Synchronous Bilateral Breast Carcinoma in a Patient with Cowden Syndrome: A Case Report with Morphologic,Immunohistochemical and Genetic Analysis

Abstract: Synchronous bilateral breast carcinoma (SBBC) and early onset are important characteristics of hereditary cases. The lifetime risk for breast carcinoma in Cowden syndrome (CS) is estimated to be 25–50%. We reported a 44‐year‐old woman presenting SBBC and characteristic mucocutaneous lesions of CS, confirmed by PTEN gene mutation analysis. Bilateral modified mastectomy and axillary dissection were performed. Histopathologic examination revealed a moderate‐differentiated invasive ductal carcinoma with mixed features of luminal A immunophenotype (Estrogen and/or Progesterone Receptors >50% and/or Ki67 < 30% of positive cells). The skin lesions showed the characteristic findings of tricholemmoma. Lack of PTEN expression was observed in all specimens. Sequencing analysis confirmed the presence of PTEN splice‐acceptor site mutation in intron 8 (c.1027‐2A>G), a germline mutation which had not been previously reported in CS. The patient received adjuvant chemotherapy and tamoxifen for 5 years. After 5 years of follow‐up, she persists recurrence‐free. SBBC with early onset suggests a hereditary predisposition. Thus, analysis of PTEN expression abnormality, easily assessed by immunohistochemistry, may be of clinical value to screen those patients with CS.     

Population and antenatal-based HIV prevalence estimates in a high contracepting female population in rural South Africa

Background  

To present and compare population-based and antenatal-care (ANC) sentinel surveillance HIV prevalence estimates among women in a rural South African population where both provision of ANC services and family planning is prevalent and fertility is declining. With a need, in such settings, to understand how to appropriately adjust ANC sentinel surveillance estimates to represent HIV prevalence in general populations, and with evidence of possible biases inherent to both surveillance systems, we explore differences between the two systems. There is particular emphasis on unrepresentative selection of ANC clinics and unrepresentative testing in the population.     

Gastro-oesophageal reflux in preterm infants.

Gastro-oesophageal reflux in very low birthweight infants was studied using a new 1 mm monocrystalline antimony oesophageal pH electrode. Gastro-oesophageal reflux was detected in 30 (85%) subjects. The mean (SEM) number of episodes of reflux in 24 hours was 12.1 (2.1), and 3.2 (0.6) lasted over five minutes. The mean reflux index was 4.5 (1.0)%, and the longest episode 17.1 (4.6) 17.1. Reflux was unrelated to postconceptional age or to resting lower oesophageal sphincter pressure. The mean reflux index was low at rest before feeds, being 1.8 (0.6)%, and increased slightly after feeds (3.8 (1.0)%), but was significantly increased after nursing care to 16.4 (3.0)%, and while xanthines were being given (5.9 (1.6)%. A subgroup of seven infants with xanthine resistant apnoea had severe gastro-oesophageal reflux that was not clinically apparent (reflux index 27.4 (3.6)%). Successful treatment of the reflux (reflux index: 3.6 (1.2)%) was associated with cessation of the apnoea. We conclude that gastro-oesophageal reflux is common, and is usually not clinically apparent, even when severe. It is important to consider gastro-oesophageal reflux in the differential diagnosis of xanthine resistant apnoea in preterm infants.     

Management of advanced cervical metastasis using intraoperative radiotherapy

Seventy-five patients who had advanced cervical metastasis with possible invasion of the deep muscles or carotid artery were approached with aggressive resection and intraoperative radiotherapy (IORT). All metastatic nodes were greater than 3 cm, 65% were fixed on clinical examination, and 35% involved the carotid artery. Forty-six (61%) of the patients had previously received irradiation. Fifteen of the patients required extended neck dissections with carotid resections and grafting. After the resection an average single dose of 2000 cGy of electron beam IORT was delivered. At 2 years, the local control rate within the IORT port was 68% and the absolute survival rate was 45%. Local control rates for close and microscopic margins (76% and 73%, respectively) were significantly better than the control rate for gross residual disease (25%, P<.05). The combination of extended neck dissection, including carotid artery resection if necessary, and IORT appears to offer improved control.     

Prevention of mother-to-child transmission of HIV in developing countries: recommendations for practice. The Ghent International Working Group on Mother-To-Child Transmission of HIV

OBJECTIVES: Different approaches to prevent mother-to-child transmission of HIV are being evaluated in developing countries. The first trials using a short regimen of zidovudine have been successful in Thailand, C?te d'Ivoire and Burkina Faso. International and local strategies are now being considered. The Ghent International Working Group on Mother-to-Child Transmission of HIV developed public health policy options to integrate these interventions into basic and maternal and child health (MCH) services. METHODS: The following tasks were undertaken: a critical review of randomized trials; an international pooled analysis of late postnatal transmission of HIV through breastfeeding; a review of the cost-effectiveness and cost-benefit of antiretroviral prophylaxis; a feasibility assessment of preventive strategies, including a postal survey on HIV voluntary counselling and testing (VCT) of pregnant women; the identification of requirements and research priorities for prenatal, obstetric and paediatric care. These projects provided the background for a three-day workshop in Ghent, Belgium, in November 1997. Conclusions were further refined, based on 1998 research findings. RESULTS: A summary of relevant evidence and ten public health recommendations are reported. VCT for pregnant women, a short regimen of zidovudine together with alternatives to breastfeeding currently represent the best option to reduce vertical transmission in most developing countries. The primary goal of the integrated package supporting these interventions is to alleviate overall maternal and infant morbidity and mortality. CONCLUSION: Prevention of mother-to-child transmission of HIV should now be considered for integration into basic health and MCH services of selected countries, with the involvement of governments and donor agencies.     

