Showing papers by "Paul J. van Diest published in 2009"
TL;DR: Isolated tumor cells or micrometastases in regional lymph nodes were associated with a reduced 5-year rate of disease-free survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy.
Abstract: We identified 856 patients with node-negative disease who had not received systemic adjuvant therapy (the node-negative, no-adjuvant-therapy cohort), 856 patients with isolated tumor cells or micrometastases who had not received systemic adjuvant therapy (the node-positive, no-adjuvant-therapy cohort), and 995 patients with isolated tumor cells or micrometastases who had received such treatment (the nodepositive, adjuvant-therapy cohort). The median follow-up was 5.1 years. The adjusted hazard ratio for disease events among patients with isolated tumor cells who did not receive systemic therapy, as compared with women with node-negative disease, was 1.50 (95% confidence interval [CI], 1.15 to 1.94); among patients with micrometastases, the adjusted hazard ratio was 1.56 (95% CI, 1.15 to 2.13). Among patients with isolated tumor cells or micrometastases, the adjusted hazard ratio was 0.57 (95% CI, 0.45 to 0.73) in the node-positive, adjuvant-therapy cohort, as compared with the node-positive, no-adjuvant-therapy cohort. Conclusions Isolated tumor cells or micrometastases in regional lymph nodes were associated with a reduced 5-year rate of disease-free survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy. In patients with isolated tumor cells or micrometastases who received adjuvant therapy, disease-free survival was improved.
470 citations
TL;DR: The results indicate that genital HPV infections are age‐dependent and suggest that HPV infections at young age can be transient, and the implications of these findings in the context of cervical cancer screening are discussed.
Abstract: The prevalence of human papillomavirus (HPV) genotypes in relation to age was investigated by the polymerase chain reaction (PCR) method in cytologically normal smears from 4 different groups of women. Group A consisted of young women from a district population, aged 15-34 years, using oral contraceptives and visiting general practitioners for a check-up (n = 156); group B were asymptomatic women, aged 35-55, in a district population participating in a triennial screening program for cervical cancer (n = 1555); group C and D consisted of women, seen at the gynecological outpatient department for a wide spectrum of gynecological complaints or for control of their hormonal contraception, aged 15-34 years (n = 2320), and aged 35-55 years (n = 1826) respectively. An HPV (all types) prevalence of 14.1%, 4.1%, 13.9% and 6.6% and an HPV 16/18 prevalence of 3.8%, 0.9%, 3.3% and 1.5% were found in groups A, B, C and D respectively. Statistically significant differences (p value < 0.001) in HPV prevalence were found between women aged 15-34 years and women aged 35-55 years in the district population and in the hospital population. No statistically significant differences in HPV 16/18 were observed after age-matching between women in corresponding age-classes of both populations. In a 5-year interval analysis a strong age-dependent relationship was demonstrated, with a maximum between 20 and 24 years. After the age of 35 a constant level of 1-2% HPV 16/18 was observed. These results indicate that genital HPV infections are age-dependent and suggest that HPV infections at young age can be transient. The implications of these findings in the context of cervical cancer screening are discussed.
287 citations
TL;DR: It is shown that the ADAM10 metalloprotease Kuzbanian, but not ADAM17/tumor necrosis factor α-converting enzyme, plays an essential role in executing ligand-induced extracellular cleavage at site 2 (S2) in cells and localizes this step to the plasma membrane.
262 citations
TL;DR: There is a potential role for SN biopsy following NAC, however, there is insufficient evidence to recommend this as a standard procedure and further research with subgroup analysis using variables reported to be associated with decreased SN accuracy is required.
169 citations
TL;DR: An accurate tissue processing and registration method was presented, which enables the validation of MR based tumor delineations with pathology, which yielded a tumor coverage of 85-100% in all patients.
112 citations
TL;DR: It is concluded that RFA stimulates the outgrowth of tumor cells at the lesion periphery, which is not the driving force behind RFA-stimulated tumor growth, but other hypoxia/HIF-activated pathways are likely to be important.
Abstract: Objective:The aim of this study was to assess how thermal ablation of colorectal liver metastases affects the outgrowth of micrometastases in the transition zone (TZ) between ablated tissue and the unaffected reference zone (RZ) in 2 different murine models.Background:Thermal destruction therapies o
90 citations
TL;DR: This review attempts to highlight the opportunities that exist in this field and the technologies that are now available to support this type of research.
