The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative ...immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8
cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.
Recent empirical studies point out that the firms do not fully incorporate the managers’ past performance when revising future contractual terms. This study offers a theoretical perspective on the ...firm’s executive compensation strategy that supports such latest empirical findings. Using a two-period principal-agent model, we examine firm’s compensation schemes with ratchet principle taking into account key factors such as informational rent, capability uncertainty, and performance noise. After characterizing the optimal incentive rates for a given degree of ratcheting, we examine the efficacy of ratcheting contract in executive compensation. We also explore the optimal degree of ratcheting that strikes a fine balance between informational rent and ratchet effect. We find that the capability gap-performance noise ratio plays a critical role in determining the optimal degree of ratcheting.
Funding:
I. Hwang and M. K. Lim acknowledge support from the Institute of Management Research at Seoul National University.
Supplemental Material:
The online appendix is available at
https://doi.org/10.1287/deca.2023.0467
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Neutrophils, which are the most abundant circulating leukocytes in humans, are the first line of defense against bacterial and fungal infections. Recent studies have reported the role and importance ...of neutrophils in cancers. Glioma and brain metastases are the most common malignant tumors of the brain. The tumor microenvironment (TME) in the brain is complex and unique owing to the brain-blood barrier or brain-tumor barrier, which may prevent drug penetration and decrease the efficacy of immunotherapy. However, there are limited studies on the correlation between brain cancer and neutrophils. This review discusses the origin and functions of neutrophils. Additionally, the current knowledge on the correlation between neutrophil-to-lymphocyte ratio and prognosis of glioma and brain metastases has been summarized. Furthermore, the implications of tumor-associated neutrophil (TAN) phenotypes and the functions of TANs have been discussed. Finally, the potential effects of various treatments on TANs and the ability of neutrophils to function as a nanocarrier of drugs to the brain TME have been summarized. However, further studies are needed to elucidate the complex interactions between neutrophils, other immune cells, and brain tumor cells.
Opinion statement
Immune checkpoint inhibitors have changed the landscape of cancer immunotherapy and are being integrated into the standard of care for a variety of solid and hematologic ...malignancies. Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a grave prognosis despite advances in surgical resection, chemotherapy, and radiation therapy. Implementing immunotherapy for brain tumors mandates additional considerations due to the unique structural and immunologic milieu of the central nervous system (CNS). Nevertheless, strong data from preclinical studies have driven clinical trials of immune checkpoint blockade for newly diagnosed and recurrent GBM. The focus of this review is to discuss the ongoing clinical trials of checkpoint inhibitors in GBM and review the immunologic rationale for ongoing and future trial designs.
This paper proposes a continuum approximation (CA) model to solve the dynamic facility location problem for a large-scale growing market. The objective is to determine the optimal facility location ...and deployment time that minimize the costs for facility construction and customer service in a planning horizon. To overcome computational challenges, the CA model determines the optimal facility density in the spatiotemporal continuum. Then we propose a tube model to discretize the resulting continuous facility density function into a set of time-varying facility location trajectories. To enforce consistency in facility location over time, an iterative regulation procedure based on a penalty method is applied. We present convergence properties of the proposed procedure and further derive conditions under which the CA approach and the tube model yield tight approximation error bounds. We conduct a series of numerical experiments to illustrate the applicability and computational performance (e.g., accuracy and convergence) of the proposed modeling framework, first via comparison with discrete model counterparts using hypothetical data, and then via application to an empirical case for the state of Illinois. Our results show that the proposed method effectively solves the dynamic facility location problem to reasonable accuracy. Various managerial insights are also drawn.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•Elevated pro-inflammatory cytokines are associated with neuropathic pain.•Therapies to alter cytokines levels have shown promise as potential therapies.•Indirect therapeutic options have been shown ...to modulate the immune landscape.•Additional studies are needed to determine efficacy in neuropathic pain patients.
Neuropathic pain is a challenging condition often refractory to existing therapies. An increasing number of studies have indicated that the immune system plays a crucial role in the mediation of neuropathic pain. Exploration of the various functions of individual cytokines in neuropathic pain will provide greater insight into the mechanisms of neuropathic pain and suggest potential opportunities to expand the repertoire of treatment options.
A literature review was performed to assess the role of pro-inflammatory and anti-inflammatory cytokines in the development of neuropathic pain. Both direct and indirect therapeutic approaches that target various cytokines for pain were reviewed. The current understanding based on preclinical and clinical studies is summarized.
