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P van Dam

Publications and source records attributed to P van Dam.

At least 19 recordsLinked to original sources
PubMed2006

Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer.

We studied the presence of lymphangiogenesis in lymph node (LN) metastases of breast cancer. Lymph vessels were present in 52 of 61 (85.2%) metastatically involved LNs vs 26 of 104 (25.0%) uninvolved LNs (P<0.001). Furthermore, median intra- and perinodal lymphatic endothelial cell proliferation fractions were higher in metastatically involved LNs (P<0.001). This is the first report demonstrating lymphangiogenesis in LN metastases of cancer in general and breast cancer in particular.

Adult↗
PubMed2006

Alterations in the p53 pathway and prognosis in advanced ovarian cancer: a multi-factorial analysis of the EORTC Gynaecological Cancer group (study 55865).

PURPOSE: The study was designed to determine independent prognostic variables in suboptimally debulked advanced ovarian cancer patients entered in the randomised phase III study EORTC 55865. EXPERIMENTAL DESIGN: Retrospectively collected paraffin blocks from 169 patients with stages IIb-IV epithelial ovarian cancer, taken at primary debulking surgery, were analysed. All patients were treated with cyclophosphamide and cisplatin (CP), and followed up for a median of 10 years. Expression of p53, bcl-2, P21, Ki-67 and HER-2 status was assessed by immunohistochemistry (IHC). RESULTS: Expression of p21, a downstream effector of the p53 gene, was found to be a favourable prognostic factor for survival (HR 0.58, CI 0.36-0.94, p=0.025) in addition to FIGO stage (HR 1.54, CI 1.08-2.21, p=or<0.02). For progression free survival (PFS), both p21 (HR 0.52) and Ki-67 (HR 0.6) were significant factors. CONCLUSION: P21 overexpression is a positive prognostic factor for survival and PFS in advanced ovarian carcinoma with residual lesions of more than 1 cm.

Adult↗
PubMed2006

Distinguishing blood and lymph vessel invasion in breast cancer: a prospective immunohistochemical study.

Recently, peritumoural (lympho)vascular invasion, assessed on haematoxylin-eosin (HE)-stained slides, was added to the St Gallen criteria for adjuvant treatment of patients with operable breast cancer (BC). New lymphatic endothelium-specific markers, such as D2-40, make it possible to distinguish between blood (BVI) and lymph vessel invasion (LVI). The aim of this prospective study was to quantify and compare BVI and LVI in a consecutive series of patients with BC. Three consecutive sections of all formalin-fixed paraffin-embedded tissue blocks of 95 BC resection specimens were (immuno)histochemically stained in a fixed order: HE, anti-CD34 (pan-endothelium) and anti-D2-40 (lymphatic endothelium) antibodies. All vessels with vascular invasion were marked and relocated on the corresponding slides. Vascular invasion was assigned LVI (CD34 [plus sign in circle] or [minus sign in circle]/D2-40 [plus sign in circle]) or BVI (CD34 [plus sign in circle]/D2-40 [minus sign in circle]) and intra- (contact with tumour cells or desmoplastic stroma) or peritumoural. The number of vessels with LVI and BVI as well as the number of tumour cells per embolus were counted. Results were correlated with clinico-pathological variables. Sixty-six (69.5%) and 36 (37.9%) patients had, respectively, LVI and BVI. The presence of 'vascular' invasion was missed on HE in 20% (peritumourally) and 65% (intratumourally) of cases. Although LVI and BVI were associated intratumourally (P=0.02), only peritumoural LVI, and not BVI, was associated with the presence of lymph node (LN) metastases (p(peri)=0.002). In multivariate analysis, peritumoural LVI was the only independent determinant of LN metastases. Furthermore, the number of vessels with LVI was larger than the number of vessels with BVI (P=0.001) and lymphatic emboli were larger than blood vessel emboli (P=0.004). We demonstrate that it is possible to distinguish between BVI and LVI in BC specimens using specific lymphatic endothelium markers. This is important to study the contribution of both processes to BC metastasis. Furthermore, immunohistochemical detection of lymphovascular invasion might be of value in clinical practice.

