Biomedical subjects

G H Blijham

Publications and source records attributed to G H Blijham.

At least 19 recordsLinked to original sources

PubMed2003

Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI x anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer.

A phase I study of the bispecific antibody MDX-H210 in combination with granulocyte colony-stimulating factor (G-CSF) was performed in stage IV breast carcinoma patients, overexpressing HER-2/neu. MDX-H210, constructed by crosslinking antigen binding fragments (F(ab') fragments) of monoclonal antibody (mAb) H22 to Fc gamma receptor I (FcgammaRI), and mAb 520C9 to HER-2/neu, respectively, mediates the lysis of tumour cells in vitro, and in human FcgammaRI transgenic mouse models. The proto-oncogene HER-2/neu is overexpressed in approximately 30% of breast cancer patients, and represents a promising target for antibody-based immunotherapy. Fc gamma receptor I (CD64) is an effective trigger molecule, which is expressed on monocytes/macrophages, immature dendritic cells, and G-CSF-primed polymorphonuclear cells (PMN). Patients received G-CSF (Filgrastim) for 8 consecutive days, and cohorts of three patients were treated on day 4 with escalating, single doses of MDX-H210. A total of 30 patients were included, and treatment was generally well tolerated, without reaching dose-limiting toxicity. Side effects consisted mainly of fever and short periods of chills, which were timely related to elevated plasma levels of interleukin 6 and tumour necrosis factor alpha. In the last two cohorts, MDX-H210 plasma levels exceeded 1 microg ml(-1), and on circulating myeloid cells >50% saturation of FcgammaRI was found until day 4. These effector cells were highly effective in antibody-dependent cell-mediated cytotoxicity. Immunohistochemical analyses of tumour biopsies in individual patients documented infiltration of monocytes and PMN after MDX-H210 infusion. Although the clinical course of the disease was not altered by the single dose of MDX-H210, a favourable toxicity profile--even at high doses--and remarkable biological effects were seen when combined with G-CSF. Therefore, the combination of G-CSF and MDX-H210 should be evaluated in further immunotherapeutical strategies.

Adjuvants, Immunologic↗

PubMed2003

High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

Adult↗

PubMed2002

[Shortage in admission capacity for acute cases].

According to Poolman et al. (this issue), 6% of patients visiting the casualty department of a large Amsterdam hospital and requiring hospital admission had to be transported elsewhere at the expense of a considerable administrative effort on the part of the emergency-care physicians. Contributing factors are the way the hospital handles capacity problems, discharge procedures and personnel shortages, and, at the level of the city, the system used to allocate budget for acute care according to the relative needs of the hospitals. However, the major factor is the overall capacity problem in Dutch health care resulting from tight budget control. Despite intense discussions, major changes in this system have yet to be implemented. In the near future lack of qualified medical and nursing personnel will be the main factor that will need to be addressed urgently.

Emergencies↗

PubMed2001

Prediction of depression 6 months to 3 years after treatment of head and neck cancer.

BACKGROUND: Head and neck cancer and its treatment can have important psychosocial implications. Many patients become depressed. The aim of this prospective study is to examine whether pretreatment variables can be used to predict depression up to 3 years after treatment. METHODS: Head and neck cancer patients (n = 197) treated with surgery and/or radiotherapy completed both before and after treatment a questionnaire including items on social support, coping, depressive symptoms, physical functioning, and physical symptoms. RESULTS: Eight pretreatment variables (tumor stage, sex, depressive symptoms, openness to discuss cancer in the family, available appraisal support, received emotional support, tumor-related symptoms, and size of the informal social network) were used to calculate a risk score to determine which patients were depressed at 6 months to 3 years after treatment (positive predicted value, 58%; negative predicted value, 83%). CONCLUSIONS: Eight pretreatment variables can be used to predict accurately those head and neck cancer patients who are likely to become depressed up to 3 years after treatment.

Depression↗

PubMed2001

Sociodemographic factors and quality of life as prognostic indicators in head and neck cancer.

