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Radboud University, 9 december 2016, Promotor : Mulders, P.F.A. Co-promotor : Oosterwijk, E., Contains fulltext : 161238.pdf (publisher's version ) (Open Access)

Contains fulltext : 154027.pdf (publisher's version ) (Open Access), Anti-angiogenic treatment with tyrosine kinase inhibitors (TKI) has lead to an impressive increase in progression-free survival for patients with metastatic RCC (mRCC), but mRCC remains largely incurable. We combined sunitinib, targeting the endothelial cells with Girentuximab (monoclonal antibody cG250, recognizing carbonic anhydrase IX (CAIX) targeting the tumor cells to study the effect of sunitinib on the biodistribution of Girentuximab because combination of modalities targeting tumor vasculature and tumor cells might result in improved effect. Nude mice with human RCC xenografts (NU12, SK-RC-52) were treated orally with 0.8 mg/day sunitinib, or vehicle for 7 to 14 days. Three days before start or cessation of treatment mice were injected i.v. with 0.4 MBq/5 mug (111)In-Girentuximab followed by biodistribution studies. Immunohistochemical analyses were performed to study the tumor vasculature and CAIX expression and to confirm Girentuximab uptake. NU12 appeared to represent a sunitinib sensitive tumor: sunitinib treatment resulted in extensive necrosis and decreased microvessel density (MVD). Accumulation of Girentuximab was significantly decreased when sunitinib treatment preceded the antibody injection but remained unchanged when sunitinib followed Girentuximab injection. Cessation of therapy led to a rapid neovascularization, reminiscent of a tumor flare. SK-RC-52 appeared to represent a sunitinib-resistant tumor: (central) tumor necrosis was minimal and MVD was not affected. Sunitinib treatment resulted in increased Girentuximab uptake, regardless of the sequence of treatment. These data indicate that sunitinib can be combined with Girentuximab. Since these two modalities have different modes of action, this combination might lead to enhanced therapeutic efficacy.

Contains fulltext : 117856.pdf (publisher's version ) (Open Access), Monoclonal antibody G250 (mAbG250) recognizes a determinant on carbonic anhydrase IX (CAIX). CAIX is expressed by virtually all renal cell carcinomas of the clear cell type (ccRCC), but expression in normal tissues is restricted. The homogeneous CAIX expression in ccRCC and excellent targeting capability of mAbG250 in animal models led to the initiation of the clinical evaluation of mAbG250 in (metastatic) RCC (mRCC) patients. Clinical studies confirmed the outstanding targeting ability of mAbG250 and cG250 PET imaging, as diagnostic modality holds great promise for the future, both in detecting localized and advanced disease. Confirmation of the results obtained in the non-randomized clinical trials with unmodified cG250 is needed to substantiate the value of cG250 treatment in mRCC. cG250-Based radio immuno-therapy (RIT) holds promise for treatment of patients with small-volume disease, and adjuvant treatment with unmodified cG250 may be of value in selected cases. In the upcoming years, ongoing clinical trials should provide evidence for these assumptions. Lastly, whether cG250-based RIT can be combined with tyrosine kinase inhibitors, which constitutes the current standard treatment for mRCC, needs to be established.

Item does not contain fulltext, Adoptive transfer of immune effector cells that are gene modified by retroviral transduction to express tumor-specific receptors constitutes an attractive approach to treat cancer. In patients with metastatic renal cell carcinoma, we performed a study with autologous T cells genetically retargeted with a chimeric antibody receptor (CAR) directed toward carbonic anhydrase IX (CAIX), an antigen highly expressed in renal cell carcinoma. In the majority of patients, we observed distinct humoral and/or cellular anti-CAIX-CAR T-cell immune responses in combination with a limited peripheral persistence of transferred CAIX-CAR T cells in the majority of patients. Humoral immune responses were anti-idiotypic in nature and neutralized CAIX-CAR-mediated T-cell function. Cellular anti-CAIX-CAR immune responses were directed to the complementarity-determining and framework regions of the CAR variable domains. In addition, 2 patients developed immunity directed against presumed retroviral vector epitopes. Here, we document the novel feature that therapeutic cells, which were ex vivo engineered by means of transduction with a minimal gamma-retroviral vector, do express immunogenic vector-encoded epitopes, which might compromise persistence of these cells. These observations may constitute a critical concern for clinical ex vivo gamma-retroviral gene transduction in general and CAR-retargeted T-cell therapy in particular, and underscore the need to attenuate the immunogenicity of both transgene and vector.

