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.

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.

A direct relationship between thyroid enlargement and breast cancer.

Despite extensive study, evidence to support a direct relationship between diseases of the thyroid and breast has not been established. In this study thyroid volume was assessed by ultrasound in 200 patients with breast cancer and 354 with benign breast disease. Results were compared to appropriate female control groups. Both mean thyroid volume (21.1 +/- 1.4 mL) and the percentage of individual patients with enlarged (> 18.0 mL) thyroid glands (41.5%) were significantly greater in the breast cancer group than equivalent values (13.2 +/- 0.5 mL and 10.5%, respectively) in age-matched controls (P < 0.01 in both cases). The mean thyroid volume of 14.5 +/- 0.34 mL in patients with benign breast disease was also significantly greater than that of 12.5 +/- 0.38 mL in younger controls (P < 0.01). The results support a direct association between breast cancer and increased thyroid volume as mean thyroid volumes and the percentage of individual patients with enlarged thyroid glands were similar in those studied both before (20.8 +/- 1.3 mL and 43.0%) and after (21.4 +/- 1.6 mL and 40.0%) therapies for breast cancer. Although there is no evidence that thyroid enlargement represents a risk factor for breast cancer, the results emphasize the importance of raising the consciousness of the coincidence of both disorders.

Tissue iodine content and serum-mediated 125I uptake-blocking activity in breast cancer.

In the thyroid, active transport of iodide is under control of the TSH-dependent Na+/I- symporter (NIS), whereas in the breast such control is less well understood. In this study, NIS expression was demonstrated by RT-PCR in 2 of 2 fibroadenomata and 6 of 7 breast carcinoma messenger ribonucleic acid isolates. In addition, mean total tissue iodine levels of 80.9 +/- 9.5 ng I/mg protein in 23 benign tumors (fibroadenomata) were significantly higher than those in 19 breast cancers taken from either the tumor (18.2 +/- 4.6 ng I/mg) or morphologically normal tissue taken from within the tumor-bearing breast (31.8 +/- 4.9 ng I/mg; P < 0.05 in each case). Inhibition of 125I uptake into NIS-transfected CHO cells was observed in serum from 20 of 105 (19.0%) breast carcinoma, 8 of 49 (16.3%) benign breast disease, and 27 of 86 (31.4%) Graves' patients, but in only 1 of 33 (3.0%) age-matched female controls. IgG purified from serum of patients showing positive 125I uptake inhibition also inhibited iodide uptake, suggesting that such inhibition was antibody mediated. 125I uptake inhibition was significantly associated with thyroid peroxidase antibody positivity (P < 0.05) in sera from breast cancer patients, but not in those with benign breast disease, once again suggesting an association between thyroid autoimmunity and breast carcinoma.

Serum thyroid peroxidase autoantibodies, thyroid volume, and outcome in breast carcinoma.

The prevalence of thyroid peroxidase autoantibodies (TPO.Ab) was assessed in patients with either breast carcinoma or benign breast disease, and its association with disease outcome in breast carcinoma was studied. TPO.Ab were detected by direct RIA in serum from 121/356 (34.0%) of patients with breast carcinoma, compared with 36/194 (18.5%) of controls (P < 0.001); and in 31/108 (28.7%) with benign breast disease, compared with 12/88 (13.6%) of controls (P < 0.05). Survival analysis in a group of 142 women with breast carcinoma demonstrated that TPO.Ab titres > or = 0.3 U/mL were associated with a significantly better disease-free [relative risk (RR) = 1.84, P < 0.05] and overall survival (RR = 3.46, P < 0.02), compared with those who were TPO.Ab-negative. Better outcome associated with higher TPO.Ab titres was confined to those who had thyroid volumes within the intermediate range (10.1-18.8 mL) and did not further enhance the good outcome recorded when volumes were < or = 10.0 mL or > 18.8 mL. Multivariate survival analysis showed that both TPO.Ab and thyroid volume were independently associated with prognosis in breast carcinoma and that RRs for disease-free survival were of a similar order of magnitude to well-established prognostic indices such as axillary nodal status or tumor size. These findings supply evidence that manifestations of thyroid autoimmunity are associated with a beneficial effect on disease outcome in breast carcinoma and provide the strongest evidence to date of a biological link between breast carcinoma and thyroid disease.

