PubMed Health⌕ Search

Biomedical subjects

L Moonen

Publications and source records attributed to L Moonen.

10 recordsLinked to original sources
PubMed2001

Apoptosis, proliferation and p53, cyclin D1, and retinoblastoma gene expression in relation to radiation response in transitional cell carcinoma of the bladder.

PURPOSE: To determine whether the apoptotic index, the Ki67 index, and the expression of the p53, cyclin D1, and retinoblastoma genes correlate with local control, overall survival, and time to distant metastases in invasive bladder cancer treated with external beam radiation. METHODS AND MATERIALS: Paraffin-embedded pretreatment biopsies from 83 patients with invasive transitional cell carcinoma of the bladder were scored morphologically for apoptosis and immunohistochemically for Ki67, p53, cyclin D1, and retinoblastoma gene expression. Survival analysis methods were used to assess overall survival, local control, and freedom from distant metastases. A multiple proportional hazard (PH) regression analysis was performed to study the prognostic value of the abovementioned biologic parameters (all divided into two categories, except Ki67) in addition to classical prognostic factors such as T stage, histologic grade, multifocality of the tumor, and completeness of transurethral resection. All patients were treated with external beam radiation as sole treatment. Median follow-up for the 19 patients still living was 7.5 years. RESULTS: Apoptotic index varied from 0% to 3.4% with a mean of 0.8% and a median of 0.6%. Ki67 index varied from 0% to 60% with a mean of 14% and a median of 12%. P53 protein was detectable in 61% of the tumors. Overexpression of cyclin D1 was observed in 39% of the tumors and loss of retinoblastoma protein in 23% of the tumors. High Ki67 index was found to be significantly associated with p53 expression (p = 0.04) and cyclin D1 overexpression (p = 0.023). Cyclin D1 overexpression was found more often in Rb-positive tumors than in Rb-negative tumors (p = 0.006). Other associations between the markers are less clear. Biologic markers were not correlated with T stage or grade. In the PH analysis local control was found to be significantly better for tumors with wild-type p53 (p = 0.028). Also, tumors with an apoptotic index above the median value (0.6%) had a significantly better local control rate (p = 0.035). Ki67 index (p = 0.35), retinoblastoma gene expression (p = 0.30) and cyclin D1 overexpression (p = 0.61) were not found to have an additional predictive value regarding local tumor control. None of the tested biologic parameters were found to be associated with overall survival. Time to distant metastases was significantly shorter for tumors with high Ki67 index (p = 0.01) and tumors with an apoptotic index less than median (p = 0.009). CONCLUSIONS: The results of our study provide evidence for a prognostic value of p53 expression and apoptotic index with respect to the radiation response in bladder cancer in addition to more conventional prognosticators. The value of these parameters as a predictive assay for radiation response warrants confirmation in larger and prospective studies.

Adult↗
PubMed1998

Muscle-invasive bladder cancer treated with external beam radiation: influence of total dose, overall treatment time, and treatment interruption on local control.

PURPOSE: To evaluate and eventually quantify a possible influence of tumor proliferation during the external radiation course on local control in muscle invasive bladder cancer. METHODS AND MATERIALS: The influence of total dose, overall treatment time, and treatment interruption has retrospectively been analyzed in a series of 379 patients with nonmetastasized, muscle-invasive transitional cell carcinoma of the urinary bladder. All patients received external beam radiotherapy at the Netherlands Cancer Institute between 1977 and 1990. Total dose varied between 50 and 75 Gy with a mean of 60.5 Gy and a median of 60.4 Gy. Overall treatment time varied between 20 and 270 days with a mean of 49 days and a median of 41 days. Number of fractions varied between 17 and 36 with a mean of 27 and a median of 26. Two hundred and fourty-four patients had a continuous radiation course, whereas 135 had an intended split course or an unintended treatment interruption. Median follow-up was 22 months for all patients and 82 months for the 30 patients still alive at last follow-up. A stepwise procedure using proportional hazard regression has been used to identify prognostic treatment factors with respect to local recurrence as sole first recurrence. RESULTS: One hundred and thirty-six patients experienced a local recurrence and 120 of these occurred before regional or distant metastases. The actuarial local control rate was 40.3% at 5 years and 32.3% at 10 years. In a multivariate analysis total dose showed a significant association with local control (p = 0.0039), however in a markedly nonlinear way. In fact only those patients treated with a dose below 57.5 Gy had a significant higher bladder relapse rate, whereas no difference in relapse rate was found among patients treated with doses above 57.5 Gy. This remained the case even after adjustment for overall treatment time and all significant tumor and patient characteristics. The Normalized Tumor Dose (NTD) (alpha/beta = 10) and NTD (alpha/beta = 15) were not significantly related to local control (p = 0.96 and p = 0.053, respectively). Only weak evidence was found for an association between local control and overall treatment time (p = 0.067). No difference in bladder relapse rate was found among patients treated with a continuous course and patients who had treatment interruptions (p = 0.099). Neither the length of the interruption, nor the actual number of treatment days has a significant influence on local control (p = 0.04 and p = 0.09, respectively). CONCLUSION: In contrast to two earlier, but smaller reports, in this study no significant effect of treatment prolongation on outcome after radiotherapy could be demonstrated and thus no support was found for an important role for tumor proliferation as the cause of treatment failure in muscle-invasive bladder cancer. Results of large-sized phase III trials will have to be awaited to show any benefit from reduction of the overall treatment time and to quantify the potential effect of tumor proliferation.