Contains fulltext : 97857.pdf (publisher's version ) (Closed access), OBJECTIVE: To investigate the effect of three different tyrosine kinase inhibitors (TKIs) on the biodistribution of chimeric monoclonal antibody (mAb) cG250, which identifies carbonic anhydrase IX (CAIX), in nude mice bearing human renal cell carcinoma (RCC) xenografts. TKIs represent the best, but still suboptimal treatment for metastatic RCC (mRCC) and combined therapy or sequential therapy might be beneficial. CAIX is abundantly over expressed in RCC and clinical trials have shown abundant and specific tumour accumulation of cG250. Combining a TKI with mAb cG250, involved in a different effector mechanism, might lead to improved tumour responses and survival in patients with mRCC. MATERIALS AND METHODS: Nude mice bearing human RCC xenografts were treated orally with 0.75 mg/day sunitinib, 1 mg/day vandetanib, 1 mg/day sorafenib or vehicle control for 7 or 14 days. At 7 days, mice were injected i.v. with 185 kBq/5 microg (125) I-cG250. Mice were killed at predetermined days and cG250 biodistribution was determined. Tumours were analysed by immunohistochemistry for the presence of endothelial cells, laminin, smooth muscle actin, CAIX expression and uptake of mAb cG250. RESULTS: While on TKI treatment, tumour uptake of cG250 decreased dramatically, tumour growth was slightly inhibited and vascular density decreased considerably as judged by various markers. When treatment was stopped at 7 days, there was robust neovascularization, mainly at the tumour periphery. Consequently, cG250 uptake also recovered, albeit cG250 uptake appeared to be restricted to the tumour periphery where vigorous neovascularization was visible. CONCLUSIONS: Simultaneous administration of a TKI and mAb cG250 severely compromised mAb accumulation. However, shortly after discontinuation of TKI treatment mAb accumulation was restored. Combined treatment strategies with TKI and mAb should be carefully designed.

Contains fulltext : 81236.pdf (publisher's version ) (Open Access), INTRODUCTION: Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs. METHODS: We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families). RESULTS: The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p.S1655F, p.R1699W, and p.R1699Q variants in BRCA1 and the p.Y2660D, p.R2784Q, and p.R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p.L246V variant in BRCA1 and of the p.Y42C, p.E462G, p.R2888C, and p.R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p.R2784W variant in BRCA2 remains uncertain. CONCLUSIONS: The present study shows that these developed models are useful to classify UVs in clinical genetic practice.

Contains fulltext : 79746.pdf (publisher's version ) (Open Access), BACKGROUND: Assessment of the clinical significance of unclassified variants (UVs) identified in BRCA1 and BRCA2 is very important for genetic counselling. The analysis of co-segregation of the variant with the disease in families is a powerful tool for the classification of these variants. Statistical methods have been described in literature but these methods are not always easy to apply in a diagnostic setting. METHODS: We have developed an easy to use method which calculates the likelihood ratio (LR) of an UV being deleterious, with penetrance as a function of age of onset, thereby avoiding the use of liability classes. The application of this algorithm is publicly available http://www.msbi.nl/cosegregation. It can easily be used in a diagnostic setting since it requires only information on gender, genotype, present age and/or age of onset for breast and/or ovarian cancer. RESULTS: We have used the algorithm to calculate the likelihood ratio in favour of causality for 3 UVs in BRCA1 (p.M18T, p.S1655F and p.R1699Q) and 5 in BRCA2 (p.E462G p.Y2660D, p.R2784Q, p.R3052W and p.R3052Q). Likelihood ratios varied from 0.097 (BRCA2, p.E462G) to 230.69 (BRCA2, p.Y2660D). Typing distantly related individuals with extreme phenotypes (i.e. very early onset cancer or old healthy individuals) are most informative and give the strongest likelihood ratios for or against causality. CONCLUSION: Although co-segregation analysis on itself is in most cases insufficient to prove pathogenicity of an UV, this method simplifies the use of co-segregation as one of the key features in a multifactorial approach considerably.

