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Biomedical subjects

A G J van der Zee

Publications and source records attributed to A G J van der Zee.

At least 19 recordsLinked to original sources
PubMed2006

EGFR expression is associated with groin node metastases in vulvar cancer, but does not improve their prediction.

OBJECTIVES: High morbidity of elective inguinofemoral lymphadenectomy in early stage vulvar cancer patients urges the need for defining a group of low-risk patients in whom inguinofemoral lymphadenectomy can be safely omitted. Aim of the study was to evaluate whether in addition to 'classic' clinicopathological factors determination of EGFR expression in vulvar cancer can be helpful in defining such a 'low-risk' group. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples of 197 surgically treated T1/2 patients were collected in a Tissue Micro Array (TMA). On this TMA, immunohistochemistry for EGFR was performed. Logistic regression analyses were performed including histopathological characteristics with the presence of nodal metastases as outcome. A predictive model was constructed, and absolute risks were calculated. RESULTS: EGFR expression was present in 68% of the vulvar tumors and related to the presence of lymph node metastases (OR 2.12, 95% CI 1.09-4.10). Our predictive model with only clinicopathological factors was able to define a group of patients with a likelihood of absence of lymph node metastases of 13% (95% CI 5-36), which could be decreased to 6% (95% CI 0-29) after inclusion of EGFR expression (p=0.07). CONCLUSIONS: EGFR expression is present in the majority of vulvar tumors and is associated with groin node metastases in vulvar cancer. Current classic clinicopathological predictive factors for inguinofemoral lymph node metastases with or without EGFR analysis are not strong enough for identification of "sufficiently low" risk T1/2 vulvar cancer patients. Our predictive model approach however is excellent for evaluation of new cell biological parameters, associated with clinical outcome.

Adult↗
PubMed2006

The clinical trail of TRAIL.

The naturally occurring tumour necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis through two death receptors, death receptor 4 (DR4) and death receptor 5 (DR5), that are expressed on the cell membrane. Binding of the ligand to the death receptors leads to activation of the extrinsic apoptosis pathway. Chemotherapy on the other hand stimulates the intrinsic apoptosis pathway via activation of p53 in response to cellular damage. Many cancer cells have mutations in p53 causing resistance to chemotherapy-induced apoptosis. Concomitant signalling through the extrinsic pathway may overcome this resistance. Moreover, enthusiasm for TRAIL as an anticancer agent is based on the demonstration of rhTRAIL-induced selective cell death in tumour cells and not in normal cells. In this review, we provide an overview of the TRAIL pathway, the physiological role of TRAIL and the factors regulating TRAIL sensitivity. We also discuss the clinical development of novel agents, i.e. rhTRAIL and agonistic antibodies, that activate the death receptors.

Animals↗
PubMed2006

Factors influencing p53 expression in ovarian cancer as a biomarker of clinical outcome in multicentre studies.

The prognostic impact of p53 immunostaining in a large series of tumours from epithelial ovarian cancer patients in a two-centre study was analysed. The study population (n=476) comprised of a retrospective series of 188 patients (Dutch cohort) and a prospective series of 288 patients (Scottish cohort) enrolled in clinical trials. P53 expression was determined by immunohistochemistry on tissue microarrays. Association with progression-free survival (PFS) and overall survival (OS) was analysed by univariate and multivariate Cox regression analysis. Aberrant p53 overexpression was significantly associated with PFS in the Dutch and Scottish cohorts (P=0.001 and 0.038, respectively), but not with OS in univariate analysis. In multivariate analysis, when the two groups were combined and account taken of clinical factors and country of origin of the cohort, p53 expression was not an independent prognostic predictor of PFS or OS. In this well-powered study with minimal methodological variability, p53 immunostaining is not an independent prognostic marker of clinical outcome in epithelial ovarian cancer. The data demonstrate the importance of methodological standardisation, particularly defining patient characteristics and survival end-point data, if biomarker data from multicentre studies are to be combined.

Adult↗
PubMed2006

Surgery and radiotherapy in vulvar cancer.

