68 research outputs found
Culture and the Gender Gap in Competitive Inclination: Evidence from the Communist Experiment in China
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
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
Therapeutic targets in the pancreatic adenocarcinoma microenvironment: past challenges and opportunities for the future
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality, with cytotoxic chemotherapy still the mainstay of treatment. Beyond effective therapeutic agents alone, successful drug delivery is paramount. In PDAC, the tumor microenvironment represents a physical barrier that limits in vivo drug delivery and efficacy. In this review, we highlight therapeutic targets in the tumor microenvironment, focusing on past challenges and opportunities for the future. Targets discussed include the Hedgehog pathway, angiogenesis, hyaluronic acid, cancer-associated fibroblasts and associated cytokines, among others. Despite the obstacles in successfully recapitulating promising lab results to practice-changing clinical results, many important lessons have been learned to improve clinical trial design within a highly engaged and motivated scientific community. These collaborative efforts and the collective optimism will continue to propel the momentum forward to overcome these barriers and ultimately improve patient outcomes
Supportive Management of Patients with Advanced Pheochromocytomas and Paragangliomas Receiving PRRT.
Peptide receptor radionuclide therapy (PRRT) is used to treat patients with advanced malignant pheochromocytomas (PCCs) and paragangliomas (PGLs). Patients are at risk of a PRRT-induced catecholamine crisis, and standard guidelines regarding the prevention and management of infusion reactions are lacking. In this case series, the institutional experience of five sequential patients with metastatic PCCs and PGLs receiving PRRT on an outpatient basis is described, of which four had symptomatic tumors and three had a high burden of disease. All patients with symptomatic tumors were treated with preventive management prior to the initiation of PRRT, and no infusion reactions or catecholamine crises were documented. PRRT may be delivered safely on an outpatient basis for patients with metastatic PCCs and PGLs with the involvement of an interdisciplinary team
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Factors Associated With Geographic Disparities in Gastrointestinal Cancer Mortality in the United States
Significant geographic variability in gastrointestinal (GI) cancer-related death has been reported in the United States. We aimed to evaluate both modifiable and nonmodifiable factors associated with intercounty differences in mortality due to GI cancer.
Data from the Centers for Disease Control and Prevention’s Wide-ranging Online Data for Epidemiologic Research platform were used to calculate county-level mortality from esophageal, gastric, pancreatic, and colorectal cancers. Multivariable linear regression models were fit to adjust for county-level covariables, considering both patient (eg, sex, race, obesity, diabetes, alcohol, and smoking) and structural factors (eg, specialist density, poverty, insurance prevalence, and colon cancer screening prevalence). Intercounty variability in GI cancer-related mortality explained by these covariables was expressed as the multivariable model R2.
There were significant geographic disparities in GI cancer-related county-level mortality across the US from 2010–2019 with the ratio of mortality between 90th and 10th percentile counties ranging from 1.5 (pancreatic) to 2.1 (gastric cancer). Counties with the highest 5% mortality rates for gastric, pancreatic, and colorectal cancer were primarily in the Southeastern United States. Multivariable models explained 43%, 61%, 14%, and 39% of the intercounty variability in mortality rates for esophageal, gastric, pancreatic, and colorectal cancer, respectively. Cigarette smoking and rural residence (independent of specialist density) were most strongly associated with GI cancer–related mortality.
Both patient and structural factors contribute to significant geographic differences in mortality from GI cancers. Our findings support continued public health efforts to reduce smoking use and improve care for rural patients, which may contribute to a reduction in disparities in GI cancer–related death.
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The highest rates of death from gastrointestinal cancers occur in rural counties and in the Southeastern United States, with differences in county-level mortality from esophagus, stomach, pancreas, and colon cancer being associated with higher rates of smoking, diabetes, and obesity
Efficacy and Prognostic Factors for Y-90 Radioembolization (Y-90) in Metastatic Neuroendocrine Tumors with Liver Metastases
Background. Yttrium-90 (Y-90) can be an effective liver-directed therapy for patients with metastatic neuroendocrine tumors (NETs), but population-based data are limited. We characterized the use of Y-90 in NET patients and identified factors associated with response. Methods. We identified 49 patients with metastatic liver-dominant NETs across BC Cancer’s six regional centres who received Y-90 between June 2011 and January 2017 in British Columbia, Canada. Baseline characteristics, radiographic responses, and outcomes were summarized. Results. Of the 49 patients who received Y-90, the median age was 56 years (range 21–78), 49% were male, and 94% had an ECOG performance status of 0–1. The primary location of the NET included pancreas (31%), small bowel (41%), large bowel (6%), unknown (14%), and others (12%). 69% of these patients had liver metastases alone, and tumors were graded as G1 (61%), G2 (25%), G3 (2%), and unknown (12%). Prior therapies included surgery (63%), local ablative therapy (25%), somatostatin analogue (69%), and systemic therapy (35%). The median Y-90 dose was 2.2 GBq (range 0.8–3.6), as SIR-spheres (69%) or TheraSpheres (29%). Median time to Y-90 from diagnosis of metastases measured 1.54 years. 88% received segmental Y-90, with 1 (69%), 2 (29%), and 3 (2%) treatments. Y-90 resulted in partial response (53%), stable disease (33%), and progressive disease (12%). Y-90 was well-tolerated, with infrequent grade 3-4 biochemical toxicities (2%) and grade 3 abdominal pain (6%). Longer overall survival (OS) was associated with resection of primary tumor, well-differentiated histology, and low Ki-67. Median OS was 27.2 months (95% CI 8.0–46.5).Conclusions. In our population-based cohort, Y-90 was well-tolerated in patients with metastatic liver-dominant NETs. Prior surgical resection was an important predictor of OS
879 Post-treatment neutrophil-to-lymphocyte ratio and gMDSCs as independent prognostic factors for treatment efficacy with monoclonal antibody NEO-201 and pembrolizumab
Incidence of exercise-induced arterial hypoxemia in prepubescent females
Due to the recent discovery of exercise-induced arterial hypoxemia (EIAH) in healthy active women with normal levels of peak oxygen uptake (V′), this study examined the incidence of EIAH in prepubescent females. Nineteen healthy, active, prepubescent females (X ± SD: age = 11.1 ± 1.6 years; height = 145.8 ± 9.1 cm; weight = 35.6 ± 7.0 kg) performed a progressive maximal exercise test on an electronically braked cycle ergometer starting at 0 W and increasing power by 15 W min. During this test, expired gases, heart rate (HR), and percent arterial oxyhemoglobin saturation (%SaO) were measured. Results for physiological variables at maximal exercise were as follows: V′ = 43.7 ± 7.0 ml·kg·min; HR = 199 ± 5 beats·min; %SaO = 96.6 ± 1.2%. For nearly all subjects, the %SaO at maximal exercise was above levels that would reduce V′Opeak. Therefore, in comparison to previous reports of EIAH in adult women with similar V′Opeak, EIAH does not appear to occur in the prepubescent female population
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