Adult↗
PubMed2005

Angiogenesis and hypoxia in lymph node metastases is predicted by the angiogenesis and hypoxia in the primary tumour in patients with breast cancer.

Hypoxia and angiogenesis are important factors in breast cancer progression. Little is known of hypoxia and angiogenesis in lymph node metastases of breast cancer. The aim of this study was to quantify hypoxia, by hypoxia-induced marker expression levels, and angiogenesis, by endothelial cell proliferation, comparing primary breast tumours and axillary lymph node metastases. Tissue sections of the primary tumour and a lymph node metastasis of 60 patients with breast cancer were immunohistochemically stained for the hypoxia-markers carbonic anhydrase 9 (CA9), hypoxia-inducible factor-1alpha (Hif-1alpha) and DEC-1 and for CD34/Ki-67. Endothelial cell proliferation fraction (ECP%) and tumour cell proliferation fraction (TCP%) were assessed. On haematoxylin-eosin stain, the growth pattern and the presence of a fibrotic focus were assessed. Hypoxia-marker expression, ECP% and TCP% in primary tumours and in lymph node metastases were correlated to each other and to clinico-pathological variables. Median ECP% and TCP% in primary tumours and lymph node metastases were comparable (primary tumours: ECP%=4.02, TCP%=19.54; lymph node metastases: ECP%=5.47, TCP%=21.26). ECP% correlated with TCP% (primary tumours: r=0.63, P<0.001; lymph node metastases: r=0.76, P<0.001). CA9 and Hif-1alpha expression were correlated (primary tumours P=0.005; lymph node metastases P<0.001). In primary tumours, CA9 and Hif-1alpha expression were correlated with DEC-1 expression (P=0.05), presence of a fibrotic focus (P<0.007) and mixed/expansive growth pattern (P<0.001). Primary tumours and lymph node metastases with CA9 or Hif-1alpha expression had a higher ECP% and TCP% (P<0.003); in primary tumours, mixed/expansive growth pattern and fibrotic focus were characterised by higher ECP% (P=0.03). Furthermore, between primary tumours and lymph node metastases a correlation was found for ECP%, TCP%, CA9 and Hif-1alpha expression (ECP% r=0.51, P<0.001; TCP r=0.77, P<0.001; CA9 and Hif-1alpha P<0.001). Our data demonstrate that the growth of breast cancer lymph node metastases is angiogenesis dependent and that angiogenesis and hypoxia in the primary tumour predict angiogenesis and hypoxia in the lymph node metastases. Together with previous findings in breast cancer liver metastases, which grow in 96% of cases angiogenesis independently, these data suggest that both the intrinsic growth characteristics and angiogenic potential of breast cancer cells and the site-specific tumour microenvironment determine angiogenesis and hypoxia in breast cancer.

Adult↗
PubMed2004

Real-time RT-PCR correlates with immunocytochemistry for the detection of disseminated epithelial cells in bone marrow aspirates of patients with breast cancer.

Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) is a technique with the potential of improving the quantification of disseminated epithelial cells (DEC) in haematological tissues due to its exquisite sensitivity. This sensitivity may lead to false positivity. Immunocytochemistry (ICC) is regarded as the standard methodology to diagnose DEC. In this study, detection with ICC was compared with quantitative real-time RT-PCR for CK-19 and mammaglobin (hMAM) mRNA in bone marrow (BM) of patients with metastatic breast cancer (MBC). Bone marrow was aspirated from 14 control patients and from 29 patients with MBC. Mononuclear cells (MNC) were isolated. Immunostaining was carried out with the Epimet kit. Quantitative PCR was performed on the ABI Prism 7700. The CK-19 and hMAM mRNA quantities were normalised against beta-Actin and calculated relative to a calibrator sample (relative gene expression). All controls were negative by ICC and for hMAM expression measured by RT-PCR, whereas the median RGE value for CK-19 was 0.57. For the MBC patients, the median RGE for hMAM was 0 and 10 out of 25 (40%) tested positive. Median RGE for CK-19 was 2.9 and 20 out of 25 (80%) tested positive. With ICC, the median value was 1 stained cell per sample, and 15 out of 24 (62%) samples were positive. A correlation was observed between CK-19 and hMAM expression (r=0.7; P=0.0003), and between hMAM expression and ICC (r=0.6; P=0.003). CK-19 expression and ICC (r=0.9; P<0.0001) showed the strongest correlation. Reverse transcriptase-polymerase chain reaction for CK-19 resulted in a higher number of positive BM samples of patients with MBC than ICC. Since an excellent correlation is observed between ICC and RT-PCR, and RT-PCR is probably more sensitive with the advantage of being less observer dependent and thus also more easy to automate, we consider our quantitative real-time RT-PCR method as validated for the detection of DEC in the bone marrow of breast cancer patients.