Contains fulltext : 81404.pdf (publisher's version ) (Closed access), Immunotherapeutic targeting of G250/Carbonic anhydrase IX (CA-IX) represents a promising strategy for treatment of renal cell carcinoma (RCC). The well characterized human-mouse chimeric G250 (cG250) antibody has been shown in human studies to specifically enrich in CA-IX positive tumors and was chosen as a carrier for site specific delivery of TNF in form of our IgG-TNF-fusion protein (cG250-TNF) to RCC xenografts. Genetically engineered TNF constructs were designed as CH2/CH3 truncated cG250-TNF fusion proteins and eucariotic expression was optimized under serum-free conditions. In-vitro characterization of cG250-TNF comprised biochemical analysis and bioactivity assays, alone and in combination with Interferon-gamma (IFNgamma). Biodistribution data on radiolabeled [(125)J] cG250-TNF and antitumor activity of cG250-TNF, alone and in combination with IFNgamma, were measured on RCC xenografts in BALB/c nu/nu mice. Combined administration of cG250-TNF and IFNgamma caused synergistic biological effects that represent key mechanisms displaying antitumor responses. Biodistribution studies demonstrated specific accumulation and retention of cG250-TNF at CA-IX-positive RCC resulting in growth inhibition of RCC and improved progression free survival and overall survival. Antitumor activity induced by targeted TNF-based constructs could be enhanced by coadministration of low doses of nontargeted IFNgamma without significant increase in side effects. Administration of cG250-TNF and IFNgamma resulted in significant synergistic tumoricidal activity. Considering the poor outcome of renal cancer patients with advanced disease, cG250-TNF-based immunotherapeutic approaches warrant clinical evaluation.

Contains fulltext : 53266.pdf (publisher's version ) (Closed access), OBJECTIVE: To evaluate the prognostic information of carbonic anhydrase (CA) IX expression in patients with renal cell carcinoma (RCC), as increased expression of CA IX is correlated with a worse prognosis in several malignancies. PATIENTS AND METHODS: CA IX expression was assessed in RCC tumours from 228 patients, using a tissue microarray technique on archival material. The expression was related to RCC cell type, Tumour-Node-Metastasis (TNM) stage, nuclear grade and survival. RESULTS: CA IX expression was significantly higher (P < 0.001) in 183 conventional than in 31 papillary RCC and 14 chromophobe RCC. For conventional RCC there was no correlation of CA IX expression with TNM stage or nuclear grade. To evaluate the prognostic information conventional RCC tumours were subdivided arbitrarily into three groups according to the CA IX expression, of 0-10%, 11-90% and 91-100% expression, respectively. Patients with tumours with 0-10% expression had a less favourable prognosis than those with 11-90% and 91-100% expression (P = 0.012, and 0.001), respectively. A multivariate analysis of prognostic factors for patients with conventional RCC showed that TNM stage, nuclear grade and CA IX were independent predictors of prognosis. CONCLUSION: These results show that CA IX expression is higher in conventional than other RCC cell types; furthermore, patients with conventional RCC with low CA IX expression had a less favourable prognosis.

Contains fulltext : 52228tiemessen.pdf (publisher's version ) (Closed access), Carbonic anhydrase-IXG250/MN (CA9) is a renal cell carcinoma (RCC)-associated antigen ubiquitously expressed in the clear-cell subtype of RCC. Two CA9-derived peptides have been identified defining a cytotoxic T-lymphocyte epitope and human leukocyte antigen (HLA)-DR epitope, able to induce T-cell responses in vitro. A phase I clinical trial was performed with CA9-peptide-loaded dendritic cells (DCs) in patients with progressive, cytokine-refractory metastatic RCC to assess the safety, toxicity, and induction of CA9-specific immunity. Patients with objective progressive metastatic RCC received 5 vaccinations of mature DCs pulsed with the CA9-derived peptides and keyhole limpet hemocyanine (KLH). Peripheral blood was collected at regular intervals, delayed-type hypersensitivity (DTH) was tested at baseline and after the last vaccination, and skin biopsies of positive DTH sites were collected for immunomonitoring purposes. Patients were also monitored for clinical responses. No significant toxicity was observed. All patients developed humoral responses against KLH, and demonstrated DTH conversion. Evaluation of biopsy material suggested an increased influx of T-helper cells. In none of the immunomonitoring assays was evidence for the induction of CA9-peptide-specific immunity observed. No clinical responses were observed. The vaccination of DCs pulsed with KLH and 2 CA9-derived peptides was well tolerated. The lack of induction of CA9-peptide-specific immune responses indicates that this particular vaccine regimen is poor in inducing CA9-peptide-specific immune responses.

