Biomedical subjects

W L van Putten

Publications and source records attributed to W L van Putten.

At least 19 recordsLinked to original sources

PubMed2001

The morbidity of treatment for patients with Stage I endometrial cancer: results from a randomized trial.

PURPOSE: To compare the treatment complications for patients with Stage I endometrial cancer treated with surgery and pelvic radiotherapy (RT) or surgery alone in a multicenter randomized trial. METHODS AND MATERIALS: The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial included patients with endometrial cancer confined to the uterine corpus, either Grade 1 or 2 with more than 50% myometrial invasion, or Grade 2 or 3 with less than 50% myometrial invasion. Surgery consisted of an abdominal hysterectomy and oophorectomy, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy), or no further treatment. A total of 715 patients were randomized. Treatment complications were graded using the French-Italian glossary. RESULTS: The analysis was done at a median follow-up duration of 60 months. 691 patients were evaluable. Five-year actuarial rates of late complications (Grades 1-4) were 26% in the RT group and 4% in the control group (p < 0.0001). Most were Grade 1 complications, with 5-year rates of 17% in the RT group and 4% in the control group. All severe (Grade 3-4) complications were observed in the RT group (3%). Most complications were of the gastrointestinal tract. The symptoms resolved after some years in 50% of the patients. Grade 1-2 genitourinary complications occurred in 8% of the RT patients, and 4% of the controls. Bone complications occurred in 4 RT patients (1%). Seven patients (2%) discontinued their RT due to acute RT-related symptoms. Patients with acute morbidity had an increased risk of late RT complications (p = 0.001). The 4-field box technique was associated with a lower risk of late complications (p = 0.06). CONCLUSION: Pelvic RT increases the morbidity of treatment in Stage I endometrial cancer. In the PORTEC trial, severe complications occurred in 3% of treated patients, and over 20% experienced mild (mostly Grade 1) symptoms. Patients with acute RT-related morbidity had an increased risk of late complications. As pelvic RT in Stage I endometrial carcinoma was shown to significantly reduce the rate of locoregional recurrence, but without a survival benefit, its use in the adjuvant setting requires careful patient selection (treating those at increased risk of relapse), and the use of treatment schemes with the lowest risk of morbidity.

Aged↗

PubMed2001

Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.

BACKGROUND: Women with a BRCA1 or BRCA2 mutation have a high risk of breast cancer and may choose to undergo prophylactic bilateral total mastectomy. We investigated the efficacy of this procedure in such women. METHODS: We conducted a prospective study of 139 women with a pathogenic BRCA1 or BRCA2 mutation who were enrolled in a breast-cancer surveillance program at the Rotterdam Family Cancer Clinic. At the time of enrollment, none of the women had a history of breast cancer. Seventy-six of these women eventually underwent prophylactic mastectomy, and the other 63 remained under regular surveillance. The effect of mastectomy on the incidence of breast cancer was analyzed by the Cox proportional-hazards method in which mastectomy was modeled as a time-dependent covariate. RESULTS: No cases of breast cancer were observed after prophylactic mastectomy after a mean (+/-SE) follow-up of 2.9+/-1.4 years, whereas eight breast cancers developed in women under regular surveillance after a mean follow-up of 3.0+/-1.5 years (P=0.003; hazard ratio, 0; 95 percent confidence interval, 0 to 0.36). The actuarial mean five-year incidence of breast cancer among all women in the surveillance group was 17+/-7 percent. On the basis of an exponential model, the yearly incidence of breast cancer in this group was 2.5 percent. The observed number of breast cancers in the surveillance group was consistent with the expected number (ratio of observed to expected cases, 1.2; 95 percent confidence interval, 0.4 to 3.7; P=0.80). CONCLUSIONS: In women with a BRCA1 or BRCA2 mutation, prophylactic bilateral total mastectomy reduces the incidence of breast cancer at three years of follow-up.

Adult↗

PubMed2001

Improved prognostic significance of cytokine-induced proliferation in vitro in patients with de novo acute myeloid leukemia of intermediate risk: impact of internal tandem duplications in the Flt3 gene.