The majority of patients with vulvar cancer have squamous cell carcinomas (SCC). The cornerstone of the treatment is surgery. Radical vulvectomy with "en bloc" inguinofemoral lymphadenectomy has led to a favorable prognosis but with impressive morbidity. Nowadays, treatment is more individualized with wide local excision with uni- or bilateral inguinofemoral lymphadenectomy via separate incisions as the standard treatment for early stage patients with SCC of the vulva with depth of invasion >1 mm without suspicious groins. In case of more than one intranodal lymph node metastasis and/or extranodal growth, postoperative radiotherapy on the groins and pelvis is warranted. Until now there is a limited role for primary radiotherapy on the vulva and/or groins in early stage disease. The sentinel lymph node (SLN) procedure with the combined technique (preoperative lymphoscintigraphy with a radioactive tracer and intraoperative blue dye) is a promising staging technique for patients with early stage vulvar cancer. The safety of clinical implementation of the SLN procedure and the role of additional histopathological techniques of the SLNs need to be further investigated before its wide-scale application. Patients with advanced vulvar cancer are difficult to treat. One of the problems in patients with locally advanced vulvar cancer is the high incidence of concomitant bulky lymph nodes in the groin(s). Ultraradical surgery in case of resectable disease will lead to impressive morbidity because of the exenterative-type procedure. (Chemo)radiation with or without surgery should be regarded as the first choice for patients with locally advanced vulvar cancer only when primary surgery will necessitate performance of a stoma. Further studies are needed to determine the optimal combined modality treatment in these patients. Due to the fact that vulvar cancer is a rare disease, further clinical studies will only be possible, when international collaborative groups will join forces in order to perform clinical trials, in which different treatment options such as SLN procedure, primary radiotherapy on the groins and multimodality treatment for advanced disease will be investigated.

Carcinoma, Squamous Cell↗
PubMed2006

Management of vulvar cancers.

AIM: The radical surgical approach in the treatment of vulvar cancer patients has led to a favorable prognosis for the majority of the patients with early stage squamous cell cancer. However, the morbidity is impressive, leading to more individualized treatment. The aim of this review is to give an overview of the management of vulvar cancer. METHODS: We have reviewed the literature on the modifications in treatment of vulvar cancer with the emphasis on surgery and radiotherapy for primary disease. RESULTS: While surgery is the cornerstone of treatment for early stage squamous cell vulvar cancer (with wide local excision and uni- or bilateral inguinofemoral lymphadenectomy via separate incisions as standard treatment), until now there has been a limited role for primary radiotherapy although this may be an attractive alternative for the inguinofemoral lymphadenectomy in the future. The sentinel lymph node procedure with the combined technique (preoperative lymphoscintigraphy with (99m)technetium-labeled nanocolloid and Patente Blue) is a promising staging technique for patients with vulvar cancer. The clinical implementation of the sentinel lymph node procedure and the role of additional histopathological techniques of the sentinel lymph nodes have to be investigated. In advanced vulvar cancer, chemoradiation followed by surgery should be regarded as the treatment of first choice for these patients. CONCLUSIONS: Due to the rarity of vulvar cancer it is quite clear that further studies will have to be performed by international collaborative groups. The sentinel lymph node procedure and primary radiotherapy are promising methods to reduce morbidity of treatment, but their safety needs to be studied in clinical trials.

Combined Modality Therapy↗
PubMed2006

Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer.

