Irradiation to Improve the Response to Immunotherapeutic Agents in Glioblastomas.

PurposeGlioblastoma (GBM) remains an incurable disease despite extensive treatment with surgical resection, irradiation, and temozolomide. In line with many other forms of aggressive cancers, GBM is currently under consideration as a target for immunotherapy. However, GBM tends to be nonimmunogenic and exhibits a microenvironment with few or no effector T cells, a relatively low nonsynonymous somatic mutational load, and a low predicted neoantigen burden. GBM also exploits a multitude of immunosuppressive strategies.Methods and materialsA number of immunotherapeutic approaches have been tested with disappointing results. A rationale exists to combine immunotherapy and radiation therapy, which can induce an immunogenic form of cell death with T-cell activation and tumor infiltration.ResultsVarious immunotherapy agents, including immune checkpoint modulators, transforming growth factor beta receptor inhibitors, and indoleamine-2,3-dioxygenase inhibitors, have been evaluated with irradiation in preclinical GBM models, with promising results, and are being further tested in clinical trials.ConclusionsThis review aims to present the basic rationale behind this emerging complementary therapeutic approach in GBM, appraise the current preclinical and clinical data, and discuss the future challenges in improving the antitumor immune response

Tumor Size Matters-Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy.

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Pulse oximetry and high-dose vasopressors: a comparison between forehead reflectance and finger transmission sensors.

International audiencePURPOSE: Pulse oximetry (SpO(2)) measured at finger site via transmission mode may fail in situations of hypoperfusion. Forehead sensors using reflectance technology might be useful in these circumstances. We hypothesized that reflectance SpO(2) would be more accurate than finger SpO(2) in patients with severe shock. METHODS: A prospective observational study was conducted in an intensive care unit of a university hospital of patients in shock who were treated with high norepinephrine and/or epinephrine doses (≥0.1 μg kg(-1) min(-1)). When blood gas determinations were requested, forehead SpO(2) and finger SpO(2) values were simultaneous recorded. Agreement between SpO(2) measurements with arterial saturation (SaO(2)), obtained by blood analysis with a co-oximeter, was assessed using the Bland-Altman method. The number of outliers, defined by the formula SaO(2) - SpO(2) > ±3 %, indicated the proportion of measurements considered to be clinically unacceptable. RESULTS: Thirty-two patients were enrolled in the study. With the forehead sensor no reading failure occurred, and 140 paired data sets (forehead SpO(2) vs. SaO(2)) were obtained. Bias and precision were +1.0 and +2.5 %, respectively, and the limits of agreement ranged from -4.0 to 6.0 %. The finger sensor failed to give a value in four cases, thus providing 136 paired data sets (finger SpO(2) vs. SaO(2)) for analysis. Bias and precision were +1.4 and +4.8 %, respectively, and the limits of agreement ranged from -8.0 to 10.9 %. There were 21 (15 %) outliers for the forehead sensor and 43 (32 %) for the finger sensor (P < 0.001). CONCLUSIONS: Forehead SpO(2) measurements were more accurate than finger SpO(2) when compared with SaO(2) in critically ill patients requiring high-dose vasopressor therapy and should therefore be the preferred method considered

Irradiation to Improve the Response to Immunotherapeutic Agents in Glioblastomas.

PurposeGlioblastoma (GBM) remains an incurable disease despite extensive treatment with surgical resection, irradiation, and temozolomide. In line with many other forms of aggressive cancers, GBM is currently under consideration as a target for immunotherapy. However, GBM tends to be nonimmunogenic and exhibits a microenvironment with few or no effector T cells, a relatively low nonsynonymous somatic mutational load, and a low predicted neoantigen burden. GBM also exploits a multitude of immunosuppressive strategies.Methods and materialsA number of immunotherapeutic approaches have been tested with disappointing results. A rationale exists to combine immunotherapy and radiation therapy, which can induce an immunogenic form of cell death with T-cell activation and tumor infiltration.ResultsVarious immunotherapy agents, including immune checkpoint modulators, transforming growth factor beta receptor inhibitors, and indoleamine-2,3-dioxygenase inhibitors, have been evaluated with irradiation in preclinical GBM models, with promising results, and are being further tested in clinical trials.ConclusionsThis review aims to present the basic rationale behind this emerging complementary therapeutic approach in GBM, appraise the current preclinical and clinical data, and discuss the future challenges in improving the antitumor immune response

Étude de la réponse induite par le lipopolysaccharide et l'adrénalineadrénaline dans un modèle de co-culture hépatocytes - macrophages humains. [Study of the response induced by lipopolysaccharide and adrenaline in a hepatocyte - human macrophage co-culture model]

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Mortality due to hospital-acquired infection after cardiac surgery

