Biomedical subjects

Michael Schaapveld

Publications and source records attributed to Michael Schaapveld.

11 recordsLinked to original sources

PubMed2006

The prognostic effect of the number of histologically examined axillary lymph nodes in breast cancer: stage migration or age association?

BACKGROUND: The number of pathologically examined axillary nodes has been associated with breast cancer survival, and examination of >or=10 nodes has been advocated for reliable axillary staging. The considerable variation observed in axillary staging prompted this population-based study, which evaluated the prognostic effect of a variable number of pathologically examined nodes. METHODS: In total, 5314 consecutive breast cancer patients who underwent mastectomy or breast-conserving surgery and axillary dissection between 1994 and 1999 were included. The prognostic effect of the examined number of nodes was assessed with crude and relative survival analysis. RESULTS: A median number of 12 (range, 1-43) nodes were histologically examined, and 59% of the patients had no nodal tumor involvement. The number of examined nodes decreased with age (P<.001) and increased with tumor size (P<.001). Stratified for the number of tumor-positive nodes, overall survival seemed to be worse for patients with <10 compared with patients with >or=10 examined nodes (P<.001), whereas the relative survival did not differ. After adjusting for age, tumor size, number of positive nodes, and detection by screening in a multivariate analysis, the number of examined nodes was not associated with relative survival. CONCLUSIONS: This study shows that the association between the number of pathologically examined axillary nodes and overall survival in node-negative and node-positive patients results from stage migration. The absence of an association between the number of examined nodes and relative survival further indicates that the association between the number of examined nodes and crude survival is confounded by age.

Age Factors↗

PubMed2006

Surgery by consultant gynecologic oncologists improves survival in patients with ovarian carcinoma.

BACKGROUND: Consultant gynecologic oncologists from the regional Comprehensive Cancer Center assisted community gynecologists in the surgical treatment of patients with ovarian carcinoma when they were invited. For this report, the authors evaluated the effects of primary surgery by a gynecologic oncologist on treatment outcome. METHODS: The hospital files from 680 patients with epithelial ovarian carcinoma who were diagnosed between 1994 and 1997 in the northern part of the Netherlands were abstracted. Treatment results were analyzed according to the operating physician's education by using survival curves and univariate and multivariate Cox regression analyses. RESULTS: Primary surgery was performed on 184 patients by gynecologic oncologists, and on 328 patients by general gynecologists. Gynecologic oncologists followed surgical guidelines more strictly compared with general gynecologists (patients with International Federation of Gynecology and Obstetrics [FIGO] Stage I-II disease, 55% vs. 33% [P=0.01]; patients with FIGO Stage III disease, 60% vs. 40% [P=0.003]) and more often removed all macroscopic tumor in patients with FIGO Stage III disease (24% vs. 12%; P=0.02). When patients were stratified according to FIGO stage, the 5-year overall survival rate was 86% versus 70% (P=0.03) for patients with Stage I-II disease and 21% versus 13% (P=0.02) for patients with Stage III-IV disease who underwent surgery by gynecologic oncologists and general gynecologists, respectively. The hazards ratio for patients who underwent surgery by gynecologic oncologists was 0.79 (95% confidence interval [95%CI], 0.61-1.03; adjusted for patient age, disease stage, type of hospital, and chemotherapy); when patients age 75 years and older were excluded, the hazards ratio fell to 0.71 (95% CI, 0.54-0.94) in multivariate analysis. CONCLUSIONS: The surgical treatment of patients with ovarian carcinoma by gynecologic oncologists occurred more often according to surgical guidelines, tumor removal more often was complete, and survival was improved.

Adult↗

PubMed2005

Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients.

