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L Y Dirix

Publications and source records attributed to L Y Dirix.

At least 37 records · Page 2Linked to original sources
PubMed2001

PNU-145156E, a novel angiogenesis inhibitor, in patients with solid tumors: a phase I and pharmacokinetic study.

Our aim was to establish, in patients with solid tumors, the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacology of PNU-145156E, a new sulfonated distamycin A derivative that blocked circulating angiogenesis-promoting growth factors in animal studies and exhibited an antitumor effect in murine solid tumors. In a Phase I study, PNU-145156E was administered i.v. every 6 weeks. Included were patients with solid tumors; an Eastern Cooperative Oncology Group performance score </=1; and normal bone marrow, renal, and liver functions and blood clotting tests. Excluded were patients with brain metastases or on steroid medication. Toxicity was scored with the National Cancer Institute Common Toxicity Criteria. Plasma and urine PNU-145156E was measured for pharmacokinetic analysis. The effect of PNU-145156E on serum basic fibroblast growth factor (bFGF) was measured by sandwich ELISA. Twenty-nine patients (median age, 54 years; range, 33-71 years; 19 males and 10 females; median performance score = 1) were treated at dose levels of 100-1050 mg/m(2). We observed, during 47 treatment cycles, erratic but short-lasting decreases of antithrombin III levels (<75%) at all dose levels. Other clotting tests remained normal except during thromboembolic events. Dose-limiting toxicity was thrombophlebitis, pulmonary embolism, and grade 3 dyspnea. PNU-145156E disappeared from the circulation, decreasing triexponentially with a long terminal half-life of 1 month. No significant change in bFGF and no objective tumor responses were observed. Disease stabilization was achieved in four patients. In conclusion, the MTD of PNU-145156E was 1050 mg/m(2). Serum bFGF level was not affected by PNU-145156E up to the MTD.

Adult↗
PubMed2000

High activity and tolerability demonstrated for exemestane in postmenopausal women with metastatic breast cancer who had previously failed on tamoxifen treatment.

This phase II, multicentre, open-label, clinical trial evaluated antitumoral efficacy, tolerability and endocrine effects following 25 mg of treatment with oral exemestane given daily to postmenopausal women with metastatic breast cancer. Eligibility criteria included oestrogen and/or progesterone positivity or a prior response to hormonal therapy if receptor status was unknown; prior failure to tamoxifen therapy; and progressive disease. Patients were divided into three strata: patients who did not respond to tamoxifen or progressed after disease stabilisation (SD) for less than 6 months (stratum 1); patients who, after an initial response or SD lasting at least 6 months, experienced disease progression whilst on tamoxifen (stratum 2); patients with recurrent metastatic disease during or within 12 months of discontinuing adjuvant tamoxifen (stratum 3). Of the 137 patients who received exemestane, 4 experienced a complete response (CR) and 28 a partial response (PR), for an overall response rate of 23%. Another 33 patients had SD for > or = 24 weeks, resulting in an overall success rate of 47%. The median time to objective response was 16.1 weeks (95% confidence interval (CI) 9.9-24.1). The median response duration was 69.4 weeks, the median duration of overall success 59.1 weeks, the median time to progression (TTP) 25.1 weeks and the median time to treatment failure (TTF) 24 weeks. Response to previous hormonal therapy had little effect on the results, except that there was a trend toward a higher overall success rate in patients who did not respond to previous hormonal therapy. After 8 weeks of therapy, serum levels of oestradiol (E2), oestrone (E1) and oestrone sulphate (E1S) were suppressed to 15.2%, 9.7% and 10.7% of baseline, respectively. The most common adverse events of drug-related or indeterminate cause were hot flushes (14%), dizziness (9%), nausea (8%) and increased sweating (5%). Exemestane had a favourable effect on performance status and tumour-related signs and symptoms, both of which improved or stabilised in approximately 67% and 68% of patients respectively. Exemestane is a unique therapy that is highly active and well tolerated as a new treatment for women with metastatic breast cancer.

Adult↗
PubMed2000

Exemestane improves survival compared with megoestrol acetate in postmenopausal patients with advanced breast cancer who have failed on tamoxifen. results Of a double-blind randomised phase III trial.

