We conducted a systematic review of this issue. Studies published from January 1, 1977, until August 11, 2008, were identified by use of MEDLINE, EMBASE, and the Cochrane Library. A total of 58 studies (total number of patients = 297,533) were included and divided into three categories according to the method for pathological assessment of the lymph nodes: cohort studies with single-section pathological examination of axillary lymph nodes (n = 285,638 patients), occult metastases studies with retrospective examination of negative lymph nodes by step sectioning and/or immunohistochemistry (n = 7740 patients), and sentinel lymph node biopsy studies with intensified work-up of the sentinel but not of the nonsentinel lymph nodes (n = 4155 patients). We used random-effects meta-analyses to calculate pooled estimates of the relative risks (RRs) of 5- and 10-year disease recurrence and death and the multivariably corrected pooled hazard ratio (HR) of overall survival of the cohort studies. In the cohort studies, the presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes was associated with poorer overall survival (pooled HR of death = 1.44, 95% confidence interval [CI] = 1.29 to 1.62). In the occult metastases studies, the presence (vs the absence) of occult metastases was associated with poorer 5-year disease-free survival (pooled RR = 1.55, 95% CI = 1.32 to 1.82) and overall survival (pooled RR = 1.45, 95% CI = 1.11 to 1.88), although these endpoints were not consistently assessed in multivariable analyses. Sentinel lymph node biopsy studies were limited by small patient groups and short follow-up. The presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes detected on single-section examination was associated with poorer disease-free and overall survival.
    CancerSpectrum Knowledge Environment 02/2010; 102(6):410-25. · 14.07 Impact Factor

Publication Stats

1k Citations
278.58 Total Impact Points


  • 2009–2013
    • Maastricht Universitair Medisch Centrum
      Maestricht, Limburg, Netherlands
  • 2008–2013
    • University Medical Center Utrecht
      • Department of Pathology
      Utrecht, Provincie Utrecht, Netherlands
  • 2003–2013
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
    • IJsselland Ziekenhuis
      Kapelle, South Holland, Netherlands
  • 2010–2012
    • Maastricht University
      • • Interne Geneeskunde
      • • GROW School for Oncology & Developmental Biology
      Maastricht, Provincie Limburg, Netherlands
  • 2000–2009
    • Radboud University Nijmegen
      • • Department of Surgical Oncology
      • • Department of Surgery
      • • Department of Pathology
      Nijmegen, Provincie Gelderland, Netherlands