Severin Olesen Larsen

Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours

Among the cytostatic drugs only the alkylating agents have been firmly established as being leukaemogenic. This report describes 4 cases of acute myeloid leukaemia and 1 of myelodysplasia occurring in a cohort of 212 patients with germ-cell tumours treated with etoposide, cisplatin, and bleomycin. The mean cumulative risk of leukaemic complications was 4.7% (SE 2.3) 5.7 years after start of etoposide-containing chemotherapy, and, compared with the risk in the general population, the relative risk of overt leukaemia was 336 (95% CI 92-861). No leukaemias were detected in a previous cohort of 127 patients with germ-cell tumours treated with cisplatin, bleomycin, and vinblastine. The increased risk of leukaemia was most probably due to etoposide alone or in combination with cisplatin or bleomycin, since other published work has also not revealed an excess of leukaemias among patients with germ-cell tumours treated with only cisplatin, bleomycin, and vinblastine. The risk of leukaemia was dose related since all 5 patients with leukaemic complications were among the 82 who had received a cumulative dose of more than 2000 mg/m2 etoposide, whereas no leukaemias were observed among 130 patients who had received up to 2000 mg/m2 (p = 0.004). 3 of the leukaemic patients had balanced chromosome translocations affecting bands 11q23 and 21q22. These translocations, and perhaps also other balanced aberrations, seem to be characteristic of myelodysplasia and acute leukaemia occurring after therapy with cytostatic agents acting on DNA-topoisomerase II.

RISK OF THERAPY-RELATED LEUKAEMIA AND PRELEUKAEMIA AFTER HODGKIN'S DISEASE: Relation to Age, Cumulative Dose of Alkylating Agents, and Time from Chemotherapy

391 patients treated intensively for Hodgkins disease were followed for up to 15 years to evaluate the risk of therapy-related acute non-lymphocytic leukaemia (t-ANLL) and preleukaemia. Only two independent factors, patient age and cumulative dose of alkylating agents, were related to the risk of t-ANLL. The hazard rate of t-ANLL was roughly proportional to the square of patient age and to the total cumulative dose of alkylating agents. In 320 patients treated with alkylating agents the cumulative risk of t-ANLL increased steadily from 1 year after the start of treatment and reached 13.0% (SE 3.0) at 10 years after which time there were no further cases. Calculated from cessation of therapy with alkylating agents, however, the cumulative risk curve increased steeply during the first 1-2 years then gradually levelled out and no new cases were observed beyond 7 years. With a 15-year follow-up the general risk of solid tumours was not increased.

Maternal serum markers in screening for Down syndrome.

The addition of two new markers in maternal serum, estriol and HCG, to those already known, namely the level of maternal serum alfa‐fetoprotein and maternal age, considerably improves the expected results of a screening strategy for Down syndrome. The detection rate is slightly increased from 53.0% to 57.6%, but, more importantly, the false‐positive rate decreases from 9.4% to 7.3%. It is our belief that, at least in women aged less than 35 years, a screening strategy based on a combination of maternal age and biochemical markers should be incorporated into antenatal care. For older women, the results of such a maternal serum test may refine counseling for genetic amniocentesis, as a much more explicit risk calculation can be performed than that based on age alone.

Screening for Down's syndrome using an iso-risk curve based on maternal age and serum alpha-fetoprotein level

On the basis of the significantly different distributions of maternal serum alpha‐fetoprotein (AFP) levels in 86 pregnancies associated with fetal Downs syndrome and in 2018 unaffected pregnancies, an iso‐risk curve for Downs syndrome was constructed. An iso‐risk curve shows, for women of all ages, which combinations of maternal age and level of maternal serum AFP result in the same risk of carrying a fetus with Downs syndrome. A 1:400 risk of Downs syndrome, corresponding to the risk of a 35‐year‐old woman, was chosen as the lowest risk indicating referral for amniocentesis. If all women, irrespective of their age, are offered amniocentesis, when their risk of carrying a Downs syndrome fetus is 1;400 or higher, 53% of the affected fetuses can be detected as compared with 28% of the affected fetuses diagnosed at present in women above 35 years of age.

A new simple and rapid dual assay for AFP and free β hCG in screening for Down syndrome

We have evaluated a simple and rapid 2‐step dual‐label assay (DELFIA®) for alphafetoprotein (AFP) and free β subunit of human gonadotropin (hCGβ) in second‐trimester screening for Down syndrome. Based on stored serum samples from 1059 normal control pregnancies and 72 cases of Down syndrome, we have found the mean Multiple of Median (MoM) for AFP and free hCGβ to be 0.70 and 2.31, respectively. This is slightly but not significantly better than the values for the separate assay for AFP (0.76 MoM) and for intact hCG (2.11 MoM). However, the dual assay is much simpler than the separate assays and therefore prospective comparison trials should be carried out.