Contains fulltext : 52475.pdf (publisher's version ) (Closed access)

Contains fulltext : 49625.pdf (publisher's version ) (Closed access), To establish an efficient, reliable and easy to apply risk assessment tool to select families with breast and/or ovarian cancer patients for BRCA mutation testing, using available probability models. In a retrospective study of 263 families with breast and/or ovarian cancer patients, the utility of the Frank (Myriad), Gilpin (family history assessment tool) and Evans (Manchester) model was analysed, to select 49 BRCA mutation-positive families. For various cutoff levels and combinations, the sensitivity and specificity were calculated and compared. The best combinations were subsequently validated in additional sets of families. Comparable sensitivity and specificity were obtained with the Gilpin and Evans models. They appeared to be complementary to the Frank model. To obtain an optimal sensitivity, five 'additional criteria' were introduced that are specific for the selection of small or uninformative families. The optimal selection is made by the combination 'Frank >or=16% or Evans2 >or=12 or one of five additional criteria'. The efficiency of the selection of families for mutation testing of BRCA1 and BRCA2 can be optimised by using a combination of available easy to apply risk assessment models.

Contains fulltext : 49322.pdf (publisher's version ) (Closed access), BACKGROUND: The MRISC study is a screening study, in which women with an increased risk of hereditary breast cancer are screened by a yearly mammography and MRI, and half-yearly clinical breast examination. The sensitivity found in this study was 40% for mammography and 71% for MRI and the specificity was 95 and 90%, respectively. In the current subsequent study we investigated whether these results are influenced by age, a BRCA1/2 mutation, menopausal status and breast density. PATIENTS AND METHODS: From November 1999 to October 2003, 1909 eligible women were screened and 50 breast cancers were detected. For the current analysis, data of 4134 screening rounds and 45 detected breast cancers were used. For both imaging modalities, screening parameters, receiver operating characteristic (ROC) curves and uni- and multivariate odds ratios (ORs) were calculated. All analyses were separately performed for age at entry (< 40, 40-49, >/=50), mutation status, menopausal status and breast density. RESULTS: Sensitivity of MRI was decreased in women with high breast density (adjusted OR 0.08). False-positive rates of both mammography (OR(adj) 1.67) and MRI (OR(adj) 1.21) were increased by high breast density, that of MRI by pre-menopausal status (OR(adj) 1.70), young age (OR(adj) 1.58 for women 40-49 years versus women >/=50 years) and decreased in BRCA1/2 mutation carriers (OR(adj) 0.74). In all investigated subgroups the discriminating capacity (measured by the area under the ROC-curve) was higher for MRI than for mammography, with the largest differences for BRCA1/2 mutation carriers (0.237), for women between 40 and 49 years (0.227) and for women with a low breast density (0.237). CONCLUSIONS: This report supports the earlier recommendation that MRI should be a standard screening method for breast cancer in BRCA1/2 mutation carriers.

Contains fulltext : 51002.pdf (publisher's version ) (Closed access), Rapid and reliable identification of deleterious changes in the breast cancer genes BRCA1 and BRCA2 has become one of the major issues in most DNA services laboratories. To rapidly detect all possible changes within the coding and splice site determining sequences of the breast cancer genes, we established a semiautomated denaturing gradient gel electrophoresis (DGGE) mutation scanning system. All exons of both genes are covered by the DGGE scan, comprising 120 amplicons. We use a semiautomated approach, amplifying all individual amplicons with the same PCR program, after which the amplicons are pooled. DGGE is performed using three slightly different gel conditions. Validation was performed using DNA samples with known sequence variants in 107 of the 120 amplicons; all variants were detected. This DGGE mutation scanning, in combination with a PCR test for two Dutch founder deletions in BRCA1 was then applied in 431 families in which 52 deleterious changes and 70 unclassified variants were found. Fifteen unclassified variants were not reported before. The system was easily adopted by five other laboratories, where in another 3,593 families both exons 11 were analyzed by the protein truncation test (PTT) and the remaining exons by DGGE. In total, a deleterious change (nonsense, frameshift, splice-site mutation, or large deletion) was found in 661 families (16.4%), 462 in BRCA1 (11.5%), 197 in BRCA2 (4.9%), and in two index cases a deleterious change in both BRCA1 and BRCA2 was identified. Eleven deleterious changes in BRCA1 and 36 in BRCA2 had not been reported before. In conclusion, this DGGE mutation screening method for BRCA1 and BRCA2 is proven to be highly sensitive and is easy to adopt, which makes screening of large numbers of patients feasible. The results of screening of BRCA1 and BRCA2 in more than 4,000 families present a valuable overview of mutations in the Dutch population.