The heterogeneity of acute myeloid leukemia is reflected in many clinical, biological and genetic features that are used to predict the response to therapy. On the basis of chromosome aberrations patients can be stratified in groups reflecting either good or poor prognosis. However, the majority of patients fall in an 'intermediate risk' group. Internal tandem duplications in the hematopoietic growth factor receptor Flt3 have been shown to separate a subset of high risk patients from intermediate or low risk cases. In an attempt to further characterize the heterogeneity of prognosis among the cytogenetic intermediate risk group of AML, we investigated the overall survival, failure-free survival, initial therapy response and relapse rates of 103 patients with de novo AML in relation to autonomous proliferation and the proliferative response to a panel of 10 cytokines in a short-term thymidine incorporation assay. To exclude perturbation of the responses by other (known) risk factors our final intermediate risk population was comprised of patients with intermediate risk cytogenetics, having an age of 60 years of younger and not showing tandem duplications in the Flt3 gene. Among this intermediate risk group, only the responses to M-CSF and IL-1alpha were found to be predictive for therapy outcome. Results obtained by a 7-day culture with these cytokines revealed two subpopulations characterized by a good and a poor prognosis, respectively. The complete remission rates in these subpopulations were similar, but the relapse rates, failure-free survival and overall survival differed. If further study extends and supports our data, it should be considered to include these patients in the poor risk arms of treatment protocols and offer them intensified treatment or bone marrow transplantation.

Adolescent↗

PubMed2001

Somatostatin receptor scintigraphy useful in stage I-II Hodgkin's disease: more extended disease identified.

Somatostatin receptor (SS-R) scintigraphy successfully shows primary cancers and metastases in patients with a variety of SS-R-positive tumours. In vitro studies have shown that SS-Rs are present in lymph nodes from patients with Hodgkin's disease (HD). We performed a prospective study in 126 newly diagnosed patients with HD and compared the results of SS-R scintigraphy with conventional staging procedures, i.e. physical examination, computerized tomography (CT) scanning and other imaging techniques. We report positive scintigraphy in all patients. The lesion-related sensitivity was 94% and varied from 98% for supradiaphragmatic lesions to 67% for infradiaphragmatic lesions. In comparison with CT scanning and ultrasonography, SS-R scintigraphy provided superior results for the detection of Hodgkin's localizations above the diaphragm. In the intra-abdominal region, the CT scan was more sensitive than the SS-R scan. A false-positive scan was rarely seen. In stages I and II supradiaphragmatic HD patients, SS-R scintigraphy detected more advanced disease in 18% (15 out of 83) of patients, resulting in an upstaging to stage III or IV, thus directly influencing patient management. Our data would support the validity of SS-R scanning as a powerful imaging technique for the staging of patients with HD.

Adolescent↗

PubMed2001

Somatostatin receptor scintigraphy in the initial staging of low-grade non-Hodgkin's lymphomas.

UNLABELLED: In this prospective study, somatostatin receptor (SS-R) scintigraphy was compared with conventional staging procedures for the initial staging of patients with low-grade non-Hodgkin's lymphoma (NHL). METHODS: Fifty consecutive untreated patients with low-grade NHL underwent SS-R scintigraphy as part of their initial staging. Planar images were obtained 24 and 48 h after intravenous injection of 220 MBq (111)In-pentetreotide. SPECT images of the upper abdomen were obtained from all patients. SS-R scans were evaluated blindly without knowledge of the results of the conventional staging methods. SS-R scintigraphy findings were compared with the results of physical and radiologic examinations. RESULTS: SS-R scintigraphy findings were positive in 42 of 50 patients (84%). In 10 patients (20%), the SS-R scan revealed new lesions that had not been revealed by conventional staging procedures. These 10 patients were all upgraded to a higher stage. Consequently, the treatment plan would have been altered in 5 patients (10%). However, in 19 patients (38%), lesions apparent after conventional staging methods were missed by SS-R scintigraphy. The sensitivity of SS-R scintigraphy varied from 62% for supradiaphragmatic lesions to 44% for infradiaphragmatic lesions. The specificity of SS-R scintigraphy was high (98%-100%). In comparison with CT scanning and sonography, SS-R scintigraphy is inferior for the visualization of NHL lesions in the thorax and abdomen. CONCLUSION: Although SS-R scintigraphy findings are positive in a large proportion of patients with low-grade NHL, in most patients only part of the lesions can be visualized. Because of the limited sensitivity, we recommend SS-R scintigraphy for initial staging of patients with low-grade NHL only in selected conditions and not for the general work-up.