Exemestane is an aromatase inactivator. 769 Postmenopausal women with advanced breast cancer who had failed on tamoxifen were randomised to exemestane or megoestrol acetate in this double-blind trial. Objective response rate was similar between treatments. Median time to progression, time to treatment failure and overall survival was significantly longer with exemestane. Drug-related withdrawals and drug-related deaths were more common with megoestrol acetate.

Androstadienes↗
PubMed2000

Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group.

PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen. PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated. RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P =.039), as were the median duration of overall success (OR or stable disease > or = 24 weeks; 60.1 v 49.1 weeks; P =.025), time to tumor progression (20.3 v 16.6 weeks; P =.037), and time to treatment failure (16.3 v 15.7 weeks; P =.042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P =.001). CONCLUSION: EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

Administration, Oral↗
PubMed2000

Exemestane improves survival in metastatic breast cancer: results of a phase III randomized study.

We compared the efficacy and safety of the oral aromatase inactivator exemestane (EXE) with megestrol acetate (MA) in women with metastatic breast cancer. This phase III randomized, double-blind, multicenter study was conducted in 769 postmenopausal women who had experienced tamoxifen failure. Treatment arms consisted of EXE 25 mg once daily (n=366) or MA 40 mg four times daily (160 mg daily; n=403). Peer-reviewed, intent-to-treat analyses demonstrated that EXE induced a trend toward higher rates of complete response (CR)+partial response (PR) (15.0% vs. 12.4%) and of CR+PR+stable disease (SD)=24 weeks (37.4% vs. 34.6%), but differences were not statistically significant. Statistically significant differences favoring EXE were seen in median duration of CR+PR+SD=24 weeks (60.1 vs. 49.1 weeks; P=0.025), time to tumor progression (20.3 vs. 16.6 weeks; P=0.037), time to treatment failure (16.3 vs. 15.7 weeks; P=0.042), and overall survival (not reached vs. 123.4 weeks; P=0.039). Both treatments were well tolerated, but MA was associated with more grade 3 or 4 weight gain (8% vs. 17%, P=0.001); the pain score was sim-ilar in both groups. There was a trend toward superiority in treatment-related signs and symptoms (TRSS) with EXE. There was greater improvement in the pain score and TRSS in patients achieving an objective response with EXE vs. MA. Quality of life improved or was similar for EXE in most domains. Exemestane offers an important new treatment option for postmenopausal women with hormone-responsive breast cancer.

Administration, Oral↗
PubMed1999

Prospective study of intratumoral microvessel density, p53 expression and survival in colorectal cancer.

Adjuvant treatment of patients with colorectal cancer is hampered by a lack of reliable prognostic factors in addition to the clinicopathological staging system. A poorly defined but considerable fraction of Astler-Coller stage B patients will experience tumour recurrence, and some of the stage C patients will probably survive for a prolonged time after surgery without adjuvant treatment. Assessing parameters related to tumour angiogenesis has provided valuable prognostic information in different tumour types. The formation of new microvessels is part of the malignant phenotype in the majority of tumours. Alterations in tumour-suppressor genes, such as the p53 gene, or oncogenes, such as the ras gene, have been found to be responsible for changing the local balance of pro- and antiangiogenic factors in favour of the former. In this prospective study, intratumoral microvessel density (IMD) was assessed by immunostaining tissue sections for CD31 and counting individual microvessels in selected and highly vascular regions in specimens of 145 colorectal cancer patients. p53 protein overexpression was semiquantitatively determined after immunohistochemistry. In both uni- and multivariate analysis, high IMD was significantly associated with shorter survival in the patients undergoing surgery with curative intent (Astler-Coller stages A-C). p53 added prognostic power to IMD, both in Astler-Coller stage B and stage C patients. An association between IMD and mode of metastasis was also noted. High IMD was strongly associated with the incidence of haematogenous metastasis during follow-up, but not with the presence of lymphogenic metastasis observed at surgery. This study confirms the results of previous retrospective analyses of IMD and survival in colorectal cancer and warrants a clinical validation by randomizing stage B tumour patients with high IMD and p53 overexpression between adjuvant treatment or not.

Adult↗
PubMed1999

Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients.

