31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Nitric oxide metabolism in ischaemic preconditioning of the liver

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Tetrad: Actively Secure 4PC for Secure Training and Inference

In this work, we design an efficient mixed-protocol framework, Tetrad, with applications to privacy-preserving machine learning. It is designed for the four-party setting with at most one active corruption and supports rings. Our fair multiplication protocol requires communicating only 5 ring elements improving over the state-of-the-art protocol of Trident (Chaudhari et al. NDSS'20). The technical highlights of Tetrad include efficient (a) truncation without any overhead, (b) multi-input multiplication protocols for arithmetic and boolean worlds, (c) garbled-world, tailor-made for the mixed-protocol framework, and (d) conversion mechanisms to switch between the computation styles. The fair framework is also extended to provide robustness without inflating the costs. The competence of Tetrad is tested with benchmarks for deep neural networks such as LeNet and VGG16 and support vector machines. One variant of our framework aims at minimizing the execution time, while the other focuses on the monetary cost. We observe improvements up to 6x over Trident across these parameters

Seifalian, “Effect of ischaemic preconditioning on hepatic oxygenation, microcirculation and function in a rat model of moderate hepatic steatosis

A B S T R A C T IPC (ischaemic preconditioning) may protect the steatotic liver, which is particularly susceptible to I/R (ischaemia/reperfusion) injury. Hepatic steatosis was induced in Sprague-Dawley rats with a high-cholesterol (2 %) diet for 12 weeks after which rats were subjected to I/R (ischaemia/reperfusion; 45 min of lobar ischaemia followed by 2 h of reperfusion). Rats were divided into three study groups (n = 6 each) receiving: (i) sham laparotomy alone, (ii) I/R, and (iii) IPC (5 min of ischaemia, followed by 10 min of reperfusion) before I/R. Hepatic extra-and intra-cellular oxygenation and HM (hepatic microcirculation) were measured with near-infrared spectroscopy and laser Doppler flowmetry respectively. Plasma liver enzymes and hepatic tissue ATP were measured as markers of liver injury. Histology showed moderate-grade steatosis in the livers. At the end of 2 h of reperfusion, I/R significantly decreased extra-and intra-cellular oxygenation concomitant with a failure of recovery of HM (21.1 + − 14.4 % of baseline; P &lt; 0.001 compared with sham animals). IPC increased intracellular oxygenation (redox state of the copper centre of cytochrome oxidase; P &lt; 0.05 compared with rats receiving I/R alone) and flow in HM (70.9 + − 17.1 % of baseline; P &lt; 0.001 compared with rats receiving I/R alone). Hepatocellular injury was significantly reduced with IPC compared with I/R injury alone (alanine aminotransferase, 474.8 + − 122.3 compared with 5436.3 + − 984.7 units/l respectively; P &lt; 0.01; aspartate aminotransferase, 630.8 + − 76.9 compared with 3166.3 + − 379.6 units/l respectively; P &lt; 0.01]. In conclusion, IPC has a hepatoprotective effect against I/R injury in livers with moderate steatosis. These data may have important clinical implications in liver surgery and transplantation

Inflammatory pseudotumour of the liver : the residuum of a biliary cystadenoma?

Inflammatory pseudotumour is a rare form of a liver mass. We report the case of a 28-year-old man presenting with obstructive jaundice, in whom an inflammatory pseudotumour arose with the resolution of a mucus secreting cystic liver lesion. The initial features suggested an intrahepatic cystadenoma or cystadenocarcinoma, which on its involution left a solid mass. Histopathology showed an inflammatory pseudotumour with no evidence of malignancy. A similar case has been reported recently, with the development of an inflammatory pseudotumour following collapse of a liver cyst seen on imaging. These two cases may shed some light on the origins of these rare liver lesions.<br /

Cardiac output Optimisation following Liver Transplant (COLT) trial: study protocol for a feasibility randomised controlled trial

