Charles P. T. Schijf

Pharmacokinetics, biodistribution and biological effects of intravenously administered bispecific monoclonal antibody OC/TR F(ab')2 in ovarian carcinoma patients.

The bispecific monoclonal antibody (biMAb) OC/TR combines the anti‐ovarian‐cancer reactivity of the MOv18 monoclonal antibody (MAb) with the reactivity of an anti‐CD3 MAb. Pre‐clinical studies have indicated that this biMAb is able to redirect the cytolytic activity of T cells towards tumour cells, resulting in efficient tumour‐cell lysis. To assess the clinical potential of systemic biMAb‐based cancer therapy we initiated a study in ovarian‐cancer patients. Five patients suspected of ovarian cancer received 123I‐OC/TR F(ab′)2 i.v. Unexpectedly, the first patient developed side effects (grade III–IV toxicity) starting 30 min after infusion (p.i.) of 1 mg of OC/TR F(ab′)2. After approval of the Ethical Committee, the study was continued at lower dose levels (0.1 mg; 0.2 mg). However, at the 0.2‐mg dose level similar side effects were observed. FACS analysis indicated that all peripheral T cells were coated with biMAb immediately following the infusion. The cytokines tumour necrosis factor‐α, interferon‐γ and interleukin‐2 showed maximum serum concentrations 2 h p.i. Tumour uptake ranged from 0.8 to 1.9% ID/kg, resulting in tumour/background ratios of 3 to 8. Our results suggest that at higher antibody dose levels OC/TR F(ab′)2 causes T‐cell activation with acute release of cytokines. Only low doses of biMAb can be administered safely. Despite the interaction with T cells, OC/TR F(ab′)2 preferentially localizes in tumours following i.v. administration, thus offering therapeutic perspectives.

Identification of patients with persistent trophoblastic disease by means of a normal human chorionic gonadotropin regression curve

OBJECTIVE Data from the Dutch Central Registry of Hydatidiform Mole were used to establish a reference human chorionic gonadotropin regression curve after molar pregnancy. STUDY DESIGN A normal serum human chorionic gonadotropin regression corridor was constructed after fitting data from 130 patients with uneventful human chorionic gonadotropin regression after evacuation of a complete hydatidiform mole. Retrospectively, data from 77 patients with persistent trophoblastic disease were analyzed by means of this normal corridor. Measurements were performed with a radioimmunoassay for both native and free human chorionic gonadotropin beta-subunits. RESULTS Human chorionic gonadotropin disappearance curves showed a biphasic decline with median serum half-lives of 1.8 and 12.8 days. Median time until normalization was 74 days (range 28 to 430). With the 95th percentile line, 71 of 77 patients (92%) with persistent trophoblastic disease could be identified. In > 50% of cases this could be achieved within 6 weeks from evacuation. CONCLUSION The normal regression corridor allows identification of patients with persistent trophoblastic disease and an expectant attitude within the limits of the corridor.

Early Identification of Resistance to First-Line Single-Agent Methotrexate in Patients With Persistent Trophoblastic Disease

PURPOSE A generally accepted definition for resistance to first-line single-agent chemotherapy for persistent trophoblastic disease (PTD) is lacking. In the present study, a normogram for serum human chorionic gonadotropin (hCG) from patients with normalization of serum hCG after first-line single-agent chemotherapy for PTD was constructed to identify patients resistant to this chemotherapy. PATIENTS AND METHODS Between 1987 and 2004, data from 2,132 patients were registered at the Dutch Central Registry for Hydatidiform Moles. A normal serum hCG regression corridor was constructed for 79 patients with low-risk PTD who were cured by single-agent methotrexate (MTX) chemotherapy (control group). Another group of 29 patients with low-risk PTD needed additional alternative therapies (dactinomycin and multiagent chemotherapy) for failure of serum hCG to normalize with single-agent chemotherapy (study group). RESULTS Serum hCG measurement preceding the fourth and sixth single-agent chemotherapy course proved to have excellent diagnostic accuracy for identifying resistance to single-agent chemotherapy, with an area under the curve (AUC) for receiver operating characteristic curve analysis of 0.949 and 0.975, respectively. At 97.5% specificity, serum hCG measurements after 7 weeks showed 50% sensitivity. CONCLUSION In the largest study to date, we describe the regression of serum hCG levels in patients with low-risk PTD successfully treated with MTX. At high specificity, hCG levels in the first few courses of MTX can identify half the number of patients who are extremely likely to need alternative chemotherapy to cure their disease and for whom further treatment with single-agent chemotherapy will be ineffective.

Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein(a) in postmenopausal women: a randomized, placebo-controlled study.

Objective To assess the effects of low-dose oral and transdermal estrogen therapy on the lipid profile and lipoprotein(a) [Lp(a)] levels in healthy, postmenopausal women and to study the additional influence of gestodene administration. Design In a multicenter, randomized, double-blind, placebo-controlled study, 152 healthy, hysterectomized, postmenopausal women received daily either placebo (n = 49), 50 &mgr;g transdermal 17&bgr;-estradiol (tE2, n = 33), 1 mg oral 17&bgr;-estradiol (oE2, n = 37), or 1 mg oE2 combined with 25 &mgr;g gestodene (oE2 + G, n = 33) for 13 cycles of 28 days, followed by 4 cycles of placebo in each group. Fasting serum concentrations of total, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp(a) were measured at baseline and in cycles 4, 13, and 17. Results In cycle 13, a significant mean percentage decrease from baseline was found in all treatment groups compared with placebo in total cholesterol (tE2, −4.7%; oE2, −6.9%; oE2 + G, −10.5%) and LDL cholesterol (tE2, −5.8%; oE2, −12.6%; oE2 + G, −13.6%). For both oral groups, the reductions were already significant in cycle 4. None of the treatment groups showed a significant change in HDL cholesterol or triglycerides. In cycle 13, Lp(a) was decreased compared with placebo in the oE2 group (−6.6%) and the oE2 + G group (−8.2%). After washout, all observed changes had returned to baseline level, except for the decreases in total and LDL cholesterol in the oE2 + G group. Conclusions Oral E2 and E2 + G, and to a lesser extent transdermal E2, decreased total and LDL cholesterol. Lp(a) was lowered only by the oral treatments.

Ovarian cancer incidence (1989-1991) and mortality (1954-1993) in the Netherlands

Objective To examine ovarian cancer incidence and mortality in the Netherlands, and to relate trends in mortality to changes in parity and use of oral contraceptives. Methods Age-standardized and age-specific incidence and mortality rates are presented using incidence data from the Netherlands Cancer Registry, 1989–1991, and mortality data from the Netherlands Central Bureau of Statistics, 1954–1993. Results In the period 1989–1991, age-standardized incidence of ovarian cancer was 14.9 per 105 woman-years. The majority (89%) of these tumors had an epithelial origin. Two-thirds of all newly diagnosed ovarian cancers already showed extension to the pelvis or beyond at diagnosis. From the period 1954–1958 to 1969–1973, age-standardized mortality rates increased from 10.6 to 13.1 per 105 woman-years. Thereafter, a decline was noted to 11.4 per 105 woman-years in the period 1989–1993. Age-specific mortality rates showed a pattern of rising mortality in the elderly, whereas mortality in the younger age categories was declining. The number of live births has declined gradually, and oral contraceptive use has increased. Conclusion Incidence of ovarian cancer is high in the Netherlands, but comparable to other countries in north-western Europe and North America. Mortality rates are rising in the elderly and declining in the young. Further research is needed concerning the effects of oral contraceptives, fertility drugs, and hormone replacement therapy on the incidence and mortality of ovarian cancer.

Decreased expression of Ki-67 in atrophic cervical epithelium of post-menopausal women