Pre-treatment quality of life (QOL) has been found to be an independent prognostic factor for survival in cancer patients, in particular in patients with advanced cancer. Sociodemographic factors such as marital and socioeconomic status have also been recognised as prognostic factors. We studied the influence of QOL and mood (measured with the European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) and the Head and Neck Cancer Questionnaire (EORTC QLQ-H&N35), and with the Center for Epidemiologic Studies-Depression Scale (CES-D)) as measured before treatment, the use of cigarettes and alcohol and sociodemographic factors (age, gender, marital status, income and occupation) on recurrence and survival in 208 patients with head and neck cancer prior to treatment with surgery and/or radiotherapy, using Kaplan-Meier and Cox regression analyses. Cognitive functioning and, to a lesser degree, marital status were independent predictors of recurrence and survival, along with medical factors (stage and radicality). Patients with less than optimal cognitive functioning and unmarried patients had a relative risk (RR) of recurrence of 1.72 (95% confidence interval (95% CI) 1.01-2.93) and 1.85 (95% CI 1.06-3.33), respectively, and a RR of dying of 1.90 (95% CI 1.10-3.26) and 1.82 (95% CI 1.03-3.23), respectively. Performance status, physical functioning, mood and global QOL and smoking and drinking did not predict for recurrence and survival. The influence of cognitive functioning might be related to the use of alcohol. Marital status may influence prognosis through mechanisms of health behaviour and/or social support mechanisms.

Alcohol Drinking↗

PubMed2001

Aromatase and COX-2 expression in human breast cancers.

We have investigated aromatase and the inducible cyclooxygenase COX-2 expression using immunocytochemistry in tumors of a series of patients with advanced breast cancer treated with aromatase inhibitors. Aromatase was expressed in 58/102 breast cancers. This is similar to the percentage previously reported for aromatase activity. Interestingly, aromatase was expressed in a variety of cell types, including tumor, stromal, adipose, and endothelial cells. Since prostaglandin E2 is known to regulate aromatase gene expression and is the product of COX-2, an enzyme frequently overexpressed in tumors, immunocytochemistry was performed on the tissue sections using a polyclonal antibody to COX-2. Aromatase was strongly correlated (P<0.001) with COX-2 expression. These results suggest that PGE2 produced by COX-2 in the tumor may be important in stimulating estrogen synthesis in the tumor and surrounding tissue. No correlation was observed between aromatase or COX-2 expression and the response of the patients to aromatase inhibitor treatment. However, only 13 patients responded. Nine of these patients were aromatase positive. Although similar to responses in other studies, this low response rate to second line treatment suggests that tumors of most patients were no longer sensitive to the effects of estrogen. Recent clinical studies suggest that greater responses occur when aromatase inhibitors are used as first line treatment. In the intratumoral aromatase mouse model, expression of aromatase in tumors is highly correlated with increased tumor growth. First line treatment with letrozole was effective in all animals treated and was more effective than tamoxifen in suppressing tumor growth. Letrozole was also effective in tumors failing to respond to tamoxifen, consistent with clinical findings. In addition, the duration of response was significantly longer with the aromatase inhibitor than with tamoxifen, suggesting that aromatase inhibitors may offer better control of tumor growth than this antiestrogen.

Adipocytes↗

PubMed2001

Adjuvant chemo-hormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate (MPA) for node-positive cancer patients, update at 12 years follow up.

An update with 10 years of follow up of a study adding adjuvant MPA to CAF chemotherapy is presented. A total of 409 patients were entered, of which 200 were randomized to receive 500 mg of MPA i.m. on days 1-28 and twice per week thereafter for 6 months. There was a significant improvement in metastases-free and overall survival in women >60 years of age receiving MPA (P=0.01 and P=0.02 respectively). A detrimental effect of MPA was seen in women <40 years. Possible reasons for these results are discussed.

Clinical Trial↗

PubMed2001

Importance of local aromatase activity in hormone-dependent breast cancer: a review.

