Robert Carpenter

The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma

BACKGROUND Endometrial carcinoma is the most common extracolonic malignancy associated with hereditary nonpolyposis colorectal carcinoma syndrome (HNPCC). The risk of endometrial carcinoma in HNPCC mutation carriers is approximately ten times that of the general population, and endometrial ultrasound surveillance to detect early cancer in asymptomatic individuals is recommended by the International Collaborative Group on HNPCC. There is little, if any, published data addressing the effectiveness of surveillance in HNPCC and familial colorectal carcinoma. METHODS The outcomes of endometrial carcinoma surveillance scans were collected from the St Marks Hospital Imperial Cancer Research Fund Family Cancer Clinic in the UK and the Netherlands Foundation for the Detection of Hereditary Tumors. Two hundred ninety two women from HNPCC (171) or HNPCC-like (98) families between the ages of 25-65 years were offered pelvic ultrasound surveillance scans for a period of up to 13 years. RESULTS Results were available from 269 women. The study period included a total of 825.7 years of risk. Two cases of endometrial carcinoma were reported. Neither case was detected by surveillance scanning. Both cases presented at an early stage with symptoms and were subsequently cured. CONCLUSIONS Endometrial carcinoma surveillance in hereditary colorectal carcinoma may not offer obvious clinical benefits.We read with interest the recent article by Dove-Edwin et al. concerning endometrial carcinoma (EC) screening in women from hereditary nonpolyposis colorectal cancer (HNPCC) and HNPCC-like families. There are a number of issues we would like to raise in relation to their conclusions. Women with HNPCC pedigrees are at risk for two gynecologic malignancies: EC and epithelial ovarian carcinoma (EOC). The lifetime risk of EC in women from HNPCC families has been quoted as high as 60%; this equates to their risk of colorectal carcinoma (CRC), which is lower for women than for men in these families. For EOC, the cumulative lifetime risk in the general population is 1%; in HNPCC families, this risk is increased to 9%. To date, there is no proven satisfactory screening modality for either of these gynecologic malignancies in the general population or in high-risk groups. The most studied form of screening has been for EOC in the general population and in breast/ovarian cancer families with or without identified BRCA1/BRCA2 mutations. A combination of transvaginal ultrasound with Doppler studies (TV USS) and the tumor marker CA125 appears to be the best strategy, but this approach lacks sensitivity and specificity in the premenopausal population and, to date, has not been shown to lead to a reduction in mortality in the postmenopausal population. There are currently two large randomized controlled trials to assess its role, and until then, the consensus opinion is for women in defined high-risk groups to receive annual screening with TV USS and CA125 with an understanding of its limitations. This has significant resource implications in the United Kingdom, where radiology services already are overstretched and are unable to meet their commitment for diagnostic services, let alone screening services. The attention to finding a satisfactory method of screening has been greater for EOC than for EC because of the dramatically different survival rates for the two diseases. EOC typically presents as Stage III disease, and the overall 5-year survival rate is 30%. In contrast, EC typically presents as Stage I disease with the symptom of postmenopausal bleeding. However, in the general population, one in four women diagnosed with EC will die from their disease. This differs from the study, quoted by Dove-Edwin et al., of 125 women in HNPCC families; that study yielded a mortality rate of 12% due to EC. EC also differs from EOC in that there is a loosely defined, premalignant phase of simple/complex hyperplasia with or without atypia. There is also a move to define more carefully a morphologic description of endometrial intraepithelial neoplasia. This is a more quantitative, reproducible definition supported with molecular evidence of mono1772

Integrin expression in breast cancer cytology: a novel predictor ofaxillary metastasis

The integrins are heterodimeric transmembrane receptors of varying alpha and beta subunits that modulate cell adhesion to each other and to the extracellular matrix. Loss of integrin expression on primary breast cancer frozen sections measured by immunohistochemistry may be related to the presence of axillary metastasis. The clinical application of this finding would be increased if integrin expression could also be shown to be reliably measured on breast cancer cells obtained by fine needle aspiration cytology. Axillary operations may be planned as a single stage procedure from outpatients, and neoadjuvant therapy protocols may be developed without surgery to the axilla. Expression of the alpha 1, alpha 2, alpha 3, alpha 6, alpha v, beta 1, beta 3 and beta 5 integrin subunits were measured by immunohistochemistry and immunocytochemistry in 58 patients. Integrin measurement by both these methods were found to be closely associated using the kappa-test. Loss of expression of the alpha 1, alpha 2, alpha 3, alpha 6, alpha v, beta 1 and beta 5 integrin subunits measured by cytology and histology were each related to positive nodal status (chi(2) test). Measuring integrin expression on cytology is of clinical value and may prove to have prognostic significance.

