[Nipple areola complex conservation in immediate breast reconstruction: prospective study of 66 cases]. / Conservation aréolo-mamelonnaire en reconstruction mammaire immédiate: étude prospective de 66 cas.

OBJECTIVE OF THE STUDY: Our objective is to define a sub-group of patients in whom skin-sparing mastectomy with immediate reconstruction and preservation of the nipple-areola complex is technically and oncologically feasible without increasing the risk of complications and local recurrence. PATIENTS AND METHODS: Between September 1999 and December 2005, 66 patients presenting an in situ and/or invasive breast carcinoma justifying a mastectomy underwent immediate breast reconstruction preserving the skin and nipple-areolar complex. RESULTS: After a median follow-up of 37 months, definitive conservation of the nipple-areolar complex with good esthetic results was achieved in 71% of the cases. CONCLUSION: This preliminary study provides encouraging results in a selected patient population but requires a longer term follow-up in order to draw definitive conclusions on the oncological safety preserving the nipple-areolar complex.

Specimen radiography as predictor of resection margin status in non-palpable breast lesions.

AIM: This study aimed to evaluate the role of specimen radiography in predicting margin status for non-palpable breast malignancies. METHODS: We retrospectively reviewed the clinical and pathological data together with specimen radiographs of 164 women with ductal carcinoma in situ, who were referred to our centre between January 1997 and December 2000. In all cases microcalcifications were discovered on mammography. Lesions were localized preoperatively using a guide-wire. Specimen radiography findings and clinicopathological data were correlated with pathological findings. RESULTS: Findings comprised 122 pure ductal carcinomas in situ (74%) and 42 mixed carcinomas, both infiltrating and in situ (26%). On the specimen radiographs, the lesions were close (<1mm) to one edge of the lumpectomy in 34 (21%) cases. Histologically, there were 103 positive resection margins (<1mm, 63%) and only 61 negative margins (> or =1mm, 37%). On univariate analysis, factors associated with positive resection margins were found to be distance from microcalcifications to edge of lesion on specimen radiographs, and radiological multifocality. On multivariate analysis (logistic regression), a radiological margin <5mm and multifocality were the only risk factors for close histological margins. Radiological margins were not associated with surgical findings. CONCLUSION: Our results demonstrate that there is a correlation between specimen radiographs and histological results. The clinical relevance of this should be evaluated in a prospective study.

Genomic imprinting in plants and mammals: how life history constrains convergence.

In both flowering plants and mammals, DNA methylation is involved in silencing alleles of imprinted genes, but surprising differences in imprinting control are emerging between the two taxa which may be traced to differences in their life cycles. Imprinted gene expression in plants occurs in the endosperm, a separate fertilisation product which transmits nutrients to the embryo and does not contribute a genome to the next generation. Regulation of expression of the known imprinted genes in Arabidopsis involves a cascade of gene expression beginning in the gametophyte, a haploid life phase interposed between the meiotic products and the gametes, which evolved from free-living organisms that constitute the dominant life phase of lower plants. Although the gametophytes of flowering plants are highly reduced they still express large numbers of genes, perhaps reflecting their evolutionary legacy, and which may now be recruited for control of imprinting. Strikingly, the genes at the top of the expression cascade appear to be specifically activated by demethylation, rather than targeted for silencing. Unlike in mammals, there is no evidence for global resetting of methylation in plants, and although imprinting involves the activity of a maintenance methyltransferase, de novo methyltransferases do not appear to be required. Plants do not set aside a germline; instead the cells that undergo meiosis to produce gametophytes differentiate in the adult plant during flower development. Both the late differentiation of the lineage producing germ cells, and the extent of gene expression during the haploid phase, may be incompatible with global resetting of methylation. Resetting may be unnecessary in any case because the adult plant expresses imprinted loci either biallelically or not at all, suggesting there is no chromosomal memory of parent-of-origin in the lineage that produces the gametophytes. Thus several features of the plant life cycle may account for the different strategies used by plants and animals to regulate parent-specific gene expression.

Acceptability and technical problems of the female condom amongst commercial sex workers in a rural district of Malawi.

A study was conducted among commercial sex workers (CSWs) in rural southern Malawi, in order to (a) assess the acceptability of the female condom and (b) identify common technical problems and discomforts associated with its use. There were 88 CSWs who were entered into the study with a total of 272 female condom utilizations. Eighty-six (98%) were satisfied with the female condom, 80% preferred it to the male condom and 92% were ready to use the device routinely. Of all the utilizations, the most common technical problem was reuse of the device with consecutive clients, 6% after having washed it, and 2% without any washing or rinsing. The most common discomfort that were reported included too much lubrication (32%), device being too large (16%), and noise during sex (11%). This study would be useful in preparing the introduction of the female condom within known commercial sex establishments in Malawi.