BACKGROUND: Patients with early-onset colorectal cancer (CRC) or those with multiple tumours associated with hereditary non-polyposis colorectal cancer (HNPCC) raise suspicion of the presence of germline DNA mismatch repair (MMR) gene mutations. AIM: To analyse the value of family history, microsatellite instability (MSI) analysis and MMR protein staining in the tumour to predict the presence of an MMR gene mutation in such patients. METHODS: In 281 patients diagnosed with CRC before the age of 50 years or with CRC and at least one additional HNPCC-associated cancer, germline mutation analysis in MLH1, MSH2 and MSH6 was carried out with denaturing gradient gel electrophoresis and multiplex ligation-dependent probe amplification. MSI analysis with five consensus markers and MMR protein staining for MLH1, MSH2 and MSH6 were carried out in the tumours. RESULTS: 25 pathogenic mutations (8 in MLH1, 9 in MSH2 and 8 in MSH6) were found. MSI analysis missed three and immunohistochemistry (IHC) missed two mutation carriers. Sensitivities of family history, MSI analysis and IHC for the presence of a mutation were 76%, 82% and 88%, specificities were 64%, 70% and 84%, and positive predictive values were 19%, 23% and 38%, respectively. Multivariate analysis showed the highest odds ratio for IHC (38.3, 95% confidence interval 9.0 to 184). Prevalence of pathogenic germline MMR gene mutations in patients with CRC before the age of 50 years was 6% and in those with > or =2 HNPCC-associated tumours was 22%. In the second group, no mutation carriers were found among the 29 patients who were diagnosed with their first tumour after the age of 60 years. CONCLUSION: Family history, MSI analysis and IHC are indicative parameters to select patients with CRC for MMR gene mutation analysis. The data show that IHC is the best single selection criterion.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Analysis of human serum by liquid chromatography-mass spectrometry: improved sample preparation and data analysis.

Discovery of biomarkers is a fast developing field in proteomics research. Liquid chromatography coupled on line to mass spectrometry (LC-MS) has become a powerful method for the sensitive detection, quantification and identification of proteins and peptides in biological fluids like serum. However, the presence of highly abundant proteins often masks those of lower abundance and thus generally prevents their detection and identification in proteomics studies. To perform future comparative analyses of samples from a serum bank of cervical cancer patients in a longitudinal and cross-sectional manner, methodology based on the depletion of high-abundance proteins followed by tryptic digestion and LC-MS has been developed. Two sample preparation methods were tested in terms of their efficiency to deplete high-abundance serum proteins and how they affect the repeatability of the LC-MS data sets. The first method comprised depletion of human serum albumin (HSA) on a dye ligand chromatographic and immunoglobulin G (IgG) on an immobilized Protein A support followed by tryptic digestion, fractionation by cation-exchange chromatography, trapping on a C18 column and reversed-phase LC-MS. The second method included depletion of the six most abundant serum proteins based on multiple immunoaffinity chromatography followed by tryptic digestion, trapping on a C18 column and reversed-phase LC-MS. Repeatability of the overall procedures was evaluated in terms of retention time and peak area for a selected number of endogenous peptides showing that the second method, besides being less time consuming, gave more repeatable results (retention time: <0.1% RSD; peak area: <30% RSD). Application of an LC-MS component detection algorithm followed by principal component analysis (PCA) enabled discrimination of serum samples that were spiked with horse heart cytochrome C from non-spiked serum and the detection of a concentration trend, which correlated to the amount of spiked horse heart cytochrome C to a level of 5 pmol cytochrome C in 2 microl original serum.

Animals↗
PubMed2005

Immunologic aspect of ovarian cancer and p53 as tumor antigen.

Ovarian cancer represents the fifth leading cause of death from all cancers for women. During the last decades overall survival has improved due to the use of new chemotherapy schedules. Still, the majority of patients die of this disease. Research reveals that ovarian cancer patients exhibit significant immune responses against their tumor. In this review the knowledge obtained thus far on the interaction of ovarian cancer tumor cells and the immune system is discussed. Furthermore the role of p53 as tumor antigen and its potential role as target antigen in ovarian cancer is summarized. Based on the increased knowledge on the role of the immune system in ovarian cancer major improvements are to be expected of immunotherapy based treatment of this disease.

Journal Article↗
PubMed2005

Presentations of endometrial activity after curative radiotherapy for cervical cancer.