Benign biopsies in the prevalent round of breast screening : a review of 137 cases

In the first round of the National Health Service Breast Screening Programme, 35,533 women attended for screening at the two breast screening units served by St Bartholomews Hospital. Further assessment was necessary in 2212 women (6.2%), of whom 412 (1%) subsequently underwent surgical biopsy. Of these 137 had benign lesions. The predominant mammographic abnormality leading to biopsy was microcalcification in 55, a mass in 48, parenchymal asymmetry in 18 and architectural distortion in 16. Histology revealed fibrocystic change in 66, fibroadenoma in 27, radial scar/complex sclerosing lesion in 23, atypical ductal hyperplasia only in eight, and a variety of unusual benign lesions in 13. In an attempt to determine criteria which would minimize unnecessary biopsy of benign lesions in future, the mammographic and cytological features of these benign lesions were reviewed and compared with the final histology. The most common diagnostic problems were clustered and variable microcalcification, the radial scar/complex sclerosing lesion, and mammographic features shown to be atypical hyperplasia on histology.

Transcription of the prorenin gene in normal and diseased breast.

The angiotensin II type 1 (AT1) receptor is present in a wide variety of human and animal tissues, and is particularly abundant in epithelial cells. Because of this, and because it is known that tissue renin angiotensin systems (RASs) exist that have specific local functions, we investigated the expression and localisation of components of the RAS in normal and diseased breast tissue. Using a monoclonal antibody to the AT1 receptor, immunocytochemistry confirmed that the AT1 receptor was characteristically distributed in ductal epithelial cells in both normal and malignant tissue, and in most, although not all, cells in invasive tumours. Transcription of prorenin mRNA was studied by in situ hybridisation, using a DIG-ddUTP tail-labelled probe specific for the human prorenin gene. In normal tissue, and in cases of ductal carcinoma in situ, prorenin mRNA was distributed in myoepithelial cells and in a band of connective tissue cells completely surrounding the AT1-containing ductal epithelial cells. This prorenin transcribing tissue was disrupted and attenuated in invasive tumours, and in some of these, prorenin mRNA transcription could not be detected at all. Functions ascribed to the tissue RASs include regulation of mitosis and tissue modelling, as well as fluid and electrolyte transport. The results presented here strongly suggest the possibility that a tissue RAS may also be present in the breast, closely coupled to the provision of angiotensin II to the AT1 receptors in ductal epithelial cells. This mechanism is disrupted in cancer.

Clinical and functional significance of α9β1 integrin expression in breast cancer: a novel cell-surface marker of the basal phenotype that promotes tumour cell invasion.

Integrin α9β1 is a receptor for ECM proteins, including Tenascin‐C and the EDA domain of fibronectin, and has been shown to transduce TGFβ signalling. This study has examined the expression pattern of α9β1 in 141 frozen breast carcinoma samples and related expression to prognostic indices, molecular subtype and patient outcome. Effects of α9β1 on tumour cell migration and invasion were assessed using blocking antibody and gene transduction approaches. Integrin α9β1 localized to myoepithelial cells in normal ducts and acini, a pattern maintained in DCIS. A subset (17%) of invasive carcinomas exhibited tumour cell expression of α9β1, which related significantly to the basal‐like phenotype, as defined by either CK5/6 or CK14 expression. Tumour expression of α9β1 showed a significant association with reduced overall patient survival (p < 0.0001; HR 5.94, 95%CI 3.26–10.82) and with reduced distant‐metastasis‐free survival (p < 0.0001; HR 6.37, CI 3.51–11.58). A series of breast cancer cell lines was screened for α9β1 with the highly invasive basal‐like GI‐101 cell line expressing significant levels. Both migration and invasion of this line were reduced significantly in the presence of α9‐blocking antibody and following α9‐knockdown with siRNA. Conversely, migratory and invasive behaviour of α9‐negative MCF7 cells and α9‐low MDA MB468 cells was enhanced significantly by over‐expression of α9. Thus, α9β1 acts as a novel marker of the basal‐like breast cancer subtype and expression is associated with reduced survival, while its ability to promote breast cancer cell migration and invasion suggests that it contributes to the aggressive clinical behaviour of this tumour subtype. Copyright

A prospective evaluation of postural stimulation testing, computed tomography and adrenal vein sampling in the differential diagnosis of primary aldosteronism

Context  In primary aldosteronism (PA), discriminating unilateral from bilateral disease is crucial because adrenalectomy is frequently curative in the former case but rarely helps in the latter. Various series have reported the utility of postural stimulation testing (PST), cross‐sectional imaging and adrenal vein sampling (AVS) in the assessment of PA, but most of these studies were retrospective.