Contains fulltext : 50189.pdf (publisher's version ) (Closed access)

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Contains fulltext : 48202.pdf (publisher's version ) (Closed access), There are several instruments to assess how patients evaluate their medical treatment choice. These are used to evaluate decision aids. Our objective is to investigate which psychological factors play a role when patients evaluate their medical treatment choices. A pool of 36 items was constructed, covering concepts such as uncertainty about and satisfaction with the decision, informed choice, effective decision making, responsibility for the decision, perceived riskiness of the choice, and social support regarding the decision. This pool was presented to patients at high risk for breast and ovarian cancer, awaiting a genetic test result, and facing the choice between prophylactic surgery or screening. Additional measures were assessed for validation purposes. Factor and Rasch analyses were used for factor and item selection. Construct validity of emerging scales was assessed by relating them with the additional measures. Three factors summarised the psychological factors concerning decision evaluation: Satisfaction-Uncertainty, Informed Choice, and Decision Control. Reliabilities (Cronbach's alpha) of the three scales were 0.79, 0.85, and 0.75, respectively. Construct validity hypotheses were confirmed. The first two scales were similar to previously developed scales. Of these three scales, the Decision Control scale correlated most strongly with the well-being measures, was associated with partner's agreement and physician's preferences as perceived by patients, and with a negative emotional reaction to the information material. In conclusion, the Decision Control scale is a new scale to evaluate decision aids, and it appears to be rooted in health psychological theories.

Contains fulltext : 48740.pdf (publisher's version ) (Closed access), Women at risk of breast and ovarian cancer due to a genetic predisposition may opt for preventive surgery or surveillance. The aim of this study was to determine the effectiveness of surveillance in families with a BRCA mutation. Sixty-eight BRCA-families underwent surveillance using annual mammography, transvaginal ultrasound, and estimation of CA125. Two hundred and two women had at least one breast examination, and 138 at least one examination of the ovaries. After a mean follow-up of 33 months, breast cancer was detected in 21 women, four with lymph node metastases. After a mean follow-up of 37 months, six advanced ovarian cancers were detected. The percentage of metastatic breast cancers in the current study appeared to be acceptable. However, because these women have a high-risk of developing breast cancer, they still have a substantial risk of developing metastatic disease under surveillance. Surveillance for ovarian cancer was not effective.

Contains fulltext : 47763.pdf (publisher's version ) (Closed access), Imaging is often performed yearly for the surveillance of BRCA1/2 mutation carriers and women at high familial breast cancer risk. Growth of cancers in carriers may be faster as these tumours are predominantly high grade. Quantitative data on tumour growth rates in these 2 groups are lacking. Here, we have examined 80 high-risk women under surveillance for tumour size at diagnosis and preceding examinations at mammography and/or MRI. Tumour volume doubling time (DT) was assessed in 30 cancers in BRCA1/2 mutation carriers and 25 non-carriers. Impact of age and menopausal status were also evaluated. Mean DT of all invasive cancers was shorter in carriers (45 days CI: 26-73) than non-carriers (84 days CI: 58-131) (P = 0.048). Mean age at diagnosis was lower in carriers (40 years) than non-carriers (45 years) (P = 0.007). At multivariable analysis only age (P = 0.03), not risk-group (P = 0.26) nor menopause (P = 0.58) correlated significantly with DT. The mean growth rate slowed down to half in each successive 10 years-older group. In conclusion, age at detection indicated the growth rates of hereditary and familial breast cancers. It is recommended that the screening frequency should be adjusted according to a woman's age and a high-sensitive biannual test may be appropriate before the age of 40 years.