Abstract: Reliable pathological interpretation is vital to so many aspects of tissue-based research as well as being central to patient care. Understanding the complex processes involved in decision-making is the starting point to improve both diagnostic reproducibility and the definition of diagnostic groups that underpin our experiments. Unfortunately, there is a paucity of research in this field and it is encouraging to see The Journal of Pathology publishing work in this area. This review attempts to highlight the opportunities that exist in this field and the technologies that are now available to support this type of research. Key amongst these are the use of decision analysis tools such as inference networks, and virtual microscopy that allows us to simulate diagnostic decision-making. These tools have roles, not only in studying the subtleties of diagnostic decision-making, but also in delivering new methods of training and proficiency testing. Research which helps us to better understand what we see, why we see it, and standardizing interpretative reasoning in pathological classification is essential for improving the wide range of activities that pathologists support, including clinical diagnosis, teaching, training, and experimental research.
59 citations
TL;DR: MRP2 and RB were found to be associated with outcome in patients treated with concurrent chemoradiation, and the prognostic value of biomarkers for the outcome is described.
Abstract: Not all patients with squamous cell carcinomas of the head and neck (HNSCC) benefit from concurrent cisplatin-based chemoradiation, but reliable predictive markers for outcome after chemoradiation are scarce. We have investigated potential prognostic biomarkers for outcome in a large group of patients. Ninety-one tumor biopsies taken from consecutive HNSCC patients were evaluated for protein expression on a tissue microarray. Using immunohistochemistry, 18 biomarkers, involved in various cellular pathways were investigated. Univariable and multivariable proportional hazard analyses were performed to investigate associations between each individual marker and outcome. In addition, the global test was used to test all variables simultaneously and selected combinations of markers for an overall association with local control. Univariable analysis showed statistically significant increased relative risks of RB, P16 and MRP2 for local control and MDR1 and HIF-1alpha for overall survival. MRP2, MDR1 and P16 levels were positively associated with outcome whereas RB and HIF-1alpha had a negative relationship. Using Goeman's global testing no combination of markers was identified that was associated with local control. Grouping the markers according to their function revealed an association between a combination of 3 markers (P16, P21 and P27) and outcome (p = 0.05) was found. In the multivariable analysis, MRP2 and RB remained significant independent predictive markers for local control. This study describes the prognostic value of biomarkers for the outcome in patients uniformly treated with concurrent chemoradiation. MRP2 and RB were found to be associated with outcome in patients treated with concurrent chemoradiation.
57 citations
TL;DR: This study validated a new PCR based test, called Multiplex Ligation-dependent Probe Amplification (MLPA), as a simple and quick method to assess HER-2/neu gene amplification status in invasive breast cancer, and thereby a reliable alternative to FISH and CISH.
Abstract: Background: Assessment of HER-2/neu status in invasive breast cancer is crucial to establish eligibility for trastuzumab and taxane based chemotherapy. Next to immunohistochemistry (IHC) to evaluate protein overexpression, a second line gene amplification test is required for cases with equivocal protein expression. This study aimed to validate a new PCR based test, called Multiplex Ligation-dependent Probe Amplification (MLPA), as a simple and quick method to assess HER-2/neu gene amplification status in invasive breast cancer.
54 citations
TL;DR: In this paper, the authors characterized the mechanism by which COMMD1 regulates HIF-1 alpha protein degradation independent of ubiquitin and pVHL and showed that COMMD-1 competes with the chaperone heat shock protein HSP90b for binding to the NH2-terminal DNA-binding and heterodimerization domain of HIF1 alpha to regulate alpha stability together with HSP70.
Abstract: Background: The Copper Metabolism MURR1 Domain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-kappa B signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for Commd1 have increased expression of hypoxia/HIF-regulated genes i.e. VEGF, PGK and Bnip3. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell survival/proliferation under normal and pathologic conditions. Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL. Principal Findings: Here we characterized the mechanism by which COMMD1 regulates HIF-1 alpha protein degradation. We show that COMMD1 competes with the chaperone heat shock protein HSP90b for binding to the NH2-terminal DNA-binding and heterodimerization domain of HIF-1 alpha to regulate HIF-1 alpha stability together with HSP70. Inhibition of HSP90 activity with 17-Allylamino-17-demethoxygeldanamycin (17-AAG) increased COMMD1-mediated HIF-1 alpha degradation independent of ubiquitin and pVHL. Conclusion/Significance: These data reveal a novel role for COMMD1 in conjunction with HSP90 beta/HSP70 in the ubiquitin and O-2-independent regulation of HIF-1 alpha.
49 citations
TL;DR: BNIP3 expression is lost in a significant portion of invasive breast cancers, which is correlated with poor prognostic features such as positive lymph node status and high proliferation, but not with the hypoxic response.
Abstract: Background
Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is a pro-apoptotic member of the Bcl-2 family induced under hypoxia. Low or absent expression has recently been described in human tumors, including gastrointestinal tumors, resulting in poor prognosis. Little is known about BNIP3 expression in invasive breast cancer. The aim of the present study was to investigate the expression of BNIP3 in invasive breast cancer at the mRNA and protein level in correlation with the hypoxic response and clinicopathological features.