TETRASPORE encodes a kinesin required for male meiotic cytokinesis in Arabidopsis.

A key step in pollen formation is the segregation of the products of male meiosis into a tetrad of microspores, each of which develops into a pollen grain. Separation of microspores does not occur in tetraspore (tes) mutants of Arabidopsis thaliana, owing to the failure of male meiotic cytokinesis. tes mutants thus generate large 'tetraspores' containing all the products of a single meiosis. Here, we report the positional cloning of the TES locus and details of the role played by the TES product in male cytokinesis. The predicted TES protein includes an N-terminal domain homologous to kinesin motors and a C-terminus with little similarity to other proteins except for a small number of plant kinesins. These include the Arabidopsis HINKEL protein and NACK1 and two from tobacco (Nishihama et al., 2002), which are involved in microtubule organization during mitotic cytokinesis. Immunocytochemistry shows that the characteristic radial arrays of microtubules associated with male meiotic cytokinesis fail to form in tes mutants. The TES protein therefore is likely to function as a microtubule-associated motor, playing a part either in the formation of the radial arrays that establish spore domains following meiosis, or in maintaining their stability.

The epigenetic basis of gender in flowering plants and mammals.

What makes a sperm male or an egg female, and how can we tell? A gamete's gender could be defined in many ways, such as the sex of the individual or organ that produced it, its cellular morphology, or its behaviour at fertilization. In flowering plants and mammals, however, there is an extra dimension to the gender of a gamete--due to parental imprinting, some of the genes it contributes to the next generation will have different expression patterns depending on whether they were maternally or paternally transmitted. The non-equivalence of gamete genomes, along with natural and experimental modification of imprinting, reveal a level of sexual identity that we describe as 'epigender'. In this paper, we explore epigender in the life history of plants and animals, and its significance for reproduction and development.

Genomic imprinting in plants.

Genomic imprinting, though most extensively studied in mammals, has long been known to perform an important role in seed development in flowering plants. In this chapter, an overview of what is known to date about genomic imprinting in flowering plants and how this knowledge came into being will be given.

Hypomethylation promotes autonomous endosperm development and rescues postfertilization lethality in fie mutants.

In most flowering plants, fertilization is necessary for development of the central cell into endosperm, but in the fie-1 mutant of Arabidopsis, the central cell can proliferate autonomously. However, autonomous fie-1 endosperms do not develop completely: They have fewer nuclei than sexually produced endosperms, cellularization does not take place, and no clear distinction is seen between the different endosperm compartments. Here, we show that autonomous endosperm develop much further in hypomethylated than normally methylated fie-1 mutants, undergoing cellularization and regional specification to resemble endosperm in sexually produced wild-type seeds. Therefore, the combination of maternal hypomethylation and loss of FIE function enables formation of differentiated endosperm without fertilization. A maternal fie-1 mutation is also lethal to sexual seeds, even if the pollen donor is wild type. We report that sexual mutant fie-1 endosperms fail to cellularize and overproliferate, consistent with the hypothesis that embryo abortion may be due, at least in part, to a defect in endosperm development. Finally, we show that pollen from hypomethylated plants rescues fie-1 mutant seeds provided that it also donates a wild-type paternal FIE allele. These results are discussed in light of models for parent-of-origin effects on seed development.

Parent-of-origin effects on seed development in Arabidopsis thaliana require DNA methylation.

Some genes in mammals and flowering plants are subject to parental imprinting, a process by which differential epigenetic marks are imposed on male and female gametes so that one set of alleles is silenced on chromosomes contributed by the mother while another is silenced on paternal chromosomes. Therefore, each genome contributes a different set of active alleles to the offspring, which develop abnormally if the parental genome balance is disturbed. In Arabidopsis, seeds inheriting extra maternal genomes show distinctive phenotypes such as low weight and inhibition of mitosis in the endosperm, while extra paternal genomes result in reciprocal phenotypes such as high weight and endosperm overproliferation. DNA methylation is known to be an essential component of the parental imprinting mechanism in mammals, but there is less evidence for this in plants. For the present study, seed development was examined in crosses using a transgenic Arabidopsis line with reduced DNA methylation. Crosses between hypomethylated and wild-type diploid plants produced similar seed phenotypes to crosses between plants with normal methylation but different ploidies. This is consistent with a model in which hypomethylation of one parental genome prevents silencing of alleles that would normally be active only when inherited from the other parent - thus phenocopying the effects of extra genomes. These results suggest an important role for methylation in parent-of-origin effects, and by inference parental imprinting, in plants. The phenotype of biparentally hypomethylated seeds is less extreme than the reciprocal phenotypes of uniparentally hypomethylated seeds. The observation that development is less severely affected if gametes of both sexes (rather than just one) are 'neutralized' with respect to parent-of-origin effects supports the hypothesis that parental imprinting is not necessary to regulate development.

Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients.

PURPOSE: To identify predictive factors for efficacy and safety in advanced breast cancer (ABC) patients treated in the French compassionate-use docetaxel program. PATIENTS AND METHODS: A total of 825 ABC patients treated with docetaxel (100 mg/m(2) every 3 weeks) were source-reviewed and analyzed for prognostic factors associated with overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), febrile neutropenia, mucositis, and severe fluid retention syndrome by univariate and multivariate analysis. RESULTS: The ORR was 22.9% (95% confidence interval, 20.2% to 26.2%). The median TTF and OS were 4.0 and 9.8 months, respectively. By multivariate analysis, secondary anthracycline-resistant disease was significantly associated (P <. 05) with lower ORR and shorter TTF and OS, whereas anthracycline-refractory disease was associated with shorter OS. Poor performance status was associated with lower ORR, shorter TTF, and shorter OS. Liver dysfunction (transaminase levels > 1.5 times the upper limit of normal [ULN] and alkaline phosphatase [AP] level > three times ULN) and time since first relapse less than 24 months were associated with shorter TTF and OS. Other significant correlations included the following: elevated CA 15-3 serum level with lower ORR; more than two involved sites, and minor transaminase and AP level abnormalities with shorter OS; and no previous chemotherapy for ABC with shorter TTF. According to multivariate analysis, ORR, TTF, and OS were not decreased in patients with liver metastases but without liver dysfunction. CONCLUSION: Docetaxel activity was maintained in heavily pretreated ABC patients and in those with liver metastasis; docetaxel must be used cautiously, however, in patients with liver dysfunction in whom high morbidity risk necessitates strict adherence to dose-adaptation guidelines.

Efficacy and safety of docetaxel (Taxotere) in heavily pretreated advanced breast cancer patients: the French compassionate use programme experience.

The aim of this investigation was to assess retrospectively docetaxel safety and efficacy in advanced breast cancer patients in a French compassionate use programme. Patients had received > 1 prior chemotherapy regimen for advanced disease, were either anthracycline-resistant (that is progressed within 6 months after anthracycline-based chemotherapy) or had received the maximum cumulative dose. The recommended docetaxel dose was 100 mg/m2/cycle (75 mg/m2 in case of liver function impairment: transaminases > 1.5 x upper limit of normal (ULN), alkaline phosphatases > 3 x ULN). Between August 1993 and December 1995, 889 patients were treated in 67 French centres, of whom 870 were evaluable for safety and 825 were evaluable for patient and treatment characteristics and efficacy. 20.5% (of the 825 patients evaluable for baseline characteristics) had poor performance status (PS > or = 2), 49.3% liver metastasis and 9.6% biological liver dysfunction. 98.4% had been previously treated by anthracyclines, 50.8% had resistant disease and 37.1% had received > 2 prior palliative chemotherapy lines. The most frequent severe toxicity, febrile neutropenia (reported in 223/870 (25.6%) patients evaluable for safety), caused 10 deaths, 6 of these being patients with severe liver impairment before inclusion. Fluid retention syndrome and other common non-haematological toxicities were well tolerated. 3.1% (28/889) of all patients and 11.4% of those with liver dysfunction, died from treatment-related causes. The overall response rate in 825 assessable patients was 22.9% (95% confidence interval (CI): 20.2-26.2%). Median time to treatment failure was 4 months (95% CI: 3.6-4.3) and median survival was 9.8 months (95% CI: 8.8-10.7). This report on the largest series of unselected advanced breast cancer patients treated with docetaxel, supports previous phase II studies, confirming docetaxel's utility in patients relapsing after failing anthracycline-containing palliative chemotherapy.

Parent-of-origin effects on seed development in Arabidopsis thaliana.

Many flowering plants are polyploid, but crosses between individuals of different ploidies produce seeds that develop abnormally and usually abort. Often, seeds from interploidy crosses develop differently depending on whether the mother or father contributes more chromosome sets, suggesting that maternal and paternal genomes are not functionally equivalent. Here we present the first cytological investigation of seed development following interploidy crosses in Arabidopsis thaliana. We find that crosses between diploid and tetraploid plants in either direction, resulting in double the normal dose of maternal or paternal genomes in the seed, produce viable seeds containing triploid embryos. However, development of the seed and in particular the endosperm is abnormal, with maternal and paternal genomic excess producing complementary phenotypes. A double dose of maternal genomes with respect to paternal contribution inhibits endosperm development and ultimately produces a smaller embryo. In contrast, a double dose of paternal genomes promotes growth of the endosperm and embryo. Reciprocal crosses between diploids and hexaploids, resulting in a triple dose of maternal or paternal genomes, produce seeds that begin development with similar but more extreme phenotypes than those with a double dose, but these invariably abort. One explanation of our observations is that seeds with maternal or paternal excess contain different doses of maternally or paternally expressed imprinted loci affecting endosperm development.

