Newsletter

Table of Contents

05.06.2006

Newsletter No. 6/2005 (November 2005)

Prenatal Medicine

First trimester uterine artery Doppler abnormalities predict subsequent intrauterine growth restriction

Gynecologic Oncology

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

Reproductive Medicine

Fertility and ageing
Frequency of aneuploidy in sperm from patients with extremely severe male factor infertility
Patients with abnormal sperm parameters have an increased sex chromosome aneuploidy rate in peripheral leukocytes.

1. First trimester uterine artery Doppler abnormalities predict subsequent intrauterine growth restriction.

This study was undertaken to evaluate the association between uterine artery Doppler velocimetry performed between 10 and 14 weeks gestation and intrauterine growth restriction (IUGR). Uterine artery Doppler velocimetry data were collected on 1067 women enrolled in the FASTER trial at the University of Colorado site. The data were analyzed by using univariate and multivariable logistic regression analysis. The uterine artery mean resistance index (RI) for the entire cohort was equal on the right and left sides (0.59 +/- 0.14). Of the 1067 women, 34.2% had unilateral or bilateral diastolic notches, 1 notch was observed in 23.8%, and bilateral notches in 10.4%. Women with a high uterine artery mean RI (> or = 75th percentile) were 5.5 times more likely to have IUGR (95% CI 1.6-18.7). There was no significant relationship between notching and IUGR. Elevated first trimester uterine artery mean RI is significantly associated with IUGR.

Dugoff L, Lynch AM, Cioffi-Ragan D, Hobbins JC, Schultz LK, Malone FD, D'Alton ME; FASTER Trial Research Consortium First trimester uterine artery Doppler abnormalities predict subsequent intrauterine growth restriction. Am J Obstet Gynecol. 2005 Sep;193(3 Pt 2):1208-12

2. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.

Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. Its efficacy and safety were investigated after excision of early-stage breast cancer and completion of chemotherapy. This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (ClinicalTrials.gov number, NCT00045032.)

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72.

3. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.

BACKGROUND: The combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer are presented. The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel. By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831. Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.).

Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84.

4. Fertility and ageing.

The late 20th century trend to delay birth of the first child until the age at which female fecundity or reproductive capacity is lower has increased the incidence of age-related infertility. The trend and its consequences have also stimulated interest in the possible factors in the female and the male that may contribute to the decline in fecundity with age; in the means that exist to predict fecundity; and in the consequences for pregnancy and childbirth. In the female, the number of oocytes decreases with age until the menopause. Oocyte quality also diminishes, due in part to increased aneuploidy because of factors such as changes in spindle integrity. Although older male age affects the likelihood of conception, abnormalities in sperm chromosomes and in some components of the semen analysis are less important than the frequency of intercourse. Age is as accurate as any other predictor of conception with assisted reproductive technology. The decline in fecundity becomes clinically relevant when women reach their mid-30s, when even assisted reproduction treatment cannot compensate for the decline in fecundity associated with delaying attempts at conceiving. Pregnancies among women aged >40 years are associated with more non-severe complications, more premature births, more congenital malformations and more interventions at birth.

Baird DT, Collins J, Egozcue J, Evers LH, Gianaroli L, Leridon H, Sunde A, Templeton A, Van Steirteghem A, Cohen J, Crosignani PG, Devroey P, Diedrich K, Fauser BC, Fraser L, Glasier A, Liebaers I, Mautone G, Penney G, Tarlatzis B; ESHRE Capri Workshop Group Fertility and ageing. Hum Reprod Update. 2005 May-Jun;11(3):261-76. Epub 2005 Apr 14. Review

5. Frequency of aneuploidy in sperm from patients with extremely severe male factor infertility.

A protocol for the chromosomal analysis of sperm samples with a severely reduced number of sperm cells was designed. A severe male factor condition was the main cause of infertility for 38 couples: 27 were oligoasthenoteratospermic (OAT) and 11 with non-obstructive azoospermia underwent testicular sperm extraction (TESE). A two-round fluorescence in situ hybridization (FISH) protocol was performed with probes specific for the chromosomes X, Y, 13, 15, 16, 17, 18, 21 and 22. The recording of the position of each sperm cell at the microscope allowed diagnosis of each spermatozoon for the nine tested chromosomes. A mean number of 122+/-78.5 sperm were diagnosed per patient with an incidence of total abnormalities corresponding to 13.4%. chi2-tests for the observed frequencies and goodness-of-fit test were highly significant in all cases. A significantly higher proportion of total aneuploidy was detected in 79% of the tested samples compared to the normal population. Testicular sperm were significantly more prone to aneuploidy than ejaculated sperm. The designed FISH protocol for the analysis of severe OAT and TESE sperm samples is reliable, implying that the studied sample is representative of the original population. In view of the high incidence of aneuploidy in most severe OAT and TESE sperm, the FISH analysis of pathological sperm samples can be routinely performed in order to estimate the chances of the paternal contribution to aneuploidy in the resulting embryos.

Gianaroli L, Magli MC, Cavallini G, Crippa A, Nadalini M, Bernardini L, Menchini Fabris GF, Voliani S, Ferraretti AP. Frequency of aneuploidy in sperm from patients with extremely severe male factor infertility. Hum Reprod. 2005 Aug;20(8):2140-52. Epub 2005 Apr 21.

6. Patients with abnormal sperm parameters have an increased sex chromosome aneuploidy rate in peripheral leukocytes.

Patients with oligoasthenoteratozoospermia (OAT) and normal karyotypes have an increased sperm aneuploidy rate. This may be due to an altered intratesticular environment that affects the chromosomal segregation mechanism(s). Alternatively, it may be due to a generalized meiotic and mitotic abnormality. In this case, patients with abnormal spermatogenesis should also have an increased somatic cell aneuploidy rate. To test this hypothesis, we evaluated peripheral leukocyte aneuploidy rate in patients with spermatogenic impairment. In all, 38 patients were enrolled, of whom 20 had OAT, 15 non-obstructive azoospermia and three Y chromosome (Yq) microdeletions (AZF). Eight healthy normozoospermic men with proven fertility were recruited as controls. Conventional karyotype analysis, AZF microdeletion evaluation and triple-colour FISH for chromosomes X, Y and 12 were conducted in all patients and controls. A total of 1000 lymphocytes were scored for each patient and control. All patients and controls had a normal karyotype. Sex chromosome aneuploidy rates in peripheral lymphocytes was significantly higher in patients with OAT (0.74+/-0.09%), azoospermia (1.15+/-0.15%) or Yq microdeleted (1.54+/-0.40%), compared with controls (0.15+/-0.03%) (P <0.05). Patients with OAT, azoospermia or Yq microdeletions had a slight, but significant, increase of sex chromosome aneuploidy rate in lymphocytes, suggesting the presence of a generalized defective cell division mechanism. In contrast with recent observations, Yq microdeletions do not seem to predispose to a higher number of malsegregation events in somatic cells compared with patients with azoospermia.

De Palma A, Burrello N, Barone N, D'Agata R, Vicari E, Calogero AE. Patients with abnormal sperm parameters have an increased sex chromosome aneuploidy rate in peripheral leukocytes. Hum Reprod. 2005 Aug;20(8):2153-6. Epub 2005 May 5.

Gerhard Leyendecker