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.

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.

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.

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.

Anti-human epidermal growth factor receptor 2 monoclonal antibody therapy for breast cancer.

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.

Granulomatous appendicitis revisited: report of a case.

BACKGROUND: Isolated granulomatous appendicitis is uncommon and previously was considered to be a form of localised Crohn's disease. However more recent series have noted that relapse is rare after appendicectomy and concluded that the condition is a distinct entity unrelated to Crohn's disease. Following a case of granulomatous appendicitis at St. Vincent's University Hospital Dublin, the condition was reviewed and the results are detailed herein. METHODS: A case of granulomatous appendicitis is presented with discussion of 4 previous cases encountered in our practice and the literature is reviewed. RESULTS: The clinical presentation was sub-acute appendicitis with a mass palpable in the right iliac fossa. At operation an enlarged, inflamed appendix with a broad base was noted and appendicectomy performed. Histopathology showed numerous granulomata on microscopic examination. The yersinia serology tests were negative. Review of computerised histopathology records in the hospital for the last 7 years showed 4 additional cases of granulomatous appendicitis. This is a total of 5 of 1,615 appendectomies (an incidence of 0.31%). In all cases, the post-operative course was uneventful and the patients have had no further complaints. CONCLUSION: This small series provides further evidence that granulomatous appendicitis is a distinct clinical entity unrelated to Crohn's disease and is cured by appendicectomy. It should be suspected when there is a sub-acute onset of appendicitis and an enlarged, broad-based appendix is found at operation.

Parathyroid carcinoma: diagnosis and management.

Parathyroid carcinoma is a rare and difficult diagnosis to make based on the histological features alone. We review five cases of parathyroid carcinoma in the past 30 years and the clinical and biochemical features that facilitate the making of the diagnosis. A favourable outcome can be expected with adequate surgical treatment.