To characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain ...metastases (BMs).
We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs.
A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio HR, 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64).
Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.
Strategic supply chain design decisions are critical to the long-term success of a business. Traditional facility location models for supply chain design focus on the trade-offs between the costs and ...benefits of proximity, i.e., the distance between facilities and customers. These strategic-focused models do not consider the supply chain’s agility, i.e., its ability to quickly respond to unexpected fluctuations in customer needs. In this paper, we study the problem of designing a supply chain distribution network under demand uncertainty and analyze how the optimal design characteristics of proximity and agility depend on various input parameters. We are able to draw managerial insights on how agility considerations may invalidate well-established and widely accepted qualitative results derived from traditional models. In particular, we show that it is optimal to increase the density of distribution centers (DCs) when the shortage penalty cost increases, and to decrease the density of DCs when a certain unit transportation cost parameter increases. Through these findings, our work conveys the message that traditional, proximity-based facility location models can be inadequate for designing modern responsive supply chains, and calls for the need to develop a new class of models for the task.
This paper was accepted by Yossi Aviv, operations management
.
Chimeric antigen receptor T cells (CAR T cells) are engineered cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen (TA) that allows for the identification and ...elimination of cancer cells. The remarkable clinical effect seen with CAR T cell therapies against hematological malignancies have attracted interest in developing such therapies for solid tumors, including brain tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with poor prognosis due to its highly aggressive nature. Pediatric brain cancers are similarly aggressive and thus are a major cause of pediatric cancer-related death. CAR T cell therapy represents a promising avenue for therapy against these malignancies. Several specific TAs, such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and HER2, have been targeted in preclinical studies and clinical trials. Unfortunately, CAR T cells against brain tumors have showed limited efficacy due to TA heterogeneity, difficulty trafficking from blood to tumor sites, and the immunosuppressive tumor microenvironment. Here, we review current CAR T cell approaches in treating cancers, with particular focus on brain cancers. We also describe a novel technique of focused ultrasound controlling the activation of engineered CAR T cells to achieve the safer cell therapies. Finally, we summarize the development of combinational strategies to improve the efficacy and overcome historical limitations of CAR T cell therapy.
Glioblastoma (GBM) is the most common and fatal primary central nervous system malignancy in adults with a median survival of less than 15 months. Surgery, radiation, and chemotherapy are the ...standard of care and provide modest benefits in survival, but tumor recurrence is inevitable. The poor prognosis of GBM has made the development of novel therapies targeting GBM of paramount importance. Immunotherapy via dendritic cells (DCs) has garnered attention and research as a potential strategy to boost anti-tumor immunity in recent years. As the "professional" antigen processing and presenting cells, DCs play a key role in the initiation of anti-tumor immune responses. Pre-clinical studies in GBM have shown long-term tumor survival and immunological memory in murine models with stimulation of DC activity with various antigens and costimulatory molecules. Phase I and II clinical trials of DC vaccines in GBM have demonstrated some efficacy in improving the median overall survival with minimal to no toxicity with promising initial results from the first Phase III trial. However, there remains no standardization of vaccines in terms of which antigens are used to pulse DCs ex vivo, sites of DC injection, and optimal adjuvant therapies. Future work with DC vaccines aims to elucidate the efficacy of DC-based therapy alone or in combination with other immunotherapy adjuvants in additional Phase III trials.
Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive ...microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45⁺ immune cells and the percentage of active CD8⁺ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.
•Cerebrovascular disease was associated with mortality and severity of COVID-19 (borderline).•Cardiovascular disease was associated with mortality and severity of COVID-19.•Gender, age, hypertension, ...diabetes, and respiratory comorbidities did not influence the associations•The association between cerebrovascular disease and poor outcome in COVID-19 was not affected by cardiovascular diseases and vice versa .
We conducted a systematic review and meta-analysis to evaluate the latest evidence on the association between cerebrovascular, and cardiovascular diseases and poor outcome in patients with Coronavirus Disease 2019 (COVID-19) pneumonia.
A comprehensive systematic literature search was performed using PubMed, SCOPUS, EuropePMC, and Cochrane Central Database. The outcome of interest was composite poor outcome that comprised of mortality and severe COVID-19.
A total of 4448 patients were obtained from 16 studies. Cerebrovascular disease was associated with an increased composite poor outcome (RR 2.04 1.43,2.91, p<0.001; I2: 77%). Subgroup analysis revealed that cerebrovascular disease was associated with mortality (RR 2.38 1.92,2.96, p<0.001; I2: 0%) and showed borderline significance for severe COVID-19 (RR 1.88 1.00,3.51, p = 0.05; I2: 87%). Cardiovascular disease was associated with increased composite poor outcome (RR 2.23 1.71,2.91, p<0.001; I2: 60%), mortality (RR 2.25 1.53,3.29, p<0.001; I2: 33%) and severe COVID-19 (RR 2.25 1.51,3.36, p<0.001; I2: 76%). Meta-regression demonstrate that the association was not influenced by gender, age, hypertension, diabetes, and respiratory comorbidities. Furthermore, the association between cerebrovascular disease and poor outcome was not affected by cardiovascular diseases and vice versa.
Cerebrovascular and cardiovascular diseases were associated with an increased risk for poor outcome in patients with COVID-19.