OBJECTIVES: The treatment of choice for patients with advanced stage cervical cancer is (chemo)radiotherapy. Gynaecologic side effects consist of loss of ovarian function and destruction of the endometrium, resulting in infertility and premature ovarian failure. In premenopausal patients estrogens are prescribed to prevent climacteric symptoms. In general, no progestagens are added to the hormone replacement therapy because of the assumption of complete destruction of the basal layer of the endometrium after pelvic radiotherapy. The aim of this report is to show the different presentations of endometrial activity after curative radiotherapy in patients with cervical cancer. METHODS: Presentation of four patients who developed symptoms of residual endometrial activity. RESULTS: In two patients, proliferation of functional endometrium led to hematocolpos and hematometrum with abdominal pain. The third patient underwent ovarian transposition and developed regular periods 3 months after finishing the radiotherapy. The fourth patient underwent trachelectomy with radiotherapy because of narrow tumour free margins. She developed vaginal blood loss after starting estrogens. CONCLUSIONS: These patients show that in premenopausal patients, curative radiotherapy until 80Gy, may lead to symptoms of residual functional endometrium, e.g. hematometrum, hematocolpos, (ir)regular vaginal blood loss. In our opinion patients should be advised to use estrogens in combination with a progestogen, instead of unopposed estrogens, to prevent stimulation of residual functional endometrium. Tibolone may be an appropriate alternative hormone replacement therapy especially with the advantage of low androgen effects which might support the sexual functions, and the decrease of breast density.

Adult↗
PubMed2005

[Surgical treatment of early-stage vulva carcinoma and the complications of the operation].

The treatment of patients with early-stage squamous-cell carcinoma of the vulva (with a depth of invasion > 1 mm), i.e. stage T1 with a tumour diameter < or = 2 cm or T2 with a diameter > 2 cm without suspect groin nodes on palpation, has become less radical; in this way, the complications can be reduced without compromising the generally favourable prognosis. Wide local excision with tumour-free margins of 2 cm appears to be a safe option for the local treatment. Uni- or bilateral inguinofemoral lymphadenectomy with separate incisions is currently part of the standard treatment. The complications associated with this standard surgical treatment remain significant: there are frequent disorders of wound healing, wound infections, lymphoceles, lymphoedema and effects on psychosexual behaviour. The minimal invasive sentinel lymph-node procedure is a promising technique in patients with early-stage squamous-cell carcinoma of the vulva, but the safety of the procedure must still be proven.

Carcinoma, Squamous Cell↗
PubMed2005

A phase I study of intraperitoneal topotecan in combination with intravenous carboplatin and paclitaxel in advanced ovarian cancer.

The aim of this study was to determine the maximum tolerated dose (MTD) of intraperitoneal (i.p.) topotecan combined with standard doses of intravenous (i.v.) carboplatin and paclitaxel and to investigate its pharmacokinetics. Women with primary ovarian cancer stage IIb - IV received six cycles of i.v. carboplatin and paclitaxel with escalating topotecan doses i.p. of 10, 15, 20 and 25 mg/m(2). Twenty-one patients entered this trial. Febrile neutropenia, thrombocytopenia requiring platelet transfusion and fatigue grade 3 were dose-limiting toxicities (DLT) at 25 mg/m(2) i.p. and 20 mg/m(2) i.p. of topotecan was considered to be the MTD. The mean plasma t(1/2) was 3.8 +/- 2.3 h for total topotecan and 4.4 +/- 3.9 h for active lactone. The area under the curve (AUC) was proportional with dose, R = 0.54, p < 0.05 for total topotecan and the peritoneal / plasma AUC ratio was 46 +/- 30. Fifteen patients who completed treatment had a median progression-free survival (PFS) of 27 months. In this setting the MTD of topotecan is 20 mg/m(2) i.p. The efficacy of this regimen should be explored further in a formal phase III study.

Adult↗
PubMed2005

Death receptors and ligands in cervical carcinogenesis: an immunohistochemical study.