Female↗

PubMed2000

Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma.

BACKGROUND: Postoperative radiotherapy for International Federation of Gynaecology and Obstetrics (FIGO) stage-1 endometrial carcinoma is a subject of controversy due to the low relapse rate and the lack of data from randomised trials. We did a multicentre prospective randomised trial to find whether postoperative pelvic radiotherapy improves locoregional control and survival for patients with stage-1 endometrial carcinoma. METHODS: Patients with stage-1 endometrial carcinoma (grade 1 with deep [> or =50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were enrolled. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, without lymphadenectomy, 715 patients from 19 radiation oncology centres were randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints. FINDINGS: Analysis was done according to the intention-to-treat principle. Of the 715 patients, 714 could be evaluated. The median duration of follow-up was 52 months. 5-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 14% in the control group (p<0.001). Actuarial 5-year overall survival rates were similar in the two groups: 81% (radiotherapy) and 85% (controls), p=0.31. Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=0.37). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<0.0001). Two-thirds of the complications were grade 1. Grade 3-4 complications were seen in eight patients, of which seven were in the radiotherapy group (2%). 2-year survival after vaginal recurrence was 79%, in contrast to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly (p=0.02) better for patients in the control group. Multivariate analysis showed that for locoregional recurrence, radiotherapy and age below 60 years were significant favourable prognostic factors. INTERPRETATION: Postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion.

Adenocarcinoma↗

PubMed2000

Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer.

TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients. TP53 mutation was significantly associated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI), 0.12-0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and progesterone receptor, TP53 mutation was a significant predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.0014). TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors appeared to be the most resistant phenotype. Interestingly, the response of patients with TP53 mutations to chemotherapy after tamoxifen was not worse than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant). The median progression-free survival after systemic treatment was shorter for patients with a TP53 mutation than for patients with wild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy, respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy. The type of mutation and its biological function should be considered in the analyses of the predictive value of TP53.

Aged↗

PubMed2000

Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group.

BACKGROUND: Local-control rates after radiotherapy for locally advanced tumours of the bladder, cervix, and rectum are disappointing. We investigated the effect of adding hyperthermia to standard radiotherapy. METHODS: The study was a prospective, randomised, multicentre trial. 358 patients were enrolled from 1990 to 1996, in cancer centres in the Netherlands, who had bladder cancer stages T2, T3, or T4, NO, MO, cervical cancer stages IIB, IIIB, or IV, or rectal cancer stage M0-1 were assessed. Patients were randomly assigned radiotherapy (median total dose 65 Gy) alone (n=176) or radiotherapy plus hyperthermia (n=182). Our primary endpoints were complete response and duration of local control. We did the analysis by intention to treat. FINDINGS: Complete-response rates were 39% after radiotherapy and 55% after radiotherapy plus hyperthermia (p<0.001). The duration of local control was significantly longer with radiotherapy plus hyperthermia than with radiotherapy alone (p=0.04). Treatment effect did not differ significantly by tumour site, but the addition of hyperthermia seemed to be most important for cervical cancer, for which the complete-response rate with radiotherapy plus hyperthermia was 83% compared with 57% after radiotherapy alone (p=0.003). 3-year overall survival was 27% in the radiotherapy group and 51% in the radiotherapy plus hyperthermia group. For bladder cancer, an initial difference in local control disappeared during follow-up. INTERPRETATION: Hyperthermia in addition to standard radiotherapy may be especially useful in locally advanced cervical tumours. Studies of larger numbers of patients are needed for other pelvic tumour sites before practical recommendations can be made.

Aged↗

PubMed2000

The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients.

