Estrogen receptor-beta mRNA is associated with adverse outcome in patients with breast cancer.

BACKGROUND/AIMS: Estrogen receptor (ER) is the prototype therapy predictive marker in oncology. The ER is now known to exist in two main forms with similar overall structure: ER-alpha and ER-beta. Both forms may be expressed in breast cancer. The aim of this study was to examine breast cancer outcome in relation to expression of ER-beta. METHODS: In this investigation, we measured the expression of ER-alpha protein and ER-beta mRNA in 121 extracts of invasive breast cancer. Association of expression with clinical outcome was examined using Kaplan-Meier and Cox regression analyses. RESULTS: While ER-alpha expression was associated with good patient outcome [hazard ratio (HR) for death from breast cancer 0.37; 95% confidence interval (CI) 0.17-0.84; p = 0.017], ER-beta predicted poor outcome (HR for death from breast cancer 2.49; 95% CI 1.10-5.63; p = 0.028). CONCLUSION: Based on these findings, we conclude that ER-beta may have a different biological role from that of ER-alpha in breast cancer.

Acute colonic obstruction due to benign prostatic hypertrophy.

A seventy two year old man presented to the Emergency Department with clinical features of colonic obstruction. Subsequent radiological investigations confirmed this impression and revealed the aetiology to be compression of the sigmoid colon against the sacrum by a massively distended urinary bladder. Chronic urinary retention due to benign prostatic hypertrophy is an extremely unusual cause of large bowel obstruction. Little in this patient's clinical findings suggested this aetiology. We reviewed the literature in this area and highlight the benefits of CT scanning over contrast studies.

Lacunar stroke attributable to radiation-induced intracranial arteriopathy.

We report the rare presentation of lacunar stroke syndrome secondary to single perforator mouth occlusion from radiation-induced middle cerebral artery (MCA) stem arteriopathy. A 30-year-old female had acute-onset right-sided ataxic hemiparesis and dysarthria. As a child, she had a medulloblastoma of the posterior fossa and had surgery followed by cranial radiotherapy. She had no significant vascular risk factors. Acute CT showed extensive bilateral basal ganglia and left thalamic calcification; DWI showed a left internal capsule lacunar infarct; and MRA and CTA showed a 50% stenosis of the proximal left MCA.

Neuroanatomical correlates of memory deficits in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a multisystem syndrome classically associated with the occurrence of focal brain dysplasias. We used structural magnetic resonance imaging to test for neuroradiological abnormalities in TSC (tubers, white matter lesions, and subependymal nodules) and to explore the relationships between these lesions and computational morphometric abnormalities of gray and white matter distribution. We tested memory function in TSC and investigated the relationship between memory function and both morphometric variation and lesion load. Patients demonstrated deficits bilaterally in volume of subcortical gray matter regions including thalamus, basal ganglia, insula, and cerebellum, as well as white matter deficits bilaterally in intrahemispheric tracts. Morphometric deficits could not be explained as local effects of lesions. Patients demonstrated deficits in executive working memory and recall memory, sparing recognition. Structure-function mapping showed long-term and working memory function was positively correlated with gray matter density (in thalamus, caudate nucleus, and frontal cortex) but not with lesion load. The neuroanatomical endophenotype of TSC is more extensive than previously recognized and comprises abnormalities in the distribution of gray and white matter in addition to classical lesions. Normal intelligence quotient patients with TSC show a profile of long-term and working memory impairment that is related to gray matter deficits in thalamus and basal ganglia components of fronto-striatal circuits.

A positive role for PEA3 in HER2-mediated breast tumour progression.

Overexpression of HER2 is associated with an adverse prognosis in breast cancer. Despite this, the mechanism of its transcriptional regulation remains poorly understood. PEA3, a MAP kinase (MAPK)-activated member of the Ets transcription factor family has been implicated in the transcriptional regulation of HER2. The direction of its modulation remains controversial. We assessed relative levels of PEA3 expression and DNA binding in primary breast cultures derived from patient tumours (n=18) in the presence of an activated MAPK pathway using Western blotting and shift analysis. Expression of PEA3 in breast tumours from patients of known HER2 status (n=107) was examined by immunohistochemistry. In primary breast cancer cell cultures, growth factors induced interaction between PEA3 and its DNA response element. Upregulation of PEA3 expression in the presence of growth factors associated with HER2 positivity and axillary lymph node metastasis (P=0.034 and 0.049, respectively). PEA3 expression in breast cancer tissue associated with reduced disease-free survival (P<0.001), Grade III tumours (P<0.0001) and axillary lymph node metastasis (P=0.026). Co-expression of PEA3 and HER2 significantly associated with rate of recurrence compared to patients who expressed HER2 alone (P=0.0039). These data support a positive role for PEA3 in HER2-mediated oncogenesis in breast cancer.

