Efficacy of low-dose topotecan in second-line treatment for patients with epithelial ovarian carcinoma

BACKGROUND: The high incidence of dose-limiting myelosuppresion using the U.S. Food and Drug Administration-approved topotecan dose of 1.5 mg/m(2) for 5 days every 3 weeks may have limited its utility in the treatment of patients with epithelial ovarian carcinoma. The objective of the study was to evaluate the treatment results and toxicity of a low-dose topotecan regimen as second-line treatment for patients with epithelial ovarian carcinoma. METHODS: A retrospective analysis was conducted of 203 consecutive patients with primary epithelial ovarian carcinoma who were referred to the Finsen Center during the period from June, 1996 to June, 2000. Eligibility criteria included histopathologically documented, International Federation of Gynecology and Obstetrics (FIGO) Stage IC-IV epithelial ovarian carcinoma; first-line treatment with paclitaxel and a platinum compound; and second-line treatment with topotecan (1.0 mg/m(2) intravenously for 5 days every 3 weeks). Efficacy and toxicity were compared with published results from pivotal trials using the approved dose of topotecan of 1.5 mg/m(2) for the same indication. RESULTS: A total of 56 patients received second-line treatment with the reduced-dose topotecan regimen because of refractory, persistent, or recurrent disease. In the subgroup of patients with platinum-resistant and paclitaxel-resistant disease (n = 43 patients), the response rate of 11.6% (95% confidence interval [95%CI], 3.9-25.1%) was similar to the response rate of 12.4% (95%CI, 6.9-19.9%) in a pivotal trial using standard-dose topotecan. In patients with platinum-resistant and paclitaxel-resistant disease, the median progression free survival and overall survival from the first day of second-line topotecan treatment were 2.7 months (range, 0.7-19.5 months) and 6.0 months (range, 1.0-32.8 months), respectively. In a multivariate Cox analysis, the initial performance status (0 vs. 1-2; P = 0.040; hazard ratio [HR], 2.05) and the performance status at the time of second-line treatment (0 vs. 1-2; P < 0.001; HR, 4.50) were identified as independent prognostic factors for overall survival from the start of second-line treatment. Grade 4 neutropenia was noted in only 5.1% of reduced-dose topotecan cycles (95%CI, 2.8-8.4%) compared with 33% and 57% of standard-dose cycles in pivotal studies. CONCLUSIONS: Topotecan at a dose of 1.0 mg/m(2) has similar efficacy based on response rate and lower toxicity compared with the approved schedule of 1.5 mg/m(2) for 5 days every 3 weeks in second-line treatment for patients with platinum-resistant and paclitaxel-resistant epithelial ovarian carcinoma. However, a comparison of different topotecan doses and schedules preferably should be made in a randomized setting in well-characterized populations with regard to established prognostic factors.     

Dissecting karyotypic patterns in colorectal tumors: two distinct but overlapping pathways in the adenoma-carcinoma transition

More than 500 colorectal tumors with clonal chromosomal abnormalities have been reported. Although the pattern of aberrations is nonrandom, no specific primary or secondary karyotypic abnormality has been identified. Also, the chronological order in which the aberrations appear during disease progression is not well known. One reason why our understanding of the cytogenetic evolution is unclear is the high degree of karyotypic complexity seen in these tumors. To overcome some of these difficulties we have previously used several statistical methods that allow identification and interpretation of karyotypic pathways as well as establishment of a temporal order of appearance of the imbalances. These methods were applied on 531 colorectal tumor karyotypes. By using a resampling strategy, 1p-, +7, 7q-, and +12p were identified as early events. Two major and two minor cytogenetic pathways were identified by means of principal component analysis. The two major pathways were initiated with 1p- and +7, and the minor pathways were initiated with +12p and 7q-. The +7/+12p tumors were found to be hyperdiploid, whereas those with 1p-/7q- were pseudodiploid. We also show that the adenoma-carcinoma transition in the 1p- pathway is strongly linked to karyoytypic evolution, whereas the +7 pathway is not, and that the cytogenetic pathways are separated at both early and late stages.     