We have compared the platelet number and the serum concentration of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and interleukin-6 (IL-6) in 80 blood samples of 50 patients with advanced cancer. We have also measured the mitogenic effect of patient sera on endothelial cells in vitro in order to estimate the biological activity of serum VEGF. Serum VEGF concentration correlated with platelet number (r = 0.61; P < 10(-4)). Serum IL-6 levels correlated with platelet count (r = 0.36; P < 10(-3)), with serum VEGF levels (r = 0.55; P < 10(-4)) and with the calculated load of VEGF per platelet (r = 0.4; P = 3 x 10(-4)). Patients with thrombocytosis had a median VEGF serum concentration which was 3.2 times higher (P < 10(-4)) and a median IL-6 serum level which was 5.8 times higher (P = 0.03) than in other patients. Serum bFGF did not show an association with any of the other parameters. Patient sera with high VEGF and bFGF content stimulated endothelial cell proliferation significantly more than other sera (P = 4 x 10(-3)). These results support the role of platelets in the storage of biologically active VEGF. Platelets seem to prevent circulating VEGF from inducing the development of new blood vessels except at sites where coagulation takes place. IL-6, besides its thrombopoietic effect, also seems to affect the amount of VEGF stored in the platelets. This is in accordance with the indirect angiogenic action of IL-6 reported previously. The interaction of IL-6 with the angiogenic pathways in cancer might explain the stimulation of tumour growth occasionally observed during IL-6 administration. It also conforms to the worse outcome associated with high IL-6 levels and with thrombocytosis in several tumour types and benign angiogenic diseases.

Angiogenesis Inducing Agents↗
PubMed1999

Soft tissue sarcoma in adults.

Soft tissue sarcomas are a heterogeneous group of tumors, consisting of numerous histiotypes that all share a putative common mesenchymal origin. Although prognosis of these tumors is determined by clinical parameters (size, location, and resection margin status) and pathologic features (mitotic activity and necrosis), the histologic subtype has never been shown to be a consistent independent prognostic factor. Some relevant differences among these histiotypes are emerging, in specific biological parameters such as proliferation indices, in integrin expression profiles, and with regard to drug sensitivity. Several biological factors are considered to be prognostically important. Most attention is directed to regulators of cell-cycle progression. The significance of p53 dysregulation is confirmed by the inhibition of cellular proliferation, both in in-vitro and in in-vivo sarcoma models, after reintroduction of wild type p53. A multidisciplinary approach is essential for the optimal treatment of soft tissue sarcomas. Multimodality treatment has led to a patient-tailored approach with limb-sparing resections integrated with external and/or interstitial irradiation. The value of chemotherapy both in the neoadjuvant and the adjuvant setting, although of critical value in other sarcomas such as Ewing's sarcoma and osteosarcoma, remains to be established for soft tissue sarcomas.

Adult↗
PubMed1998

Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer.

Blood vessel density is a prognostic indicator of multiple tumor types. Recently, it has been established that tumor-associated blood vessels express elevated levels of integrin alpha(v)beta3. In fact, there is evidence that integrin alpha(v)beta3 identifies the most proliferative endothelial cells within human breast carcinomas. Therefore, we evaluated breast cancer tissue in terms of both blood vessel density and alpha(v)beta3 expression. We found that the antibody LM609 to integrin alpha(v)beta3 preferentially stains the blood vessels of small caliber. Furthermore, comparative studies between LM609 and anti-CD31 antibodies on normal breast indicate that very low and weak expression of integrin alpha(v)beta3 was found on vessels within normal tissue, whereas CD31 antigen was expressed in almost all vasculature. Indeed, expression of integrin alpha(v)beta3 was significantly higher in tumors of patients with metastasis than in those without metastasis. In a series of 197 consecutive patients with invasive breast cancer and long follow-up, vascular expression of integrin alpha(v)beta3 in tumor vascular "hot spots" was found to be the most significant prognostic factor predictive of relapse-free survival in both node-negative and node-positive patients. These findings support the contention that angiogenesis plays a critical role in breast cancer progression and suggest that integrin alpha(v)beta3 is an endothelial cell marker with significant prognostic value and potential usefulness as a target for specific antiangiogenic therapy.

Adult↗
PubMed1997

Evaluation of tumour angiogenesis as a prognostic marker in malignant mesothelioma.

