FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity.

Cancer stem-like cells (CSC) contribute to therapy resistance and recurrence. Focal adhesion kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies. FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and paclitaxel reduced self-renewal in triple negative cell lines. An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population. Combined FAK and paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative patient derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.

Comparison of Local Recurrence After Simple and Skin-Sparing Mastectomy Performed in Patients with Ductal Carcinoma In Situ.

BACKGROUND: The incidence of ductal carcinoma in situ (DCIS) is increasing with the use of screening mammography, and approximately 30% of all women diagnosed with DCIS are treated by mastectomy. There is increasing use of a skin-sparing mastectomy (SSM) approach to surgically excise DCIS as this facilitates immediate breast reconstruction. The rates of locoregional recurrence (LRR) after simple mastectomy performed for pure DCIS are historically reported as 1%; however, international data suggest that LRR after SSM may be higher. METHODS: To determine our rates of LRR and compare the effect of the type of mastectomy performed, we undertook a retrospective review of all patients who underwent a mastectomy for pure DCIS at our institution between 2000 and 2010. RESULTS: In total, 199 patients underwent a mastectomy for pure DCIS (with eight local recurrences), all of which were invasive ductal carcinoma. The recurrences all occurred after SSM, which was associated with a higher 5-year LRR of 5.9% (5/102) compared with 0% in the simple mastectomy group (0/97; p = 0.012), log-rank. Univariate analysis showed the two factors that predicted the risk of recurrence were a young age at mastectomy and close or involved margins. CONCLUSIONS: These data highlight the importance of achieving clear margins, especially in young women with estrogen receptor-negative DCIS who have a higher risk of invasive recurrence. Women undergoing a mastectomy for DCIS should be counseled as to the importance of achieving clear margins and the potential increased need for further excision, post-mastectomy radiotherapy and post-reconstruction mammography in order to prevent LRR after SSM.

Necrotising soft tissue infection of the lower limb due to a perforated caecal carcinoma: a case report.

INTRODUCTION: We report the first case to our knowledge where an ascending colorectal tumour presented as a necrotising lower leg infection. CASE PRESENTATION: We describe the unusual presentation of a previously unknown caecal carcinoma in a 69-year-old Caucasian man, which presented as a rapidly spreading limb infection due to a perforated caecal adenocarcinoma. This case presented a diagnostic dilemma and we document the investigation and management in our patient and compare this to the current published literature. CONCLUSIONS: Although rare, this case highlights how leg swelling and in particular, thigh and gluteal swelling, have the potential to be an unusual presentation of a caecal carcinoma.

Lactic acidosis secondary to metformin overdose: a case report.

INTRODUCTION: Metformin is a commonly used treatment modality in type 2 diabetes mellitus, with a well documented side effect of lactic acidosis. In the intensive care setting lactate and pH levels are regularly used as a useful predictor of poor prognosis. In this article we highlight how high lactate levels are not an accurate predictor of mortality in deliberate metformin overdose. CASE PRESENTATION: We present the case of a 70-year-old Caucasian man who took a deliberate metformin overdose of unknown quantity. He had a profound lactic acidosis at presentation with a pH of 6.93 and a lactate level of more than 20mmol/L. These figures would normally correspond with a mortality of more than 80%; however, with appropriate management this patient's condition improved. CONCLUSION: We provide evidence that the decision to treat severe lactic acidosis in deliberate metformin overdose should not be based on arterial lactate and pH levels, as would be the case in other overdoses. We also demonstrate that appropriate treatment with hemodiafiltration and 8.4% sodium bicarbonate, even in patients with a very high lactate and low pH, can be successful.