Biomarkers, Tumor↗
PubMed2004

Circulating basic fibroblast growth factor is partly derived from the tumour in patients with colon, cervical and ovarian cancer.

In order to investigate whether the high bFGF serum levels encountered in cancer patients are derived from the tumour, we analysed serum bFGF levels in 18 untreated randomly selected patients with operable colorectal, cervical and ovarian cancer in the blood draining the tumour, i.e., in mesenteric and uterine veins, and compared these with arterial samples. No significantly elevated bFGF levels were found in the veins draining the tumours compared with arterial samples in our patient population. This suggests that, in contrast to what is generally presumed, serum bFGF levels might also be derived from other sources besides the tumour, e.g., platelets.

Aged↗
PubMed2004

Validation of a tissue microarray to study differential protein expression in inflammatory and non-inflammatory breast cancer.

AIMS: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with poor prognosis. The mechanisms responsible for the aggressive clinical evolution are incompletely understood. We constructed a tissue microarray (TMA) and validated its use in translational IBC research. Differential expression of proteins that might play a role in causing the IBC phenotype was studied. METHODS AND RESULTS: A TMA containing 34 IBC and 41 non-stage matched non-IBC tumours was constructed. Five core biopsies were taken for each IBC and three cores for each non-IBC tumour. The TMA was validated using three approaches: (1) the excellent concordance between immunohistochemical results of the initial pathological examination and the results obtained with the TMA for ER, PR and HER2/neu (kappa > 0.74); (2) the known differential expression between IBC and non-IBC for four bio-markers in IBC (ER, PR, p53 and HER2/neu) was confirmed ( p < 0.01); (3) the HER2/neu status using three different antibodies (CB11, TAB250 and HercepTest) was highly concordant (kappa > 0.75). Furthermore, the overexpression of E-Cadherin and RhoC GTPase in IBC ( p < 0.05) was confirmed. We did not find a differential expression pattern for carbonic anhydrase IX (CA IX) and EGFR. CONCLUSIONS: Using different approaches, we have validated the use of our TMA for studying differential protein expression in IBC and non-IBC. We confirm the overexpression of E-Cadherin and RhoC GTPase in IBC. The lack of differential expression for CA IX and EGFR might suggest the pathways are equally utilised in both types of breast cancer.

Adenocarcinoma↗
PubMed2003

Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression.

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Improved understanding of the mechanisms responsible for the differences between IBC and non-IBC might provide novel therapeutic targets. We studied 35 consecutive patients with IBC, biopsied prior to the initiation of chemotherapy. Angiogenesis was evaluated by Chalkley counting and by assessment of endothelial cell proliferation (ECP) and vessel maturity. The presence of fibrin, expression of the hypoxia marker carbonic anhydrase IX (CA IX) and epithelialcadherin (E-cadherin) expression were immunohistochemically detected. The same parameters were obtained in a group of 104 non-IBC patients. Vascular density, assessed by Chalkley counting (P<0.0001), and ECP (P=0.01) were significantly higher in IBC than in non-IBC. Abundant stromal fibrin deposition was observed in 26% of IBC and in only 8% of non-IBC (P=0.02). Expression of CA IX was significantly less frequent in IBC than in non-IBC with early metastasis (P=0.047). There was a significant positive correlation between the expression of CA IX and ECP in IBC (r=0.4, P=0.03), implying that the angiogenesis is partly hypoxia driven. However, the higher ECP in IBC and the less frequent expression of CA IX in IBC vs non-IBC points at a role for other factors than hypoxia in stimulating angiogenesis. Strong, homogeneous E-cadherin expression was found at cell-cell contacts in all but two IBC cases, both in lymphovascular tumour emboli and in infiltrating tumour cells, challenging our current understanding of the metastatic process. Both the intense angiogenesis and the strong E-cadherin expression may contribute to the highly metastatic phenotype of IBC.

