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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Deriving literature-based benchmarks for surgical complications in high-income countries: a protocol for a systematic review and meta-analysis

Introduction: To improve surgical safety, health systems must identify preventable adverse outcomes and measure changes in these outcomes in response to quality improvement initiatives. This requires understanding of the scope and limitations of available population-level data. To derive literature-based summary estimates of benchmarks of care, we will systematically review and meta-analyse rates of postoperative complications associated with several common and/or high-risk operations performed in five high-income countries (HICs). Methods and analysis An electronic search of PubMed, Embase, Web of Science, Cochrane Central, the NHS Economic Evaluations Database and Health Technology Assessment database will be performed to identify studies reviewing national surgical complication rates between 2000 and 2016. Two reviewers will screen titles and abstracts and full texts of potentially relevant studies to determine eligibility for inclusion in the systematic review. We will include English-language publications using data from health databases in the USA, Canada, the UK, Australia and New Zealand. We will include studies of patients who underwent hip or knee arthoplasty, appendectomy, cholecystectomy, oesophagectomy, abdominal aortic aneurysm repair, aortic valve replacement or coronary artery bypass graft. Outcomes will include mortality, length of hospital stay, pulmonary embolism, pneumonia, sepsis or septic shock, reoperation, surgical site infection, wound dehiscence/disruption, blood transfusion, bile duct injury, stroke and myocardial infarction. We will calculate summary estimates of cumulative incidence, incidence rate, prevalence and occurrence rate of complications using DerSimonian and Laird random effects models. Heterogeneity in these estimates will be examined using subgroup analyses and meta-regression. We will correlate findings within contemporary clinical databases. Ethics and dissemination This study of secondary data does not require ethics approval. It will be presented internationally and published in the peer-reviewed literature. Results will inform a future quality improvement tool and provide benchmarks of surgical complication rates within HICs. Trial registration International Prospective Register of Systematic Reviews (PROSPERO). Registration number CRD42016037519

Outcomes after emergency abdominal surgery in patients with advanced cancer

BACKGROUND: There is increasing emphasis on the appropriateness and quality of acute surgical care for patients with serious illness and at the end of life. However, there is a lack of evidence regarding outcomes after emergent major abdominal surgery among patients with advanced cancer to guide treatment decisions. This analysis sought to characterize adverse outcomes (mortality, complications, institutional discharge) and to identify factors independently associated with 30-day mortality among patients with disseminated cancer who undergo emergent abdominal surgery for intestinal obstruction or perforation. METHODS:This is a retrospective cohort study of 875 disseminated cancer patients undergoing emergency surgery for perforation (n = 499) or obstruction (n = 376) at hospitals participating in the American College of Surgeons' National Surgical Quality Improvement Program from 2005 to 2012. Predictors of 30-day mortality were identified using multivariate logistic regression. RESULTS:Among patients who underwent surgery for perforation, 30-day mortality was 34%, 67% had complications, and 52% were discharged to an institution. Renal failure, septic shock, ascites, dyspnea at rest, and dependent functional status were independent preoperative predictors of death at 30 days. When complications were considered, postoperative respiratory complications and age (75-84 years) were also predictors of mortality.Patients who had surgery for obstruction had a 30-day mortality rate of 18% (n = 68), 41% had complications, and 60% were discharged to an institution. Dependent functional status and ascites were independent predictors of death at 30 days. In addition to these predictors, postoperative predictors of mortality included respiratory and cardiac complications. Few patients (4%) had do-not-resuscitate orders before surgery. CONCLUSION:Emergency abdominal operations in patients with disseminated cancer are highly morbid, and many patients die soon after surgery. High rates of complications and low rates of preexisting do-not-resuscitate orders highlight the need for targeted interventions to reduce complications and integrate palliative approaches into the care of these patients

Updated 5-year local control (LC), metastasis-free survival (MFS), and overall survival (OS) data from a phase I study of nilotinib plus radiation (RT) in high-risk chordoma

e23505 Background: Chordomas are malignant tumors arising from remnant notochordal tissue. Despite improved local control with preoperative/postoperative RT, progression-free survival and OS remain poor in patients (pts) with high-risk features. Chordoma has been identified to express and activate platelet-derived growth factor receptor signaling. We conducted a phase 1 trial to identify the maximum tolerated dose (MTD), safety, and feasibility of nilotinib with RT as either preoperative or definitive treatment for patients with high-risk chordoma. Enclosed is an updated report on LC, MFS, and OS. Methods: We recruited 23 pts with nonmetastatic chordoma to the phase I and dose expansion arms of the study. High-risk was defined as the presence of any of the following: local recurrence after surgery, previous intralesional resection, unplanned incomplete resection, unresectable/marginally resectable disease, or declining surgery due to excessive morbidity. Pts were treated with nilotinib and concurrent RT to 50.4 Gy relative biological effectiveness (RBE) followed by surgery and postoperative RT to a cumulative dose up to 70.2 Gy RBE or definitively up to 77.4 Gy RBE without surgery. On completion of RT, pts were eligible to continue nilotinib until disease progression. Results: The dose escalation arm of the study identified nilotinib 200 mg daily as the maximum tolerated dose (MTD). Eighteen evaluable pts were treated with nilotinib plus RT at the MTD. The objective best response rate was 6% (1 of 18 pts). The 4 and 5-year LC rates were 94.3% (95% CI 83.2-100) and 70.7% (95% CI 20.8-100), respectively. The MFS rate was 74.3 at 4 and 5 years (95% CI 51.8-96.7). The 4 and 5-year OS rates were 70.2% (95% CI 44.4-95.9) and 54.6% (95% CI 20.5-88.6). Conclusions: In updated data from a cohort of high-risk chordoma pts nilotinib 200 mg/d with RT +/- surgery, with long-term follow-up, local control and distant metastasis free survival remains favorable. Clinical trial information: NCT01407198 . [Table: see text

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health