Contains fulltext : 57884.pdf (publisher's version ) (Open Access), PURPOSE: To evaluate a shared decision-making intervention (SDMI) for BRCA1/2 mutation carriers who have to make a choice between screening and prophylactic surgery for breasts and/or ovaries. PATIENTS AND METHODS: The SDMI consisted of two value assessment sessions, using the time trade-off method, followed by individualized treatment information based on (quality-adjusted) life expectancy. After the baseline assessment (2 weeks after a positive DNA test result), women were randomly assigned to the SDMI group (n = 44), receiving the SDMI 2 months after the test result, or to the control group (n = 44). The short- and long-term effects, 3 and 9 months after the test result, were assessed using questionnaires. Data were collected on well-being, treatment choice, and decision-related outcomes. RESULTS: In the short term, the SDMI had no effect. In the long term, with respect to well-being, patients in the SDMI group had less intrusive thoughts (P =.05) and better general health (P =.01) and tended to be less depressed (P =.07). With respect to decision-related outcomes for the breasts, the SDMI group held stronger preferences (P =.02) and agreed more strongly to having weighed the pros and cons (P =.01). No effect was found on treatment choice. In the long term, interaction effects between the SDMI and cancer history were found. The SDMI showed an overall beneficial effect for unaffected women, whereas affected women tended to experience detrimental effects. CONCLUSION: We conclude that the SDMI improved decision making in unaffected BRCA1/2 mutation carriers. Supporting decision making in a systematic way using trade-offs is beneficial for these women.

Contains fulltext : 58179.pdf (publisher's version ) (Closed access), To evaluate the impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with cancer. Longitudinal cohort study including women affected and unaffected with breast or ovarian cancer testing for a BRCA1/2 mutation. Data on well-being (anxiety, depression, cancer related distress, general health), treatment choice, and decision making about cancer prevention were collected at baseline (1 week after blood sampling; affected n = 192, unaffected n = 176) and at follow-up (2 weeks after disclosure of a positive test result; affected n = 23, unaffected n = 66). Women affected and unaffected with breast or ovarian cancer were compared using univariate statistics. Change over time was examined using repeated measures analysis of variance. With respect to well-being, affected women scored worse at baseline. At follow-up, both affected and unaffected women experienced a decline in well-being, which tended to be stronger in affected women. Women diagnosed with cancer less than 1 year previously tended to report a worse well-being than those diagnosed longer ago. With respect to treatment choice, more affected women intended to obtain prophylactic surgery and valued it higher at both time points. With respect to decision making, affected women had a lower preference for participation in decision making at baseline; no differences were found at follow-up. At follow-up, both affected and unaffected women showed an increase in strength of treatment preference and a decrease in decision uncertainty. Disclosure of a positive test result had a negative impact on well-being. Affected women, especially those who have been recently diagnosed with cancer, experienced the worst well-being and could benefit from psychosocial support.

Contains fulltext : 58587.pdf (publisher's version ) (Open Access), BACKGROUND: The value of regular surveillance for breast cancer in women with a genetic or familial predisposition to breast cancer is currently unproven. We compared the efficacy of magnetic resonance imaging (MRI) with that of mammography for screening in this group of high-risk women. METHODS: Women who had a cumulative lifetime risk of breast cancer of 15 percent or more were screened every six months with a clinical breast examination and once a year by mammography and MRI, with independent readings. The characteristics of the cancers that were detected were compared with the characteristics of those in two different age-matched control groups. RESULTS: We screened 1909 eligible women, including 358 carriers of germ-line mutations. Within a median follow-up period of 2.9 years, 51 tumors (44 invasive cancers, 6 ductal carcinomas in situ, and 1 lymphoma) and 1 lobular carcinoma in situ were detected. The sensitivity of clinical breast examination, mammography, and MRI for detecting invasive breast cancer was 17.9 percent, 33.3 percent, and 79.5 percent, respectively, and the specificity was 98.1 percent, 95.0 percent, and 89.8 percent, respectively. The overall discriminating capacity of MRI was significantly better than that of mammography (P<0.05). The proportion of invasive tumors that were 10 mm or less in diameter was significantly greater in our surveillance group (43.2 percent) than in either control group (14.0 percent [P<0.001] and 12.5 percent [P=0.04], respectively). The combined incidence of positive axillary nodes and micrometastases in invasive cancers in our study was 21.4 percent, as compared with 52.4 percent (P<0.001) and 56.4 percent (P=0.001) in the two control groups. CONCLUSIONS: MRI appears to be more sensitive than mammography in detecting tumors in women with an inherited susceptibility to breast cancer.