Adjuvant therapies in the treatment of stage II and III malignant melanoma.

BACKGROUND: The incidence of cutaneous melanoma has increased during the past three decades. The development of sentinel lymph node biopsy has facilitated better staging. Despite these improvements, 5-year survival rates for American Joint Committee on Cancer stage II and III disease range from 50%-90%. METHODS: A review of the current literature concerning adjuvant therapies in patients with stage II and III malignant melanomas was undertaken. RESULTS: The focus of adjuvant therapies has shifted from radiotherapy, BCG and levamisole to newer biological agents. Interferon, interleukin and vaccines have been evaluated but none of these agents have demonstrated an increase in overall survival in patients with stage II and III melanoma. Interferon can prolong disease-free interval. CONCLUSION: At present, no adjuvant therapy improves overall survival in patients with stage II and III melanoma. New staging allows more accurate stratification of patients for clinical trials.

Detection and evaluation of intracranial aneurysms with 16-row multislice CT angiography.

AIM: The aim of this study was to assess the usefulness of 16-row multislice CT angiography (CTA) in evaluating intracranial aneurysms, by comparison with conventional digital subtraction angiography (DSA) and intraoperative findings. METHODS: A consecutive series of 57 patients, scheduled for DSA for suspected intracranial aneurysm, was prospectively recruited to have CTA. This was performed with a 16-detector row machine, detector interval 0.75 mm, 0.5 rotation/s, table speed 10mm/rotation and reconstruction interval 0.40 mm. CTA studies were independently and randomly assessed by two neuroradiologists and a vascular neurosurgeon blinded to the DSA and surgical findings. Review of CTA was performed on workstations with an interactive 3D volume-rendered algorithm. RESULTS: DSA or intraoperative findings or both confirmed 53 aneurysms in 44 patients. For both independent readers, sensitivity and specificity per aneurysm of DSA were 96.2% and 100%, respectively. Sensitivity and specificity of CTA were also 96.2% and 100%, respectively. Mean diameter of aneurysms was 6.3mm (range 1.9 to 28.1 mm, SD 5.2 mm). For aneurysms of less than 3 mm, CTA had a sensitivity of 91.7% for each reader. Although the neurosurgeon would have been happy to proceed to surgery on the basis of CTA alone in all cases, he judged that DSA might have provided helpful additional anatomical information in 5 patients. CONCLUSION: The diagnostic accuracy of 16-slice CTA is promising and appears equivalent to that of DSA for detection and evaluation of intracranial aneurysms. A strategy of using CTA as the primary imaging method, with DSA reserved for cases of uncertainty, appears to be practical and safe.

Positron emission tomography in the staging and management of breast cancer.

BACKGROUND: Breast cancer is the commonest cause of cancer death in women in the Western world, and imaging is essential in its diagnosis and staging. Metabolic imaging is a novel approach to improving the detection of cancers, as malignant transformation of cells is often associated with increased metabolic activity. This review assesses the possible role of positron emission tomography (PET) as a single non-invasive imaging modality to replace or complement current imaging and surgical practices in the diagnosis and staging of breast cancer. METHODS AND RESULTS: A Medline search was performed and articles were cross-referenced with other relevant material. Evaluation of primary breast cancer with PET has shown a sensitivity of between 64 and 100 per cent and a specificity of 33-100 per cent; diagnostic accuracy appears to be related to tumour size. Difficulties arise in altered fluorodeoxyglucose uptake in lobular carcinoma, carcinoma in situ and benign inflammatory breast disease. In axillary staging, sensitivities of between 25 and 100 per cent have been reported, but with a false-negative of up to 20 per cent. In the assessment of distant metastasis and asymptomatic patients with raised levels of tumour markers, PET was superior to conventional imaging modalities. CONCLUSION: PET is not a single diagnostic and staging tool that can replace current surgical, histological and radiological staging. Its main role in breast cancer lies in the investigation of metastatic disease and the evaluation of pathological response to various chemotherapeutic regimens.

Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer.

The oestrogen receptor (ER) interacts with coactivator proteins to modulate genes central to breast tumour progression. Oestrogen receptor is encoded for by two genes, ER-alpha and ER-beta. Although ER-alpha has been well characterized, the role of ER-beta as a prognostic indicator remains unresolved. To determine isoform-specific expression of ER and coexpression with activator proteins, we examined the expression and localisation of ER-alpha, ER-beta and the coactivator protein steroid receptor coactivator 1 (SRC-1) by immunohistochemistry and immunofluorescence in a cohort of human breast cancer patients (n=150). Relative levels of SRC-1 in primary breast cultures derived from patient tumours in the presence of beta-oestradiol and tamoxifen was assessed using Western blotting (n=14). Oestrogen receptor-beta protein expression was associated with disease-free survival (DFS) and inversely associated with the expression of HER2 (P=0.0008 and P<0.0001, respectively), whereas SRC-1 was negatively associated with DFS and positively correlated with HER2 (P<0.0001 and P<0.0001, respectively). Steroid receptor coactivator 1 protein expression was regulated in response to beta-oestradiol or tamoxifen in 57% of the primary tumour cell cultures. Protein expression of ER-beta and SRC-1 was inversely associated (P=0.0001). The association of ER-beta protein expression with increased DFS and its inverse relationship with SRC-1 suggests a role for these proteins in predicting outcome in breast cancer.

Expression of SRC-1, AIB1, and PEA3 in HER2 mediated endocrine resistant breast cancer; a predictive role for SRC-1.

BACKGROUND: In human breast cancer, the growth factor receptor HER2 is associated with disease progression and resistance to endocrine treatment. Growth factor induced mitogen activated protein kinase activity can phosphorylate not only the oestrogen receptor, but also its coactivator proteins AIB1 and SRC-1. AIM: To determine whether insensitivity to endocrine treatment in HER2 positive patients is associated with enhanced expression of coactivator proteins, expression of the HER2 transcriptional regulator, PEA3, and coregulatory proteins, AIB1 and SRC-1, was assessed in a cohort of patients with breast cancer of known HER2 status. METHODS: PEA3, AIB1, and SRC-1 protein expression in 70 primary breast tumours of known HER2 status (HER2 positive, n = 35) and six reduction mammoplasties was assessed using immunohistochemistry. Colocalisation of PEA3 with AIB1 and SRC-1 was determined using immunofluorescence. Expression of PEA3, AIB1, and SRC-1 was correlated with clinicopathological parameters. RESULTS: In primary breast tumours expression of PEA3, AIB1, and SRC-1 was associated with HER2 status (p = 0.0486, p = 0.0444, and p = 0.0012, respectively). In the HER2 positive population, PEA3 expression was associated with SRC-1 (p = 0.0354), and both PEA3 and SRC-1 were significantly associated with recurrence on univariate analysis (p = 0.0345; p<0.0001). On multivariate analysis, SRC-1 was significantly associated with disease recurrence in HER2 positive patients (p = 0.0066). CONCLUSION: Patients with high expression of HER2 in combination with SRC-1 have a greater probability of recurrence on endocrine treatment compared with those who are HER2 positive but SRC-1 negative. SRC-1 may be an important predictive indicator and therapeutic target in breast cancer.

Expression and prognostic relevance of Mcl-1 in breast cancer.