TETRASPORE is required for male meiotic cytokinesis in Arabidopsis thaliana.

In flowering plants, male meiosis occurs in the microsporocyte to produce four microspores, each of which develops into a pollen grain. Here we describe four mutant alleles of TETRASPORE (TES), a gene essential for microsporocyte cytokinesis in Arabidopsis thaliana. Following failure of male meiotic cytokinesis in tes mutants, all four microspore nuclei remain within the same cytoplasm, with some completing their developmental programmes to form functional pollen nuclei. Both of the mitotic divisions seen in normal pollen development take place in tes mutants, including the asymmetric division required for the differentiation of gametes; some tes grains perform multiple asymmetric divisions in the same cytoplasm. tes pollen shows a variety of abnormalities subsequent to the cytokinetic defect, including fusion of nuclei, formation of ectopic internal walls, and disruptions to external wall patterning. In addition, ovules fertilized by tes pollen often abort, possibly because of excess paternal genomes in the endosperm. Thus tes mutants not only reveal a gene specific to male meiosis, but aid investigation of a wide range of processes in pollen development and function.

Ethics in the neonatal intensive care unit: parental perceptions at four years postdischarge.

Ethical issues for the parents of neonates in neonatal intensive care units (NICUs) have not been widely researched. A multistage, qualitative project explored 23 families' perceptions of moral conflict and ethical decision making related to the NICU experience. Through in-depth interviews and the use of content analysis at 4 years postdischarge, life goes on (the major theme) and three conceptual categories were identified as characterizations of this phase. This phase, combined with two earlier phases (predischarge and 6 months postdischarge), represents a clinical manifestation of Reich's Theory of Suffering and provides a framework for understanding the parents' ethical perspective. Strategies for nurses that will facilitate parental participation in ethical decision making are presented.

Ethical perceptions of parents and nurses in NICU: the case of baby Michael.

A case was used to examine ethical challenges in the neonatal intensive care unit from the perspective of parents and nurses. Discussion focuses on issues of treatment versus nontreatment, informed consent, and decision making. An integration of crisis intervention techniques and caring processes is presented for nurses to assist parents through the neonatal intensive care unit experience.

Locally advanced breast cancer: contrast-enhanced subtraction MR imaging of response to preoperative chemotherapy.

PURPOSE: To determine the value of contrast material-enhanced subtraction magnetic resonance (MR) imaging in assessment of response to chemotherapy in locally advanced breast cancer. MATERIALS AND METHODS: Eighteen women treated with chemotherapy because of locally advanced breast cancer underwent preoperative MR examination including both routine and dynamic MR sequences after injection of gadolinium tetraazacyclododecanetetraacetic acid. Any early contrast enhancement, concomitant with early vascular enhancement during the dynamic MR study, was considered pathologic. RESULTS: Dynamic MR studies showed early contrast enhancement in all women with residual tumor except one with nodular residual tumor. Histopathologic analysis and dynamic MR images of contrast-enhanced lesions correlated well, but in one patient, intraductal extension was not seen on MR images, and in another, additional isolated tumor cells were seen in the histologic specimen. Subtraction images always facilitated visualization of vascular and pathologic contrast enhancement. CONCLUSION: Dynamic MR contrast-enhanced subtraction studies are useful in assessment of residual tumor after chemotherapy.

The parents' perspective: ethical decision-making in neonatal intensive care.

Ethical debate abounds in the literature relative to treatment decisions for the high risk neonate in the intensive care nursery. A systematic examination of the parents' perspective is missing. To fill this existing gap, the ethical dimension of care was explored with 32 families of high risk newborns from a Level III nursery, using a moral conflict interview guide in order to describe their perspective. A concept of the medicalization of parenting appears to best reflect the parents' view of ethical decision-making responsibility. This concept evolved through the parents' reflection on conflict naming, content of decision-making, context of decision-making, information sharing and perception of infant status. These concerns differ profoundly from those of health professionals, philosophers, theologians and others active in this debate who cite lower limits of viability, iatrogenic effects of treatment, use of multiple invasive procedures, and the role of paternalism as ethical issues.

Ethical decision making for high-risk infants. The parents' perspective.

The experiences of 32 families with high-risk infants provide the foundation for a discussion of the parents' perception of the ethical dimension of intensive newborn care. The families' focus on the need for support in the NICU crisis rather than a plea for rights, justice, and autonomous decision making leads to a suggested professional response guided by an ethic of care. Through a caring professional, ethical decision making in the NICU can be implemented to encompass a shared moral responsibility for the high-risk infant during this process.