Purpose:This study investigates the role of the p160 coactivators AIB1and SRC-1independently, and their interactions with the estrogen receptor, in the development of resistance to endocrine treatments. Experimental Design: The expression of the p160s and the estrogen receptor, and their interactions, was analyzed by immunohistochemistry and quantitative coassociation immunofluorescent microscopy, using cell lines, primary breast tumor cell cultures, and a tissue microarray with breast cancer samples from 560 patients. Results: Coassociation of the p160s and estrogen receptor a was increased in the LY2 endocrine-resistant cell line following treatment with tamoxifen in comparison with endocrinesensitive MCF-7 cells. In primary cultures, there was an increase in association of the coactivators with estrogen receptor a following estrogen treatment but dissociation was evident with tamoxifen. Immunohistochemical staining of the tissue microarray revealed that SRC-1 was a strong predictor of reduced disease-free survival (DFS), both in patients receiving adjuvant tamoxifen treatment and untreated patients (P < 0.0001 and P = 0.0111, respectively). SRC-1 was assigned a hazard ratio of 2.12 using a Cox proportional hazards model. Endocrine-treated patients who coexpressed AIB1with human epidermal growth factor receptor 2 had a significantly shorter DFS compared with all other patients (P = 0.03). Quantitative coassociation analysis in the patient tissue microarray revealed significantly stronger colocalization of AIB1and SRC-1with estrogen receptor a in patients who have relapsed in comparison with those patients who did not recur (P = 0.026 and P = 0.00001, respectively). Conclusions: SRC-1is a strong independent predictor of reduced DFS, whereas the interactions of the p160 proteins with estrogen receptor a can predict the response of patients to endocrine treatment.Adjuvant endocrine therapy offers substantial benefit in terms of reduction in risk of tumor recurrence in women with estrogen receptor -positive tumors. However, although most patients initially respond to tamoxifen, in 30% to 40% of cases these tumors recur within 5 years. This precipitates cessation of the regime and the initiation of second-line therapy. However, despite new targeted treatments for breast cancer, the vast majority of patients still depend on endocrine manipulation for management of their breast cancer.The magnitude of estrogen receptor gene regulation is influenced not only by the ligand but also by the presence of specific coregulatory proteins, present at rate-limiting levels, which modulate transcription. Over the past 10 years a number of nuclear receptor -interacting proteins have been isolated using various screening strategies. These include the p160 family coactivator proteins -steroid receptor coactivator-1 (SRC-1/NCoA-1), SRC-2 (TIF2/GRIP1), and SRC-3 (AIB1/ pCIP/RAC3/ACTR). The coactivator proteins drive nuclear receptor transcriptional activity by doing the significant reactions required for control of enhancer-d...

Cyclooxygenase-2 (COX-2) is associated with breast tumour progression. Clinical and molecular studies implicate human epidermal growth factor receptor 2 (HER2) in the regulation of COX-2 expression. Recent reports raise the possibility that HER2 could mediate these effects through direct transcriptional mechanisms. The relationship between HER2 and COX-2 was investigated in a cohort of breast cancer patients with or without endocrine treatment. A tissue microarray comprising tumours from 560 patients with 10-year follow-up was analysed for HER2, ERK1/2, polyoma enhancer activator 3 (PEA3) and COX-2 expression. Subcellular localisation of HER2 was assessed by immunofluorescence and confocal microscopy. Expression of markers examined was analysed in relation to classic clinicopathological parameters and disease-free survival in the presence and absence of tamoxifen. COX-2 expression associated with both membranous and nuclear expression of HER2 (PZ0.0033 and P!0.00001 respectively). No association was detected between COX-2 and either ERK1/2 or PEA3 (PZ0.7 and PZ0.3 respectively). None of the markers were found to be independently prognostic. Membrane HER2, nuclear HER2 and COX-2, however, were all found to predict poor disease-free survival in patients on endocrine treatment (PZ0.0017, PZ0.0003 and PZ0.0202 respectively). Moreover, patients who were positive for COX-2 predicted adverse effects of tamoxifen (PZ0.0427). These clinical ex vivo data are consistent with molecular observations that HER2 can regulate COX-2 expression through direct transcriptional mechanisms. COX-2 expression correlates with disease progression on endocrine treatment. This study supports a role for COX-2 as a predictor of adverse effects of tamoxifen in breast cancer patients.

SummaryNeurological complications (NCs) can frequently and significantly affect morbidity and mortality of liver transplant (LT) recipients. We analysed incidence, risk factors, outcome and impact of the immunosuppressive therapy on NC development after LT. We analysed 478 LT in 440 patients, and 93 (19.5%) were followed by NCs. The average LOS was longer in patients experiencing NCs. The 1-, 3-and 5-year graft survival and patient survival were similar in patients with or without a NC. Multivariate analysis showed the following as independent risk factors for NC: a MELD score ≥20 (OR = 1.934, CI = 1.186-3.153) and an immunosuppressive regimen based on calcineurin inhibitors (CNIs) (OR = 1.669, CI = 1.009-2.760). Among patients receiving an everolimus-based immunosuppression, the 7.1% developed NCs, vs. the 16.9% in those receiving a CNI (P = 0.039). There was a 1-, 3-and 5-year NC-free survival of 81.7%, 81.1% and 77.7% in patients receiving a CNI-based regimen and 95.1%, 93.6% and 92.7% in those not receiving a CNI-based regimen (P < 0.001). In patients undergoing a LT and presenting with nonmodifiable risk factors for developing NCs, an immunosuppressive regimen based on CNIs is likely to result in a higher rate of NCs compared to mTOR inhibitors.

Pancreatic surgery is one of the most technically challenging and complex types of surgery. Most pancreatic surgery is performed with the open technique, yet minimally invasive surgery has become the standard of care for many other intra-abdominal operations. The unique qualities of the robotic platform have made this approach to pancreatic surgery safe and feasible with at least equivalent if not better results than the open platform in terms of surgical and oncological outcomes.

Background. Pioneered by the Mayo Clinic, multimodal therapy with neoadjuvant chemoradiotherapy and orthotopic liver transplant has emerged as a promising option for unresectable hilar cholangiocarcinoma (hCCA). This study reports the experience of the Irish National Liver Transplant Programme with the Mayo Protocol. Methods. All patients diagnosed with unresectable hCCA between 2004 and 2016, who were eligible for the treatment protocol, were prospectively studied. Results. Thirty-seven patients commenced chemoradiotherapy. Of those, 11 were excluded due to disease progression and 26 proceeded to liver transplantation. There were 24 males, the median age was 49, and 88% had underlying primary sclerosing cholangitis. R0 and pathologic complete response rates were 96% and 62%, respectively. Overall median survival was 53 months and 1-, 3-, and 5-year survival was 81%, 69%, and 55%, respectively. The median survival of patients achieving a pathologic complete response was 83.8 months compared with 20.9 months in the group with residual disease (P = 0.036). Six patients (23%) developed disease recurrence. Among the patients who developed metastatic disease during neoadjuvant treatment, median survival was 10.5 months compared with 53 months in patients who proceeded to transplant (P < 0.001). Conclusions. Neoadjuvant chemoradiotherapy followed by liver transplantation substantially increases the survival of patients with unresectable hCCA. Achieving a pathologic complete response confers a significant survival benefit.