BACKGROUND: Bcl-2, an anti-apoptotic protein, is frequently associated with favourable prognosis in breast cancer. The potential role of mcl-1, another bcl-2 family member, in breast cancer has not yet been defined. PATIENTS AND METHODS: This study examined the expression of mcl-1 and bcl-2 in 170 cases of invasive primary breast carcinoma, using reverse-transcriptase polymerase chain reaction and immunohistochemical analyses. RESULTS: Expression of bcl-2 mRNA and protein were found to be favourably associated with outcome for patients, supporting a prognostic role for bcl-2 in breast cancer, whereas mcl-1 expression, at the mRNA or protein level, did not correlate with tumour size, grade, lymph node or ER status, age of patient at diagnosis, or disease outcome. CONCLUSION: As these analyses of mcl-1 expression may have co-detected mcl-1(S/deltaTM) (a more recently identified, shorter variant, that may be pro-apoptotic) with the anti-apoptotic wild-type of mcl-1, it is possible that future studies may indicate some significant clinical correlations if the isoforms can be independently investigated.

Contrast-enhanced MR angiography for carotid disease: diagnostic and potential clinical impact.

OBJECTIVE: To compare contrast-enhanced MR angiography (CEMRA) with intra-arterial digital subtraction angiography (DSA) for evaluating carotid stenosis. METHODS: A total of 167 consecutive symptomatic patients, scheduled for DSA following screening duplex ultrasound (DUS), were prospectively recruited to have CEMRA. Three independent readers reported on each examination in a blinded and random manner. Agreement was assessed using the Bland-Altman method. Diagnostic and potential clinical impact of CEMRA was evaluated, singly and in combination with DUS. RESULTS: CEMRA tended to overestimate stenosis by a mean bias ranging from 2.4 to 3.8%. A significant part of the disagreement between CEMRA and DSA was directly caused by interobserver variability. For detection of severe stenosis, CEMRA alone had a sensitivity of 93.0% and specificity of 80.6%, with a diagnostic misclassification rate of 15.0% (n = 30). More importantly, clinical decision-making would, however, have been potentially altered only in 6.0% of cases (n = 12). The combination of concordant DUS and CEMRA reduced diagnostic misclassification rate to 10.1% (n = 19) at the expense of 47 (24.9%) discordant cases needing to proceed to DSA. An intermediate approach of selective DUS review resulted in a marginally worse diagnostic misclassification rate of 11.6% (n = 22) but with only 6.8% of discordant cases (n = 13). CONCLUSIONS: DSA remains the gold standard for carotid imaging. The clinical misclassification rate with CEMRA, however, is acceptably low to support its safe use instead of DSA. The appropriateness of combination strategies depends on institutional choice and cost-effectiveness issues.

Intraoperative margin assessment and re-excision rate in breast conserving surgery.

AIM: The aim of this study was to assess the efficacy of intraoperative margin assessment in obtaining clear margins in conserving surgery for breast cancer. METHODS: Two hundred and twenty patients undergoing wide local excision (WLE) for core biopsy proven primary invasive breast cancer, during a 30 months period, were included in the study. Following surgical excision the breast specimen was orientated with sutures, inked using India ink and coloured pigments and incised to identify the tumour, maintaining orientation. The distance to the individual radial margins were estimated macroscopically by the pathologist and conveyed intraoperatively to the surgeon. A macroscopic tumour-margin distance of less than 10 mm was considered compromised and the margin(s) in question was then excised if feasible. RESULTS: Eighty-one patients (37%) were judged to have compromised margins following intraoperative macroscopic evaluation and had at least one margin re-excised. Sixteen of the 81 patients (20%) in this subgroup had compromised margins on microscopy and required a second operation. One hundred and thirty-nine patients (63%) were deemed to have clear margins intraoperatively, subsequently confirmed on microscopic examination in 135 patients (97%). Intraoperative macroscopic assessment of margin status was associated with 9.1% of patients requiring a second operation. In the absence of intraoperative assessment of margin status a further 47 patients (21.4%) would have required a second operation. CONCLUSION: Intraoperative macroscopic margin assessment is an effective technique in reducing the number of second operative procedures in patients undergoing conserving surgery for primary invasive breast cancer.

Intradermal radioisotope injection optimises sentinel lymph node identification in breast cancer.