Adult↗
PubMed2002

Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer.

Plasma levels of D-dimer are elevated in cancer patients. Activation of the extrinsic coagulation system and the fibrinolytic cascade within a tumour is thought to be related with growth, invasion and metastasis. We have investigated the relationship between these markers of fibrin metabolism, standard clinicopathological variables and serum levels of angiogenic cytokines in three cohorts: group A (n=30) consisted of 30 healthy female volunteers, group B (n=23) of consecutive patients with operable breast cancer and group C (n=84) of patients with untreated or progressive metastatic breast cancer. Plasma D-dimers, fibrinogen, IL-6, vascular endothelial growth factor and calculated vascular endothelial growth factor load in platelets are clearly increased in patients with breast cancer. D-dimers were increased in nearly 89% of patients with progressive metastatic disease. The level of D-dimers was positively correlated with tumour load (P<0.0001), number of metastatic sites (P=0.002), progression kinetics (P<0.0001) and the cytokines related to angiogenesis: serum vascular endothelial growth factor (P=0.0016, Spearman correlation=0.285), calculated vascular endothelial growth factor load in platelets (P<0.0001, Spearman correlation=0.37) and serum interleukin-6 (P<0.0001, Spearman correlation=0.59). Similarly increased D-dimer levels were positively correlated with increased fibrinogen levels (P<0.0001, Spearman correlation=0.38). The association between markers of fibrin degradation in patients with progressive breast cancer suggests that the D-dimer level is a clinically important marker for progression and points towards a relation between haemostasis and tumour progression. A role of interleukin-6, by influencing both angiogenesis and haemostasis, is suggested by these observations.

Antifibrinolytic Agents↗
PubMed2002

Comparative analysis of the biochemical and immunohistochemical determination of hormone receptors in invasive breast carcinoma influence of the tumor-stroma ratio.

Tumor samples obtained from 106 primary breast cancer patients were examined biochemically (DCCA) and immunohistochemically (IHC) for estrogen (ER) and progesterone receptors (PR) to assess a quantitative relationship between both assays and to study the influence of the tumor-stroma ratio on this quantitative relationship. We used a model of logit transformation of IHC values (% of positive cells) and logarithmic transformation of DCCA values (fmol receptor/mg cytosolic protein). Tumors were subdivided into three categories according to the tumor-stroma ratio (more (t > s), equal amounts (t = s) or less (t < s) tumor than stroma), and the influence of the tumor-stroma ratio was studied using multiple regression analysis. We report a mathematical relationship between the results of the biochemical and immunohistochemical assays for the determination of ER status and PR status in primary breast cancer patients (ER: log DCCA(fmol/mg) = 0.369 logit (IHC(%pos cells)) + 2.328 (r = 0.573; p < 0.0001); PR: log DCCA (fmol/mg) = 0.474 logit (IHC(%pos cells)) + 0, 00 (r = 0.634; p < 0.0001)). In tumors overexpressing ER immunohistochemically (>10% nuclear positivity), median ER-DCCA is significantly higher if the tumor-stroma ratio is greater than 1. As these patients respond to hormonal treatment, depending on the degree of expression of both receptors, this study suggests that the biochemical assay be avoided because this technique is hampered by false-negative or falsely low results due to the loss of morphological information on the tumor-stroma ratio.

Biochemistry↗
PubMed2001

The evaluation of proliferative activity in CIN III and microinvasive cervical cancer and its role in recurrence.