In both human and animal studies, neuropathic pain has been associated with a pro-inflammatory state. Analgesic therapies involving direct manipulation of various cytokines and indirect methods to alter the balance of the immune system have been explored, although there have been few large-scale clinical trials evaluating the efficacy of immune modulators in the treatment of neuropathic pain. TNF-α is perhaps the widely studied pro-inflammatory cytokine in the context of neuropathic pain, but other pro-inflammatory (IL-1β, IL-6, and IL-17) and anti-inflammatory (IL-4, IL-10, TGF-β) signaling molecules are garnering increased interest. With better appreciation and understanding of the interaction between the immune system and neuropathic pain, novel therapies may be developed to target this condition.
Immunotherapy is emerging as the newest pillar of cancer treatment, with the potential to assume a place alongside surgical debulking, radiotherapy, and chemotherapy. Early experiences with antitumor ...vaccines demonstrated the feasibility and potential efficacy of this approach, and newer agents, such as immune checkpoint blocking antibodies and modern vaccine platforms, have ushered in a new era. These efforts are headlined by work in melanoma, prostate cancer, and renal cell carcinoma; however, substantial progress has been achieved in a variety of other cancers, including high-grade gliomas. A recurrent theme of this work is that immunotherapy is not a one-size-fits-all solution. Rather, dynamic, tumor-specific interactions within the tumor microenvironment continually shape the immunologic balance between tumor elimination and escape. High-grade gliomas are a particularly fascinating example. These aggressive, universally fatal tumors are highly resistant to radiotherapy and chemotherapy and inevitably recur after surgical resection. Located in the immune-privileged central nervous system, high-grade gliomas also use an array of defenses that serve as direct impediments to immune attack. Despite these challenges, vaccines have shown activity against high-grade gliomas, and anecdotal, preclinical, and early clinical data bolster the notion that durable remission is possible with immunotherapy. Realizing this potential, however, will require an approach tailored to the unique aspects of glioma biology.
Linear erythematous rash over the trunk Kunaseelan, Shangari; Al‐Jabri, Majid; Goh, Daniel YT ...
Journal of paediatrics and child health,
12/2022
Journal Article
Standard therapy for newly diagnosed glioblastoma (GBM) is surgical resection, followed by concurrent radiotherapy and temozolomide chemotherapy. In this phase II clinical trial, the addition of an ...autologous heat-shock protein vaccine to standard therapy was evaluated. Tumor-induced immunosuppression, mediated by expression of PD-L1 on tumor and circulating immune cells, may impact the efficacy of vaccination. Expression of PD-L1 on peripheral myeloid cells was evaluated for the first time as a predictor of survival.
In this single arm, phase II study, adult patients with GBM underwent surgical resection followed by standard radiation and chemotherapy. Autologous vaccine (Prophage) was generated from resected tumors and delivered in weekly vaccinations after completion of radiotherapy. The primary endpoint was overall survival.
Forty-six patients received the vaccine with a median overall survival of 23.8 months 95% confidence interval (CI), 19.8-30.2. Median overall survival for patients with high PD-L1 expression on myeloid cells was 18.0 months (95% CI, 10.0-23.3) as compared with 44.7 months (95% CI, incalculable) for patients with low PD-L1 expression (hazard ratio 3.3; 95% CI, 1.4-8.6;
= 0.007). A multivariate proportional hazards model revealed MGMT methylation, Karnofsky performance status, and PD-L1 expression as the primary independent predictors of survival.
Vaccination with autologous tumor-derived heat shock proteins may improve survival for GBM patients when combined with standard therapy and warrants further study. Systemic immunosuppression mediated by peripheral myeloid expression of PD-L1 is a recently identified factor that may significantly impact vaccine efficacy.
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By convention, a total obstruction of the coronary artery with no flow at the occluded segment that has been
present for at least 3 months is termed as chronic total occlusion or CTO. This is to be ...distinguished from a sudden occlusion
of the coronary artery lumen by a thrombus during an acute myocardial infarction. Percutaneous coronary intervention
(PCI) of CTO is increasingly being performed by interventional cardiologists with improved success rates. In this article,
the focus will be on antegrade techniques that will assist the operator to maximise the success rates and to minimise
the complications.
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