PURPOSE: Microsatellite instability (MSI), TP53 mutation, and KRAS mutation status have been reported as prognostic factors in colon cancer. Most studies, however, have included heterogeneous groups of patients with respect to cancer stage. We determined the prognostic relevance of high-frequency MSI (MSI-H), TP53 mutations, and KRAS mutations in a well-defined group of patients with stage III colon cancer (N = 391), randomly assigned for adjuvant treatment with fluorouracil-based chemotherapy. METHODS: Three hundred ninety-one tumor specimens were available. MSI was determined in 273 specimens, and mutation analyses of TP53 and KRAS were performed in 220 and 205 specimens, respectively. RESULTS: In a univariate analysis, MSI-H (44 of 273; 16%) was associated with a longer disease-free survival (DFS; P = .038), but in a multivariate model adjusting for nodal involvement, histology, invasion, and grade of tumor, the association of MSI status with DFS did no longer reach statistical significance, though the risk estimate for microsatellite stability versus MSI-H tumors did not change much. Mutant TP53, found in 116 (53%) of 220 tumors, was associated with a shorter DFS, both in univariate (P = .009) and multivariate analyses (P = .018), whereas KRAS mutations (58 of 205; 28%) did not show any prognostic significance. CONCLUSION: Both mutant TP53 and MSI-H seem to be prognostic indicators for disease-free survival, but only TP53 retains statistical significance after adjusting for clinical heterogeneity. Thus, in adjuvantly treated patients with stage III colon cancer, presence or absence of a TP53 mutation should be considered as a better predictor for DFS than MSI status.

Analysis of Variance↗

PubMed2005

A substantial proportion of microsatellite-unstable colon tumors carry TP53 mutations while not showing chromosomal instability.

Chromosomal instability in colon tumors implies the presence of numerical and structural chromosome aberrations and is further characterized by the absence of microsatellite instability and the occurrence of KRAS and/or TP53 mutations. In a previous screening of 194 colon tumors for both microsatellite instability and TP53 mutation, we found 25 microsatellite-unstable tumors, in 9 (36%) of which, presumed to be chromosomally stable, there were TP53 mutations. This prompted us to investigate whether a TP53 mutation in these microsatellite-unstable tumors would be an indicator of chromosomal instability, that is, whether this would be a category of tumors showing both microsatellite and chromosomal instability. For chromosomal instability assessment, we performed array-comparative genomic hybridization analysis of tumor and control DNA extracted from formalin-fixed, paraffin-embedded stage III colon tumor specimens. The array consisted of 435 subtelomere-specific BACs. We compared all but one (whose DNA was of bad quality) of the microsatellite-unstable TP53 mutation-containing tumors (8) with a similarly sized group of microsatellite-unstable tumors without TP53 mutation (11). Microsatellite-unstable tumors with a TP53 mutation showed on average 0.9 aberrations (range 0-3) when assessed with this array system. Those without a TP53 mutation showed on average 0.7 aberrations (range 0-2). Thus, microsatellite-unstable tumors showed few chromosomal abnormalities regardless of TP53 mutation status. Because, in our study, the microsatellite-stable tumors had on average 3.4chromosomal abnormalities (range 0-7), a clear difference exists between microsatellite-unstable and -stable tumors. Because a substantial proportion of microsatellite-unstable colon tumors carry a TP53 mutation while showing relativelyfewchromosomal aberrations, a TP53 mutation in these tumors cannot be considered to be an indicator of chromosomal instability.

Chromosomes, Artificial, Bacterial↗

PubMed2005

Colorectal cancer and the CHEK2 1100delC mutation.

The CHEK2 1100delC mutation was recently identified as a low-penetrance breast cancer susceptibility allele. The mutation occurred more frequently in families with clustering of breast and colorectal cancers (CRCs) than in families with clustering of breast cancer only. Hence, the 1100delC mutation could also be a low-penetrance CRC susceptibility allele. To test this hypothesis, we examined the mutation in 629 unselected CRC cases, 230 controls, and 105 selected CRCs diagnosed in patients before age 50. The mutation was observed in 1.6% of unselected patients and in 0.3% of controls (Not significant (NS)). After stratifying unselected patients according to defined genetic risk (on the basis of age at diagnosis and family history of colorectal and endometrial cancer), the highest frequency was observed in high-risk patients (12.5%), followed by moderate-risk patients (3.3%), and was lowest in low-risk patients (1.0%, P(trend) 0.014). In selected patients, 1.6% carried the mutation (NS). Subgroup analyses for tumor localization, gender, and age at diagnosis did not reveal an association with the 1100delC genotype. In addition, a pooled analysis, combining data of one published study in unselected CRC cases and our study, also did not reveal an association. In conclusion, the frequency of the 1100delC genotype was neither significantly increased in unselected CRC patients nor in selected CRC patients diagnosed before age 50. However, after stratifying unselected CRC patients according to defined genetic risk, a significant trend of increasing frequency was observed. Together, the results are consistent with a low-penetrance effect (OR 1.5-2.0) of the CHEK2 1100delC on CRC risk. Large case-control studies are required to clarify the exact role of the CHEK2 1100delC mutation in CRC.

