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Biomedical subjects

K Hoekman

Publications and source records attributed to K Hoekman.

At least 37 records · Page 2Linked to original sources
PubMed2000

[Coagulation disorders in cancer patients: possible opportunity for therapy].

Coagulation disorders occur often in cancer patients. Thrombosis or embolism may be the first sign of an underlying malignancy. In addition, subclinical coagulation disturbances have been found in the blood of cancer patients, for example elevated concentrations of tissue factor or thrombin-antithrombin complexes. In 20% of the patients thrombocytosis occurs, and for lung and colon cancer it was found that thrombocytosis is an independent negative prognostic factor for survival. The role of an activated coagulation cascade in tumour growth is not completely clear, but there is strong evidence that the formation of a temporary fibrin matrix stimulates the formation of new blood vessels (angiogenesis) and supports tumour growth and metastasis formation. Preclinical investigations demonstrated that tumour growth and metastasis formation can be inhibited by anticoagulants. Clinical studies suggest a beneficial effect of anticoagulants on the survival of cancer patients, but phase III randomised clinical trials should be performed to determine the effect of longterm administration of anticoagulants.

Anticoagulants↗
PubMed2000

Immunochemotherapy with interleukin-2, interferon-alpha and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study. Dutch Immunotherapy Working Party.

In patients with metastatic renal cell carcinoma response rates of 7-26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993a) Eur J Cancer29A: S6-8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m(-2) was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m(-2) t.i.w. in weeks 2 and 3. Recombinant human IFN-alpha 2a 6 MU m(-2) was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m(-2) t.i.w. in weeks 5-8. 5-FU (750 mg m(-2)) was given as a bolus injection intravenous once a week in weeks 5-8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1-5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1-153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9-20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8-22.4+) months. Median survival was 16.5 (range 1.8-30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-alpha, IL-2 and 5-FU, as described by Atzpodien et al.

Adult↗
PubMed2000

Targeting vascular endothelial growth factor blockade: ascites and pleural effusion formation.

PRIMARY PURPOSE: Formation of ascites and pleural effusion (PE) is a common problem for patients with advanced-stage cancer. These fluid accumulations cause severe symptoms such as abdominal distention, shortness of breath, cachexia, anorexia, and fatigue. Preclinical models have demonstrated that vascular endothelial growth factor (VEGF) plays a pivotal role in the accumulation of malignant PE or ascites. This study investigated whether blockade of VEGF activity would reduce biological activity of PE and ascites on endothelial cells of cancer patients. PATIENTS AND METHODS: The activity of VEGF in PE and ascites of 58 patients (39 with PE and 19 with ascites) was measured. An endothelial cell proliferation assay with human umbilical vein endothelial cells was used to determine the biological activity of ascites and PE. RESULTS: VEGF concentrations ranged from 67-6,245 pg/ml. A significantly higher concentration of VEGF was detected in the ascites and PE of patients with cancer (median, 1,290 pg/ml) than in patients with nonmalignant disease (median, 250 pg/ml; p = 0.02). Of the 58 PE and ascites samples, 41 were biologically active, based on a two- to fourfold stimulation of endothelial cell proliferation in 72 hours. VEGF concentrations were significantly higher in the biologically active samples compared with the 17 nonactive samples (2,056 pg/ml versus 771 pg/ml; p = 0.02). Coincubation of the samples with either a neutralizing polyclonal antibody against VEGF or SU5416, a small molecule inhibitor of the VEGF receptor Flk-1/KDR, inhibited endothelial cell proliferation by 66% and 100%, respectively. The inhibition caused by the antibody and that caused by SU5416 correlated significantly (r = 0.8, p<0.001). CONCLUSION: We conclude that malignant ascites and PE contain high levels of biologically active VEGF. This study strongly supports the hypothesis that blockade of VEGF, such as that afforded by SU5416, may benefit cancer patients with recurrent ascites or PE formation.

Angiogenesis Inhibitors↗
PubMed2000

Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas.

Angiogenesis and activated blood coagulation are involved in tumor growth and metastasis. Although some have suggested that activation of coagulation in tumors is not linked to activation of platelets, no data exist to either support or refute this concept. However, platelet turnover in cancer patients is often increased, and platelets are carriers of angiogenic growth factors. We hypothesized that platelets are involved in tumor-associated angiogenesis. To obtain evidence supporting this hypothesis, we have studied whether the angiogenic and coagulation pathways and platelets are concomitantly activated in cancer patients with soft tissue sarcomas (STSs) using a novel method to detect activated platelets in tumor specimens. Twelve patients with STS were selected on the basis of having intratumoral accumulation of fluid, which was aspirated. These accumulations demonstrated very high concentrations of vascular endothelial growth factor and coagulation factors (including thrombin-antithrombin-complex). Tumor specimens showed dense vascularization with intense vascular endothelial growth factor expression and the presence of activated platelets. Taken together, these results support the concept that angiogenesis, blood coagulation, and platelets are concomitantly activated in STS and support the hypothesis that platelets contribute to tumor-induced angiogenesis.