AIM: Currently there is no consensus on the optimal technique for sentinel lymph node (SLN) identification in patients with breast cancer. The aim was to compare the efficacy of intraparenchymal and intradermal isotope injection in sentinel lymph node mapping for breast cancer. METHODS: One hundred and twenty-five patients with histologically confirmed invasive breast cancer underwent SLN mapping using radioisotope and isosulphan blue dye followed by a back-up axillary dissection. The first 80 patients had intraparenchymal (IP) injection of radioisotope given in four portions around the tumor. The remaining 45 patients had an intradermal (ID) injection given at a single site over the tumour. Both groups had isosulphan blue dye injected around the tumour. Sentinel node(s) were identified using a combination of lymphoscintigraphy, blue dye and an intra-operative hand held gamma probe. RESULTS: The preoperative lymphoscintigram (LSG) demonstrated a SLN significantly more often in the ID isotope group compared to the IP isotope group (P=0.002). A combination of blue dye and isotope successfully located the SLN in 96% of the intraparenchymal group and 100% of the intradermal group. CONCLUSION: Our results suggest that intradermal isotope injection in combination with intraparenchymal blue dye optimises the localization of the sentinel lymph node in breast cancer.

The prevention of breast cancer.

BACKGROUND: Despite advances in the early detection and treatment of breast carcinoma, the mortality and morbidity rates associated with this disease remain high. Primary prevention, therefore, offers the best chance of making a major impact on outcome. METHODS: The aim was to review the rationale, current stage of development and adverse effects of the strategies involved in the primary prevention of breast carcinoma. A review of the literature was undertaken by searching the MEDLINE database for the period 1966-2002 without language restrictions. RESULTS AND CONCLUSION: Currently, the only agent to have general approval for chemoprevention of breast carcinoma is tamoxifen. Women who derive the greatest benefit in terms of risk reduction from tamoxifen are premenopausal with a 5-year Gail risk factor of more than 1.66 per cent, postmenopausal with a 5-year Gail risk factor of more than 3 per cent, and postmenopausal without a uterus. In these specific subgroups, tamoxifen should be considered for the chemoprevention of breast carcinoma. Raloxifene, retinoids, aromatase inhibitors and cyclo-oxygenase 2 inhibitors require further clinical investigation before adoption in this context. Surgical intervention should largely be limited to those women who have a BRCA1 or BRCA2 mutation.

Prognostic importance of survivin in breast cancer.

Survivin is a member of the inhibitor of apoptosis (IAP) family, and is also involved in the regulation of cell division. Survivin is widely expressed in foetal tissues and in human cancers, but generally not in normal adult tissue. This study examined the expression of surviving protein in a series of 293 cases of invasive primary breast carcinoma. Survivin immunoreactivity was assessed using two different polyclonal antibodies, and evaluated semiquantitatively according to the percentage of cells demonstrating distinct nuclear and/or diffuse cytoplasmic staining. Overall, 60% of tumours were positive for survivin: 31% demonstrated nuclear staining only, 13% cytoplasmic only, and 16% of tumour cells demonstrated both nuclear and cytoplasmic staining. Statistical analysis revealed that survivin expression was independent of patient's age, tumour size, histological grade, nodal status, and oestrogen receptor status. In multivariate analysis, nuclear survivin expression was a significant independent prognostic indicator of favourable outcome both in relapse-free and overall survival (P<0.001 and P=0.01, respectively). In conclusion, our results show that survivin is frequently overexpressed in primary breast cancer. Nuclear expression is most common and is an independent prognostic indicator of good prognosis.

The role of molecular staging in malignant melanoma.

AIMS: To review the role of tyrosinase RT-PCR in the detection of clinically occult metastatic disease, both within the regional lymph nodes and peripheral blood of patients with malignant melanoma. Secondly, to assess whether the detection of such minimal disease has clinical implications for patients with melanoma. METHODS: A review of the literature was undertaken by searching the MEDLINE database for the period 1966-2002 without any language restrictions. Keywords included 'Molecular staging of melanoma', 'Reverse transcription polymerase chain reaction', 'Malignant melanoma' and 'Tyrosinase'. CONCLUSIONS: Detection of tyrosinase RT-PCR positive cells within the peripheral blood correlates with the clinical stage of malignant melanoma, the primary tumour thickness and other known prognostic indicators. Positive tyrosinase RT-PCR is associated with a reduction of disease-free survival and overall survival. Current studies demonstrate a higher rate of recurrence in RT-PCR positive patients with clinical stage II and III disease. Implications of a positive result within the regional lymph nodes are less well defined. A significant correlation has been demonstrated between positive results and increasing primary melanoma thickness. However, a large number of false-positive results have been demonstrated, due to benign naevi and schwann cells, which may hamper any statistically significant conclusions being reached.