Abstract Background Patients with liver cirrhosis undergoing liver transplantation have a hyperdynamic circulation which persists into the early postoperative period making accurate assessment of fluid requirements challenging. Goal-directed fluid therapy (GDFT) has been shown to reduce morbidity and mortality in a number of surgery settings. The impact of GDFT in patients undergoing liver transplantation is unknown. A feasibility trial was designed to determine patient and clinician support for recruitment into a randomised controlled trial of GDFT following liver transplantation, adherence to a GDFT protocol, participant withdrawal, and to determine appropriate endpoints for a subsequent larger trial to evaluate the efficacy of GDFT in patients undergoing liver transplantation. Methods The Cardiac output Optimisation following Liver Transplant (COLT) trial is designed as a prospective, single-centre, randomised controlled study to assess the feasibility and safety of GDFT in liver transplantation for patients with cirrhosis. Consenting adults (aged between 18 and 80 years) with biopsy-proven liver cirrhosis who have been selected to undergo a first liver transplantation will be included in the trial and randomised into GDFT or standard care starting immediately after surgery and continuing for the first 12 h thereafter. Both groups will have cardiac output and stroke volume monitored using the FloTrac (EV1000) device. The intervention will consist of a protocolised GDFT approach to patient management, using stroke volume optimisation. The control group will receive standard care, without stroke volume and cardiac output measurement. After 12 h the patient’s fluid management will revert to standard of care. The primary endpoint of this study is feasibility. Secondary endpoints will include a safety assessment of the intervention, graft and patient survival, liver function, postoperative complications graded by Clavien-Dindo criteria, length of intensive care and hospital stay and quality of life across the intervention and control groups. Discussion There is a growing body of evidence that the use of perioperative GDFT in surgical patients can improve outcomes; however, signals of harm have also been detected. Patients with liver cirrhosis undergoing liver transplantation have markedly different cardiovascular physiology than general surgical patients. If GDFT is proven to be feasible and safe in this patient group, then a multicentre trial to demonstrate efficacy and cost-effectiveness will be required. Trial registration International Standard Randomised Controlled Trial Registry, ID: ISRCTN10329248. Registered on 4 April 2016

Meta-analysis of randomized controlled trials on the effectiveness of somatostatin analogues for pancreatic surgery: a Cochrane review

AbstractBackgroundThe use of synthetic analogues of somatostatin following pancreatic surgery is controversial. The aim of this meta-analysis is to determine whether prophylactic somatostatin analogues (SAs) should be used routinely in pancreatic surgery.MethodsRandomized controlled trials were identified from the Cochrane Library Trials Register, MEDLINE, EMBASE, Science Citation Index Expanded and reference lists. Data were extracted from these trials by two independent reviewers. The risk ratio (RR), mean difference (MD) and standardized mean difference (SMD) were calculated with 95% confidence intervals (95% CIs) based on intention-to-treat or available case analysis.ResultsSeventeen trials involving 2143 patients were identified. The overall number of patients with postoperative complications was lower in the SA group (RR 0.71, 95% CI 0.62–0.82), but there was no difference between the groups in perioperative mortality (RR 1.04, 95% CI 0.68–1.59), re-operation rate (RR 1.15, 95% CI 0.56–2.36) or hospital stay (MD −1.04 days, 95% CI −2.54 to 0.46). The incidence of pancreatic fistula was lower in the SA group (RR 0.64, 95% CI 0.53–0.78). The proportion of these fistulas that were clinically significant is not clear. Analysis of results of trials that clearly distinguished clinically significant fistulas revealed no difference between the two groups (RR 0.69, 95% CI 0.34–1.41). Subgroup analysis revealed a shorter hospital stay in the SA group than among controls for patients with malignant aetiology (MD −7.57 days, 95% CI −11.29 to −3.84).ConclusionsSomatostatin analogues reduce perioperative complications but do not reduce perioperative mortality. However, they do shorten hospital stay in patients undergoing pancreatic surgery for malignancy. Further adequately powered trials of low risk of bias are necessary