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In this review we discuss the features of a new class of antiretroviral combinations, namely "Virostatics". Virostatics are characterized by the combination of a drug directly inhibiting virus production (viro), and another drug indirectly inhibiting the virus by reducing cellular proliferation (static). In particular, we will focus on the combination of hydroxyurea and didanosine against HIV-1. Hydroxyurea and didanosine synergize to control viral replication and present with a favorable resistance profile, suppressing several resistant quasi-species. Because virostatics target essential cellular proteins, they exert an immune modulating activity and reduce viral targets (CD4 T cells), possibly with limited immunosuppressive effects. Importantly, a dose-finding clinical study has shown that decreasing the dose of hydroxyurea not only diminishes toxicity but also increases antiviral potency. Therefore, the combination of hydroxyurea and didanosine strikes a balance between viral suppression, drug-related toxicity and viral escape, and could have a role both in induction and maintenance therapy. In this review we would like to appraise what is known about hydroxyurea and didanosine and specifically address the major advantages, i.e. novel mechanism of action leading to a new class of drugs and resistance profile providing durability, as well as the major criticisms of this combination, i.e. toxicity and reasons for prescribing a perceived immune suppressant to immune compromised patients.

The combination of three or more antiretroviral drugs is referred to as highly active antiretroviral therapy (HAART) and constitutes the standard of care for HIV-1 patients in industrialized nations. Although HAART is usually effective in reducing viral load and re-constituting CD4 counts, latent virus reservoirs persist, and as many as 60 years therapy [1, 2] may be required to eradicate the virus. Meanwhile, patients are likely to experience drug related toxicity and may have to change therapy due to the emergence of drug resistant strains. For these reasons, the search for different therapeutic approaches continues. A new concept of antiviral/cytostatic ("virostatics") drugs has been proposed within the context of HAART to restrict virus target populations (CD4(+) T lymphocytes), target viral reservoirs, and possibly restore immune functions, by reducing excess immune activation, a fundamental component of HIV/AIDS pathogenesis. These virostatics include drugs such as hydroxyurea, mycophenolic acid, leflunomide and rapamycin, which are currently used for other therapeutic indications; and other experimental drugs, which are not for human use. They utilize multiple novel mechanisms of action to impede HIV by targeting host cellular proteins that are not susceptible to mutation. Therefore, their resistance profile appears to be quite favorable. Since many of these drugs act by inhibiting the synthesis of deoxynucleotides, essential for HIV reverse transcription, they favor the incorporation of nucleoside analogues into viral DNA, thus synergizing with the antiviral activity of currently used nucleoside reverse transcriptase inhibitors (NRTI). The rationale for the use of virostatics in HIV/AIDS, their mechanism of action, and ongoing preclinical and clinical research will be reviewed.

Aims: Cyclo-oxygenase (Cox) catalyses the conversion of arachidonic acid into prostaglandins (PG) and other eciosanoids. The prostaglandins, especially PGE2 are implicated in tumorigenesis via angiogenesis and suppression of immune reactivity. There are two known isoforms of the enzyme, Cox-1, which is constitutively expressed and the inducible isoform, Cox-2. Cox-2 is induced in response to inflammatory mediators, growth factors, oncogenes and mitogens. Non-selective Cox inhibitors may reduce the relative risk of colonic and breast carcinoma. Methods: We studied the expression of Cox-2 by immunohistochemistry in 106 primary breast carcinoma specimens collected over a three-year period, using a commercially available polyclonal antibody on formalin-fixed, paraffin-embedded tissue. The slides were examined independently by two pathologists. Tumours were classified according to accepted criteria and an immunohistochemical score (IHS) was calculated for each specimen. The IHS combines the percentage of immunoreactive cells (quantity score) and an estimate of staining intensity (staining intensity score). Results: All patients were female. The mean age was 53 years, range 28–86 years. Forty percent (n=42) of tumours were node negative and 60% (n=64) node positive. Forty-nine percent (n=52) of tumours were grade 3, a further 49% (n=52) grade 2 and 2% (n=2) grade 1. There was no statistically significant correlation between IHS and tumour size, grade, histology, nodal status, estrogen receptor or progesterone receptor positivity. A trend was observed showing an IHS of zero is associated with prolonged survival compared with an IHS of 9–12. Conclusion: Cox-2 expression in primary breast cancer does not correlate with accepted pathological or biochemical prognostic indicators.

With the increasing incidence of breast cancer in patients over 70 years, there is interest in the best therapeutic approach.To review the management of breast cancer in elderly women and to identify the factors involved in the decision to treat patients with tamoxifen as first line therapy.Between 1986 and 1999, 302 female patients agedor = 70 years presented with primary breast cancer, of whom 219 underwent surgery, 79 received tamoxifen as first line treatment and four received primary radiotherapy. A retrospective review was performed on these 79 patients and the outcome recorded.Of these 79 patients, data was available on 68. Follow-up ranged from one to 63 months (median 17 months). Co-morbidity was the principal reason for choosing first line tamoxifen therapy in 61% and patient preference in 11%. Tumour size was less than 5cm in 51%. In 25% tumour size decreased, in 24% it remained stable and in 27% it increased in size following tamoxifen therapy. Additional treatment was prescribed for 33% of patients.In the authors' experience, for those elderly patients suffering considerable co-morbidity or who refuse surgical intervention, tamoxifen is an acceptable alternative.