Aged↗
PubMed1998

The use of a transverse CT image for the estimation of the dose given to the rectum in intracavitary brachytherapy for carcinoma of the cervix.

BACKGROUND AND PURPOSE: The three-dimensional (3D) dose distribution in combination with 3D anatomy of 13 patients treated for cervical carcinoma with intracavitary brachytherapy was analyzed. The aim of this study was to determine the correlation between a dose value obtained from the integral dose volume histogram (DVH) of the rectum and (a) the Nederlands Kanker Instituut (NKI) point of reference for the rectum dose (R) and (b) the highest dose to the frontal rectum wall in the transverse CT slice near the top of the vagina through point R. RESULTS: The correlation between the DVH rectum dose value for 2 cm3 in the highest dose region and the rectum dose at point R was poor (regression coefficient 0.50). On the contrary, however, the correlation between the DVH rectum dose value for 2 cm3 in the highest dose region and the maximum rectum dose value in a transverse CT slice through point R was good (regression coefficient 0.90). CONCLUSIONS: The maximal rectum dose value obtained from a transverse CT slice near the top of the vagina through point R was found to be a more representative point for the rectal dose burden and might therefore show a good correlation with complications. The point of reference for the rectal dose (R) was found not to be a reliable estimation of the maximal dose in the rectum.

Brachytherapy↗
PubMed1998

Muscle-invasive bladder cancer treated with external beam radiotherapy: pretreatment prognostic factors and the predictive value of cystoscopic re-evaluation during treatment.

PURPOSE: To determine the relationship between tumour and patient characteristics and local control and survival for patients with T2 and T3 bladder cancer treated with radical external beam radiotherapy and to evaluate the predictive value of cystoscopic response evaluation during radiation on final outcome. MATERIALS AND METHODS: Records from 379 patients with non-metastasized T2 or T3 transitional cell carcinoma of the bladder were reviewed. All patient received external beam radiotherapy at The Netherlands Cancer Institute during the period from 1977 to 1990. The total dose varied from 50 to 75 Gy with a mean of 60.5 Gy and a median of 60.4 Gy. The median follow-up was 22 months for all patients and 82 months for the 30 patients still alive at last follow-up. A stepwise procedure using proportional hazard regression was used to identify prognostic factors with respect to local recurrence and survival. RESULTS: One hundred thirty-six patients experienced a local recurrence and 120 of these occurred before regional or distance metastases. The actuarial results at 5 years were 40.3% local control (SE 4.0%), 24.9% disease-free rate (SE 3.0%) and 22.2% overall survival (SE 2.2%). In the univariate analysis age, performance status, result of intravenous pyelography (IVP) and T-stage were found to be related to overall survival and multifocality was related to local control. Multivariate analysis revealed that only age and T-stage were related to survival and only multifocality was related to local control. In patients with solitary tumours who were identified as having the most favourable outcome. local control was 50% at 5 years. Local control in 89 patients who had a cystoscopic evaluation during treatment was identical regardless of whether a complete, partial or no response was observed. Furthermore, local control was identical in patients selected on the basis of a favourable response and in unselected patients. CONCLUSIONS: Although we identified some significant prognostic factors, their predictive value is not strong enough to allow accurate estimation of treatment effect and disease outcome. Cystoscopic response evaluation during treatment was found not to provide reliable information to direct further treatment. Prospective studies to identify ways to select patients for bladder conservation using definitive radiotherapy are urgently needed.