The antigen levels of components of the urokinase-type plasminogen activator (uPA) system of plasminogen activation are correlated with prognosis in several types of cancers, including breast cancer. In the present study involving 2780 patients with primary invasive breast cancer, we have evaluated the prognostic importance of the four major components of the uPA system [uPA, the receptor uPAR (CD87), and the inhibitors PAI-1 and PAI-2]. The antigen levels were determined by ELISA in cytosols prepared from primary breast tumors. The levels of the four factors significantly correlated with each other; the Spearman rank correlation coefficients (r(s)) ranged from 0.32 (between PAI-2 and PAI-1 or uPAR) to 0.59 (between uPA and PAI-1). The median duration of follow-up of patients still alive was 88 months. In the multivariate analyses for relapse-free survival (RFS) and overall survival (OS), we defined a basic model including age, menopausal status, tumor size and grade, lymph node status, adjuvant therapy, and steroid hormone receptor status. uPA, uPAR, PAI-1, and PAI-2 were considered as categorical variables, each with two cut points that were established by isotonic regression analysis. Compared with tumors with low levels, those with intermediate and high levels showed a relative hazard rate (RHR) and 95% confidence interval (95% CI) of 1.22 (1.02-1.45) and 1.69 (1.39-2.05) for uPA, and 1.32 (1.14-1.54) and 2.17 (1.74-2.70) for PAI-1, respectively, in multivariate analysis for RFS in all patients. Compared with tumors with high PAI-2 levels, those with intermediate and low levels showed a poor RFS with a RHR (95% CI) of 1.30 (1.14-1.48) and 1.76 (1.38-2.24), respectively. Similar results were obtained in the multivariate analysis for OS in all patients. Furthermore, uPA and PAI-1 were independent predictive factors of a poor RFS and OS in node-negative and node-positive patients. PAI-2 also added to the multivariate models for RFS in node-negative and node-positive patients, and in the analysis for OS in node-negative patients. uPAR did not further contribute to any of the multivariate models. A prognostic score was calculated based on the estimates from the final multivariate model for RFS. Using this score, the difference between the highest and lowest 10% risk groups was 66% in the analysis for RFS at 10 years and 61% in the analysis for OS. Moreover, separate prognostic scores were calculated for node-negative and node-positive patients. In the 10% highest risk groups, the proportion of disease-free patients was only 27 +/- 6% and 9 +/- 3% at 10 years for node-negative and node-positive patients, respectively. These proportions were 86 +/- 4% and 61 +/- 6% for the corresponding 10% lowest risk groups of relapse. We conclude that several components of the uPA system are potential predictors of RFS and OS in patients with primary invasive breast cancer. Knowledge of these factors could be helpful to assess the individual risk of patients, to select various types of adjuvant treatment and to identify patients who may benefit from targeted therapies that are currently being developed.

Adult↗

PubMed2000

Value of estrogenic recruitment before chemotherapy: first randomized trial in primary breast cancer.

PURPOSE: Several preclinical studies showed that short-term pretreatment of breast cancer cells with estrogens can increase the antitumor efficacy of different cytotoxic drugs. Some early clinical studies in patients with advanced breast cancer did seem to support these findings. Therefore, the efficacy of estrogenic recruitment followed by chemotherapy was compared with that of chemotherapy alone in a randomized phase III study in women with lymph node-positive primary breast cancer. PATIENTS AND METHODS: Three hundred twenty-eight patients with stage II/IIIA breast cancer who were younger than 66 years of age were randomly allocated to chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC plus pretreatment with ethinyl estradiol (EE(2)). FAC (500, 50, and 500 mg/m(2), respectively) was administered intravenously once every 4 weeks for four cycles. EE(2) (0.5 mg) was administered orally, both 24 hours and immediately preceding FAC chemotherapy. RESULTS: Patient and tumor characteristics and chemotherapy dosages were comparable in both treatment groups. Of 318 assessable patients, with a median follow-up of 6.8 years, 177 patients had a relapse and 127 died. No significant differences were observed between the two treatment groups with respect to relapse-free, local recurrence-free, and overall survival according to univariate and multivariate analyses adjusted for age, menopausal status, tumor size, grade, number of positive nodes, and steroid-receptor status. The power for the detection of an increase of 50% in the median relapse-free survival was 80%. CONCLUSION: Estrogenic recruitment of breast cancer cells before FAC chemotherapy did not influence the efficacy of adjuvant chemotherapy in stage II/IIIA breast cancer patients after a follow-up of 6.8 years.