Antithrombin III↗
PubMed2000

Prognostic role of thymidylate synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor, and proliferation markers in colorectal cancer.

5-Fluorouracil (5FU)-based therapy is given to patients with advanced colorectal cancer and as adjuvant treatment. Thymidylate synthase (TS) is the target for 5FU, and may have a prognostic role for the outcome of 5FU-based therapy together with proliferation markers such as p53 and Ki67. Thymidine phosphorylase (TP, also known as platelet-derived endothelial cell growth factor) may be of importance both in the 5FU drug activation pathway and in tumor angiogenesis, similar to vascular endothelial growth factor (VEGF). TS and TP levels were determined biochemically in fresh-frozen tumor specimens of 32 untreated patients with colorectal cancer, whereas in paraffin-embedded tissue samples, immunohistochemistry was performed for TS, TP, and additional prognostic markers such as p53, Ki67, and VEGF as well as microvessel density. All factors were correlated with patient characteristics such as age, gender, Dukes' stage, angio-invasion, and differentiation grade. TS and TP as measured by various assays were correlated with overall and disease-free survival in this patient group. TP enzyme activity and protein expression correlated with each other. A significant correlation was found between TP enzyme activity and 5-fluoro-2'-deoxyuridine-5'-monophosphate binding activity. VEGF expression correlated significantly with TP immunostaining and Ki67 index. Survival analysis revealed a significant relation of TS levels to the overall survival in this small patient group and a significant correlation between TP activity and disease-free survival. TS and TP both were of prognostic significance in these patients with colorectal cancer. The interesting relationship of TS and TP with angiogenesis and proliferation needs further investigation.

Aged↗
PubMed1999

[Inhibition of tumor angiogenesis as a cancer treatment].

Angiogenesis is the process of new vessel formation from pre-existing vasculature. In preclinical as well as clinical research it has been demonstrated that tumour growth and formation of metastases are angiogenesis dependent. High microvessel density in most tumour types is associated with a bad prognosis. A variety of angiogenic stimuli and inhibitors have been discovered and are expressed in tumours of cancer patients. In addition to specific angiogenic factors, the synthesis and breakdown of the extracellular matrix, the adherence of endothelial cells, the coagulation process and the immune system are important for tumour-induced angiogenesis. Preclinical research has demonstrated that tumour growth can be inhibited by angiogenesis inhibitors. These findings stimulated the development of angiogenesis inhibitors, which are currently under investigation in phase I, phase II and phase III studies for toxicity and efficacy. In the future angiogenesis inhibitors, like insulin therapy in diabetes, may be used to inhibit tumour growth and to induce stabilization of the disease.

Angiogenesis Inducing Agents↗
PubMed1999

MMP-9 activity in urine from patients with various tumors, as measured by a novel MMP activity assay using modified urokinase as a substrate.

Matrix metalloproteinases (MMPs) play an important role in many pathologic processes, but their activities are difficult to determine since no simple specific and/or chromogenic substrate exists. We have developed a novel MMP activity assay using a modified urokinase as a substrate. Protein engineering enabled the plasmin activation site in this urokinase to be substituted by a specific activation site recognized by MMPs. In this way the MMP activity can be monitored via urokinase activity as measured by a simple chromogenic assay. The assay was made specific for MMP-9 by a capture step using MMP-9-specific antibodies that do not interfere with MMP-activity. This assay monitors the amount of active enzyme as well as the latent, but potentially active proform. Using this assay the levels of MMP-9 were investigated in urine from patients with various kinds of carcinoma. High levels of both active and latent MMP-9 were detected in urine from patients with carcinoma of the bladder, whereas hardly any activity was observed in urine from healthy controls. MMP-9 in urine was present in its intact form. Surprisingly, MMP-9 was also increased in the urine of patients with nonurogenital carcinoma. Therefore, measurement of urinary MMP-9 activity levels may be a convenient diagnostic tool for various types of carcinoma.

Adult↗
PubMed1999

Clostridium septicum myonecrosis and ovarian cancer: a case report and review of literature.