Aged↗
PubMed1997

A feasibility study of accelerated fractionation in radiotherapy of carcinoma of the urinary bladder.

PURPOSE: To establish the shortest possible overall treatment time, with respect to acute and late toxicity, in which a radiation dose of 66 Gy in 2 Gy/fraction can be administered to the urinary bladder. METHODS AND MATERIALS: In a stepwise fashion the overall treatment time of our routinely used conventional treatment schedule (66 Gy in 2 Gy/fraction in 6.5 weeks) was reduced to 5 weeks (Step 1) and then 4 weeks (Step 2). Shortening of the overall treatment time was obtained by giving two daily fractions during the last part of the treatment. The interfraction interval was a minimum of 6 h. Toxicity was scored according to a modified scheme of the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer. Fifteen patients received the 5-week schedule and 25 patients received the 4-week schedule. RESULTS: Note that feasibility was very good for the 5-week schedule. No Grade > or = 3 acute bowel or bladder toxicity was seen in these patients. Severe late complications did not occur. In the 4-week schedule, acute bladder toxicity was unaffected but acute bowel toxicity was considerably increased. Of the 25 patients, 16 suffered from Grade 3 toxicity, 3 from Grade 4, and 1 from Grade 5 toxicity. Actuarial analysis at 3 years showed a 31% incidence of Grade 4 late bladder complications. CONCLUSION: It is concluded that the 5-week schedule is well tolerated. In contrast, the 4-week schedule shows unacceptable acute bowel toxicity and an increased incidence of late bladder complications (p = 0.043).

Aged↗
PubMed1990

The predictive value of cell kinetic measurements in a European trial of accelerated fractionation in advanced head and neck tumors: an interim report.

The value of cell kinetic measurements in head and neck tumors in predicting which patients will benefit from accelerated fractionation radiotherapy regimens is being tested in a multicenter European trial (EORTC trial 22851). This paper reports on the first analysis of the correlation of kinetics with outcome in this trial. A proportion of patients in both the accelerated arm (72 Gy in 5 weeks, 1.6Gy per fraction, 45 fractions) and the conventional arm (70-72 Gy in 7-8 weeks, 1.8-2.0 Gy per fraction, 35-40 fractions) were given an i.v. injection of 100 mg/m2 IUdR (iododeoxyuridine) before treatment, and a tumor biopsy was taken several hours later. The potential doubling time of the tumor (Tpot) was obtained from a flow cytometric analysis of tumor cell nuclei using an anti-IUdR antibody. From a total of 260 patients entered in the trial, 53 have undergone kinetic analysis. Adequate IUdR labeling was seen in 47 patients (88.7%), from which the mean value for Tpot was found to be 4.5 +/- 2.5 days (+/- S.D.). Of the IUdR labeled patients, 30 have now been followed up for at least 1 year, 17 with conventional and 13 with accelerated radiotherapy. These patients were split into those with fast and those with slowly growing tumors, the dividing line being the median Tpot value of 4.6 days. After conventional 7-week radiotherapy, 2 of 6 patients with "fast" growing tumors obtained local control compared with 8 of 11 with "slow" growing tumors. A small difference in local control was seen been fast and slow tumors in the accelerated arm (5/9 vs. 3/4). These preliminary data support the hypothesis that patients with fast growing tumors do poorly with conventional radiotherapy and that pretreatment kinetic measurements can select patients at risk. The predictive power of the method must await the final analysis of trial results.

Cell Division↗
PubMed1988

Human tumour cell kinetics using a monoclonal antibody against iododeoxyuridine: intratumour sampling variations.