Studies on oestrogen receptor-alpha and -beta mRNA in breast cancer.

The oestrogen receptor (ER) is widely used to predict response to tamoxifen in patients with breast cancer. Recently a new form of ER known as ER-beta was discovered, the original ER is now designated ER-alpha. In this investigation, ER-alpha and ER-beta were measured in 107 breast carcinomas and 22 fibroadenomas. Using reverse transcriptase-polymerase chain reaction (RT-PCR), ER-beta mRNA, but not ER-alpha mRNA was expressed more frequently in fibroadenomas than carcinomas. In the carcinomas, ER-beta mRNA was present in a greater proportion of samples positive for ER-alpha mRNA than in those lacking this form of the receptor. ER-alpha, but not ER-beta mRNA, was significantly associated with ER protein-positivity in the cancers. ER-alpha mRNA was also positively related to progesterone receptors (PR), but ER-beta mRNA showed an inverse relationship with PR. We conclude that the presently used enzyme-linked immunosorbent assay (ELISA) for ER appears to be mostly measuring ER-alpha and is unlikely to be detecting ER-beta.

Audit of complete axillary dissection in early breast cancer.

The role of complete axillary dissection (CAD) in the management of breast cancer is controversial and largely unresolved. Acceptance of the results of trials incorporating CAD assumes that the axillary dissection is truly complete. To address this point, and also to define quality control criteria for this operation within our unit, we audited 100 consecutive axillary dissections as follows: the primary surgeon performed what he/she felt to be a thorough CAD and submitted separately the contents of level I, II and III for pathological evaluation; a second surgeon then independently assessed the dissection and arbitrarily labelled any further excised tissue as level IV. Level IV nodes were retrieved in 38% of cases. Tumour involvement of level IV nodes was noted in 5% (2/38) of dissections where lymph nodes were retrieved, but in neither instance was pathological staging altered. There was a significant decrease in the incidence of level IV node retrieval from 47% (28/60) in the first 6 months of audit to 20% (8/40) subsequently. This novel approach to our continuing audit identified quality control criteria for this procedure in our unit and suggested that audit of this kind benefits training.

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.

Thyroid disorders and breast cancer.

We have investigated the controversial association between diseases of the thyroid gland and breast carcinoma using methodology which allows positive exclusion of cases of breast disease from control groups and the detection of subclinical alterations in thyroid volume using high resolution ultrasonography, thus addressing the deficiencies of earlier studies. Whereas the prevalence of hyperthyroidism and hypothyroidism in patients with breast carcinoma and in healthy controls without clinical evidence of breast disease was similar, non-toxic goitre was more than twice as common in the breast carcinoma patients. Thyroid volumes were also significantly higher in breast carcinoma patients than in controls; using World Health Organisation criteria, 45.5% of breast carcinoma patients had thyroid enlargement compared with only 10.5% of controls. Finally, antithyroid peroxidase autoantibodies were twice as common in breast cancer patients than in controls. These findings provide clear evidence of a relationship between thyroid disease and breast carcinoma, although the mechanisms underlying this relationship require further study, future studies of breast cancer risk factors should therefore include assessment of thyroid function, antibody status and volume.

Dietary alcohol intake does not increase the incidence of experimentally induced mammary carcinoma.

There is considerable evidence from epidemiological studies that even moderate dietary alcohol intake increases the risk of breast cancer in women. The aim of this study was to test the hypothesis that dietary alcohol intake increases the incidence of mammary carcinoma in a rodent model. Two matched groups of female Sprague-Dawley rats were given 7,12-dimethylbenz[a]anthracene 15 mg by gavage when 50 days old. One group of 20 animals was given dietary ethanol at a dose of 4.4 g/kg/day in their drinking water. The incidence of tumors was significantly less in the group given ethanol (P less than 0.001). In those developing tumors, there was no significant difference between the two groups in the mean number of tumors per animal, the tumor growth rate or the time to the appearance of the first tumor. This study fails to support the hypothesis established by previous epidemiological studies.

Ductal carcinoma in situ of the breast--current management.