A case report of lethal distant myonecrosis with gas gangrene is presented. Cultures from blood and suppuration of our patient revealed Clostridium septicum. At obduction the patient appeared to have a necrotic metastasis of a known ovarian carcinoma in the cecum wall. Predisposing conditions for this type of infection are hematologic malignancies, colon carcinoma, neutropenia, diabetes mellitus, and disruption of the bowel mucosa. Clostridium septicum is highly associated with the presence of a malignancy, either known or occult at the time infection occurs. Occult tumors are mostly situated in the cecal area of the bowel. Clinical symptoms of the syndrome and therapeutic options are discussed.

Female↗
PubMed1999

Peripheral neuropathy due to biweekly paclitaxel, epirubicin and cisplatin in patients with advanced ovarian cancer.

We assessed the peripheral neuropathic changes induced by biweekly combination chemotherapy including paclitaxel 100-165 mg/m2 (in a 3-h infusion), epirubicin 75 mg/m2 and cisplatin 50 mg/m2 (TEC) in patients with advanced ovarian cancer. Neurologic evaluation, including a standardized questionnaire, bed-side neurological examination, and quantitative determination of vibratory perception thresholds (VPT) and grip strength took place before therapy, after 3 and 6 cycles, and thereafter whenever possible. During chemotherapy all patients received granulocyte colony-stimulating factor from days 2 to 12. Pretreated patients received amifostine two times, before epirubicin and before cisplatin administration. Neuropathic symptoms developed in 11/13 non-pretreated patients and in 7/9 chemotherapy-pretreated patients. Neuropathic signs developed in all patients. Neuropathic symptoms and signs were predominantly sensory in character. VPT changes developed primarily in the feet. According to National Cancer Institute of Canada Common Toxicity Criteria, grade 3 peripheral neuropathy after 6 cycles developed in 1/6 and 2/4 non-pretreated patients who received TEC containing paclitaxel 150 and 165 mg/m2, respectively. We conclude that peripheral neuropathy is dose-limiting in chemonaïve patients treated with biweekly TEC combination chemotherapy, at paclitaxel dose level 165 mg/m2 in a 3-h intravenous administration.

Adult↗
PubMed1999

Hypoglycaemia associated with the production of insulin-like growth factor II and insulin-like growth factor binding protein 6 by a haemangiopericytoma.

Non-islet-cell tumour-induced hypoglycaemia (NICTH) is, in most cases, attributable to tumour production of insulin-like growth factor II (IGF-II). Tumour-derived IGF-II has a higher than normal molecular weight (big 'IGF-II') and an impaired ability to form the normal ternary 150 kD complex with IGF binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). Consequently, tumoral IGF-II circulates mainly in smaller binary complexes which have a higher bioavailability than the ternary complex. We had the opportunity to analyze IGFs and IGF-related factors in both pre- and post-operative blood, tumour tissue and tumour cyst fluid from a patient with a disseminated haemangiopericytoma and severe hypoglycaemia. In addition, the effect of serum and tumour cyst fluid on autophosphorylation of the insulin receptor was examined. Patient serum contained low levels of IGF-I, IGFBP-3 and ALS, while the concentrations of IGFBP-2 and IGFBP-6 were markedly elevated. The total level of circulating IGF-II was within the normal range, but Biogel P-60 gel filtration of patient serum revealed that 77% of the IGF-II was present in high molecular weight forms (normal: 10-15%), which decreased to 53% after partial removal of the tumour. Most of the IGF-II immunoreactivity in pre- and post-operative patient serum was associated with 50-60 kD complexes with only a minimal contribution (<10%) from the 150 kD complex. Tumour cyst fluid contained excessive amounts of both big IGF-II and IGFBP-6. Northern blot analysis of total mRNA isolated from the tumour demonstrated high expression of the IGF-II gene and abundant 1.1 kb IGFBP-6 transcript, while the genes encoding IGFBP-3, -4 and -5 were only weakly expressed and mRNA of IGFBP-1, -2 and IGF-I could not be detected. mRNAs for the IGF type II receptor could be easily demonstrated, whereas those for the insulin- and IGF type I receptor were hardly detectable. In contrast to patient serum tumour cyst fluid strongly stimulated the insulin receptor in vitro. The present study suggests an important role of the simultaneous production of IGF-II and IGFBP-6 in the pathophysiology of tumour-induced hypoglycaemia.

Blotting, Northern↗
PubMed1999

Clinical and preclinical modulation of chemotherapy-induced toxicity in patients with cancer.