Checkpoint Kinase 2↗

PubMed2005

The human leukocyte antigen region and colorectal cancer risk.

PURPOSE: Recently, we found a certain haplotype in the human leukocyte antigen Class III subregion to be associated with breast cancer. Epidemiologic studies have shown that breast cancer and colorectal cancer have several risk factors in common. In view of these studies and because polymorphisms located in the human leukocyte antigen III region have been found to be associated with colorectal cancer, we wondered whether the same region also is involved in colorectal cancer susceptibility. METHODS: The human leukocyte antigen region was genotyped with 14 microsatellite markers in germline DNA from 643 colorectal cancer patients and 841 family-based controls. Association analyses and the Haplotype Sharing Statistic were used to search for differences between patients and controls. Subgroup analyses were performed for gender, age at diagnosis, and localization of the tumor. RESULTS: The Haplotype Sharing Statistic analysis revealed neither a difference in mean haplotype sharing between all patients and controls, nor in any of the subgroups. The single allele, genotype, and two-locus association analyses for all patients and for the different subgroups did not show an association with colorectal cancer for the 14 microsatellite markers. Also, no association was observed between the tumor necrosis factor-beta polymorphism and colorectal cancer. CONCLUSIONS: No association was observed between commonly occurring haplotypes and alleles in the human leukocyte antigen region and colorectal cancer risk.

Adult↗

PubMed2005

No increased susceptibility to breast cancer from combined CHEK2 1100delC genotype and the HLA class III region risk factors.

CHEK2 is low-penetrance breast cancer susceptibility gene. The 1100delC mutation may interact with variants/mutations in other breast cancer susceptibility loci. We identified a risk haplotype in the HLA class III region in breast cancer patients [de Jong MM, Nolte IM, de Vries EGE, et al. The HLA class III subregion is responsible for an increased breast cancer risk. Hum Mol Genet 2003, 12, 2311-2319] and tested whether it interacted with 1100delC mutation. The CHEK2 1100delC mutation was analysed in the same series of patients and controls as in the HLA breast cancer study. In 962 unselected breast cancer patients, the 1100delC mutation was observed in 2.9% and in 367 controls in 1.4% (NS). The highest 1100delC frequency occurred in high-risk (4.4%), followed by moderate-risk (3.8%), and lowest in low genetic risk patients (2.4%, P(trend) 0.029). In HLA risk haplotype carriers no increased breast cancer risk was observed in the presence of 1100delC mutation. Patients more often had one than both genetic risk factors. The 1100delC mutation and the HLA risk haplotype confer increased breast cancer risks, but an interactive effect on breast cancer between both factors is unlikely. In contrast, the effect of 1100delC mutation on breast cancer risk was limited to individuals without HLA risk haplotype, suggesting a mutual excluding effect between these risk factors.

Adult↗

PubMed2004

Quality of adjuvant CMF chemotherapy for node-positive primary breast cancer: a population-based study.

PURPOSE: Adjuvant 'classical' oral cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) has long been the mainstay of adjuvant chemotherapy for premenopausal breast cancer patients. The Comprehensive Cancer Center North Netherlands (CCCN) breast cancer working group performed a retrospective audit of treatment guideline adherence and quality of CMF in hospitals in the CCCN area. METHODS: The CMF treatment data of 251 consecutive axillary lymph node-positive breast cancer patients <50 years old, diagnosed between 1993 and 1996, were analyzed. RESULTS: Ninety-four patients (42%) completed adjuvant CMF without dose adjustment or delay. Overall median relative dose intensity (RDI) was 92.6 (IQR 85.5-97.7). Sixty patients (24%) had an RDI <85, and 7% had an RDI <65. Myelotoxicity was the main reason for reductions and delays. Of 176 irradiated patients, 96% received radiotherapy simultaneously with CMF. Median CMF dose intensity nor median duration differed between patients who underwent mastectomy, mastectomy and radiotherapy, or breast-conserving therapy. Radiotherapy did not influence the median RDI (94 without versus 92 with radiotherapy). G-CSF, administered at least once to 76 patients, did not result in a higher median RDI. Median RDI was slightly higher when >3 patients/year (P=0.014) were treated by one specialist or >10 patients classified for adjuvant chemotherapy yearly in a hospital (P=0.037). CONCLUSION: The adherence to CMF treatment guidelines was generally good. Simultaneous radiotherapy did not affect the median RDI of CMF. G-CSF had no impact on the median RDI but patient volume did influence the RDI.

