BAG-1 predicts patient outcome and tamoxifen responsiveness in ER-positive invasive ductal carcinoma of the breast.

BAG-1 (bcl-2-associated athanogene) enhances oestrogen receptor (ER) function and may influence outcome and response to endocrine therapy in breast cancer. We determined relationships between BAG-1 expression, molecular phenotype, response to tamoxifen therapy and outcome in a cohort of breast cancer patients and its influence on tamoxifen sensitivity in MCF-7 breast cancer cells in vitro. Publically available gene expression data sets were analysed to identify relationships between BAG-1 mRNA expression and patient outcome. BAG-1 protein expression was assessed using immunohistochemistry in 292 patients with invasive ductal carcinoma and correlated with clinicopathological variables, therapeutic response and disease outcome. BAG-1-overexpressing MCF-7 cells were treated with antioestrogens to assess its effects on cell proliferation. Gene expression data demonstrated a consistent association between high BAG-1 mRNA and improved survival. In ER+ cancer (n=189), a high nuclear BAG-1 expression independently predicted improved outcome for local recurrence (P=0.0464), distant metastases (P=0.0435), death from breast cancer (P=0.009, hazards ratio 0.29, 95% CI: 0.114-0.735) and improved outcome in tamoxifen-treated patients (n=107; P=0.0191). BAG-1 overexpression in MCF-7 cells augmented antioestrogen-induced growth arrest. A high BAG-1 expression predicts improved patient outcome in ER+ breast carcinoma. This may reflect both a better definition of the hormone-responsive phenotype and a concurrent increased sensitivity to tamoxifen.

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy.

Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1alpha, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (P<0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (P<0.001). Fifty percent of basal-like tumours expressed HIF-1alpha, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (P<0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P=0.005), tumour grade (P<0.001) and oestrogen receptor (ER) negativity (P<0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (P<0.001 and P=0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients.

The role of echocardiography in the evaluation of cardiac damage in hypertensive obese patient.

Obesity rates are rising worldwide. Often obesity is associated with hypertension leading to an increased cardiovascular risk. Both obesity and hypertension induce several modifications in cardiac structure and function, particularly atrial and ventricular remodeling is a common finding shared by these two conditions. It has been demonstrated obesity leads to: left ventricular (LV) mass increase, LV systolic and diastolic dysfunction, left atrium (LA) size increase, LA function alterations and pericardial fat accumulation. Nowadays, the development of cardiac imaging techniques allows to early identifying any preclinical damage related to hypertension and obesity. This could be very important in order to improve patient management and medical therapy.

Herd-level risk factors of bovine tuberculosis in England and Wales after the 2001 foot-and-mouth disease epidemic.

OBJECTIVES: We present the results of a 2005 case-control study of bovine tuberculosis (bTB) breakdowns in English and Welsh herds. The herd management, farming practices, and environmental factors of 401 matched pairs of case and control herds were investigated to provide a picture of herd-level risk factors in areas of varying bTB incidence. METHODS: A global conditional logistic regression model, with region-specific variants, was used to compare case herds that had experienced a confirmed bTB breakdown to contemporaneous control herds matched on region, herd type, herd size, and parish testing interval. RESULTS: Contacts with cattle from contiguous herds and sourcing cattle from herds with a recent history of bTB were associated with an increased risk in both the global and regional analyses. Operating a farm over several premises, providing cattle feed inside the housing, and the presence of badgers were also identified as significantly associated with an increased bTB risk. CONCLUSIONS: Steps taken to minimize cattle contacts with neighboring herds and altering trading practices could have the potential to reduce the size of the bTB epidemic. In principle, limiting the interactions between cattle and wildlife may also be useful; however this study did not highlight any specific measures to implement.

Vascular access catheters for chemotherapy. Long-term follow-up.

Accessible surface veins become increasingly difficult to find after repeated venepunctures. This unfortunate situation often arises in patients on long-term chemotherapy, and can lead to soft tissue infiltration of toxic agents with resultant necrosis. A solution to this problem is the placement of long term indwelling vascular access catheters. Three different catheters are here described-the Raimondi, the Hickman, and the Broviac. They have been used 90 times in 78 patients over the last 2 1/2 years. All have been very successful in terms of ease of insertion, inertness, lack of post-operative infection, and prolonged duration of function. Thirty-five patients were available for long-term follow-up (greater than 6 months). Results in these show a mean catheter life varying from three to five months with a very low incidence of septicaemia, even in the immunologically compromised patients. The advantages of the various catheters are compared.