Adult↗

PubMed1999

Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study.

PURPOSE: To study the effects on gastrointestinal and urological acute morbidity, a randomized toxicity study, comparing conventional and three-dimensional conformal radiotherapy (3DCRT) for prostate carcinoma was performed. To reveal possible volume effects, related to the observed toxicity, dose-volume histograms (DVHs) were used. METHODS AND MATERIALS: From June 1994 to March 1996, 266 patients with prostate carcinoma, stage T1-4N0M0 were enrolled in the study. All patients were treated to a dose of 66 Gy (ICRU), using the same planning procedure, treatment technique, linear accelerator, and portal imaging procedure. However, patients in the conventional treatment arm were treated with rectangular, open fields, whereas conformal radiotherapy was performed with conformally shaped fields using a multileaf collimator. All treatment plans were made with a 3D planning system. The planning target volume (PTV) was defined to be the gross target volume (GTV) + 15 mm. Acute toxicity was evaluated using the EORTC/RTOG morbidity scoring system. RESULTS: Patient and tumor characteristics were equally distributed between both study groups. The maximum toxicity was 57% grade 1 and 26% grade 2 gastrointestinal toxicity; 47% grade 1, 17% grade 2, and 2% grade > 2 urological toxicity. Comparing both study arms, a reduction in gastrointestinal toxicity was observed (32% and 19% grade 2 toxicity for conformal and conventional radiotherapy, respectively; p = 0.02). Further analysis revealed a marked reduction in medication for anal symptoms: this accounts for a large part of the statistical difference in gastrointestinal toxicity (18% vs. 14% [p = ns] grade 2 rectum/sigmoid toxicity and 16% vs. 8% [p < 0.0001] grade 2 anal toxicity for conventional and conformal radiotherapy, respectively). A strong correlation between exposure of the anus and anal toxicity was found, which explained the difference in anal toxicity between both study arms. No difference in urological toxicity between both treatment arms was found, despite a relatively large difference in bladder DVHs. CONCLUSIONS: The reduction in gastrointestinal morbidity was mainly accounted for by reduced toxicity for anal symptoms using 3DCRT. The study did not show a statistically significant reduction in acute rectum/sigmoid and bladder toxicity.

Colon, Sigmoid↗

PubMed1999

Comparison of the clinical effectiveness of the 433 MHz Lucite cone applicator with that of a conventional waveguide applicator in applications of superficial hyperthermia.

PURPOSE: This report presents the final stage of our program to improve the quality of our superficial hyperthermia treatments. We have already demonstrated that the Lucite cone applicator (LCA), our technically improved water-filled, wave-guide applicator (WGA), is superior to the conventional WGA. The main objective of the present study was to investigate whether the technical improvements of a WGA were reflected in an improved clinical performance, e.g., a better temperature distribution. METHODS AND MATERIALS: Power and temperature analyses were performed retrospectively on 128 treatments of superficially located tumors (less than 4 cm depth). Twenty-three patients were treated alternately with a WGA setup and a LCA setup. RESULTS: The average power level per antenna in an array was 48 W and 62 W for the WGA and LCA respectively. The average invasively measured temperatures increased by 0.27 degrees C when the LCAs were used. The temperature difference between the center and the periphery of an antenna, averaged over the complete array of antennae, was 0.43 degrees C using WGAs and -0.05 degrees C using LCAs indicating a more uniform heating. The T90 of the invasively measured temperatures remained unchanged (WGA: 39.4 degrees C versus LCA: 39.5 degrees C). CONCLUSION: The LCA is now our standard applicator for superficial hyperthermia treatments as it is technically and clinically proven to be superior to the WGA.

Analysis of Variance↗

PubMed1999

[Re-irradiation with hyperthermia in patients with recurrent breast cancer].