Intelligence in preterm children at four years of age as a predictor of school function: a longitudinal controlled study

The aim of the study was to examine whether school performance was reduced in children with very-low birthweight beyond what could be explained by the deficit in intelligence-score at 4 years of age. Participants (n=333) examined at 4 years of age included three subgroups on the basis of birthweight: very-low birthweight (VLBW < 1501 g; n=102), low birthweight (LBW 1500-2300 g; n=139), and normal birthweight (NBW > or = 2500 g; n=92). The general cognitive index index (CGI) from the McCarthy Scales of Children's Abilities was used as an intelligence measurement at this assessment. At 18 to 20 years of age a telephone interview concerning school performance was conducted. Two hundred and fifty-seven participants (53% male, 47% female) entered the analysis. A model with School Performance score after the last year of compulsory school as the outcome variable, and McCarthy GCI and birthweight group as predicting variables, was used in linear regression analyses. Twenty-four per cent of the variance was explained. Birthweight had no influence in this model. In conclusion, the study did not find that birthweight influenced school performance beyond that represented by the McCarthy GCI found at age 4 years.     

The acute and short-time effect of supplementation with the combination of n-3 fatty acids and acetylsalicylic acid on platelet function and plasma lipids

Antiplatelet therapy with acetylsalicylic acid (ASA) is commonly used to reduce the risk of cardio- and cerebrovascular events. Fish consumption has been inversely related to coronary disease, which has been partly attributed to an inhibitory effect of n-3 polyunsaturated fatty acids (n-3 PUFA) on platelet production of tromboxane A2. In this study, we investigated the acute and short-time effect of supplementation with n-3 PUFA and intravenous ASA on platelet function, platelet fatty acid composition and plasma lipids. Eighteen healthy men were randomly allocated to a daily intake of 10 g n-3 PUFA or placebo. After this supplement (14 h and 14 days), blood was sampled before and after intravenous injection of 100 mg ASA. n-3 PUFA given for 14 days caused a minor inhibition of platelet reactivity but negligible compared to 100 mg ASA. No additive effect of n-3 PUFA and ASA could be demonstrated.     

Gender comparisons of control of breathing and metabolism in conscious mice exposed to cold

We evaluated the effects of 2 h of warm (24 degrees C) and cold (6 degrees C) exposure on metabolism and ventilation (V(E)) in conscious male and female Harlan ICR Swiss Webster mice exposed to air, and 8% O(2) in N(2) (hypoxia) and to 5% CO(2) in O(2) (hypercapnia) for 2 min each at both temperatures. All cold-exposed mice increased O(2) consumption (V(O2)), and maintained body temperature. Cold-exposed females doubled their tidal volume, increased their V(E) fivefold, and doubled their ventilatory equivalent to V(O2) (V(E)/V(O2)). In contrast, cold-exposed males decreased tidal volume and doubled V(E) relative to warm exposure. The ventilatory equivalent of males was similar during warm and cold exposure. During warm exposure, mice of both genders increased their ventilatory responses to both hypoxia and to hypercapnia by different mechanisms. In contrast, during cold exposure, these responses were blunted relative to air measurements in females and decreased below air values in males. Thus, cold exposure was able to elicit gender-specific ventilatory and metabolic responses.     

Development of mortality in western and eastern Germany since 1991

At the beginning of the 1990s, life expectancy was clearly higher in the western part of Germany than in the eastern part (life table 1991/93, difference in life expectancy of newborn boys 3.25 years, girls 2.3 years). Since then the life expectancy has increased in western and eastern Germany differently. Despite a harmonization, differences still exist (life table 1997/99: boys 1.8 years, girls 0.8 years). Based on age-specific mortality rates, the decrease of mortality between 1991 and 1999 was particularly strong in the group of 25- to 35-year-old persons in eastern Germany as well as in the group of 30- to 35-year-old persons in western Germany. The largest differences in mortality - based on the probabilities of death in 1997/99 - are evident in the group of 18-year-old men and women as well as in the group of men between 35 and 44 years. At present women in eastern Germany show a lower mortality in some age groups than in western Germany.     