TL;DR: Manual and laser microdissection similarly increase the dynamic range of MLPA copy number ratios which is a technical advantage, and may be advisable in case of very low tumor content, when MLPA results are equivocal, or when extensive ductal carcinoma in situ is present.
Abstract: Background
Accurate assessment of HER-2/neu status is crucial for proper prognostic information and to offer direct appropriate treatment for breast cancer patients. Next to immunohistochemistry (IHC) to evaluate HER2 protein overexpression, a second line gene amplification test is generally deemed necessary for cases with equivocal protein expression. Recently, a new PCR based test, called Multiplex Ligation-dependent Probe Amplification (MLPA), was introduced as a simple and quick method to assess HER-2/neu gene amplification status in invasive breast cancer. MLPA was previously shown to correlate well with IHC and in situ hybridization (ISH), but a low tumor percentage in the tissue tested could negatively affect the accuracy of MLPA results.
TL;DR: This study confirms the upregulation of proteins involved in the HIF-1α hypoxia pathway in prostate cancer cells, indicative of a hypoxic tumor state, and identifies 2 novel markers, GLUT1 and prolyl-4-hydroxylases 1, with prognostic significance for patients undergoing radical prostatectomy.
TL;DR: Whereas most PT showed chromosomal instability, fibroadenomas lacked copy number changes, and some copy number aberrations had not previously been associated with PT, genomic instability may be an early event in PT genesis.
Abstract: Breast phyllodes tumour (PT) is a rare fibroepithelial tumour. The genetic alterations contributing to its tumorigenesis are largely unknown. To identify genomic regions involved in pathogenesis and progression of PTs we obtained genome-wide copy number profiles by array comparative genomic hybridization (CGH).DNA was isolated from fresh-frozen tissue samples. 11 PTs and 3 fibroadenomas, a frequently occurring fibroepithelial breast tumour, were analyzed. Arrays composed of 2464 genomic clones were used, providing a resolution of ~1.4 Mb across the genome. Each clone contains at least one STS for linkage to the human genome sequence.No copy number changes were detected in fibroadenomas. On the other hand, 10 of 11 PT (91%) showed DNA copy number alterations. The mean number of chromosomal events in PT was 5.5 (range 0-16) per case. A mean of 2.0 gains (range 0-10) and 3.0 losses (range 0-9) was seen per case of PT. Three cases showed amplifications. DNA copy number change was not related to PT grade. We observed recurrent loss on chromosome 1q, 4p, 10, 13q, 15q, 16, 17p, 19 and X. Recurrent copy number gain was seen on 1q, 2p, 3q, 7p, 8q, 16q, 20.In this study we used array CGH for genomic profiling of fibroepithelial breast tumours. Whereas most PT showed chromosomal instability, fibroadenomas lacked copy number changes. Some copy number aberrations had not previously been associated with PT. Several well-known cancer related genes, such as TP53 and members of the Cadherin, reside within the recurrent regions of copy number alteration. Since copy number change was found in all benign PT, genomic instability may be an early event in PT genesis.
TL;DR: In this paper, a reverse proteomic approach was used to identify the cognate proteins recognized by enriched VHH on HeLa cells and one of these VHH bound the integrin α3β1 (VLA-3) and was further characterized.
TL;DR: The previously claimed prognostic power of DNA ploidy and morphometry could not be corroborated in this prospective study and can therefore not be recommended to direct clinical management in BOTs.
Abstract: To evaluate if morphometric features (mitotic activity index, volume percentage of epithelium, and DNA ploidy) are prognostic markers in borderline ovarian tumors (BOTs). Ninety-three serous and mucinous consecutive BOTs diagnosed between 1989 and 2002 were studied. In all tumors, mitotic activity index, volume percentage of epithelium, and DNA ploidy were determined prospectively. Consecutively, age at diagnosis, calculated tumor volume, International Federation of Gynecology and Obstetrics (FIGO) stage, and treatment by extensive staging were evaluated after a median follow-up of 52 months. Serous BOTs presented at a younger age (P<0.05), with smaller volume (P<0.001), with higher FIGO stage (P<0.001), and were more frequently bilateral (P<0.001) than mucinous BOTs. Patients with serous BOT (P<0.05) and beyond stage Ia (P<0.01) showed worse recurrence-free survival. No prognostic significance could be established for DNA ploidy or morphometry. The previously claimed prognostic power of DNA ploidy and morphometry could not be corroborated in this prospective study and can therefore not be recommended to direct clinical management in BOTs. In contrast, histologic subtype and FIGO stage seem to be stable prognosticators in BOTs.