Background:
Patients critically ill with coronavirus disease-2019 (COVID-19) feature hyperinflammation, and the associated biomarkers may be beneficial for risk stratification. We aimed to ...investigate the association between several biomarkers, including serum C-reactive protein (CRP), procalcitonin (PCT), D-dimer, and serum ferritin, and COVID-19 severity.
Methods:
We performed a comprehensive systematic literature search through electronic databases. The outcome of interest for this study was the composite poor outcome, which comprises mortality, acute respiratory distress syndrome, need for care in an intensive care unit, and severe COVID-19.
Results:
A total of 5350 patients were pooled from 25 studies. Elevated CRP was associated with an increased composite poor outcome risk ratio (RR) 1.84 (1.45, 2.33), p < 0.001; I2: 96% and its severe COVID-19 (RR 1.41; I2: 93%) subgroup. A CRP ⩾10 mg/L has a 51% sensitivity, 88% specificity, likelihood ratio (LR) + of 4.1, LR- of 0.5, and an area under curve (AUC) of 0.84. An elevated PCT was associated with an increased composite poor outcome RR 3.92 (2.42, 6.35), p < 0.001; I2: 85% and its mortality (RR 6.26; I2: 96%) and severe COVID-19 (RR 3.93; I2: 63%) subgroups. A PCT ⩾0.5 ng/ml has an 88% sensitivity, 68% specificity, LR+ of 2.7, LR- of 0.2, and an AUC of 0.88. An elevated D-dimer was associated with an increased composite poor outcome RR 2.93 (2.14, 4.01), p < 0.001; I2: 77%, including its mortality (RR 4.15; I2: 83%) and severe COVID-19 (RR 2.42; I2: 58%) subgroups. A D-dimer >0.5 mg/L has a 58% sensitivity, 69% specificity, LR+ of 1.8, LR- of 0.6, and an AUC of 0.69. Patients with a composite poor outcome had a higher serum ferritin with a standardized mean difference of 0.90 (0.64, 1.15), p < 0.0001; I2: 76%.
Conclusion:
This meta-analysis showed that an elevated serum CRP, PCT, D-dimer, and ferritin were associated with a poor outcome in COVID-19.
The reviews of this paper are available via the supplemental material section.
Understanding people's concepts of illness and health is key to crafting policies and communications campaigns to address a particular medical concern. This paper gathers cultural knowledge on ...infectious disease causation, prevention, and treatment the Philippines that are particularly relevant for the COVID-19 pandemic, and analyzes their implications for public health. This paper draws from ethnographic work (e.g. participant observation, interviews, conversations, virtual ethnography) carried out individually by each of the two authors from February to September 2020. The data was analyzed in relation to the anthropological literature on local health knowledge in the Philippines. We find that notions of hawa (contagion) and resistensiya (immunity) inform people's views of illness causation as well as their preventive practices - including the use of face masks and 'vitamins' and other pharmaceuticals, as well as the ways in which they negotiate prescriptions of face mask use and physical distancing. These perceptions and practices go beyond biomedical knowledge and are continuously being shaped by people's everyday experiences and circulations of knowledge in traditional and social media. Our study reveals that people's novel practices reflect recurrent, familiar, and long-held concepts - such as the moral undertones of hawa and experimentation inherent in resistensiya. Policies and communications efforts should acknowledge and anticipate how these notions may serve as either barriers or facilitators to participatory care and improved health outcomes.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Supply chain disruptions come with catastrophic consequences in spite of their low probability of occurrence. In this paper, we consider a facility location problem in the presence of random facility ...disruptions where facilities can be protected with additional investments. Whereas most existing models in the literature implicitly assume that the disruption probability estimate is perfectly accurate, we investigate the impact of misestimating the disruption probability. Using a stylized continuous location model, we show that underestimation in disruption probability results in greater increase in the expected total cost than overestimation. In addition, we show that, when planned properly, the cost of mitigating the misestimation risk is not too high. Under a more generalized setting incorporating correlated disruptions and finite capacity, we numerically show that underestimation in both disruption probability and correlation degree result in greater increase in the expected total cost compared to overestimation. We, however, find that the impact of misestimating the correlation degree is much less significant relative to that of misestimating the disruption probability. Thus, managers should focus more on accurately estimating the disruption probability than the correlation.
Rac2 is an essential regulator of NET formation via pathways involving both ROS and NO.
Neutrophils play a critical role as a first line of defense against invading pathogens. Recently, a new defense ...strategy of neutrophils was described, in which pathogens are trapped and killed by NETs. However, the exact underlying mechanisms leading to the formation of NETs remain elusive. Here, we explored the role of the Rac small GTPases in the formation of NETs using neutrophils that lack Rac1, Rac2, or both isoforms. Efficient NET formation was observed in WT and Rac1null neutrophils. In contrast, NET formation was markedly impaired in cells lacking Rac2 or both Rac2 and Rac1. The defect in NET formation in Rac2null cells was rescued by exogenous ROS sources, suggesting that Rac2‐mediated ROS generation is required for NET formation. In addition, we assessed the role of NO in NET formation in mouse neutrophils. Blocking NO production with the NOS inhibitor L‐NAME significantly reduced NET formation. Moreover, we show that Rac2null cells produce significantly less NO than Rac1null cells or their WT counterparts. Our data suggest that Rac2 is essential for NET formation via pathways involving ROS and NO.
PDF