Perioperative ManagementInternational audiencePurpose: Hospital-acquired infections have been associated with significant morbidity and mortality in critically ill surgical patients. However, little is known about mortality due to hospital-acquired infections in cardiac surgery.Methods: We conducted a retrospective analysis of prospectively collected data from the cardiac surgery unit of a university hospital. All patients who underwent cardiac surgery over a 7-year period were included. Patients with hospital-acquired infections were matched 1:1 with patients with nonhospital-acquired infections based on risk factors for hospital-acquired infections and death after cardiac surgery using propensity score matching. We performed a competitive risk analysis to study the mortality fraction due to hospital-acquired infections.Results: Of 8853 patients who underwent cardiac surgery, 370 (4.2%) developed 500 postoperative infections (incidence density rate 4.2 hospital-acquired infections per 1000 patient-days). Crude hospital mortality was significantly higher in patients with hospital-acquired infections than in matched patients who did not develop hospital-acquired infections, 15.4% and 5.7%, respectively (P < .001). The in-hospital mortality fraction due to hospital-acquired infections in our cohort was 17.1% (12.3%-22.8%). Pseudomonas aeruginosa infection (hazard ratio, 2.09; 95% confidence interval, 1.23-3.49; P = .005), bloodstream infection (hazard ratio, 2.08; 95% confidence interval, 1.19-3.63; P = .010), and pneumonia (hazard ratio, 1.68; 95% confidence interval, 1.02-2.77; P = .04) were each independently associated with increased hospital mortality.Conclusions: Although hospital-acquired infections are relatively uncommon after cardiac surgery (4.2%), these infections have a major impact on postoperative mortality (attributable mortality fraction, 17.1%)

Porcine bioprostheses for surgical aortic valve replacement: very long-term performance of a third-generation device

Aims We aimed at investigating the long-term durability of the Epic bioprosthesis for surgical aortic valve replacement (SAVR) in a single-centre series of 888 implantations (2001–2018), expanding previous evaluations with shorter follow-up. Methods We retrieved prospectively collected in-hospital data and performed a systematic follow-up focusing on valve-related events (SVD, structural valve deterioration; PPM, patient–prosthesis mismatch; reoperation) (competing risks, CIF and Kaplan--Meier methods). We distinguished between SVD (permanent changes in valve function due to evolutive structural deterioration, ≥10 mmHg average gradient vs. reference echocardiography) and PPM. Results Average age at SAVR was 75.4 ± 7 years; 855 (96.3%) bioprostheses entered the follow-up and 396 (46.4%) were alive at last assessment. Follow-up was 99.9% complete, median duration was 7.7 years (entire cohort) and 9.9 years (survivors). At 10 years, overall survival was 50% ± 1.9, freedom from SVD was 99.4% ± 0.3 (competing risks) (seven SVD events after 8.1 ± 4.3 years). Freedom from SVD at 15 years was 98.4% ± 0.8 (competing risks). Prevalence of severe PPM was higher in 19 mm (6.5%) and 21 mm (10.2%) size cohorts. PPM (severe or moderate/severe) had no significant impact on overall survival (log-rank P = 0.27 and P = 0.21, respectively). Freedom from any reintervention (reoperation or TAVI Valve-in-Valve) for SVD at 10 years was 99.4% ± 0.3 (competing risks); freedom from any valve-related reintervention was 97.4% ± 0.6 (competing risks). Conclusion The Epic bioprosthesis for SAVR is limited by nonnegligible rates of PPM, which have nonetheless no impact on late survival. This device shows excellent durability and low rates of adverse valve-related events

Epidemiology and prognosis of anti-infective therapy in the ICU setting during acute pancreatitis: a cohort study

International audienceBACKGROUND: Recent international guidelines for acute pancreatitis (AP) recommend limiting anti-infective therapy (AIT) to cases of suspected necrotizing AP or nosocomial extrapancreatic infection. Limited data are available concerning empirical and documented AIT prescribing practices in patients admitted to the intensive care unit (ICU) for the management of AP.METHODS: Using a multicentre, retrospective (2009-2014), observational database of ICU patients admitted for AP, our primary objective was to assess the incidence of AIT prescribing practices during the first 30 days following admission. Secondary objectives were to assess the independent impact of centre characteristics on the incidence of AIT and to identify factors associated with crude hospital mortality in a logistic regression model.RESULTS: In this cohort of 860 patients, 359 (42%) received AIT on admission. Before day 30, 340/359 (95%) AIT patients and 226/501 (45%) AIT-free patients on admission received additional AIT, mainly for intra-abdominal and lung infections. A large heterogeneity was observed between centres in terms of the incidence of infections, therapeutic management including AIT and prognosis. Administration of AIT on admission or until day 30 was not associated with an increased mortality rate. Patients receiving AIT on admission had increased rates of complications (septic shock, intra-abdominal and pulmonary infections), therapeutic (surgical, percutaneous, endoscopic) interventions and increased length of ICU stay compared to AIT-free patients. Patients receiving delayed AIT after admission and until day 30 had increased rates of complications (respiratory distress syndrome, intra-abdominal and pulmonary infections), therapeutic interventions and increased length of ICU stay compared to those receiving AIT on admission. Risk factors for hospital mortality assessed on admission were age (adjusted odds ratio [95% confidence interval] 1.03 [1.02-1.05]; p < 0.0001), Balthazar score E (2.26 [1.43-3.56]; p < 0.0001), oliguria/anuria (2.18 [1.82-4.33]; p < 0.0001), vasoactive support (2.83 [1.73-4.62]; p < 0.0001) and mechanical ventilation (1.90 [1.15-3.14]; p = 0.011), but not AIT (0.63 [0.40-1.01]; p = 0.057).CONCLUSIONS: High proportions of ICU patients admitted for AP receive AIT, both on admission and during their ICU stay. A large heterogeneity was observed between centres in terms of incidence of infections, AIT prescribing practices, therapeutic management and outcome. AIT reflects the initial severity and complications of AP, but is not a risk factor for death