Abstract: Aims: To determine the incidence of activating v-raf murine sarcoma viral oncogene (BRAF) mutations in 30 serous borderline tumors (SBTs) of the ovary and the accompanying implants and to link BRAF mutation status to the clinical behavior of these tumors. Methods and Results: Serous borderline tumors and noninvasive implants of 30 patients were analyzed for the presence of the BRAF V599E mutation, and mutation status was correlated to 70 months of clinical follow-up. Mutation status could be assessed in 27 SBTs. Eleven (41%) showed a BRAF mulation. Four (80%) of 5 patients with bilateral SBT showed a BRAF mutation in both ovaries. From the 8 implants that were analyzed for BRAF, 2 (25%) were mutated together with their primary tumor. v-Raf murine sarcoma viral oncogene mutation positive SBTs tend to present with a lower International Federation of Gynecology and Obstetrics stage and a higher tumor volume and are less frequently aneuploid. Seventy months9 follow-up indicated no significant recurrence-free survival difference between these groups. Conclusions: v-Raf murine sarcoma viral oncogene mutations are common in ovarian SBT, are strongly associated with bilateral tumors, and are also found in implants. A larger number of tumors should be investigated to assess clinical importance of BRAF mutation status in SBTs.
TL;DR: Evaluation of isolated tumor cells by immunohistochemistry for proteins often overexpressed in breast cancer such as cyclin D1 and p53 supports the hypothesis that some of these cells may be displaced benign cells or concern tumor cells with limited malignant potential compared with micro- and macrometastases.
TL;DR: There are differences in the 3-D nuclear chromatin distribution between AA and CA men with similar prognosis, further evidence that the differences of prostate cancer in AA andCA men are not only related to socioeco- nomic differences, but also to genomic differences.
Abstract: Purpose: There is a significant difference in prostate cancer incidence and stage corrected mortality between African-American (AA) and Caucasian-American (CA) men. These differences have largely been contributed to social- economic factors, yet variation in prostate cancer related gene expression has been found as well. The aim of this study was to analyze whether these differences are reflected also in the 3-D distribution patterns of the nuclear chromatin. Materials and Methods: Prostatectomy sections from 21 prostate cancer patients (10 AA and 11 CA) were cut and nuclear DNA was stained with TO-PRO-3. 3-D image stacks of selected malignant areas were obtained by confocal laser scan- ning microscopy. Image analysis was performed using in-house developed software for 3-D semi-automated segmentation and computation of DNA content and our previously developed 3-D nuclear texture features. The power of these features to discriminate between AA and CA patients was established by univariate ROC and linear discriminant analyses, stratify- ing for prognosis. Results: Five 3-D texture features discriminated between AA and CA men irrespective of prognosis, 27 features had dis- criminative value for AA and CA men in the subgroup of bad prognosis patients, and 8 features in the good prognosis subgroup. Several features had additional discriminative value in multivariate discriminant analysis. Conclusions: There are differences in the 3-D nuclear chromatin distribution between AA and CA men with similar prog- nosis. This is further evidence that the differences of prostate cancer in AA and CA men are not only related to socioeco- nomic differences, but also to genomic differences.
TL;DR: SCN may, albeit very rarely, be encountered in paratesticular sites, and pathologists should be aware of this possibility when faced with unusual extratesticular tumourous lesions, especially if malignancy is considered.
Abstract: ination into tubular lumina gives a special diagnostic clue. As with testicular SCN, epididymal SCN occurred in a patient with cryptorchism. The histogenesis of this peculiar lesion, however, remains unclear. Differential diagnosis includes metastatic Sertoli cell tumour. Lack of a Sertoli cell tumour within the ipsilateral testis and the bland morphology of the epididymal lesion, however, argue against this diagnosis. In addition, primary epididymal tumours such as adenomatoid tumours and tumours of the rete testis including rete adenocarcinoma and sertoliform (clear cell papillary) cystadenoma should be excluded. In select cases, immunohistochemical analysis applying a panel of markers identifying either Sertoli cells (e.g. inhibin) or mesothelial cells and their neoplastic descendants (e.g. calretinin, keratin 5 ⁄ 6) may be helpful. Finally, metastatic diseases due to non-scrotal malignancies mimicking SCN should be considered. Thus, Ulbright and Young recently reported a series of 11 patients with metastatic prostatic carcinoma to the testis. The authors specifically mention two cases presenting with vacuolated pale cells arranged in cordlike structures, reminiscent of Sertoli cell tumours. In conclusion, SCN may, albeit very rarely, be encountered in paratesticular sites. Pathologists should be aware of this possibility when faced with unusual extratesticular tumourous lesions, especially if malignancy is considered.