Contains fulltext : 57413.pdf (publisher's version ) (Closed access), A rabbit model was used for the evaluation of a collagen-based biomatrix of small intestinal submucosa (SIS, COOK) in comparison to a biochemically reconstructed biomatrix for bladder tissue regeneration. Rabbits underwent partial cystectomy and cystoplasty with SIS patch graft or with a biochemically defined collagen biomatrix. The grafts of the regenerated bladder wall were harvested at different intervals and tissue regeneration was evaluated. The results of the SIS and biochemically defined biomatrix grafts were comparable. At harvesting, we found five bladder stones and encrustation of the biomatrix in 21/56 animals. No stone formation was observed in the control group. The results of the molecularly defined biomatrix are thus far comparable to SIS. Both matrices show good epithelialization and ingrowth of smooth muscle cells. Both biomatrices show considerable encrustation, which appears to disappear in time. The rabbit model is suitable for bladder tissue engineering studies as it is an easy model to use. In this model, besides tissue regeneration, also some of the clinical problems are seen such as encrustation of foreign body material in the bladder. These aspects are subject for further pre-clinical studies in this animal model.

Contains fulltext : 57882.pdf (publisher's version ) (Closed access), The aim of the study was to evaluate the impact of a decision aid (DA) and its timing in women being tested for a BRCA1/2 mutation. Women with and without a previous history of cancer were included after blood sampling for genetic testing. The DA consisted of a brochure and video providing information on screening and prophylactic surgery. To evaluate the impact of the DA, women were randomised to the DA group (n=184), receiving the DA 2 weeks after blood sampling, or to the control group (n=184). To evaluate the impact of timing, mutation carriers who had received the DA before the test result (n=47) were compared to mutation carriers who received the DA after the test result (n=42). Data were collected on well-being, treatment choice, decision and information related outcomes. The impact of the DA was measured 4 weeks after blood sampling. The impact of timing was measured 2 weeks after a positive test result. The DA had no impact on well-being. Regarding decision related outcomes, the DA group more frequently considered prophylactic surgery (P=0.02) corroborated with higher valuations (P=0.04). No differences were found for the other decision related outcomes. Regarding information related outcomes, the DA group felt better informed (P=0.00), was more satisfied with the information (P=0.00), and showed more accurate risk perceptions. Timing of the DA had no effect on any of the outcomes. No interactions were found between the DA and history of cancer. In conclusion, women being tested for a BRCA1/2 mutation benefit from the DA on information related outcomes. Because timing had no effect, the DA is considered useful either before or after the test result.

Item does not contain fulltext, OBJECTIVE: The evaluation of collagen-based biomatrix (SIS COOK((R))) in comparison to a biochemically reconstructed biomatrix for replacement of the urethra in a rabbit model as a preclinical model. MATERIAL AND METHODS: Rabbits underwent partial urethra replacement (resection of 0.5 to 1.0 cm segment of the urethra), which was replaced with 1 or 4 layers Small Intestinal Submucosa (SIS COOK) patch grafts or with a biochemically defined collagen biomatrix, partly sutured with unresolvable sutures for future reference. Six animals underwent a sham control operation. The grafts of regenerated urethras were harvested at 1, 3 and 9 months after implantation. Urethrography was performed pre-operatively and before sacrificing. The animals were evaluated macroscopically and by routine histology and immunohistochemistry. RESULTS: At 1 month after implantation, the biomatrices (1 layer, 4 layers and our biochemically defined biomatrix) were well distinguishable from the normal surrounding tissues and showed blood vessels at the periphery. Macroscopically, the unresolvable reference sutures were easy to find at all time points. At 3 months the graft was still distinguishable in the 4 layers SIS group. In the 1 layer and the defined biomatrix group a good regeneration of the urethra within the graft was seen with some central fibrosis. Histological and immunohistochemical evaluation showed urothelium regeneration on the 1 layer and on biochemically defined biomatrix with decreasing number of inflammatory cells from 1 month on. In the group treated with 4 layers SIS the urothelium was completely regenerated at 3 months. Histologically, the regeneration of muscle cells in the three biomatrices was comparable. The smooth muscle cells regenerated very slowly as 1 month after implantation no muscle cells were detectable within the grafts. At 3 months a few muscle cells were present in the graft, but cell density did not increase in the following 6 months. Strictures were not obser

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Contains fulltext : 25024___.PDF (publisher's version ) (Open Access)

Contains fulltext : 25573.PDF (publisher's version ) (Open Access)

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