Patient-derived precision cut tissue slices from primary liver cancer as a potential platform for preclinical drug testing

Background: The exploitation of anti-tumour immunity, harnessed through immunomodulatory therapies, has fundamentally changed the treatment of primary liver cancer (PLC). However, this has posed significant challenges in preclinical research. Novel immunologically relevant models for PLC are urgently required to improve the translation from bench to bedside and back, explore and predict effective combinatorial therapies, aid novel drug discovery and develop personalised treatment modalities. / Methods: We used human precision-cut tissue slices (PCTS) derived from resected tumours to create a patient-specific immunocompetent disease model that captures the multifaceted and intricate heterogeneity of the tumour and the tumour microenvironment. Tissue architecture, tumour viability and treatment response to single agent and combination therapies were assessed longitudinally over 8 days of ex vivo culture by histological analysis, detection of proliferation/cell death markers, ATP content via HPLC. Immune cell infiltrate was assessed using PCR and immunofluorescence. Checkpoint receptor expression was quantified via Quantigene RNA assay. / Findings: After optimising the culture conditions, PCTS maintained the original tissue architecture, including tumour morphology, stroma and tumour-infiltrated leukocytes. Moreover, PCTS retained the tumour-specific immunophenotype over time, suggesting the utility of PCTS to investigate immunotherapeutic drug efficacy and identify non-responsiveness. / Interpretation: Here we have characterised the PCTS model and demonstrated its effectiveness as a robust preclinical tool that will significantly support the development of successful (immuno)therapeutic strategies for PLC. / Funding: Foundation for Liver Research, London

An overview of anti-diabetic plants used in Gabon: Pharmacology and Toxicology

© 2017 Elsevier B.V. All rights reserved.Ethnopharmacological relevance: The management of diabetes mellitus management in African communities, especially in Gabon, is not well established as more than 60% of population rely on traditional treatments as primary healthcare. The aim of this review was to collect and present the scientific evidence for the use of medicinal plants that are in currect by Gabonese traditional healers to manage diabetes or hyperglycaemia based here on the pharmacological and toxicological profiles of plants with anti-diabetic activity. There are presented in order to promote their therapeutic value, ensure a safer use by population and provide some bases for further study on high potential plants reviewed. Materials and methods: Ethnobotanical studies were sourced using databases such as Online Wiley library, Pubmed, Google Scholar, PROTA, books and unpublished data including Ph.D. and Master thesis, African and Asian journals. Keywords including ‘Diabetes’ ‘Gabon’ ‘Toxicity’ ‘Constituents’ ‘hyperglycaemia’ were used. Results: A total of 69 plants currently used in Gabon with potential anti-diabetic activity have been identified in the literature, all of which have been used in in vivo or in vitro studies. Most of the plants have been studied in human or animal models for their ability to reduce blood glucose, stimulate insulin secretion or inhibit carbohydrates enzymes. Active substances have been identified in 12 out of 69 plants outlined in this review, these include Allium cepa and Tabernanthe iboga. Only eight plants have their active substances tested for anti-diabetic activity and are suitables for further investigation. Toxicological data is scarce and is dose-related to the functional parameters of major organs such as kidney and liver. Conclusion: An in-depth understanding on the pharmacology and toxicology of Gabonese anti-diabetic plants is lacking yet there is a great scope for new treatments. With further research, the use of Gabonese anti-diabetic plants is important to ensure the safety of the diabetic patients in Gabon.Peer reviewedFinal Accepted Versio

Retrospective review of pelvic malignancies undergoing total pelvic exenteration

Abstract Background In patients with locally advanced or recurrent pelvic malignancies, total pelvic exenteration (TPE) may be necessary for curative treatment. Despite improvements in mortality rates since TPE was first described, morbidity rates remain high due to the extensive resection and the aggressiveness of these tumors. We have studied the outcomes of TPE surgery performed at our institution. Methods Fifty-three patients with various pelvic pathologies underwent TPE between 2004 and 2010. Patients were divided into two groups based on pathology: colorectal (n = 36) versus non-colorectal (n = 17) malignancies. Demographics, operative reports, pathology reports, periprocedural events, and outcomes were analyzed. Comparison of the two groups was performed using student’s t-test and Fisher’s exact test. Survival curves were constructed using the Kaplan–Meier method and compared using the log rank test. Results The colorectal and non-colorectal groups were similar in demographics, operative times, length of stay, estimated blood loss, and rates of preoperative and intraoperative radiation use. Chemotherapy use was increased in the colorectal group compared with the non-colorectal group (55.6% vs. 23.5%, P = 0.04). Complication rates were similar: 86% in the colorectal group and 76% in the non-colorectal group. In the colorectal group, 27.8% of patients developed perineal abscesses, whereas no patients developed these complications in the non-colorectal group (P = 0.02). No survival difference was seen in primary versus recurrent colorectal tumors; however, within the colorectal group there was a survival advantage when comparing R0 resection to R1 and R2 resection combined. Median survival rates were 27.3 months for R0 resection and 10.7 months for R1 and R2 resection combined. The median survival was 21.4 months for the colorectal group and 6.9 months for the non-colorectal group (P = 0.002). Conclusions Patients undergoing TPE for colorectal tumors have improved survival when compared with patients undergoing exenteration for pelvic malignancies of other origins. Within the colorectal group, the extent of resection demonstrated a significant survival benefit of an R0 resection compared with R1 and R2 resections. Despite TPE carrying a high morbidity rate, mortality rates have improved and careful patient selection can optimize outcomes.</p

Clinical Characteristics and Prevalence of Early Repolarization Associated With Ventricular Arrhythmias Following Acute ST-Elevation Myocardial Infarction

Early repolarization (ER) on a 12-lead electrocardiogram has recently been associated with ventricular tachyarrhythmias (VTAs) in patients without structural heart disease and in patients with healed myocardial infarction (MI). An association between ER and VTAs in the setting of acute ST-segment elevation MI (STEMI) has not been explored. In a single-center retrospective case–control design, 50 patients with STEMI complicated by VTAs (cases), defined as ventricular fibrillation, sustained ventricular tachycardia, or nonsustained ventricular tachycardia within 72 hours of the index hospitalization, were matched for age and gender with 50 subjects with STEMI without VTAs (controls). Electrocardiograms obtained an average of 1 year before STEMI were analyzed for ER pattern, defined as notching or slurring of the terminal QRS complex or J-point elevation >0.1 mV above baseline in ≥2 contiguous leads. A higher prevalence of ER was associated with VTAs overall in cases compared to controls (26% vs 4%, p = 0.01) and localized to anterior (16% vs 0%) and inferior (14% vs 2%, p = 0.07) leads but not lateral limb leads. Notching (10% vs 2%, p = 0.1) and J-point elevation (16% vs 0%) were more common in cases. Slurring was uncommon. ER was associated with VTAs (odds ratio [OR] 6.5, 95% confidence interval [CI] 1.5 to 28.8, p = 0.01), even after adjustment for creatine kinase-MB (OR 9.2, 95% CI 1.6 to 53.4, p = 0.01) and ejection fraction (OR 5.7, 95% CI 1.2 to 27.1, p = 0.03). In conclusion, ER is associated with VTAs in patients with STEMI even after adjustment for left ventricular ejection fraction or creatine kinas-MB levels. Larger prospective studies exploring potential associations and mechanisms of ventricular arrhythmogenesis with ER pattern are needed