OBJECTIVE: To evaluate the proliferation activity in CIN III lesions and Ia1 carcinoma according to the risk of recurrence. STUDY DESIGN: The proliferation markers PCNA (proliferating cell nuclear antigen) and mitotic index were studied in 75 patients with CIN III and in 20 patients with an Ia1 squamous carcinoma of the cervix by staining representative tissue sections for the PCNA and assessing the mitotic index. Associations between the studied proliferation markers and various histopathologic characteristics as well as recurrence were assessed. RESULTS: Three groups of PCNA were constituted: <20, 20--40, > OR =40% positive tumour nuclei, which contained, respectively, 45 (47%), 29 (31%), and 21 (22%) patients. Microinvasive carcinomas have a higher proliferation activity than CIN III (PCNA P=0.005; mitotic index P=0.094). For CIN III, there was a significantly lower risk for recurrence in the group with lower mitotic activity, compared to the group with higher mitotic activity (Kaplan-Meier: log-rank testing P=0.044). Significance was, however, not reached for the different PCNA categories (Kaplan-Meier, log-rank test P=0.068). Multiple regression analysis showed that in our population of CIN III lesions, only age of diagnosis and treatment modality were relevant (independent) prognostic indicators for recurrence. CONCLUSIONS: In CIN III lesions there is evidence for an association between proliferation activity and the risk of recurrence. The observed crude association weakens when adjusting for age at diagnosis and treatment modality. Apparently this feature is associated with more aggressive biological behaviour and could be used to identify women who are at higher risk of recurrence.

Adult↗
PubMed2000

Neoadjuvant chemotherapy versus primary debulking surgery in advanced ovarian cancer.

Primary surgical cytoreduction followed by chemotherapy usually is the preferred management of advanced (stage III or IV) ovarian cancer. The presence of residual disease after surgery is one of the most important adverse prognostic factors for survival. Neoadjuvant chemotherapy has been proposed as an alternative approach to conventional surgery as initial management of bulky ovarian cancer, with the goal of improving surgical quality. Since 1989, we have been treating advanced epithelial ovarian cancer with neoadjuvant chemotherapy instead of primary cytoreductive surgery in approximately half of the patients with stage III-IV disease. Selection of neoadjuvant chemotherapy was based on disease-related characteristics (eg, metastatic tumor load, stage of disease, performance status). Since 1993, open laparoscopy also has been used to aid in evaluating operability. A retrospective analysis of 338 patients was conducted to compare outcomes during 1989 to 1998, when neoadjuvant chemotherapy was used, with those observed during 1980 to 1988, when all patients underwent primary cytoreductive surgery. Crude 3-year survival rates were higher and postoperative mortality rates were lower during the second time period compared with the first. Overall, the results suggest that neoadjuvant chemotherapy results in survival rates in selected patients with advanced ovarian cancer that are comparable with those associated with primary cytoreductive surgery. Patients with stage IV disease, total metastatic tumor load greater than 1,000 g, uncountable plaque-shaped peritoneal metastases, and/or a poor performance status are probably the best candidates for this alternative approach. A prospective randomized study of neoadjuvant chemotherapy and primary cytoreductive surgery is ongoing.

Adult↗
PubMed1999

Angiogenesis in cervical intraepithelial neoplasia and the risk of recurrence.

OBJECTIVE: We sought to investigate whether angiogenesis can predict the risk of recurrence of cervical intraepithelial neoplasia after treatment. STUDY DESIGN: Microvessel density was studied in 75 patients with grade 3 cervical intraepithelial neoplasia and in 20 patients with microinvasive squamous carcinoma (International Federation of Gynecology and Obstetrics stage IA1) of the uterine cervix by staining representative tissue sections with the specific endothelial marker anti-CD31. The microvessel density was determined with a digital image analyzer. The results were correlated with clinical and histopathologic data. RESULTS: The mean vessel density was 264 per field (range, 86-674 per field) in grade 3 cervical intraepithelial neoplasia and 378 per field (range, 161-848 per field; P = .001) in microinvasive squamous carcinoma. Thirteen patients with grade 3 cervical intraepithelial neoplasia had recurrent cervical intraepithelial neoplasia (microvessel density, recurrent vs nonrecurrent; not significant). Multiple regression analysis in the noninvasive group confirmed that the mean vessel density (P = .121) had no prognostic value. Furthermore, it showed that the age at diagnosis (P = .011), menopausal status (P = .052), and treatment modality (P = .022) proved to be independent prognostic factors for recurrence. CONCLUSIONS: During the progression from noninvasive to microinvasive cervical carcinoma, the microvessel density increases significantly. However, the vessel density does not predict recurrence of noninvasive lesions.