OBJECTIVE: Increasing imbalance between proliferation and apoptosis is important in cervical carcinogenesis. The death ligands FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis by binding to their cognate cell-surface death receptors Fas or death receptor (DR) 4 and DR5. This study aims to examine if changes in death ligand and death receptor expression during different stages of cervical carcinogenesis are related to an imbalance between proliferation and apoptosis. METHODS: The immunohistochemical expression and localization of Fas/FasL and DR4/DR5/TRAIL were assessed in 11 normal cervices, 15 cervical intraepithelial neoplasia (CIN) grade I, 15 CIN II, 13 CIN III, and 25 (microinvasive) squamous cell cervical cancers. The number of apoptotic cells was determined by morphological criteria and the number of proliferating cells by counting Ki-67-positive cells. RESULTS: A marked increase in proliferation as well as apoptosis percentage was found with increasing severity of neoplasia. In normal cervix and CIN I samples, FasL, DR4, DR5, and TRAIL staining was mainly observed in the basal/parabasal layer, whereas Fas staining was localized in the superficial, more differentiated epithelial layer. Frequency of Fas-positive staining decreased with increasing severity of CIN. In contrast, homogeneous FasL, DR4, DR5, and TRAIL expression throughout the lesions was more frequently observed in CIN III and cervical cancer. FasL, DR4, DR5, and TRAIL staining patterns were correlated, although TRAIL expression was more intense in low-grade lesions. No association was found between death receptor or ligand expression with the percentage of apoptosis or proliferation. CONCLUSION: The loss of Fas and the deregulation of FasL, DR4, DR5, and TRAIL in the CIN-cervical cancer sequence suggest a possible functional role of these death ligands and receptors during cervical carcinogenesis. The frequent expression of DR4 and DR5 presents these receptors as promising targets for innovative therapy modalities in cervical cancer.

Apoptosis↗
PubMed2005

A randomized phase II study of paclitaxel with carboplatin +/- amifostine as first line treatment in advanced ovarian carcinoma.

OBJECTIVE: Will amifostine (A) protect against chemotherapy-induced neuro- and myelotoxicity. PATIENTS AND METHODS: Ninety ovarian cancer patients were randomized to receive standard paclitaxel + carboplatin without (PC) or preceded by amifostine 740 mg/m(2) (PC + A). RESULTS: The mean baseline values of hemoglobin, leukocyte, and platelets were slightly lower in the amifostine group, but the mean percentual decrease of these parameters after each treatment cycle showed no difference between both arms. Symptoms of neurotoxicity remained absent in 40% PC vs. 49% PC + A cycles; sensory neurotoxicity grade I occurred in 45% vs. 48% and grade II in 12% PC vs. 2% of PC + A cycles (overall P < 0.001). Nausea grade II was reported in 2% vs. 6% (P = 0.007) and vomiting grade II in 1% of PC vs. 8% PC + A cycles (P < 0.001). Amifostine was temporarily interrupted in five patients due to hypotension, but no dose reductions were indicated. Quality of life questionnaires showed no difference in neurotoxicity scores between both study arms at treatment completion. The median progression-free survival was 16 vs. 22 months (n.s.) for PC and PC + A patients. In a pooled analysis of four randomized studies, amifostine diminished the risk of developing neurotoxicity grade II-III (Odds Ratio 0.3, 95% confidence interval 0.15-0.63, P < 0.05), but had no effect on the risk for bone marrow toxicity. CONCLUSION: Amifostine shows only minor but significant activity in diminishing neurotoxicity without preventing paclitaxel + carboplatin-induced bone marrow toxicity.

Adult↗
PubMed2005

Analysis of the entire HLA region in susceptibility for cervical cancer: a comprehensive study.

BACKGROUND: Infection with human papillomavirus (HPV) is the main cause of cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN). Variability in host immunogenetic background is important in determining the overall cellular immune response to HPV infections. OBJECTIVE: To determine whether the HLA-DQ or HLA-DR genes, or others in their vicinity, are associated with cervical cancer. METHODS: Markers covering the entire HLA region were genotyped in a large sample of CIN and cervical cancer patients and in controls (311 CIN, 695 cervical cancer, 115 family controls, and 586 unrelated controls). RESULTS: Two markers were associated with susceptibility to cervical neoplasia, G511525 and MICA. G511525, close to the region containing the HLA-DQ and HLA-DR genes, was most strongly associated, showing a decrease in frequency of allele 221 from 6.7% to 3.3% in patients with squamous cell cancer (SCC). An association was found for MICA (allele 184) with SCC (odds ratio (OR) = 1.31 (95% confidence interval, 1.13 to 1.53); homozygotes, OR = 1.48 (1.06 to 2.06)). No associations were observed with adenocarcinoma or CIN. CONCLUSIONS: There is an association of the region containing the HLA-DQ and HLA-DR genes with the risk of developing squamous cell carcinoma. An increased risk was observed for carriers of allele 184 at the MICA locus, in particular for homozygotes, suggesting a recessive effect.

