Intracellular location of BRCA2 protein expression and prostate cancer progression in the Swedish Watchful Waiting Cohort.

Prostate cancer patients with inherited BRCA2 mutations have a survival disadvantage. However, it is unknown whether progression is associated with BRCA2 protein expression in diagnostic prostate cancer tissue, among men without inherited mutations. We conducted a nested case-control study within the Swedish Watchful Waiting cohort. The case group included all 71 patients who died from prostate cancer within 5 years from diagnosis and controls were all patients (n = 165) who lived at least 7 years after diagnosis. Tissue microarrays were stained using antibodies for C- and N-terminal domains of the BRCA2 protein. Location (nuclear, cytoplasmic and membranous) and magnitude (intensity and percentage) of expression were assessed. Logistic regression models produced odds ratios (OR) and 95% confidence intervals (CI) adjusted for age, year of diagnosis and Gleason score. Positive BRCA2 staining at the cell membrane was associated with reduced risk of death within 5 years (N-terminal: OR = 0.47, 95% CI = 0.21-1.04, P = 0.06; C-terminal: OR = 0.41, 95% CI = 0.18-0.91, P = 0.03) and low Gleason scores (P = 0.006). Positive cytoplasmic C-terminal staining was associated with higher Gleason scores and increased lethality (OR = 3.61, 95% CI = 1.61-8.07, P = 0.002). BRCA2 protein expression at the cell membrane and lack of C-terminal expression in the cytoplasm were associated with a reduced risk of rapidly fatal prostate cancer. BRCA2 protein expression in prostate cancer tissue may have independent prognostic value. The potential biological significance of BRCA2 expression at the cell membrane warrants further investigation.

Prediction of Oncotype DX and TAILORx risk categories using histopathological and immunohistochemical markers by classification and regression tree (CART) analysis.

Oncotype DX is an RT-PCR assay used to predict which patients with ER-positive node-negative (NN) disease will benefit from chemotherapy. Each patient is stratified into a risk category based on a recurrence score (RS) and the TAILORx trial is determining the benefit of chemotherapy for patients with mid-range RSs. We tested if Oncotype DX and TAILORx risk categories could be predicted by standard pathological features and protein markers corresponding to 10 genes in the assay (ER, PR, Ki67, HER2, BCL2, CD68, Aurora A kinase, survivin, cyclin B1 and BAG1) on 52 patients who enrolled on TAILORx. Immunohistochemistry for the protein markers was performed on whole tissue sections. Classification and regression tree (CART) analysis correctly classified 69% of cases into Oncotype DX risk categories based on the expression of PR, survivin and nuclear pleomorphism. All tumours with PR staining (Allred score ≥ 2) and marked nuclear pleomorphism were in the high-risk category. No case with PR <2, low survivin (≤ 15.5%) and nuclear pleomorphism <3 was high-risk. Similarly, 77% of cases were correctly classified into TAILORx categories based on nuclear pleomorphism, survivin, BAG1 and cyclin B1. Ki67 was the only variable that predicted the absolute RS with a cut-off for positivity of 15% (p = 0.003). In conclusion, CART revealed key predictors including proliferation markers, PR and nuclear pleomorphism that correctly classified over two thirds of ER-positive NN cancers into Oncotype DX and TAILORx risk categories. These variables could be used as an alternative to the RT-PCR assay to reduce the number of patients requiring Oncotype DX testing.

Through the looking glass: primary epithelioid angiosarcoma in the left atrium, a unique site for a rare malignancy.

Malignant cardiac tumours occurring on the left side are vanishingly rare entities. We describe a case of a 73-year-old male who underwent surgery for a left-sided cardiac tumour following initial presentation with transient ischaemic attacks. In addition to the unusual presentation and subsequent metastatic pattern to the femur, the tumour's pathological diagnosis was that of an epithelioid variant of an angiosarcoma which has not been previously described in this anatomical location.

Prognostic significance of deregulated dicer expression in breast cancer.