In the Daniel den Hoed Cancer Centre in Rotterdam, the Netherlands, patients with recurrent breast cancer within a previously irradiated area, are treated by application of hyperthermia in addition to reirradiation. In this development, the following issues are important: (a) the choice of an effective and tolerable reirradiation schedule; (b) the establishment of the limitations of the hyperthermia techniques available; (c) the finding that additional hyperthermia has to be applied to the total tissue volume at risk for tumour recurrence; (d) the assessment of the value of additional hyperthermia by a randomised study. With the reirradiation schedule of 8 x 4 Gy and the hyperthermia application technique at present available, local control is achieved in 76% of the patients for a median duration of 32 months. The probability of local control is related to tumour size. The treatment is tolerated well, with acceptable toxicity. In patients with recurrent breast cancer in a previously irradiated area, combined reirradiation and hyperthermia is very effective, well tolerated and little toxic.

Aged↗

PubMed1999

Cytogenetic clonality analysis of megakaryocytes in myelodysplastic syndrome by dual-color fluorescence in situ hybridization and confocal laser scanning microscopy.

In the myelodysplastic syndrome (MDS), cytogenetic abnormalities are often present and can be used as markers in studies for cell lineage involvement. Little is known of the involvement of the megakaryocytic lineage due to the variable ploidy of these cells. We applied dual-color fluorescence in situ hybridization (FISH) to routinely prepared bone marrow (BM) smears of cytogenetically normal patients and seven patients with MDS and monosomy 7 or trisomy 8. Probes specific for the centromeric regions of chromosomes 7 and 8 were detected with fluorescein isothiocyanate (FITC) and Texas Red, respectively. This enabled us to assess the ratio between the numbers of chromosomes 7 and 8 in the polyploid cells. We utilized confocal laser scanning microscopy to count the FITC and Texas Red FISH signals in the different focal layers of the megakaryocytes. Fifty-six megakaryocytes in six normal BM smears were analyzed, giving a mean ratio of 1.0, a standard deviation (SD) of 0.12, and a range of 0.8-1.33. This ratio was applied to evaluation of clonal involvement of individual megakaryocytes in the patients with MDS. In two patients with monosomy 7, the majority of the megakaryocytes were monosomic. In the five patients with trisomy 8, all or a majority of the analyzed megakaryocytes were trisomic. These results add direct evidence that in MDS megakaryocytes are involved in the malignant clone. Genes Chromosomes Cancer 25:332-338, 1999.

Adult↗

PubMed1999

The venotonic drug hydroxyethylrutosiden does not prevent or reduce docetaxel-induced fluid retention: results of a comparative study.

PURPOSE: Fluid retention, which includes peripheral edema, ascites, pleural or pericardial effusion, or a combination of these that is sometimes associated with significant weight gain, is one of the most troublesome cumulative side effects of docetaxel. A suggestive observation from the data base available at the manufacturer (Rhone-Poulenc Rorer) was that patients who received venotonic drugs appeared to tolerate more courses of docetaxel. This prompted a comparative study to investigate whether the venotonic drug hydroxyethylrutosiden could reduce or delay docetaxel-related fluid retention. METHODS: A total of 85 patients with metastatic breast cancer who were treated with docetaxel at a dose of 100 mg/m2 with corticoid comedication were allocated to receive either 300 mg hydroxyethylrutosiden given orally four times daily (group A) or no hydroxyethylrutosiden (group B). The end point for analysis was the development of fluid retention of > or = grade 2. RESULTS: Fluid retention of > or = grade 2 was reported in 14 of 42 patients (33%) in group A and in 15 of 43 patients (35%) in group B and occurred after a median of 4 cycles of docetaxel in both groups. Weight gain was similar in groups A and B. CONCLUSION: We conclude that hydroxyethylrutosiden does not reduce or delay the incidence and severity of docetaxel-related fluid retention.

Adult↗

PubMed1999

Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up.