The management options in the treatment of patients with ductal carcinoma in situ of the breast are reviewed. Results of treatment by mastectomy, wide local excision, and local surgery followed by radiotherapy are analysed. Factors which incline the surgeon towards recommending mastectomy and the conditions which should be fulfilled for breast conservation are discussed.

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.

Effect of closing dead space on seroma formation after mastectomy--a prospective randomized clinical trial.

To evaluate the effect of closing dead space on seroma formation after mastectomy, 39 patients undergoing 40 mastectomies with axillary node clearance were randomized to undergo suturing of skin flaps to underlying muscle or conventional skin closure. Duration of closed suction drainage, 72 h, and shoulder exercises, commencing on the first post-operative day, were standardized for both groups. Closed suction drainage was significantly less (P < 0.05) in the group that had flaps sutured, 272 +/- 46 ml vs 393 +/- 39 ml. Also fewer patients in the flap sutured group developed seromas, 5 (25%) vs 17 (85%) chi 2 = 12.2 P < 0.001. Three patients in the group that had conventional skin closure had breakdown of wound edges, two developing a prolonged serous discharge, while none occurred in the sutured group. A functional range of shoulder motion was attained at 6 months in 14 (70%) patients in the flap sutured group compared with nine (45%) in the conventional skin closure group (P = NS). These results confirm the value of suturing skin flaps to underlying muscle in reducing local morbidity after mastectomy and suggest that this technique should be included in the closure of all mastectomy wounds.

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.

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.

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.

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.

The clinical value of CEA and CA 15-3 in breast cancer management.

The value of tumour-associated antigens CEA and CA 15-3 was studied in patients with breast cancer over a 4-year period. A total of 252 patients with primary or recurrent disease had available and corresponding CEA and CA 15-3 values at diagnosis and during follow-up and were studied in detail. Preoperative and three-monthly serial postoperative levels were measured in each patient. Ten of 11 patients presenting with primary and concurrent metastatic disease had elevated CA 15-3 levels (> 25 I.U./ml) as compared to 6 with CEA (> 5 ng/ml). Fourty-seven patients developed locoregional recurrence of which 15 had concurrent metastatic disease. CA 15-3 was elevated in 14 cases while CEA in 11. Of 32 patients with locoregional recurrence alone, 18 later developed metastatic disease at a mean follow-up time of 17.5 months. There was a significant correlation between CA 15-3 value at locoregional recurrence and time to subsequent metastasis (r = 0.-0.57, P = 0.0133). CEA was elevated in 64%, CA 15-3 in 87% and either marker in 94% of 87 patients diagnosed with metastatic disease. Of 53 patients with serial markers and metastatic disease, 72% (38/53) had rising CA 15-3 levels prior to diagnosis with a mean lead time of 9.9 months. Use of CEA in conjunction improved lead time detection to 83%. This study demonstrates that CA 15-3 is superior to CEA at detecting metastatic disease at initial presentation and during follow-up. Use of CEA in conjunction with CA 15-3 improves the detection of systemic disease.

High levels of cathepsin B predict poor outcome in patients with breast cancer.

Cathepsin B (CB) is a thiol-stimulated protease implicated in cancer invasion and metastasis. Other proteases involved in cancer spread such as urokinase-type plasminogen activator (uPA) and cathepsin D have previously been shown to be prognostic markers in breast cancer. CB was assayed by ELISA in 193 patients with primary breast cancer. CB levels were significantly higher in both primary and metastatic breast tumors than in fibroadenomas (p = 0.0001). In the primary carcinomas, CB levels showed no significant correlation with either nodal status, tumor size or estrogen receptor (ER) status. Patients with primary breast cancers containing high levels of CB had a significantly shorter disease-free interval (p = 0.01, chi-square = 6.61) and overall survival (p = 0.014, chi-square = 6.08) than patients with low levels of the protease. However, in multivariate analysis, using nodal status, tumor size, ER status and urokinase plasminogen activator (uPA), CB was not an independent prognostic marker. In contrast, nodal status, ER status and uPA were prognostic in multivariate analysis. In conclusion, CB, like certain other proteases implicated in cancer metastasis, correlates with poor outcome in patients with breast cancer. These results thus support the evidence from model systems linking CB to cancer spread. Inhibition of CB expression or activity might therefore be exploited for anti-metastatic therapies.