Angiogenesis plays an important role in the growth, progression, and metastasis of solid tumours. Malignant mesothelioma (MM) of the pleura is a highly invasive tumour with a poor prognosis. In the present study, microvascular quantification was undertaken on 25 specimens of mesothelioma and 15 specimens of non-neoplastic mesothelium (NNM), by staining for the antigens CD34 and CD31. Areas of highest intratumoural microvascular density (IMD) were identified and counted either manually (mIMD) or on a computerized image analysis system (CIAS; iIMD). The two IMDs were significantly correlated with each other (r = 0.736; P < 0.001). The average IMD for MM was significantly (P < 0.001) higher than in NNM. Moreover, each unit increment in iIMD for MM, when regarded as a continuous variable, was significantly (P = 0.001) associated with an increased hazard of about 4 per cent. When regarded as a categorical variable, the patients in the highest tertile (> 58 vessels/field) had a significantly (P < 0.01; log-rank test) shorter survival than patients in the lowest tertile (< 45 vessels/field). This association was independent of the age of the patient and of the histological type or grade of the MM. No association was noted with p53 immunoexpression. Although the mean vascular area of blood vessels measured on the CIAS did not correlate with survival, assessment of IMDs can be an important independent prognostic indicator in malignant mesothelioma.

Antigens, CD34↗
PubMed1997

Influence of investigator experience and microscopic field size on microvessel density in node-negative breast carcinoma.

In this study on the determination of intratumoral microvessel density (MVD) in breast cancer, we have investigated the influence of the observer experience and the microscopic field size. We have used the sample set reported on earlier in the J Natl Cancer Inst 87: 1797-1798, 1995. This case-control study has shown a positive association of high MVD and unfavorable outcome when comparing node-negative pT1-2 breast carcinoma (NNBC) patients with a disease-free period of over ten years with those with an early distant relapse. Tumor sections of both outcome groups (favorable: n = 19; unfavorable: n = 19) were immunostained for factor VIII related-antigen (FVIII r-Ag). Microvessels were counted in the areas of most intense vascularization ('hot spots'), both at magnification x 200 (field size of 0.61 square mm) and x 400 (field size of 0.15 square mm), by one inexperienced and three experienced observers. Microphotographs of individual vascular hot spots were analyzed using overlays resembling the two field sizes. The main results obtained are: i) a confirmation of the prognostic value of microvessel density in the case-control sample set (n = 38) was established by all experienced but not by the unexperienced investigator; ii) both at x 200 and x 400 magnification, angiogenesis quantification in vascular hot spots contained prognostic information. The results of this study indicate that the selection of vascular hot spots in tumor sections immunostained for an antigen expressed on endothelial cells is more prone to inter-observer variability and more dependent on training than the counting of the microvessels within predefined hot spots itself. The microscopic magnification and resulting field size do not influence the prognostic significance of MVD in NNBC. This information validates the development of more objective methods of measuring the amount of angiogenesis within malignant tissue. This will allow more accurate implementation of the angiogenesis parameter in multiparametric and prospective prognostic factor studies in NNBC.

Adenocarcinoma↗
PubMed1997

Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients.

The concentration of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was determined in the serum of 90 untreated and 42 treated metastatic cancer patients, including patients with colorectal, breast, ovarian and renal carcinomas, with an enzyme-linked immunosorbent assay (ELISA). Levels higher than the 95th percentile of the concentrations of a control group, i.e. 7.5 pg ml(-1) for bFGF and 500 pg ml(-1) for VEGF, were identified as 'elevated'. One measurement during follow-up was included into the analysis per patient. For 19 treated patients, consecutive serum samples were analysed. Fifty-seven per cent of all untreated patients had elevated serum levels of one or both angiogenic factors. The fraction of patients with elevated serum levels of bFGF and/or VEGF was similar in the different tumour types. Agreement of bFGF levels and VEGF levels, classified in relation to their respective cut-off values, was present in 67% of all patients. Fifty-eight per cent of the patients with progressive disease during treatment compared with 15% of the patients showing response to treatment (chi-squared test P < 0.05) had elevated bFGF and/or VEGF serum levels. When consecutive serum samples were analysed, two-thirds of the patients showing progressive disease had increasing serum levels of the angiogenic factors compared with less than one-tenth of the patients showing response (chi-squared test P < 0.05). The lack of association between the serum bFGF and VEGF levels and the tumour type may suggest an aspecific host reaction responsible for solid tumour-related angiogenesis. The main determinants of the serum bFGF and VEGF concentration are the progression kinetics of the metastatic carcinomas.

