Rare dual surgical pathology at emergency laparotomy: a case report of concurrent small bowel obstruction and appendicitis.

Dual surgical pathology at emergency laparotomy is an uncommon finding outside of trauma scenarios. There is a scarcity of case reports of concomitant small bowel obstruction and appendicitis at laparotomy, likely in part because of advancements in investigative tools, diagnostic processes and the ready availability of medical care, which is demonstrated by harrowing statistics from developing nations where these factors are lacking. However, despite these advancements, initial diagnosis of dual pathology can be difficult. We report a case of concurrent small bowel obstruction and occult appendicitis discovered at emergency laparotomy in a previously well female with a virgin abdomen.

Factors associated with blunt internal carotid artery injury in petrous temporal bone fractures.

INTRODUCTION: Traumatic internal carotid artery (ICA) injuries are an uncommon complication of petrous temporal bone (PTB) fractures that can have devastating consequences of stroke, haemorrhage and death. Current guidelines suggest that all PTB fractures should be screened for blunt cerebrovascular injury, however clinical practice varies. The purpose of this study was to identify features associated with PTB fractures that increase the likelihood of ICA injury. METHODS: A retrospective cohort study was performed on all patients with PTB fractures who were investigated with computed-tomography angiography (CTA) scan admitted to a Level One Trauma Service in Melbourne, Australia from 2015-2020. Patient demographic and injury data were obtained from The Royal Melbourne Hospital Trauma Registry and medical records. Multivariate binomial logistic regression was performed to identify features associated with ICA injury. RESULTS: Out of 377 patients with 419 PTB fractures, 205 received a CTA scan and were included, identifying 22 ICA injuries (9.4%). The median age of ICA injuries was 33 (IQR 23-61), median Abbreviated Injury Scale (AIS) score for the head region was 5 (IQR 5-5) and the in-hospital mortality rate was 45.5%, mainly due to unsurvivable brain injury. Five patients (22.7%) developed ICA-specific complications of stroke or carotid-cavernous fistula. We identified five factors that were significantly associated with ICA injury. These included PTB fractures involving the carotid canal (OR 6.7, 95% CI 1.9-23.9, p=0.003), presenting with an initial GCS less than nine (OR 5.7, 95% CI 1.2-26.5, p=0.025) and increasing head AIS (OR 2.4, 95% CI 1.2-4.6, p=0.009). Mechanisms of injury that were associated with ICA injury were motor vehicle crash (OR 4.4, 95% CI 1.4-14.2, p=0.012) and motorbike crash (OR 4.6, 95% CI 1.2-18, p=0.029). CONCLUSION: Patients with PTB fractures and an additional feature of carotid canal involvement, presenting GCS less than nine, increasing head AIS indicative of severe head trauma or mechanism of injury by motor vehicle or motorbike crash, are at an increased risk of ICA injury and should be screened with a CTA scan.

Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer.

Unlike other breast cancer subtypes, patients with triple negative breast cancer (TNBC) have poor outcomes and no effective targeted therapies, leaving an unmet need for therapeutic targets. Efforts to profile these tumors have revealed the PI3K/AKT/mTOR pathway as a potential target. Activation of this pathway also contributes to resistance to anti-cancer agents, including microtubule-targeting agents. Eribulin is one such microtubule-targeting agent that is beneficial in treating taxane and anthracycline refractory breast cancer. In this study, we compared the effect of eribulin on the PI3K/AKT/mTOR pathway with other microtubule-targeting agents in TNBC. We found that the phosphorylation of AKT was suppressed by eribulin, a microtubule depolymerizing agent, but activated by paclitaxel, a microtubule stabilizing agent. The combination of eribulin and everolimus, an mTOR inhibitor, resulted in an increased reduction of p-S6K1 and p-S6, a synergistic inhibition of cell survival in vitro, and an enhanced suppression of tumor growth in two orthotopic mouse models. These findings provide a preclinical foundation for targeting both the microtubule cytoskeleton and the PI3K/AKT/mTOR pathway in the treatment of refractory TNBC.

Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells.

Baicalein is a natural flavone that exhibits anticancer properties. Using microarrays we found that DDIT4 was the highest transcript induced by baicalein in cancer cells. We confirmed in multiple cancer cell lines large, dose-related expression of DDIT4 by quantitative RT-PCR and immunoblot, which correlates with growth inhibition. Time course experiments demonstrate that DDIT4 is rapidly inducible, with high expression maintained for several days in vitro. Induction of DDIT4 expression is p53 independent based on evaluation of p53 knockout cells. Since DDIT4 is known to inhibit mTORC1 activity we confirmed that baicalein suppresses phosphorylation of mTORC1 targets. Using RNA interference we demonstrate that mTORC1 activity and growth inhibition by baicalein is attenuated by knockdown of DDIT4. We furthermore demonstrate suppression of established tumors by baicalein in a mouse model of breast cancer with increased DDIT4 expression in the tumors. Finally, we demonstrate that baicalein upregulates DDIT4 and causes mTORC1 and growth inhibition in platinum resistant cancer cells in marked contrast to platinum chemotherapy treatment. These studies demonstrate that baicalein inhibits mTORC1 through DDIT4 expression, and may be useful in cancer chemotherapy and chemoprevention.