The implantable "Infusaid" infusion pump. The Sydney experience using 5-fluorouracil.

The experience is reported of the use of the totally implantable "Infusaid" infusion pump in the treatment of 14 patients in our combined clinics for metastatic carcinoma in the liver by means of the antimetabolite 5-FU. At the time of this study the more active antimetabolite 5-FUDR was not available. A comparison is made of overseas reports of the use of 5-FUDR in the Infusaid infusion pump with the experience, in our clinic, of the use of 5-FU.

The intraarterial infusion of chemotherapeutic agents as "basal" treatment of cancer: evidence of increased drug activity in regionally infused tissues.

There is evidence from a number of centres that some forms of locally advanced and aggressive cancers which are difficult to eradicate by standard means can be reduced by the use of "basal" chemotherapy and/or surgery. Clinicians have been divided as to whether there is an advantage in giving the chemotherapeutic agents directly into a regional artery of supply where this is feasible, as opposed to their systemic administration. This paper documents supportive evidence that some and possibly many chemotherapeutic agents are more effective if given regionally into an artery of supply. There is a higher incidence of local side-effects in the region infused, including loss of hair, inflammatory changes, and ulceration of the skin or mucosa of the region infused. After intraarterial infusion of tagged bleomycin (indium-III bleomycin) into a limb, the radioactive isotope remained more concentrated in the limb infused than in the opposite limb for at least 24 hours. Systemic side-effects, including bone-marrow depression, are less frequent and less severe in patients given chemotherapeutic agents by intra-arterial infusion than if the same doses of agents are given intravenously. There is now sufficient evidence of the value of basal chemotherapy used in this way to make it mandatory that medical oncologists and surgeons, working together, should plan controlled studies to determine the most appropriate applications of this technique of management.

Preoperative "basal" chemotherapy in the management of cancer of the stomach.

Twenty-seven patients with infiltrating gastric carcinoma received chemotherapy as the first stage in management to reduce tumour extent and viability in preparation for subsequent surgery. All patients who had received no previous treatment for their cancers were included in the study, regardless of the type or extent of the primary gastric lesion; there was no patient selection. In 25 patients chemotherapy was administered by intra-arterial infusion, while in two patients it was given intravenously. Of 21 patients who underwent repeat gastroscopy before surgery, 11 (52%) showed endoscopic improvement. Gastric resection was carried out in 24 of the 27 patients. The perioperative mortality was 11% (three of 27 patients). Of the 27 patients, 14 were initially assessed as having advanced incurable lesions. Only two of these remain well and apparently free of tumour. The other 13 patients were considered to have resectable and potentially curable lesions at the time of referral. Of these, 11 remain well and apparently free of tumour between one and five years after diagnosis; the other two patients in this group died from postoperative complications.

Intra-arterial chemotherapy given preoperatively in the management of carcinoma of the stomach.

Intra-arterial chemotherapy has been used preoperatively in treating patients with carcinoma of the stomach. The chemotherapy was given continuously for about one month with gastrectomy planned for three to four weeks after completion of chemotherapy. The agents used were 5-fluorouracil, Adriamycin (doxorubicin hydrochloride) and mitomycin C. The objective was to reduce the size and extent of the disease prior to subsequent surgical resection. Most of the patients had a partial response to the chemotherapy infusion. Two patients had an apparent complete response. For 16 patients who presented with the most advanced lesions, initially considered to be incurable, some palliation was achieved but long term results were not significantly changed. For 17 patients with locally invasive disease which would normally have been treated by gastrectomy alone, with an expectation of about 10 per cent five year survival time, long term results appear to have been significantly improved.

Intra-arterial chemotherapy as basal treatment in advanced and fungating primary breast cancer.