Elevated expression and altered processing of fibulin-1 protein in human breast cancer.

The extracellular matrix protein fibulin-1 suppresses the motility and invasiveness of a variety of tumour cell types in vitro as well as the growth of fibrosarcoma tumours in nude mice. In this study, fibulin-1 protein expression in breast carcinoma specimens and normal breast tissue was evaluated immunohistologically. Fibulin-1 protein expression was also semiquantitatively assessed by immunoblot analysis in a collection of normal breast tissues (n=18), benign tumours (n=5) and breast carcinomas (n=39). In normal breast tissue, fibulin-1 protein expression predominated in the ductal epithelium and underlying myoepithelium, with weaker staining evident in the loose connective surrounding the ducts. Examination of breast carcinomas revealed that the tumour cells also expressed fibulin-1 protein. The level of mature fibulin-1 polypeptide (100 kDa) was higher in the breast carcinoma specimens as compared to normal breast tissue (Mann-Whitney U-test, P=0.0005). In addition to the mature fibulin-1 polypeptide, several smaller sized polypeptides of 55, 50 and 25 kDa were detected using monoclonal antibodies reactive towards an epitope located at the N-terminus of fibulin-1. The immunoreactive 50 kDa polypeptide was detected more frequently in breast carcinoma specimens than in normal breast tissue (chi(2)=17.22, P<0.0001). Furthermore, the ratio of the 50 kDa fragment to the mature fibulin-1 polypeptide correlated with the level of oestrogen receptor alpha (Spearman correlation coefficient, rs=0.49, P<0.003, n=36) and progesterone receptor (rs=0.43, P=0.008, n=36) expression in the tumour specimens. Taken together, these findings indicate that elevated expression and altered processing of fibulin-1 is associated with human breast cancer.

Percutaneous endoscopic gastrostomy: 5 years of clinical experience on 238 patients.

Since Percutaneous Endoscopic Gastrostomy (PEG) feeding was introduced, 20 years ago it has been increasingly utilised in medical practice. The aim of this study was to assess the current indications and complications associated with PEG feeding. This study was a retrospective review of hospital charts dealing with PEG placement over a period of five years. The indications for insertion were, central nervous disease 76% (n = 156), other benign disease 14% (n = 28) and malignancy 10% (n = 21). Cerebrovascular accidents (CVA) alone accounted for 47% (n = 97). Ninety seven (50%) patients had minor complications, which included 43 (22%) wound infections. There were 6 (3%) major complications, including peritonitis, perforation and aspiration pneumonia. There were four deaths (2%) related to PEG placement, of whom three developed aspiration pneumonia and one peritonitis. The overall 30 day mortality rate was 16%. There was a 75% increase in the use of PEG placement over the five year period. PEG placements were associated with a 53% morbidity and a 2% procedure related mortality. There was a 16% 30 day mortality following PEG placement suggesting that the selection criteria for PEG placement may need to be refined further.

Positron emission tomography for staging and management of malignant melanoma.

BACKGROUND: The incidence of malignant melanoma is rising; it now has an incidence of ten per 100 000 per annum in the UK. The development of metastases is unpredictable, but prognosis is linked directly to the initial stage at diagnosis. Positron emission tomography (PET) can allow the detection of malignant cells at a relatively early stage. METHODS: A review of the literature was undertaken by searching the Medline database for the period 1980-2000 without any language restrictions. RESULTS: The overall sensitivity and specificity of PET are 74-100 and 67-100 per cent respectively. PET has a reduced sensitivity and specificity for thinner lesions (less than 1 x 5 mm). Comparison with computed tomography and magnetic resonance imaging has shown a higher sensitivity and specificity for PET in all regions of the body except the thorax. CONCLUSION: Currently the accepted indication for PET is recurrent melanoma when surgical intervention is being considered. However, other potential indications include the detection of occult or distant metastasis at initial presentation and the clarification of abnormal radiological findings at follow-up. The routine use of PET for American Joint Commission on Cancer stage I or II disease is of uncertain benefit and is not indicated at present.