BACKGROUND: Dicer, an RNase III-type endonuclease, is the key enzyme involved in RNA interference and microRNA pathways. Aberrant expression of Dicer is reported in several human cancers. Our aim was to assess the prognostic role of Dicer in breast cancer. METHODS: The entire series comprised 666 invasive breast cancers (IBCs), 480 DCIS cases (397 associated with IBC and 83 pure DCIS) and 305 lymph node metastases. Cytoplasmic Dicer expression by immunohistochemistry was scored as negative (no staining) and positive (weak, moderate or strong staining). RESULTS: Dicer staining was assessable in 446 IBC, 128 DCIS and 101 lymph node metastases. Expression of Dicer was observed in 33% (145/446) of IBCs, 34% (44/128) of DCIS and 57% (58/101) of lymph node metastases. Dicer expression was increased in nodal metastases compared to primary tumours (p<0.001); and was associated with ER negativity (p<0.001), HER2 positivity (p<0.001), high Ki67 labeling index (p<0.001) and expression of basal-like biomarkers (p = 0.002). Dicer positivity was more frequent in the HER2 overexpressing (p<0.001) and basal-like (p = 0.002) subtypes compared to luminal A subtype. Dicer expression was associated with reduced overall survival (OS) on univariate analysis (p = 0.058) and remained an independent predictor of OS on multivariate analysis (HR 2.84, 95% CI 1.43-5.62, p = 0.003), with nodal status (HR 2.61, 95% CI 1.18-5.80, p = 0.018) and PR (HR 0.28, 95% CI 0.13-0.59, p = 0.001). Further, moderate or strong expression of Dicer was associated with improved disease-free survival in the HER2-overexpressing subtype compared to negative or weak expression (p = 0.038). CONCLUSION: Deregulated Dicer expression is associated with aggressive tumour characteristics and is an independent prognostic factor for OS. Our findings suggest that Dicer is an important prognostic marker in breast cancer and that its prognostic role may be subtype specific.

A presentation of glandular penile metastases from prostate adenocarcinoma.

Secondary tumours of the penis are rare; they most commonly arise from the prostate and the bladder. These lesions are often associated with disseminated malignancy and have a poor prognosis, with a 6-month mortality of up to 80% reported. Penile metastases have a variety of clinical manifestations including incidental penile nodules, cutaneous findings, urinary symptoms, pain and malignant priapism. Treatment options are mainly targeted at improving the patients' quality of life and are tailored to their clinical condition, but are primarily palliative. This study reports a case of a 92-year-old man with a presentation of glandular penile metastases from prostate adenocarcinoma treated conservatively.

RET protein expression in papillary renal cell carcinoma.

OBJECTIVE: To examine the role of RET in renal malignancy, in particular papillary renal cell carcinoma (RCC). MATERIALS AND METHODS: A cohort of 111 archival renal samples was used consisting of 94 renal cancers (66 papillary RCC, 18 conventional clear cell carcinoma, 10 chromophobe RCC), 4 benign oncocytomas, and 13 normal kidney tissues. RET protein expression was examined by immunohistochemistry and expression levels were correlated with clinicopathologic and patient survival data. RESULTS: Positive RET staining was seen in 34/66 (52%) papillary RCCs, 4/10 (40%) chromophobe carcinomas, 4/4 (100%) oncocytomas, and 11/13 (85%) normal kidney samples. All 18 cases of conventional clear cell carcinoma had negative RET staining. RET expression was associated with low Fuhrman nuclear grade. CONCLUSIONS: RET protein may be contributing in part to an adaptation of a papillary growth pattern in certain renal malignancies. Given the possible therapeutic benefit of small molecule inhibitors of RET activation, further work needs to be done to highlight the functional relevance of RET protein expression in papillary RCC.

Alcohol and unnatural deaths in the West of Ireland: a 5-year review.

AIM: To investigate the prevalence of alcohol in unnatural deaths in the West of Ireland between 2003 and 2007. METHODS: The reports of 1669 postmortem examinations carried out at Galway University Hospitals were reviewed; 379 non-homicidal unnatural deaths were eligible for the study. Alcohol levels were measured in blood and/or urine in 311 cases. For each case, gender, age, cause of death and toxicology results were recorded. RESULTS: Alcohol was detected in 162 out of 311 cases (52%); 133 (82%) cases were men and 29 (18%) were women. Alcohol levels >150 mg/100 ml were found in 99 cases (61%), most commonly in 18-49-year-olds (n=74; 75%). Road traffic crashes (RTCs) (n=38; 23%), drownings (n=38; 23%) and hangings (n=25; 15%) were common unnatural deaths associated with alcohol. The majority of RTC deaths involved the driver (n=27; 71%). The alcohol level was higher than the legal driving limit of 80 mg/100 ml in 82% (n=22) and >150 mg/100 ml in 59% (n=16) of these. Mortality of passengers (n=6; 16%) and pedestrians (n=5; 13%) was less common. CONCLUSIONS: Alcohol remains a major contributor to unnatural deaths in the West of Ireland, particularly with respect to mortality in young people. Young men are especially vulnerable. Deaths in RTCs and by drowning and hanging are commonly associated with alcohol. Many driver fatalities involve alcohol levels far above legal limits. Alcohol measurement in all unnatural deaths would facilitate more accurate determination of its role.