BACKGROUND AND PURPOSE: In patients with Hodgkin's disease treated by radiotherapy with a moderate total dose and a low (mean) fraction dose to the heart, the risk of ischemic heart disease was investigated during long-term follow-up. MATERIALS AND METHODS: The medical records of 258 patients treated in the period 1965-1980 with radiotherapy alone as the primary treatment were reviewed. The median follow-up was 14.2 years (range 0.7-26.2). The mean total dose and fraction dose to the heart were 37.2 Gy (SD 2.9) and 1.64 Gy (SD 0.09), respectively. The impact on the development of ischemic heart disease of treatment-related parameters, such as the applied (fraction) dose, irradiation technique (one or two fields per day), and chemotherapy in case of a relapse, was investigated. The incidence of ischemic heart disease in this patient population was compared with the expected incidence based on gender, age and calendar period-specific data for the Dutch population. RESULTS: Thirty-one patients (12%) experienced ischemic heart disease (actuarial risk at 20-25 years: 21.2% (95% C.I. 15-30). Twenty-five of them were hospitalized. When compared with the expected incidence, the relative risk (RR) of hospital admission for ischemic heart disease was 2.7 (95% C.I. 1.7-4.0). There were 12 deaths (4.7%) due to ischemic myocardial or sudden death (actuarial risk at 25 years: 10.2% (95% C.I. 5.3-19), compared to 2.3 cases that were expected to have died from these causes, yielding a standardized mortality ratio (SMR) of 5.3 (95% C.I. 2.7-9.3). Gender (male), pretreatment cardiac medical history and increasing age appeared to be the only significant factors for the development of ischemic heart disease. CONCLUSIONS: Despite the moderate total dose and the low (mean) fraction dose to the heart, the observed incidence of ischemic heart disease is high, especially after long follow-up periods. Treatment related cardiac disease in patients treated for Hodgkin's disease has only been reported for doses above 30 Gy. Although the optimum curative dose is still under debate, some studies recommend a dose as low as 32.5 Gy. The observed high rate of severe heart complications in this study advocates a dose reduction to this level, particularly in the regions where the coronary arteries are located.

Adolescent↗

PubMed1999

Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients.

There is controversy regarding the prognostic value of cathepsin-D in primary breast cancer. An increased level of cathepsin-D in tumour extracts has been found to be associated with a poor relapse-free and overall survival. Studies performed with immunohistochemistry or Western blotting have produced diverse results. We have analysed 2810 cytosolic extracts obtained from human primary breast tumours for cathepsin-D expression, and have correlated their levels with prognosis. The median follow-up of the patients still alive was 88 months. Patients with high cathepsin-D levels had a significantly worse relapse-free and overall survival, also in multivariate analysis (P < 0.0001). Adjuvant therapy which was associated with an improved prognosis in node-positive patients in univariate analysis, also significantly added to the multivariate models for relapse-free and overall survival. There were no statistically significant interactions between the levels of cathepsin-D and any of the classical prognostic factors in analysis for relapse-free survival, suggesting that the prognostic value of cathepsin-D is not different in the various subgroups of patients. Indeed, multivariate analyses in subgroups of node-negative and -positive patients, pre- and post-menopausal patients, and their combinations, showed that tumours with high cathepsin-D values had a significantly poor relapse-free survival, with relative hazard rates ranging from 1.3 to 1.5, compared with tumours with low cathepsin-D levels. The results presented here on 2810 patients confirm that high cytosolic cathepsin-D values are associated with poor prognosis in human primary breast cancer.

Adult↗

PubMed1999

Reirradiation combined with hyperthermia in recurrent breast cancer results in a worthwhile local palliation.

Both experimental and clinical research have shown that hyperthermia (HT) gives valuable additional effects when applied in combination with radiotherapy (RT). The purpose of this study was evaluation of results in patients with recurrent breast cancer, treated at the Daniel den Hoed Cancer Center (DHCC) with reirradiation (re-RT; eight fractions of 4 Gy twice weekly) combined with HT. All 134 patients for whom such treatment was planned were included in the analysis. The complete response rate in 119 patients with macroscopic tumour was 71%. Including the 15 patients with microscopic disease, the local control rate was 73%. The median duration of local control was 32 months, and toxicity was acceptable. The complete response (CR) rate was higher, and the toxicity was less with the later developed 433-MHz HT technique compared with the 2450-MHz technique used initially. With this relatively well-tolerated treatment, palliation by local tumour control of a worthwhile duration is achieved in the majority of patients. The technique used for hyperthermia appeared to influence the achieved results. The value of HT in addition to this re-RT schedule has been confirmed by a prospective randomized trial in a similar patient group. In The Netherlands, this combined treatment is offered as standard to patients with breast cancer recurring in previously irradiated areas.

Adenocarcinoma↗