To determine the rate of detection of the sentinel node using both blue dye and radioisotope, and the accuracy with which the sentinel node histology reflects the nodal status of the axilla in a series of patients with clinically node-negative breast cancer.During a 32-month period from May 1998 to December 2000, 73 patients with clinically node-negative breast cancer underwent sentinel node biopsy immediately followed by formal axillary lymphadenectomy. The sentinel node(s) was identified using a combination of lymphoscintigraphy, blue dye and an intraoperative hand-held gamma probe.The mean age of the 73 patients was 58 years (range 32-83 years). Twenty-six per cent (19/73) had previous surgical/excisional biopsy. Pre-operative lymphoscintigraphy was positive in 74% (54/73) of patients. Combination of blue dye and radioisotope was better than either method in isolation for identifying the sentinel node, yielding a success rate of 96% (70/73). A total of 32 cases proved to have positive nodal disease on histological examination. In 44% (14/32) of patients, the sentinel node was the only positive node. Forty-seven per cent (15/32) of patients in whom the sentinel node was positive also had positive nodes in the axillary nodal basin. There were 3/32 false negative cases, giving a false negative rate of 9.4%.Sentinel node biopsy will have a role in the management of breast cancer. However, widespread adaptation of this technique awaits the results of prospective, randomised trials.

To assess changing trends in histological types of thyroid cancer in an Irish hospital over the past 30 years. Biographical data, tumour characteristics, treatment and outcome from 190 patients with thyroid carcinoma from 1970 to 2000 were reviewed retrospectively. Detailed records of 190 patients with thyroid cancer were identified with a mean age at presentation of 50 years. From 1970 to 1979 the distribution of histological types was: papillary carcinoma; 9 patients (4.7%), follicular; 17 patients (8.9%), anaplastic; 9 patients (4.7%), medullary; 1 patient (0.5%) and lymphoma; 1 patient (0.5%). From 1980 to 1989 papillary carcinoma accounted for 32 patients (16.8%), follicular; 14 patients (7.3%), anaplastic; 13 patients (6.8%), medullary; 7 patients (3.7%) and lymphoma; 5 patients (2.6%). From 1990 to 1999 papillary cancer accounted for 48 patients (25.2%), follicular; 14 patients (7.3%), anaplastic; 8 patients (4.2%), medullary; 7 patients (3.7%) and lymphoma; 5 patients (2.6%). Survival rates were significantly better for those aged less than 45 years (P

The BRMS1 (breast cancer metastasis suppressor 1) gene has been found to suppress metastasis in animal models without inhibiting primary tumor growth. The aim of this study was to measure expression of BRMS1 mRNA in a panel of human breast carcinomas and compare its expression with parameters of local dissemination such as tumor size and lymph node metastasis. We also compared expression of BRMS1 mRNA in normal breast tissue, fibroadenomas, primary breast cancers and axillary nodal metastases from primary breast cancers. BRMS1 mRNA was detected in 10/11 (90%) specimens of normal breast tissue, 12/16 (75%) fibroadenomas, 64/82 (78%) primary breast cancer and 11/15 (64%) lymph node metastases (p, NS). In the primary cancer, expression was independent of tumor size, tumor grade, metastasis to axillary nodes and hormone receptor status. Furthermore, similar levels of BRMS1 were found in normal breast tissue, primary breast carcinomas and lymph node metastases from primary breast cancer. Our results do not suggest a role for BRMS1 in suppressing metastasis to local lymph nodes in patients with breast cancer.

Sentinel node radiolocalisation procedures are associated with low levels of radiation exposure. Radioactive material is present in the operating theatre and pathology laboratory. In most hospitals there are no official regulations in place for sentinel node radiation exposure. To establish guidelines on the safety of sentinel node mapping with emphasis on the management of radioisotopes. The current literature regarding sentinel node procedures and radiation safety was reviewed. EU and US radiation safety regulations were scrutinised. Personnel involved in sentinel node procedures are exposed to low levels of radiation. These levels are not high enough to require designated radiation workers in the theatre and pathology laboratory. Awareness of radiation safety and certain precautions during the procedure and processing of the specimen can further reduce levels of exposure. Although low levels of radiation exposure are associated with sentinel node procedures, awareness of radiation safety and adherence to regulations, along with close interdepartmental co-operation, are recommended for further reduction in radiation exposure and safe application of this technique.

Background Advances in molecular biology and improved understanding of tumour biology have led to the development of novel treatments for cancer. Trastuzumab (Herceptin; Genentech, San Francisco, California, USA) is a monoclonal antibody directed against human epidermal growth factor receptor (HER) 2 protein, which is overexpressed in a wide variety of human cancers, including 20–30 per cent of human breast cancers. HER-2 plays an important role in oncogenic transformation, tumorigenesis and metastatic spread. Overexpression is associated with a poor prognosis and predicts a poor response to several treatment modalities. Method Literature relating to the monoclonal antibody was identified by a Medline literature search and by cross-referencing from the references of seminal articles on the subject. Four major clinical trials were identified and reviewed. Results and conclusion In clinical trials approximately 15–20 per cent of patients with HER-2-overexpressing tumours benefited from treatment with trastuzumab. In sensitive patients the antibody appeared to have intrinsic anticancer activity when given as a single agent. In combination chemotherapy it appeared to act synergistically with other agents. Ongoing research is evaluating trastuzumab in combination with numerous standard chemotherapy regimens and with other novel chemotherapeutic agents. Clinical trials have also revealed several serious side-effects of monoclonal antibody therapy. Most notable is an unpredictable cardiotoxicity, especially when used in combination with anthracycline-based chemotherapy regimens.

Alterations in the levels of connexin expression in breast cancer appear to be relative rather than absolute. The heterogenicity of connexin expression may have functional implications for breast tumour progression. Pharmacological restoration of connexin 43 and 32 expression may therefore prove beneficial in cancer therapeutics.