Adult↗

PubMed2004

Variability in axillary lymph node dissection for breast cancer.

BACKGROUND: The axillary nodal status may influence the prognosis and the choice of adjuvant treatment of individual breast cancer patients. The variation in number of reported axillary lymph nodes and its effect on the axillary nodal stage were studied and the implications are discussed. METHODS: Between 1994 and 1997, a total of 4,806 axillary dissections for invasive breast cancers in 4,715 patients were performed in hospitals in the North-Netherlands. The factors associated with the number of reported nodes and the relation of this number with the nodal status and the number of positive nodes were studied. RESULTS: The number of reported nodes varied significantly between pathology laboratories, the median number of nodes ranged from 9 to 15, respectively. The individual hospitals explained even more variability in the number of nodes than pathology laboratories (range in median number 8-15, P < 0.0001). The number of reported nodes increased gradually during the study period. A decreasing trend was observed with older patient age. A higher number of reported nodes was associated with a markedly increased chance of finding tumor positive nodes, especially more than three nodes. The frequency of node positivity increased from 28% if less than six nodes to 54% if >/=20 nodes were examined, the percentage of tumors with >/=4 positive nodes increased from 4 to 31%. Multivariate analysis confirmed these results. CONCLUSIONS: This population-based study showed a large variation in the number of reported lymph nodes between hospitals. A more extensive surgical dissection or histopathological examination of the specimen generally resulted in a higher number of positive nodes. Although the impact of misclassification on adjuvant treatment will have varied, the impact with regard to adjuvant regional radiotherapy may have been considerable.

Axilla↗

PubMed2004

No association between two MLH3 variants (S845G and P844L)and colorectal cancer risk.

Recently we identified a new variant, S845G, in the MLH3 gene in 7 out of 327 patients suspected of hereditary nonpolyposis colorectal cancer but not fulfilling the Amsterdam criteria and in 1 out of 188 control subjects. As this variant might play a role in causing sporadic colorectal cancer, we analyzed its prevalence in sporadic colorectal cancer patients. We analyzed a small part of exon 1 of the MLH3 gene, including the S845G variant, in germline DNA of 467 white sporadic colorectal cancer patients and 497 white controls. The S845G variant was detected in five patients and eight controls; the results thus indicate that this variant does not confer an increased colorectal cancer risk. Another variant (P844L) was clearly a polymorphism. Three other missense variants were rare and the sample size of the study was too small to conclude whether they are pathogenic. In conclusion, no association was observed between two MLH3 variants (P844L and S845G) and colorectal cancer risk.

Carrier Proteins↗

PubMed2003

The HLA class III subregion is responsible for an increased breast cancer risk.

BRCA1 and BRCA2 germline mutations account for <5% of breast cancer cases. Less penetrant breast cancer susceptibility genes are likely to exist. Earlier studies have suggested involvement of the HLA region. The HLA region was genotyped with 24 microsatellite markers and markers for two single nucleotide polymorphisms (SNPs) in TNFalpha and TNFbeta, in germline DNA from 956 breast cancer patients and 1271 family-based controls. Association analyses and the haplotype sharing statistic (HSS) were used to search for differences in haplotype sharing between patients and controls. Based on criteria known to influence genetic breast cancer risk, patients were divided into groups of high, moderate and low risk. The HSS revealed a significant difference in mean haplotype sharing between patients and controls for four consecutive markers (D6S2671, TNFa, D6S2672 and MICA), the highest being at D6S2671 (P=0.017). Subgroup analyses showed that moderate-risk patients were responsible for this difference, with the strongest association for D6S2672 (P=0.0009). A single haplotype was more frequent and longer in moderate-risk patients than in controls. The results were confirmed with association analyses. Individuals homozygous for haplotype 110-184 (D6S2672-MICA) were observed in 9.0% of moderate-risk patients and 1.5% of controls [odds ratio (OR)=7.14], while heterozygotes were at a lower risk (OR=1.41), suggesting a recessive effect. No association was observed between the two SNPs in TNFalpha (-308) and TNFbeta (intron 1) and breast cancer risk. The results reveal a potential role of the HLA class III subregion in susceptibility to breast cancer in patients at moderate familial risk.

Adult↗