Adult↗
PubMed1999

Chest wall resection for local recurrence of breast cancer. Presented at the 99th Meeting of the Royal Belgium Society of Obstetrics and Gynecology, Brussels May 9th 1998, Belgium.

We present three cases of chest wall resection for locally recurrent breast cancer and a Medline review of the current literature. In selected cases full thickness resection of the chest wall may be used as a salvage procedure to improve the quality of life and prolong the survival at low morbidity and mortality.

Adult↗
PubMed1998

Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients.

OBJECTIVE: This study was aimed at comparison of neoadjuvant chemotherapy with primary debulking surgery in advanced ovarian carcinoma. METHODS: Retrospective analysis of 285 patients with advanced ovarian carcinoma treated between 1980 and 1997 was performed. RESULTS: In the period 1980-1988 all patients underwent primary debulking surgery and 82% were cytoreduced to less than 0.5 cm largest residual tumor mass (n = 112). Analysis of this group of patients showed that some subgroups of patients (e.g., Stage IV disease or a total metastatic tumor load of more than 1000 g prior to debulking surgery) had a poor survival despite cytoreduction to no or less than 1 g of total residual tumor load. The complication rate was high especially in the group with unfavorable prognosis (postoperative mortality, 6%). In the period 1989-1997 (n = 173) the patients were surgically evaluated to receive primary chemotherapy (43%) or primary debulking surgery (57%). Prognostic variables were similar for both treatment periods. The actuarial crude survival was higher in the second time period (3-year crude survival of 26% +/- 4. 3 and 42% +/- 4.6 for the first and second time periods, respectively; P = 0.0001). The postoperative mortality was 0% during the second time period. From 1993 on, the decision to give neoadjuvant chemotherapy or to perform primary debulking surgery in patients with clinically obvious metastatic disease was made with the help of an open laparoscopy (n = 77). Median duration of the laparoscopy, blood loss, and hospital stay due to this procedure were 25 min, 10 ml, and 2 days. Primary and interval debulking surgery was performed in 36 and 63% of this subgroup of patients, respectively. CONCLUSION: In this retrospective analysis over two different time periods, crude survival was higher when treating about half of the patients with advanced ovarian carcinoma with primary chemotherapy instead of primary debulking surgery. The role of neoadjuvant chemotherapy should be evaluated in a prospective randomized study.

Adult↗
PubMed1998

Expression of bcl-2 in invasive and in situ carcinoma of the uterine cervix.

OBJECTIVE: The oncoprotein bcl-2 inhibits apoptosis. The purpose of this study was to assess the expression of bcl-2 in human cervical carcinoma and to correlate this with clinicopathologic parameters. STUDY DESIGN: Immunohistochemical staining for bcl-2 protein (MoAB clone 124) was performed on operative tissue specimens from 22 patients with carcinoma in situ of the cervix and from 137 patients with invasive cervical carcinoma (International Federation of Gynecology and Obstetrics stages I to IV). The immunoreactivity of bcl-2 was scored as positive (> or = 5% staining cells) or negative (< 5% staining cells). RESULTS: Eighty-two percent of in situ carcinomas and 61% of invasive cervical carcinomas were bcl-2 positive. Expression of bcl-2 was correlated to tumor stage (p < 0.001) and to presence of vascular (p < 0.005) or lymphatic tumor (p < 0.023) permeation. In univariate analysis there was a strong relationship between bcl-2 expression and overall survival (p < 0.001). In multivariate analysis bcl-2 expression (p < 0.001), International Federation of Gynecology and Obstetrics stage (p = 0.011), and presence of lymphatic permeation (p = 0.014) proved to be independent prognostic factors. CONCLUSIONS: Expression of bcl-2 is lost during tumor progression and is a strong prognostic parameter, suggesting that the regulation of apoptosis plays an important role in the behavior of cervical carcinomas. Better understanding of the mechanisms involved may lead to improved medical treatment strategies.

Adult↗