Adenocarcinoma↗
PubMed1997

Soft tissue sarcoma in adults.

The importance of a multidisciplinary group in the treatment of soft tissue sarcomas is well established. This approach has led to a major shift in treatment from a single-modality radical surgery to a more sophisticated approach with limb-sparing resections integrated with external irradiation, interstitial irradiation, or both. The increasing knowledge of both the molecular mechanisms of sarcoma development and the biological characteristics (tumor cell proliferation, hypoxia, necrosis, angio-genesis) will enable us to predict prognosis on a more individual basis and thus allow for more selective treatment strategies. Studies relating these molecular markers and biological characteristics to treatment results obtained with surgery, radiotherapy, and chemotherapy are eagerly awaited.

Adult↗
PubMed1997

In vitro toxicity studies with mitomycins and bleomycin on endothelial cells.

Pulmonary side effects are increasingly observed as dose-limiting toxicity (DLT) of cancer treatment. The available preclinical models have a limited predictive value for lung toxicity in humans. We have attempted to elucidate potential mechanisms involved in these reactions, by studying the effects on cells, possibly involved in these reactions after in vitro exposure to drugs with known lung toxic effects. We have investigated the effects of bleomycin (BLM), mitomycin C (MMC), KW-2149 and its two known metabolites, M16 and M18, on oxygen radical production by granulocytes, on cytokine production: interleukin (IL)-6, transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha by a human macrophage cell line (THP-1), by human endothelial cells (HVEC and HMEC) and a human colorectal cancer cell line (DLD-1), and on the cytotoxicity on endothelial cells in both confluent and non-confluent culture. The generation of oxygen radicals by normal and pre-stimulated granulocytes was not increased after preincubation with any of the drugs, at the concentrations tested. None of the cytokines (IL-6, TNF-alpha or TGF-beta) was found significantly increased in culture medium after exposure to any of the mitomycins. This was in contrast with the effect of BLM incubation, causing a rise in TGF-beta concentration. Both types of endothelial cells showed a dose-dependent, exposure duration-dependent, proliferation inhibition for all agents tested. This inhibitory effect was clearly proliferation dependent as shown by the increased inhibition in semi-confluent as opposed to confluent endothelial cell cultures. Both mitomycins tested were more cytotoxic than BLM to both confluent and proliferating endothelial cells.

Antibiotics, Antineoplastic↗
PubMed1996

Correlation of intratumoral microvessel density and p53 protein overexpression in human colorectal adenocarcinoma.

A malignant cell population needs the development of microvessels in order to grow and metastasize. Recently, a role for the p53 gene in the regulation of this angiogenic process has been suggested. Wild-type p53 is involved in the secretion of Trombospondin-1 (TSP-1), an angiogenesis inhibitor. Mutations of the p53 gene cause a downregulation of TSP-1 mRNA in cell lines. Mutant p53 also upregulates the expression of vascular endothelial cell growth factor, a potent angiogenic factor. Together with the reported association of p53 protein overexpression and microvessel density (MVD) in head-and-neck squamous-cell carcinoma, these in vitro findings led us to investigate whether this association would also apply in colorectal adenocarcinomas. Structural changes of the p53 gene are the most frequent observed mutations in colorectal carcinoma and are suspected to be involved in the carcinogenesis at a relatively early stage. Parallel tissue sections from primary colorectal adenocarcinomas were immunostained for CD31, an endothelial cell marker, and with DO7, recognizing both mutant and wild-type p53 protein overexpression. The presence of p53 protein overexpression was found to be significantly associated with high MVD in the vascular hot spots. Our results are in accordance with the in vitro studies on the involvement of p53 in angiogenesis. Mutant p53 might stimulate tumor angiogenesis both indirectly, by augmenting the tumor cell proliferation, and directly, by upregulating angiogenic factors and downregulating angiogenic inhibitors.

Adenocarcinoma↗