Occasionally patients present with stage III breast carcinoma so advanced that local radiotherapy is unlikely to achieve more than a partial and temporary local regression. 3 such patients with grossly advanced cancer involving virtually the whole of the breast, skin, and underlying muscle were treated with a regimen of intra-arterial infusion chemotherapy as basal treatment before planned irradiation. All 3 patients responded significantly to intra-arterial chemotherapy and subsequent definitive radiotherapy seems to have resulted in total regression of tumour and involved nodes in 2 patients. In the 3rd patient the response of the tumour mass to subsequent radiotherapy was considerable but incomplete; subsequent surgical resection seems to have eradicated the small foci of residual disease buried in fibrous tissue in the breast and one axillary node. All patients were given routine adjuvant chemotherapy after completion of irradiation. A 4th patient with a huge fungating breast carcinoma which was bleeding and foul-smelling who also had evidence of liver metastasis (stage IV disease) was treated in a similar manner. Local tumour regression was achieved and although the patient still requires treatment for metastatic disease there is no evidence of residual carcinoma in the breast or axilla 12 months after treatment. Further investigation of this treatment seems worthwhile, since it may be effective not only in the management of large breast cancers but also in patients with less advanced disease who refuse mastectomy or wish to avoid it.

Intraarterial infusion chemotherapy in salvage of limbs involved with advanced neoplasms.

Partial or complete limb salvage has been achieved in seven patients by the use of basal intraarterial infusion chemotherapy. All had either refused amputation or had been considered unsuitable for it. Results in all cases showed marked tumour regression to a size where local measures were then successful in controlling the disease. Six of the patients are alive and well with no sign of recurrence at periods ranging from four months to six years.

Intra-arterial infusion chemotherapy in the treatment of advanced squamous carcinoma of the tongue and floor of the mouth.

Our present experience with Stage III disease suggests that the most effective means of treating advanced carcinoma of the floor of the mouth and tongue are with initial chemotherapy given as basal treatment by intra-arterial infusion followed by planned radiotherapy or operation, or both. Early carcinoma of the floor of the mouth and tongue can be managed effectively with conventional techniques using surgical treatment or radiotherapy, or both, and probably does not justify the increased time and increased problems of management involved in the use of chemotherapy regimens. Our experience in comparing the two programs of treatment in patients classified as having Stage IV lesions is too small to justify valid comparisons to be made at this stage, although we currently have under investigation similar management programs for these patients.

A cohort study of hormone replacement therapy given to women previously treated for breast cancer.

UNLABELLED: Women who have been previously treated for breast cancer are usually advised to avoid hormone therapy for fear of increasing their risk of tumor recurrence. However, for some women, menopausal symptoms are so severe that their quality of life is poor. Because ethic committees are reticent to permit a double-blind randomized trial, we performed a cohort study of hormone therapy after breast cancer. METHODS: The study group comprised 1472 women with breast cancer. A total of 167 subjects had used an oral or transdermal estrogen after their treatment for breast cancer. Amongst these estrogen users, 152 (91%) had also used a progestin. In total, 106 other women had used a progestin alone as a treatment for menopausal flushes and not as a treatment for breast cancer. Cox regression analysis was performed using estrogen as a time-dependent covariate with disease-free interval as the outcome. RESULTS: The uncorrected hazard ratio for the estrogen-progestin users was 0.67 (95% confidence interval (CI) 0.38-1.16) and for the progestin alone users was 0.85 (95% CI 0.44-1.65). CONCLUSIONS: This study was unable to demonstrate a significant increase in risk of breast cancer recurrence for women who used HRT and suggests that the time is now appropriate for a randomized prospective trial of hormone therapy after breast cancer.

Significance of 17alpha OH progesterone assay in the evaluation of ovarian and adrenal function.

Plasma 17alpha OH progesterone was assayed radioimmunologically, using an anti-17-OH-progesterone BSA antiserum as specific binding antigen. The method consisted in extracting steroids with ethyl ether from 1 ml plasm (to which 17alpha OH progesterone-1,2-3H had been added for the assessment of losses); the extract was then submitted to chromatography on a Sephadex LH-20 column, antiserum was added and the free steroid was separated from the bound form by Charcoal-dextran. Average recovery of 17alpha OH progesterone-1,2-3H was 75+/-5%. Minimum sensitivity of the method oscillated about 7-10 pg. MIF (Method Interfering Factors) were evaluated. The method was used for the assay of 17alpha OH progesterone plasma levels during normal menstrual cycles, in women undergoing ovarian stimulation with HMG and HCG in the follicular and luteal phase respectively. Finally, changes of plasma 17alpha OH progesterone levels were assessed during adrenal stimulation and suppression in various stages of the menstrual cycle.