The cytochrome P-450 enzyme complex aromatase is the rate-limiting step in the production of oestrogens. It catalyses the conversion of androgens to oestrogens. In the treatment of hormone-dependent breast cancer in postmenopausal women, aromatase is the target for treatment with aromatase inhibitors. Recently registered aromatase inhibitors like anastrozole, letrozole and exemestane have proven to be effective therapy for advanced breast cancer in postmenopausal patients failing to respond to treatment with tamoxifen. Intratumoural aromatase activity has predictive value for response to treatment with aromatase inhibitors. Attempts are being made to find an immunohistochemical technique to determine aromatase in tumour tissue, which may serve as a predictive factor. In situ oestrogen synthesis through local aromatase activity in the tumour and adjacent tissue is probably a very important growth-stimulating system in hormone-dependent breast cancer. This synthesis can be blocked with aromatase inhibitors. The regulation of aromatase activity and the cell types that contribute to this process are the subject of extensive research. There seems to be a complex interaction between malignant cells and adjacent cells in which factors such as IL-6 and its soluble receptor, TNF-alpha and prostaglandin E2 play an important role in stimulating aromatase activity.

Journal Article↗

PubMed2000

[Adjuvant systemic therapy for patients with resectable breast cancer: guideline from the Dutch National Breast Cancer Platform and the Dutch Society for Medical Oncology].

There is an abundance of evidence that adjuvant systemic therapy with chemotherapy or endocrine therapy results in better survival for all patients with resectable breast cancer. The absolute 10-year survival advantage however varies for the different patient groups. Therefore, for each individual patient the choice of adjuvant therapy must take into account the potential benefits and the possible side effects. A group of medical oncologists from the Dutch National Breast Cancer Platform (NABON) and the Dutch Society for Medical Oncology (NVMO) prepared a guideline for the treatment of patients with early resectable breast cancer. The criterium for choosing adjuvant systemic therapy for the individual patient is an expected increase in 10-year survival of 5% or more. In the guideline a difference is made between patients with and without axillary lymph node metastasis. In patients with axillary lymph node metastasis the choice for adjuvant systemic therapy depends on the following prognostic factors: menopausal status, age, and the presence of estrogen and progesterone receptors in the tumour. In patients without axillary lymph node metastasis the choice depends also on the following prognostic factors: the size of the tumour, the mitotic activity index, or the histopathologic grade of differentiation.

Adult↗

PubMed2000

Distress in MEN 2 family members and partners prior to DNA test disclosure. Multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant early-onset cancer disorder. In the Netherlands presymptomatic genetic testing for MEN 2 is offered to testees from the age of five years. We report on adults requesting testing for themselves (n=90) and on parents who want an at-risk child to be tested (n=26). Sociodemographic, personality, and attitude characteristics, and levels of psychological distress, were determined for applicants and their partners in the predisclosure phase of testing. These participants showed only mildly increased levels of psychological distress, defined as heightened scores on measures of general and test-related anxiety, and of psychological complaints. Compared with a normal population, high levels of anxiety and health complaints were found in applicants who were younger than 25 years and single, and in persons who generally tended to react to distressful situations with anxiety or depression. These characteristics were particularly evident in young applicants (<25 years). Our study shows that people who feel ambivalent towards DNA testing and who are more vulnerable to psychological distress are more likely to agree to participate in the test as part of a collective application by members of a hereditary cancer family.

Adolescent↗

PubMed2000

Pretreatment factors predicting quality of life after treatment for head and neck cancer.