Papanicolaou‐stained cervical smears (Pap smears) of post‐menopausal women often present difficulties in distinguishing atrophic cervical epithelium from high‐grade cervical intraepithelial neoplasia (CIN2–3). The aim of this study was to disclose differences in proliferative activity in normal cervical epithelium, cervical atrophy, and high‐grade CIN lesions, in order to develop specific and sensitive classifiers to discriminate between cervical atrophy and high‐grade CIN, both in cervical smears and in tissue sections. A case–control study was done on 83 patients. Proliferative activity was assessed in histological sections using the monoclonal antibody MIB1. An image analysis system was used to characterize different proliferation‐associated features. Preceding Pap smears were restained with MIB1 and proliferative activity was measured by a point‐counting procedure, carried out on a training set of 32 cases and a test set of 51 cases. In cervical atrophy, proliferative activity was significantly lower than in normal epithelium (p<0.001). Proliferative activity measured in both biopsies and cervical smears was considerably higher in high‐grade CIN than in normal epithelium (p<0.001). Discriminant analyses resulted in four classifiers, based on proliferation parameters, to discriminate between cervical atrophy and high‐grade CIN, and between CIN2 and CIN3, in biopsy specimens and cervical smears, respectively. The two classifiers for biopsy specimens resulted in 100% correct classification. Application of the classifier obtained from the training set of Pap smears resulted in 100% correct classification of the Pap smears in the test set. The classifier to discriminate between CIN2 and CIN3 in Pap smears, obtained from 36 patients, resulted in 87% and 90% correct classification, respectively. Copyright

The role of deoxyribonucleic acid image cytometric and interphase cytogenetic analyses in the differential diagnosis, prognosis, and clinical follow-up of hydatidiform moles: A report from the central molar registration in the Netherlands

OBJECTIVES To assess the value of deoxyribonucleic acid ploidy in the differential diagnosis and clinical follow-up of hydatidiform moles, the histopathologic features, deoxyribonucleic acid ploidy, and clinical follow-up were compared in 347 cases: 143 complete moles, 52 partial moles, and 152 abortions, of which 56 cases were hydropic abortions with histologic features of triploidy but lacked trophoblastic hyperplasia. STUDY DESIGN In all cases deoxyribonucleic acid image cytometry was performed, and in 85 of these cases interphase cytogenetics was also performed. RESULTS With use of deoxyribonucleic acid image cytometry and interphase cytogenetics, a bimodal polyploid deoxyribonucleic acid pattern was present in 97% of complete moles, 27% of partial moles, and 4% of abortions. All these cases of partial mole were reclassified to complete mole on the basis of this deoxyribonucleic acid pattern and the histopathologic features in spite of the presence of fetal blood cells, amnion, or yolk sac. Deoxyribonucleic acid triploidy was found in 95% of the remaining partial moles, in 77% of hydropic abortions with histologic features of triploidy, and in 14% of the remaining abortions. Reliable differentiation between deoxyribonucleic acid triploid partial moles and hydropic abortions with histologic features of triploidy was not possible on basis of the histopathologic features (trophoblastic hyperplasia) or 3.5c exceeding rates. Deoxyribonucleic acid diploidy was found in 1% of complete moles, 23% of hydropic abortions with features of triploidy, and 78% of the remaining abortions. Deoxyribonucleic acid tetraploidy was rarely found (1% of complete moles, 2% of partial moles, 1% of abortions). Persistent gestational trophoblastic disease developed in 33% of the bimodal deoxyribonucleic acid polyploid cases (all complete moles), in 1% of the diploid cases (concerning one of the two diploid complete moles), and in 1% of the triploid cases (partial moles). CONCLUSION Deoxyribonucleic acid analysis is essential in the diagnosis of hydatidiform moles to decide on clinical follow-up.

Effects of Quarterly Hormone Replacement Therapy on Climacteric Symptoms, Endometrial Safety, and Lipoproteins

A one-year double-blind randomized study in 80 healthy postmenopausal nonhysterectomized women was performed to investigate the effects of continuous estrogen supplementation sequentially combined with progestogen administration once every three months (once a quarter) compared with monthly progestogen administration on climacteric symptoms, bleeding pattern, endometrial histology, and lipoproteins.

Pharmacokinetics and Tissue Distribution of Indium-111-Labeled OV-TL 3 F(ab’)2 in Ovarian Cancer Patients

Twenty-two patients suspected for primary or recurrent ovarian cancer and scheduled for operation were prospectively studied using the murine monoclonal antibody OV-TL 3 F(ab’)2 labeled with Indium-111. After intravenous injection with 140 MBq of the radiolabeled antibody fragment a systematic quantitative analysis of the distribution of the radioimmunoconjugate was performed.