Adenocarcinoma↗
PubMed2004

Long-term survivors of ovarian malignancies after cisplatin-based chemotherapy; cardiovascular risk factors and signs of vascular damage.

Male germ cell tumour patients treated with cisplatin-based chemotherapy frequently develop cardiovascular risk factors and disease, but sparse information is available about long-term complications of this type of chemotherapy in women. We investigated the prevalence of cardiovascular risk factors and vascular damage in 21 women (median age 39 years; range 26-57 years) with an epithelial or germ cell tumour of the ovary cured by cisplatin-based chemotherapy after a median follow-up of 14 years (range 3-21 years). Hypercholesterolaemia was present in 62%, obesity in 24%, hypertension in 14%, insulin resistance in 14%, and microalbuminuria in 24% of patients. Microalbuminuria was more frequent in long-term cancer survivors than in a female background population with a similar age (23.8 versus 3.2%; P<0.05). A substantial portion of young female patients cured by cisplatin-based chemotherapy are likely to develop cardiovascular risk factors and signs of endothelial damage at an early stage.

Adult↗
PubMed2004

Chemotherapy induces death receptor 5 in epithelial ovarian carcinoma.

OBJECTIVES: Defects in the apoptotic pathway are a general cause for drug resistance. Chemotherapy in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has proven to be an effective strategy to induce apoptosis in vitro in ovarian tumor cells. Systemic TRAIL administration might be a therapeutic option, since no toxicity was observed in nonhuman primates. In the present study, expression of TRAIL and its apoptosis-inducing death receptors (DR4 and DR5) and inhibitory decoy receptor (DcR1) was studied in normal ovaries and in malignant ovarian tumors before and after chemotherapy to investigate the therapeutic potential of TRAIL. METHODS: DR4, DR5, DcR1, and TRAIL were studied immunohistochemically in 5 normal ovaries, 15 stages I/II, and 26 stages III/IV primary ovarian cancers, including 19 paired tumor samples (pre- and post-chemotherapy). RESULTS: Surface epithelium of normal ovaries expressed TRAIL and its receptors; ovarian stromal cells expressed only DcR1. Of the ovarian cancers, 73% expressed DR4, 51% DR5, 46% DcR1, and 34% TRAIL. Most primary ovarian cancers (88%) expressed at least one death receptor. TRAIL expression was lower in stage III/IV than in stage I/II tumors (P<0.05). In paired samples, DR5 immunostaining was more frequently (P=0.05) and stronger (P<0.01) expressed in residual tumors. CONCLUSION: Early stage tumors expressed TRAIL more frequently than advanced stage tumors. Most primary and residual ovarian tumors expressed at least one TRAIL death receptor, while in residual tumors following chemotherapy, DR5 was more frequently expressed. Therefore, human recombinant TRAIL administration might be an interesting treatment option.

Apoptosis Regulatory Proteins↗
PubMed2004

Pitfalls in the sentinel lymph node procedure in vulvar cancer.

OBJECTIVES: There is an increasing interest among gynecologic oncologists to implement the sentinel lymph node (SLN) procedure in vulvar cancer patients in clinical practice. However, the safety of this promising method of staging still has to be proven in a randomized trial. MATERIALS AND METHODS: Two vulvar cancer patients are reported to illustrate pitfalls in the sentinel lymph node procedure. RESULTS: The phenomena of bypassing the sentinel lymph node and confusion about the number of removed sentinel lymph nodes are presented and discussed. CONCLUSION: Gynecological oncologists who perform the sentinel lymph node procedure in vulvar cancer patients should perform this technique by following a strict protocol and within the protection of a clinical trial.

Aged↗