Brain function in the vegetative state

Positron emission tomography (PET) techniques represent a useful tool to better understand the residual brain function in vegetative state patients. It has been shown that overall cerebral metabolic rates for glucose are massively reduced in this condition. However, the recovery of consciousness from vegetative state is not always associated with substantial changes in global metabolism. This finding led us to hypothesize that some vegetative patients are unconscious not just because of a global loss of neuronal function, but rather due to an altered activity in some critical brain regions and to the abolished functional connections between them. We used voxel-based Statistical Parametric Mapping (SPM) approaches to characterize the functional neuroanatomy of the vegetative state. The most dysfunctional brain regions were bilateral frontal and parieto-temporal associative cortices. Despite the metabolic impairment, external stimulation still induced a significant neuronal activation (i.e., change in blood flow) in vegetative patients as shown by both auditory click stimuli and noxious somatosensory stimuli. However, this activation was limited to primary cortices and dissociated from higher-order associative cortices, thought to be necessary for conscious perception. Finally, we demonstrated that vegetative patients have impaired functional connections between distant cortical areas and between the thalami and the cortex and, more importantly, that recovery of consciousness is paralleled by a restoration of this cortico-thalamo-cortical interaction.     

Guidance of percutaneous pulmonary biopsies with real-time CT fluoroscopy

OBJECTIVE: Clinical evaluation of computed tomography (CT) fluoroscopy and comparison with conventional CT guidance for monitoring of percutaneous pulmonary biopsy procedures. METHODS: Twenty CT-guided pulmonary biopsy procedures were conducted. The interventions have prospectively been performed either with CT fluoroscopy or with conventional CT guidance. About 120 kV and 50 mA with a frame-rate of eight images per second were used for CT fluoroscopy. Number of pleural needle passages, procedure times, radiation doses and histologic results were analyzed separately for both methods. RESULTS: Compared with conventional CT guidance, CT fluoroscopy was associated with less pleural needle passages (1.8+/-0.6 vs. 1.1+/-0.3; P=0.003, t-test) and procedure times were shorter than for conventional CT guidance (12.7+/-2.2 min vs. 26.7+/-16.4 min; P=0.02). Analysis of estimated patient related radiation exposure and histologic outcome showed no significant difference between conventional and fluoroscopic CT-guided procedures (P>0.05). CONCLUSION: CT fluoroscopy facilitates guidance of percutaneous pulmonary biopsy procedures. Compared with conventional CT assistance, procedure times are decreased and less pleural needle passages are required. While patient-related radiation exposure is similar, operator-related radiation exposure remains a disadvantage associated with CT fluoroscopy.     

Iron-oxide-enhanced MR imaging of bone marrow in patients with non-Hodgkin's lymphoma: differentiation between tumor infiltration and hypercellular bone marrow

The aim of this study was to differentiate normal, hypercellular, and neoplastic bone marrow based on its MR enhancement after intravenous administration of superparamagnetic iron oxides in patients with cancer of the hematopoietic system. Eighteen patients with cancer of the hematopoietic system underwent MRI of the spine before and after infusion of ferumoxides ( n=9) and ferumoxtran ( n=9) using T1- and T2-weighted turbo spin-echo (TSE) and short tau inversion recovery sequences (STIR). In all patients diffuse or multifocal bone marrow infiltration was suspected, based on iliac crest biopsy and imaging such as conventional radiographs, MRI, and positron emission tomography. In addition, all patients had a therapy-induced normocellular ( n=7) or hypercellular ( n=11) reconversion of the normal non-neoplastic bone marrow. The MRI data were analyzed by measuring pre- and post-contrast signal intensities (SI) of hematopoietic and neoplastic marrow and by calculating the enhancement as deltaSI(%) data and the tumor-to-bone-marrow contrast as contrast-to-noise ratios (CNR). Changes in bone marrow signal intensity after iron oxide administration were more pronounced on STIR images as compared with T1- and T2-weighted TSE images. The STIR images showed a strong signal decline of normal and hypercellular marrow 45-60 min after iron oxide infusion, but no or only a minor signal decline of neoplastic bone marrow lesions; thus, deltaSI% data were significantly higher in normal and hypercellular reconverted marrow compared with neoplastic bone marrow lesions ( p<0.05). Additionally, the contrast between focal or multifocal neoplastic bone marrow infiltration and normal bone marrow, quantified by CNR data, increased significantly on post-contrast STIR images compared with precontrast images ( p<0.05). Superparamagnetic iron oxides are taken up by normal and hypercellular reconverted bone marrow, but not by neoplastic bone marrow lesions, thereby providing significantly different enhancement patterns on T2-weighted MR images; thus, superparamagnetic iron oxides are useful to differentiate normal and neoplastic bone marrow and to increase the bone marrow-to-tumor contrast.