Diagnosing unilateral primary aldosteronism - comparison of a clinical prediction score, computed tomography and adrenal venous sampling.

In patients with primary aldosteronism (PA), adrenalectomy is potentially curative for those correctly identified as having unilateral excessive aldosterone production. It has been suggested that a recently developed and published clinical prediction score (CPS) may correctly identify some patients as having unilateral disease, without recourse to adrenal venous sampling.

Integrinβ1-mediated invasion of human breast cancer cells: anex vivo assay for invasiveness

BackgroundThe integrin cell adhesion molecule (CAM) family is intimately involved in cell adhesion and invasion through tissue basement membranes (BM). As a consequence of the short survival of patient-derived human breast cancer cells, the invasion of such cells has not been previously reported. Our aims were to optimise culture conditions in order to establish a reliable invasion assay and to assess the effect on invasion of perturbations of theβ1 integrin receptors.MethodsPure suspensions of viable carcinoma cells were isolated immunomagnetically from human breast cancer (HBC) samples and introduced onto a replicated glycoprotein BM within an invasion chamber. Degree of invasion was compared to bothβ1 integrin expression and tumour grade. Additionally, the effect ofβ1 receptor blockade with monoclonal antibody (mAb) was assessed.ResultsInvasion was significantly greater in grade II than grade III tumour cells (P=0.0012). Antiintegrinβ1 monoclonal antibody inhibited cancer cell invasion by a mean of 83.96 ± 4.80%.ConclusionsThe invasion assay confirmed the fundamental importance ofβ1 integrin receptors to transmembrane invasion and reports this for the first time in cells isolated from primary breast cancer. It represents a potent research tool for investigation of the tumour biology of invasion at the integrinβ1-mediated cell-basement membrane interface. This assay has the potential clinical application of improved stratification of patients for adjuvant therapy on a more individual basis than currently available.

An audit of patient acceptance of one-stop diagnosis for symptomatic breast disease.

AIMS The impetus for optimizing outpatient provision of breast-care services has come both from the patient and management in order to reduce anxiety and make full use of scarce resources. The one-stop diagnostic clinic for the investigation of symptomatic breast lesions is a relatively recent concept with well-known service benefits. However, acceptance to the patient has not been previously investigated. RESULTS The results of this prospective audit demonstrate a high level of patient satisfaction with the multi-disciplinary, one-stop breast clinic.

Choosing early adjuvant therapy for postmenopausal women with hormone-sensitive breast cancer: Aromatase inhibitors versus tamoxifen

AIMS The aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole have demonstrated superior disease-free survival (DFS) over tamoxifen in several trials. As the choice of adjuvant endocrine treatment for early breast cancer (EBC) is evolving from tamoxifen to the AIs, this review compares the AIs with tamoxifen to help surgeons choose a treatment plan that provides the greatest reduction of recurrence risk for their patients. METHODS MEDLINE was searched to identify relevant literature on the adjuvant use of tamoxifen and AIs in EBC. RESULTS Despite the use of adjuvant tamoxifen, recurrence is a persistent threat to women with hormone-sensitive EBC. Trials of the AIs versus tamoxifen have established that patients benefit from longer DFS, and in some cases distant DFS, after the use of an AI as initial adjuvant therapy, as switch therapy following 2-3 years of tamoxifen, or as extended adjuvant therapy following 5 years of tamoxifen. The AIs are well tolerated, with a different safety profile than that of tamoxifen in all these settings. Trials addressing the optimal regimen and treatment duration for AIs are also underway. CONCLUSIONS The advantage in DFS associated with AIs over tamoxifen use should prompt physicians and patients to consider the use of an AI as the initial adjuvant endocrine therapy or, alternatively, switching patients who currently take tamoxifen to an AI for the remainder of adjuvant endocrine therapy. Prolonging the period of adjuvant therapy with letrozole after 5 years of tamoxifen reduces recurrence and is associated with a survival advantage in node-positive patients.