BACKGROUND: Quality of life (QOL) has become an important issue in head and neck cancer. Explanation of factors predicting QOL after treatment has important implications for patient management. METHODS: In this prospective study we analyzed which pretreatment factors predicted QOL after surgery and/or radiotherapy with curative intent in a cohort of 153 patients with cancer of the oral cavity, oropharynx, hypopharynx, or larynx. The patients completed the EORTC Core Questionnaire, the EORTC Head and Neck Cancer module, and the Center for Epidemiologic Studies Depression scale before treatment and 6 and 12 months later. The influence of gender, age, performance status, and depressive symptoms at baseline, site, stage, and treatment on QOL (and its dimensions) and depressive symptoms after 6 and 12 months was studied, using linear regression analysis. RESULTS: A high level of depressive symptoms and a low performance status at baseline and combination treatment were significant predictors of increased severity of symptoms and poor functioning after treatment. Treatment was a predictor of head and neck symptoms, whereas performance status and depressive symptoms were predictors of general symptoms and functioning. Gender and age had little predictive value. CONCLUSIONS: Patients with depressive symptoms or a low performance status who receive combination treatment for cancer of the head and neck are at risk for physical and psychologic morbidity after treatment. Special attention should be given to these patients in rehabilitation programs.

Adaptation, Psychological↗

PubMed2000

Prediction of depressive symptomatology after treatment of head and neck cancer: the influence of pre-treatment physical and depressive symptoms, coping, and social support.

BACKGROUND: Head and neck cancer and its treatment can have important psychosocial implications, and many patients become depressed. The aim of this prospective study is to examine whether pretreatment variables can be used to predict depression 6 and 12 months later. METHODS: Head and neck cancer patients (155) treated with surgery and/or radiotherapy completed a questionnaire including items on social support, coping, depressive symptoms, physical functioning, and physical symptoms before and after treatment. RESULTS: By using 5 variables (physical symptoms, depressive symptoms, emotional support, extent of the social network, and avoidance coping), it was possible to predict those patients who would have symptoms at 6 (81%) and 12 months (67%) after treatment. Inclusion of actual physical symptoms reported at follow-up increased these percentages to 89% and 82%. CONCLUSIONS: It is concluded that screening for psychosocial variables and physical symptoms before treatment can be used to determine which patients are at risk of developing depressive symptoms after treatment.

Adaptation, Psychological↗

PubMed2000

Interferon-alpha induced changes in CEA expression in patients with CEA-producing tumours.

Enhancement of antigen expression could result in improved tumour targeting using antibodies directed to the antigen. In this study we performed radioimmunoscintigraphy using 99mTc-CEA-Scan to analyse the effect of interferon-alpha (IFN-alpha) in enhancing the expression of carcinoembryonic antigen (CEA) in ten patients with CEA-producing tumours. Furthermore, we investigated the feasibility of a future therapeutic study with this antibody fragment labelled with rhenium-186. Although IFN-alpha gave rise to a significant increase in antibody uptake by the tumour, the absolute antibody uptake in the tumour appeared to be poor, with a mean of 0.475% of injected dose (ID) in the tumour before IFN-alpha, rising to 0.562% ID in the tumour after IFN-alpha. Pharmacokinetic analysis demonstrated no significant alterations after IFN-alpha. In conclusion, the administration of IFN-alpha is an attractive way to achieve enhanced tumour targeting, although the increase was of little clinical significance in this patient population and using this antibody fragment.

Adult↗

PubMed2000

Radioimmunodiagnosis and therapy.

Although promising results with radioimmunotherapy and radioimmunodiagnosis in haematological diseases, have been reported, they are less encouraging results in solid tumours. Experimental mathematical models suggest that optimization of antibody-based therapy and diagnosis is possible and that further research towards improvement is warranted. In this review, the major problems of radioimmunotherapy and diagnosis are discussed. Particular items adressed include tumour uptake of antibodies and antibody-fragments, the target/non-target ratio, immunogenicity and the selection of radionuclides.

Antibodies, Monoclonal↗

PubMed2000

Dose-dense epirubicin and paclitaxel with G-CSF: a study of decreasing intervals in metastatic breast cancer.