Cell kinetic parameters in human tumours were determined by in vivo labelling with iododeoxyuridine (IUdR) followed by flow cytometric analysis of tumour biopsies after staining with a monoclonal antibody against IUdR-DNA. The purpose of this study was to determine the variation in these kinetic parameters from area to area within the same tumour. Each patient received a single i.v. injection of IUdR and the biopsy or operation specimen was taken several hours later. Multiple biopsies were taken or the operation specimen was cut into several pieces. Tumour material was stored in ethanol. Each piece was subsequently processed and stained for analysis separately. The duration of DNA synthesis (Ts), the labelling index (L.I., percent IUdR-labelled cells) and the potential doubling time (Tpot) were determined for each sample. The mean and standard deviation (variation between pieces) for each parameter was calculated for each tumour. The coefficient of variation (C.V.) provided the measure of intratumoural variation. Thirteen tumours were investigated, 6 of which were transitional cell carcinomas of the bladder and 7 of which were squamous cell carcinomas, mostly of the head and neck. Ts values ranged from 4.1 to 17.2 h (mean 9.5 h), L.I. values from 1.6 to 18.6% (mean 9.7%) and Tpot values from 2.3 to 15.1 days (mean 7.2 days). Mean C.V.s for Ts, L.I. and Tpot were 10, 24 and 27%, respectively. Most of the variation in Tpot (calculated from the other two parameters), came from the L.I., with Ts showing much less intratumoural variations. It is concluded that this kinetic method using low IUdR doses can be successfully applied in human tumours and has sufficient accuracy for predictive assay applications in which tumours need to be classified according to their proliferation rates. Further developments are required to distinguish normal and malignant cells flow cytometrically, particularly for diploid tumours.

Antibodies, Monoclonal↗
PubMedDate not supplied

Translational research offers individually tailored treatments for cancer patients.

The measurement of the effect of cisplatin on DNA has become feasible with the development of antibodies against DNA adducts. In a phase II dose escalation trial with concomitant radiotherapy and daily cisplatin in lung cancer, we found that patients with high DNA adduct levels measured in the buccal mucosa had a much higher survival rate than patients with a low or undetectable amount of cisplatin-DNA adducts. The use of this assay may therefore allow the selection of individual patients for concomitant treatment with cisplatin and radiotherapy, as has been shown to be effective in randomized trials in patients with lung, head and neck, and cervix malignancies. To predict the response to radiation treatment, assays have been developed for tumor growth potential by measuring the labeling index after intravenous injection of IdUrd or by estimating cyclin D1 expression. Intrinsic radiation sensitivity of human tumors can be estimated by conventional techniques, which are probably too slow or cumbersome for routine use, or with more rapid assays, such as those for chromosome damage with fluorescent probes. These assays should be able to guide us in the adaptation of the individual radiation doses that should be applied and to select patients for an accelerated or hyperfractionated regimen. Pretreatment levels of apoptosis may also be helpful in predicting treatment outcome, although the data so far show inconsistent results. A better understanding of the signal transduction pathways involved in radiation-induced apoptosis may help in the design of studies aimed at modulating the apoptotic response, thereby increasing cell kill. We have recently shown that alkyllysophospholipids, which inhibit mitogenic signaling, induce apoptosis in a variety of tumor cell lines. In combination with ionizing radiation, these compounds cause an enhancement of apoptotic cell kill. This type of a signaling-based intervention could form the basis for new therapeutic strategies. The role of hormonal therapy in breast cancer patients, both in an adjuvant setting and for the treatment of disseminated disease, is becoming increasingly important. The development of a functional assay for the estrogen receptor (ER-FASAY), based on a yeast growth assay, provides a better way than the classical immunohistochemistry assay of estimating abnormal function of the receptor in tumors. These assays are simply examples, illustrating how clinicians could improve the therapeutic outcome for their patients by implementing knowledge obtained in the laboratory in clinical decision making. With further optimization of these assays, this holds the promise for the future that the treatment for each patient can be tailored rationally to the biology of the individual.

Antineoplastic Agents↗
PubMedDate not supplied

Implementation of anticoagulation guidelines in general practice: a practice report.

There is evidence that patients with atrial fibrillation (AF) are not being anticoagulated according to the published guidelines. Difficulty in identifying such patients may partly explain this. In this study, we examined the yield of different methods for detecting people with AF in a single general practice: hospital discharge letters, referrals to cardiology, staff recall of cases, records of relevant prescriptions from the local pharmacist and similar records from the GMS Payments Board. A review of all files of patients over 45 was undertaken as the definitive method of case identification. Recommended anticoagulation guidelines were applied using structured patient interviews. The practice population was 5,473. Sixty-eight patients with AF were identified giving a practice prevalence of 1.2%. The GMS Payment Board records for the prescribing of all specified medications was the most sensitive method (58.8%) with a positive predictive value of 21.6%. Of nine patients without cognitive impairment at consultation, four (44.4%) opted to change to the recommended treatment. Reluctance of patients to adopt current treatment guidelines points to the need for further work in this area.

Aged↗