Anticancer treatment is generally associated with toxicity to health issues. One of the reasons for this unpleasant association is that anticancer agents have been mostly selected on the basis of an empirically established toxicity towards cancer cell lines and rapidly growing tumours in animal models, and not on the basis of a sophisticated intervention in tumour-specific biology. This strategy of drug development unavoidably produces drugs with toxicity towards normal cells and tissues which also have a high cell turnover and share many characteristics with tumour cells. Therefore it is a continuing challenge to design therapy which is both effective and also has high specificity for the biology of cancer and/or is efficiently targeted to tumour tissue. This article describes the mechanisms of cytotoxicity of standard chemo- and radiotherapy and discussed the possibilities of currently available cytoprotective agents to reduce or prevent these toxicities. These agents should ideally be selective for normal cells versus cancer cells, be effective in reducing or preventing toxicity, have no negative impact on anticancer therapy and have minimal adverse effects. None of the agents described in this article fulfils these criteria completely and therefore we cannot recommend these agents for standard use in daily anticancer practice. Nevertheless, there are encouraging data concerning the beneficial effects of dexrazoxane for anthracycline-induced cardiomyopathy and amifostine for platinum- and radiotherapy-induced toxicity. These date warrant further studies.

Animals↗
PubMed1999

Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer.

BACKGROUND: Neoadjuvant chemotherapy improves survival in patients with locally advanced breast cancer (LABC). Usually three to four cycles of conventional-dose neoadjuvant chemotherapy are administered prior to local therapy, and another three cycles thereafter. In an attempt to improve results, we increased the dosages and applied GM-CSF, which, besides being a hematopoietic growth factor, has become increasingly known for its immunostimulatory effects, which might enhance the antitumor effect. METHODS: Forty-two patients with stage IIIA or IIIB breast cancer were treated with doxorubicin (A) (90 mg/m2) and cyclophosphamide (C) (1,000 mg/m2) at three-weekly intervals. In the second and fourth cycle a 10% dose reduction of both agents was applied. On the second day GM-CSF 250 micrograms/m2/day was started and given for 10 days. Initially, some patients were treated with < or = four cycles, but as the study progressed and toxicity appeared tolerable, six cycles were given whenever possible. After the chemotherapy, patients underwent surgery and postoperative radiotherapy. RESULTS: The response rate for the whole group to AC was 98% (95% confidence interval 94%-100%), with a clinical complete response rate of 50% (95% confidence interval 35%-65%). Six patients had a pathological complete response. Median follow-up from the start of chemotherapy is 49 months (range 10-100). The disease-free survival (DFS) at three years is 57% and the overall survival (OS) at three years is 79%. There is a significant trend for improved DFS (p = 0.0000) and OS (p = 0.0002) with increasing number of cycles. CONCLUSION: The results of the present study with neoadjuvant dose-intensive AC chemotherapy and GM-CSF compare favorably with previous studies in patients with LABC. This is most apparent in patients who received six cycles of neoadjuvant chemotherapy. We hypothesize that these encouraging results are probably related to the prolonged presence of the primary tumor, and to the long-term administration of GM-CSF with the primary tumor and axillary lymph nodes in situ. Therefore, a randomized study is warranted. We already initiated an international randomized trial in patients with LABC in order to answer two questions. First, does prolonged neoadjuvant chemotherapy result in an improved DFS and OS in comparison with the conventional approach, and secondly, what is the effect of GM-CSF in this approach in comparison with G-CSF?

Adult↗
PubMed1999

Doxorubicin gradients in human breast cancer.

Ten patients with locally advanced breast cancer were given doxorubicin i.v., and an incision biopsy was subsequently taken. Doxorubicin autofluorescence was examined using computerized laser scanning microscopy, and microvessels were immunostained in the same sections. Overlays of both pictures revealed doxorubicin gradients in tumor islets with high concentrations in the periphery and low concentrations in the center of the tumor islets. Gradients were most pronounced shortly after the injection, but they could still be detected 24 h later. No gradients were observed in connective tissue. This study demonstrates a serious risk of the drug not reaching all of the cancer cells in those cases in which the cancer cells are densely packed in islets. The efficacy of drug treatment will thus depend on the histology of the tumor tissue.

Antineoplastic Agents↗
PubMed1998

Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer.

