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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated cation channel family known to be expressed in the heart and central nervous system. Ivabradine, a small molecule HCN channel-blocker, is FDA-approved for clinical use as a heart rate-reducing agent. We found that HCN2 and HCN3 are overexpressed in breast cancer cells compared with normal breast epithelia, and the high expression of HCN2 and HCN3 is associated with poorer survival in breast cancer patients. Inhibition of HCN by Ivabradine or by RNAi, aborted breast cancer cell proliferation in vitro and suppressed tumour growth in patient-derived tumour xenograft models established from triple-negative breast cancer (TNBC) tissues, with no evident side-effects on the mice. Transcriptome-wide analysis showed enrichment for cholesterol metabolism and biosynthesis as well as lipid metabolism pathways associated with ER-stress following Ivabradine treatment. Mechanistic studies confirmed that HCN inhibition leads to ER-stress, in part due to disturbed Ca2+ homeostasis, which subsequently triggered the apoptosis cascade. More importantly, we investigated the synergistic effect of Ivabradine and paclitaxel on TNBC and confirmed that both drugs acted synergistically in vitro through ER-stress to amplify signals for caspase activation. Combination therapy could suppress tumour growth of xenografts at much lower doses for both drugs. In summary, our study identified a new molecular target with potential for being developed into targeted therapy, providing scientific grounds for initiating clinical trials for a new treatment regimen of combining HCN inhibition with chemotherapy.

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BACKGROUND: Tissue reinforcement with acellular dermal matrix (ADM) in implant-based breast reconstruction contributes to the coverage of the implant and avoids its direct exposure to skin incision, yet not without risk of infection. Our integrated technique makes use of the in situ serratus anterior fascia as a support of the implant following mastectomy, which serves the same purpose of ADM in terms of aesthetic outcomes, but minimizes the hazard of infective complications. METHODS: We retrospectively reviewed all the nipple-sparing mastectomies with direct-to-implant immediate reconstruction in Hong Kong Sanatorium and Hospital from 2012 to 2016. The authors made use of the serratus anterior fascial flap as inferolateral coverage for the subpectoral implant. Consequently, the implant would be completely covered by autologous tissues. RESULTS: Among the 51 women included, primary breast cancers account for 91.8% of our indications for these 61 procedures of integrated mastectomy and implant reconstruction. The remaining five (8.2%) were performed as contralateral prophylactic mastectomy. Almost three quarters of the patients had a bra cup size of B or below. After a mean follow-up of 28.9 months, there was no reported post-operative complication of skin flap or nipple-areolar complex necrosis, or infection or extrusion of the implant. CONCLUSIONS: Our series support that the serratus anterior fascial flap could provide autologous coverage in integrated mastectomy and implant breast reconstruction, especially in small- and medium-sized breasts. Appropriate patient selection, as well as meticulous surgical technique, is critical for its success.

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BACKGROUND: Statins are one of the most commonly prescribed medications in Australia. Although the cardioprotective effects of statins are well documented, questions remain regarding their risk-benefit profile in elderly adults, especially those with limited life expectancies. AIM: To describe the prevalence and pattern of statin use in elderly patients admitted to a General Medicine Unit. METHODS: We retrospectively reviewed medical records of patients aged ≥80 years who were admitted to the General Medical Unit at Monash Medical Centre between 1 January 2015 and 30 June 2015. Patients receiving statin therapy prior to admission were identified and included. Data including patient demographics, indication for statin, comorbidities, co-prescription of interacting medications, presence of muscle-related toxicity and any change to statin prescription were collected and described. RESULTS: Of 852 patients admitted to hospital, 359 (42%) were taking statins prior to admission. Statins were used for the secondary prevention of cardiovascular disease in 63% of patients and for primary prevention in 24%. Most patients were taking high- (16%) or medium-intensity statins (78%); 46% of patients were co-prescribed medications with the potential to increase the risk of statin toxicity. Statins were discontinued in 16% of patients; however, the majority of patients had no change to their statin prescription. Muscle-related toxicity was documented in 4% of patients. CONCLUSION: Statin use and the co-prescription of potentially interacting medications are common in elderly adults admitted to hospital. Statin prescription in elderly patients with multiple comorbidities is rarely reviewed unless directly relevant to their admission diagnosis.

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BACKGROUND: Nipple-sparing mastectomy (NSM) has gained widespread popularity in recent years. Nonetheless, patient selection, technical consideration and oncological safety of its extension to breast cancer treatment remain uncertain. Few publications have reviewed the application of NSM in Asian populations. METHODS: We retrospectively reviewed 91 women with malignant breast tumours, who underwent 97 NSM in Hong Kong Sanatorium and Hospital from 2009 to 2015. Breast cancer patients who required mastectomy and opted for immediate reconstruction were considered for NSM if they showed no obvious nipple involvement clinically. All breast specimens were subjected to intraoperative pathological examination of the retroareolar tissue to exclude occult tumour infiltration before the final decision of nipple-areola complex (NAC) preservation. Clinical parameters, tumour characteristics and oncological outcomes were analyzed. RESULTS: Carcinoma of the breast accounts for 99.0% of our indications for therapeutic NSM. Almost all NSM were accompanied with immediate reconstruction. Abnormal pathology was shown in retroareolar tissue of ten patients (10.3%), and seven of these NAC were excised due to tumour involvement detected by intraoperative frozen section. Six (6.2%) NSM were complicated with superficial epidermolysis. Yet, there was no delayed NAC excision because of nipple necrosis. Overall NAC preservation rate reached 92.8%. Local and/or distant recurrences occurred in four patients (4.1%) after a mean follow-up of 20.6 months. One NAC recurrence was documented. CONCLUSION: Our series support the oncological safety of NSM after exclusion of neoplastic NAC involvement preliminarily by intraoperative frozen section and definitively by final pathology. Its technical feasibility is well proven by the low nipple necrosis rate.

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BACKGROUND: Sentinel lymph node biopsy (SLNB) has become the standard treatment for patients with invasive breast cancer. Intra-operative frozen section allows for the detection of nodal metastases, thereby allowing a simultaneous axillary lymph node dissection (ALND) for those patients with nodal metastases. We herein report the accuracy of frozen section in the detection of SLN metastases. METHODS: Patients with operable breast cancer and clinically negative axillae were recruited for SLNB. The SLNs were identified by blue dye, an isotope, or a combination. Enlarged lymph nodes that were not SLNs were also excised. All nodes were examined by intra-operative frozen section. ALND was performed if frozen section was positive. For those without metastases on frozen section, ALND was not performed. All lymph nodes underwent further paraffin sectioning with immuno-histochemical staining. RESULTS: A total of 260 SLNB procedures were performed for invasive carcinoma over a 3-year period. The SLN was identified in 93.5% of patients. Of the 243 successful procedures, 53 had nodal metastases on frozen section. A total of 33 patients had false-negative frozen sections (false-negative rate, 38.4%), and 97% of them were less than 2 mm in size. The false-negative rate for macro-metastases, micro-metastases, and isolated tumour cells_were 2.4%, 57.7%, and 94.4%, respectively (p < 0.0001). A total of 22 patients had delayed ALND, and the re-operation rate was 8.5%. CONCLUSION: Frozen section was useful for the detection of nodal metastases in the SLNs and allowed for ALND to be performed in the same operation. The main failure of frozen sections was in the detection of micro-metastases.

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