Anthracyclines and taxanes are very effective drugs in the treatment of advanced breast cancer. With G-CSF support, the dose-intensity of this combination can be increased by reducing the interval between chemotherapy cycles, the so-called 'shortening of cycle time'. We treated 36 patients with advanced breast cancer in a multicentre phase I/II study. The treatment regimen consisted of epirubicin 75 mg m(-2) followed by paclitaxel 135 mg m(-2) (3 h) in combination with G-CSF. At least six patients were treated in each cohort and were evaluated over the first three cycles. Starting at an interval of 14 days, in subsequent cohorts of patients the interval could be shortened to 10 days. An 8-day interval was not feasible due mainly to incomplete neutrophil recovery at the day of the next scheduled cycle. In the 10-day interval cohort it was feasible to increase the paclitaxel dose to 175 mg m(-2). The haematological and non-haematological toxicity was relatively mild. No cumulative myelosuppression was observed over at least three consecutive cycles. In combination with G-CSF, epirubicin 75 mg m(-2) and paclitaxel 175 mg m(-2) could be safely administered every 10 days over at least three cycles, enabling a dose intensity of 52 and 122 mg m(-2) per week, respectively.

Adolescent↗

PubMed2000

Long-term quality of life of patients with head and neck cancer.

OBJECTIVES: To describe prospectively the long-term changes of quality of life and mood in patients with squamous cell carcinoma of the head and neck treated with surgery and/or radiotherapy. PATIENTS AND METHODS: One hundred seven patients completed the European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire, the EORTC Head and Neck Cancer Module, and the Center for Epidemiological Studies Depression Scale before treatment, and 6, 12, 24, and 36 months later. RESULTS: There was limited deterioration of physical and role functioning and of many head and neck symptoms at 6 months, with improvement thereafter. After 36 months only physical functioning, taste/ smell, dry mouth, and sticky saliva were significantly worse, compared with baseline. Female sex, higher cancer stage, and combination treatment were associated with more symptoms and worse functioning. Despite physical deterioration, there was a gradual improvement of depressive symptomatology and global quality of life. CONCLUSION: Treatment for head and neck cancer results in short-term morbidity, most of which resolves within 1 year. Despite an initially high level of depressive symptomatology, there is gradual improvement of psychological functioning and global quality of life over the course of 3 years. In this prospective study, the impact of the disease and its treatment in long-term survivors seems to be less severe than it is often assumed to be.

Adult↗

PubMed1999

In vitro upregulation of carcinoembryonic antigen expression by combinations of cytokines.

Interferons are able to enhance the expression of carcinoembryonic antigen (CEA) on tumour cells, allowing improved tumour targeting. In this report the hypothesis is tested that combinations of cytokines may further increase the tumour antigen expression. The combination of both IFN-gamma and IFN-alpha with interleukin-6 demonstrated a significant additive effect on the CEA-expression. This was found by quantitatively analysing the CEA-expression on human colorectal tumour cells by flow cytometry. It is concluded that combinations of cytokines show the potential of inducing tumour antigen expression for improved tumour targeting.

Carcinoembryonic Antigen↗

PubMed1999

Angiogenesis inhibitors overcome tumor induced endothelial cell anergy.

We report here that tumor angiogenesis-mediated endothelial cell (EC) anergy can be overcome by inhibitors of angiogenesis. We found previously that tumor growth, known to be dependent on angiogenesis, results in down-regulation of endothelial adhesion molecules and tumor EC anergy to inflammatory signals. We hypothesized that counteracting angiogenesis induces re-expression of adhesion molecules and normalizes responses to inflammatory cytokines. Here, we present data to show that the angiogenesis inhibitor platelet factor-4 (PF4) is able to prevent basic fibroblast growth factor (bFGF)-induced down-regulation of intercellular adhesion molecule-1 (ICAM-1). Furthermore, PF4 restores ICAM-1 expression following bFGF-induced down-regulation of ICAM-1. This PF4 effect occurs at the protein level and the RNA level and it has functional impact on leukocyte adhesion. In addition, PF4 overcomes the tumor-induced EC anergy to inflammatory signals such as tumor necrosis factor alpha (TNF alpha). Our findings may be the basis of new cancer therapies by combining anti-angiogenic therapy and immunotherapy to decrease blood vessel formation and to increase the effectiveness of inflammatory reactions against tumors.

Animals↗