Time-resolved immunofluorometric assay of pregnancy-associated plasma protein A in maternal serum screening for Down's syndrome in first trimester of pregnancy

A low maternal serum concentration of pregnancy associated plasma protein-A (MS-PAPP-A) in the first trimester has been suggested as a marker for the presence of a Downs syndrome (DS) fetus. We developed a time-resolved immunofluorometric assay (TrIFMA) for PAPP-A with a sensitivity < 3.9 mIU/l. In the 7-12 gestational weeks interval the median multiples of the median (MoM) was 0.57 (95%-confidence interval; 0.47-0.99) in DS pregnancies (n = 29) and lower than in controls (n = 223) (P < 0.005). The efficiency of MS-PAPP-A alone was evaluated using empirical receiver-operator-characteristics (ROC) and a sensitivity of about 25% was found for a false-positive rate of about 10% in the 7-12 gestational weeks interval. In parameterized ROC analysis a sensitivity of 9% was found for a false-positive rate of 5%. The TrIFMA PAPP-A assay seems to fulfil the quality criteria for an assay to be used in large-scale serum screening for Downs syndrome.

Epidemiology of chronic wound patients and relation to serum levels of mannan-binding lectin.

The aim of this study was to describe the epidemiology of chronic wounds in a large cohort of patients from a tertiary hospital out-patient clinic, and examine the significance of serum mannan-binding lectin for the occurrence and clinical presentation of such wounds. The study comprised 489 consecutive patients with chronic foot and leg ulcers. A clinical classification of wound- aetiology was performed, and mannan-binding lectin was measured in the sera of patients and healthy controls. The patients presented with 639 wounds altogether; diabetic foot ulcers (309), venous leg ulcers (188), arterial ulcers (109), and vasculitis (33). The mannan-binding lectin levels of patients with venous leg ulcer, alone or in combination with other types of wounds, differed significantly from the control group, and the frequency of values < 100 ng/ml was significantly higher. In diabetic and arterial ulcer patients the frequency of values >or= 3000 ng/ml was significantly higher than that of the control group. This suggests a role for the innate immunity in the pathology of venous leg ulcers, and indicates different roles for mannan-binding lectin in the development of ulcers with different aetiologies; it further suggests that mannan-binding lectin substitution should be tested in a controlled clinical trial.

Dating of Pregnancy in First versus Second Trimester in Relation to Post-Term Birth Rate: A Cohort Study

Objectives To evaluate in a national standardised setting whether the performance of ultrasound dating during the first rather than the second trimester of pregnancy had consequences regarding the definition of pre- and post-term birth rates. Methods A cohort study of 8,551 singleton pregnancies with spontaneous delivery was performed from 2006 to 2012 at Copenhagen University Hospital, Holbæk, Denmark. We determined the duration of pregnancy calculated by last menstrual period, crown rump length (CRL), biparietal diameter (1st trimester), BPD (2nd trimester), and head circumference and compared mean and median durations, the mean differences, the systematic discrepancies, and the percentages of pre-term and post-term pregnancies in relation to each method. The primary outcomes were post-term and pre-term birth rates defined by different dating methods. Results The change from use of second to first trimester measurements for dating was associated with a significant increase in the rate of post-term deliveries from 2.1–2.9% and a significant decrease in the rate of pre-term deliveries from 5.4–4.6% caused by systematic discrepancies. Thereby 25.1% would pass 41 weeks when GA is defined by CRL and 17.3% when BPD (2nd trimester) is used. Calibration for these discrepancies resulted in a lower post-term birth rate, from 3.1–1.4%, when first compared to second trimester dating was used. Conclusions Systematic discrepancies were identified when biometric formulas were used to determine duration of pregnancy. This should be corrected in clinical practice to avoid an overestimation of post-term birth and unnecessary inductions when first trimester formulas are used.

The Concepts of Fractal Ellipses and ISO Likelihood Ratio Curve s inTwo-dimensional Screening Procedures with Applications in Scree ningfor Down Syndrome

Background: Prenatal screening combines biochemical and biometric markers into a risk estimate for a particular adverse outcome, e.g. the birth of a child with Down syndrome. The statistical calculations are complicated. We describe a simple graphical method to perform risk estimation in the case of two biochemical markers, to assess the consequences of changes in gestational dating of the pregnancy and to perform quality control. Materials and methods: We used the formulae for the Normal distribution to establish the expression for fractal ellipses, i.e. contour ellipses describing a certain fractile of the total distribution. This expression was used to establish mathematical expressions for curves describing two-dimensional pairs of analytes giving the same likelihood-ratio, i.e. iso likelihood-ratio curves. Results: The fractal ellipses provide an overview of marker distributions that allow for an easy control of empirical marker distributions. The iso likelihood-ratio curves provide a relation between likelihood-ratio and marker values. They can be used for assessment of the consequences of changes in gestational age and introduction of truncation limits on markers. Conclusions: Fractal ellipses and iso likelihood-ratio curves can be used to make software-independent calculations and modifications of risk in prenatal screening and quality control of an ongoing screening program.