Forty-two patients with clinical stage IIIA or IIIB breast cancer were treated with neoadjuvant chemotherapy followed by mastectomy and radiotherapy. The median follow-up was 32 months (range 10-72 months) and the median time to progression was 17 months (range 10-30 months). A multivariate analysis showed that a longer disease-free survival (DFS) was related to more chemotherapy cycles given (P = 0.003), a better pathological response to chemotherapy (P = 0.04) and fewer positive axillary lymph nodes (P = 0.05). A better overall survival (OS) was related to more chemotherapy cycles given (P = 0.03) and better pathological response to chemotherapy (P = 0.04). In patients with residual tumour after neoadjuvant chemotherapy, high levels of staining for Ki-67 was correlated with a worse DFS (P = 0.008). Other biological characteristics, including oestrogen receptor status, microvessel density (CD31 staining), P-glycoprotein (P-gp) staining and nuclear accumulation of p53, were not independent prognostic factors for either DFS or OS. If both P-gp and p53 were expressed, DFS and OS were worse in the uni- and multivariate analysis. The preliminary results of this phase II study suggest that coexpression of P-gp/p53 and a high level of staining for Ki-67 after chemotherapy are associated with a worse prognosis, and that prolonged neoadjuvant chemotherapy and the attainment of a pathological complete remission are important factors in determining outcome for patients with this disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

[Bisphosphonates in the treatment and prevention of bone metastases].

Bone metastases occur frequently in cancer and are commonly associated with bone degradation due to the tumoral production of factors which stimulate the development and activation of osteoclasts. During osteolysis growth factors are released which stimulate tumour growth. Bisphosphonates inhibit osteoclastic bone resorption. Recently, in several large randomised studies of patients with multiple myeloma or bone metastases of breast cancer, long-term treatment with clodronate or pamidronate gave significant bone protection.

Bone Neoplasms↗
PubMed1997

Expression of drug resistance proteins in breast cancer, in relation to chemotherapy.

Drug resistance plays an important role in chemotherapy failure in breast cancer. We studied the expression of MDR1, MRP, LRP, DNA topoisomerases, p53 and Ki-67 in different groups of breast cancer patients in relation to chemotherapy. Tissues from 6 normal breasts and 20 primary operable, 40 locally advanced and 10 anthracycline-resistant metastatic breast cancers were assessed. Sequential samples of the same patient were available from 17 patients with locally advanced breast cancer undergoing neo-adjuvant chemotherapy and in 7 metastatic patients undergoing paclitaxel treatment. Protein expression was investigated by immunohistochemistry. Significantly higher protein expression was observed for Pgp, Ki-67 and p53 in the locally advanced breast cancers than in primary operable breast cancers. No other significant differences in protein expression were found among the 3 breast cancer groups. Expression of none of the markers that could be assessed (Pgp, MRP, LRP, p53 and Ki-67) in locally advanced breast cancer had predictive value for pathological response. Interestingly, after chemotherapy a significant decrease in percentage of Ki-67 positive tumor cells was observed, whereas the other markers did not vary substantially. Furthermore, considering all breast cancer samples, a cumulative dose of doxorubicin >400 mg/m2 inversely correlated with Ki-67 positivity. However, 2 patients with a pathological complete remission had only 5-10% Ki67-positive tumor cells before chemotherapy, indicating that Ki67 negativity itself is not responsible for chemoresistance. In conclusion, none of the known proteins related to multidrug resistance predicted response to chemotherapy in breast cancer, and resistant clones left behind generally had a low proliferation rate.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

5-fluorouracil/leucovorin-induced inhibition of thymidylate synthase in normal tissues of mouse and man.

We evaluated the effects of 5-fluorouracil (5FU) and leucovorin (LV) on thymidylate synthase (TS) in normal rapidly dividing tissues, which may contribute to toxic side-effects of treatment with 5FU and LV. TS levels were determined in biopsies of human liver and colon mucosa and murine bone marrow, liver and intestinal mucosa at several time points after administration of therapeutic doses of 5FU or LV/5FU. In murine liver, after treatment with 100 mg/kg 5FU, TS inhibition was significantly higher than after LV/5FU administration (P < 0.001). A similar trend was observed in human liver tissue. Murine intestinal mucosa had TS levels below the limit of detection after 5FU or LV/5FU treatment. In human colon mucosa samples, administration of 500 mg/m2 5FU resulted in a large extent of TS inhibition but the small number of samples did not allow a time- or 5FU-LV/5FU-related evaluation. TS activity in murine bone marrow cells was strongly inhibited to 10% of the control value during 48 h. LV/5FU administration resulted in a slightly higher inhibition. No human bone marrow was available to measure TS levels. Both in mice and humans the most pronounced TS inhibition occurred in the tissue that was involved in dose-limiting toxicity. Therefore it is very likely that TS inhibition in normal tissues contributes to the toxic side-effects of 5FU treatment.

Adult↗