Fungal Biomass in Saltmarsh Grass Blades at Two Contaminated Sites

Ascomycetous fungi are the principal drivers of the decomposition of shoots of smooth cordgrass (Spartina alterniflora). Shoots of smooth cordgrass move into the saltmarsh food web via the decomposition system. Therefore, influences on saltmarsh ascomycetes by pollutants of saltmarshes could have far-reaching impacts. Earlier examination of impacts of severe contamination of a Georgia saltmarsh by mercury and polychlorinated biphenyls (PCBs) revealed little or no influence of the toxicants on living standing crops or sexual productivities of cordgrass ascomycetes. Extension of the examination of saltmarsh-ascomycete response to sites containing other toxic pollutants (the chlorinated organocyclic insecticide toxaphene; chromium, copper, and lead; and polycyclic aromatic hydrocarbons [PAHs]) has shown that none of the additional toxicants engendered saltmarsh-fungal responses in the form of reduced living standing crops or sexual productivities. Thus the ascomycetes of the cordgrass-decay system appear to be as resistant to anthropogenic-pollutant poisoning as smooth cordgrass itself. Unless the fungal and plant resistance mechanisms involve degradation of the toxicants, this may imply that saltmarshes are especially dangerous as receiving sites for toxic waste because they may have the potential to readily move toxicants into the food web. Received: 27 July 1999/Accepted: 29 September 1999     

Preventing perinatal transmission of HIV-1 infection

It is now known that with the use of antiretroviral prophylaxis with zidovudine, elective caesarean section delivery and refraining from breastfeeding the rate of mother-child transmission of HIV infection can be reduced to less than 2%.     

Development of a whole cell assay to measure methotrexate-induced inhibition of thymidylate synthase and de novo purine synthesis in leukaemia cells

The cellular pharmacology of methotrexate (MTX) is complex, involving the inhibition of both de novo thymidylate and purine biosynthesis. Measurement of MTX-induced inhibition of de novo thymidylate and purine biosynthesis may allow optimisation of MTX therapy, and the aim of this study was to develop an assay to measure the activity of both pathways in the same cell sample, and so determine the effects of MTX treatment. In situ thymidylate synthase (EC 2.1.1.45) activity was measured by the release of 3H2O from [5'-3H]deoxyuridine and de novo purine synthesis by the incorporation of [14C]formate into adenine and guanine. Incubation of human leukaemia CCRF-CEM cells for 22 hr with 50 nM MTX resulted in approximately 90% inhibition of in situ thymidylate synthase activity, relative to control untreated cells, and after exposure to 1000 nM MTX activity could not be detected. In contrast, de novo purine synthesis, measured in the same sample, was not inhibited by exposure to 50 nM MTX, although activity was again completely abolished by exposure to 1000 nM MTX. To demonstrate the utility of the assay, lymphoblasts isolated from a child with acute lymphoblastic leukaemia (ALL) were also incubated for 22 hr with 1000 nM MTX. Both in situ thymidylate synthase activity and de novo purine synthesis were significantly inhibited, by 70% and 60% respectively, relative to the activity in untreated cells.     

Postoperative epidural analgesia following elective major abdominal surgery in high risk patients: a retrospective cohort study

AIM: To describe the effect of post-operative epidural analgesia on morbidity and mortality rates in a group of high-risk patients undergoing elective major abdominal surgery. METHODS: Retrospective chart review of patients in American Society of Anaesthetists Physical Status (ASA) category III or IV, who underwent elective major I or II general surgical procedures between 01/01/1996 and 01/09/1998. Patients were identified from a prospective audit database. Patients who had epidural analgesia or conventional parenteral opioids were compared for outcome measures. RESULTS: There were 167 patients identified (72 epidural, 95 non-epidural group). There was no significant difference in demographic data, inpatient stay, intensive care unit stay, or mortality rates (11% epidural v 17% non-epidural, p>0.05). There was no significant difference in morbidity rates, however there was a non-significant trend towards a lower morbidity in the epidural group. CONCLUSIONS: This study does not show any benefit from post-operative epidural analgesia on morbidity and mortality rates in high risk patients undergoing major abdominal surgery. It does illustrate that ASA 3 and 4 patients undergoing major abdominal surgery have a high morbidity and mortality.     

Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design,synthesis, and X-ray cocrystal structure

A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.