Glioblastoma (GBM) is the most common, and aggressive, primary brain tumor in adults. With a median patient survival of less than two years, GBM represents one of the biggest therapeutic challenges ...of the modern era. Even with the best available treatment, recurrence rates are nearly 100% and therapeutic options at the time of relapse are extremely limited. Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has provided significant clinical benefits in the treatment of various advanced cancers and represented a promising therapy for primary and recurrent GBM. CheckMate 143 (NCT 02017717) was the first large randomized clinical trial of PD pathway inhibition in the setting of GBM, including a comparison of nivolumab and the anti-VEGF antibody, bevacizumab, in the treatment of recurrent disease. However, preliminary results, recently announced in a WFNOS 2017 abstract, demonstrated a failure of nivolumab to prolong overall survival of patients with recurrent GBM, and this arm of the trial was prematurely closed. In this review, we discuss the basic concepts underlying the rational to target PD pathway in GBM, address implications of using immune checkpoint inhibitors in central nervous system malignancies, provide a rationale for possible reasons contributing to the failure of nivolumab to prolong survival in patients with recurrent disease, and analyze the future role of immune checkpoint inhibitors in the treatment of GBM.
Oncolytic viruses (OVs) are an emerging class of targeted anticancer therapies designed to selectively infect, replicate in, and lyse malignant cells without causing harm to normal, healthy tissues. ...In addition to direct oncolytic activity, OVs have shown dual promise as immunotherapeutic agents. The presence of viral infection and subsequently generated immunogenic tumor cell death trigger innate and adaptive immune responses that mediate further tumor destruction. However, antiviral immune responses can intrinsically limit OV infection, spread, and overall therapeutic efficacy. Host immune system can act both as a barrier as well as a facilitator and sometimes both at the same time based on the phase of viral infection. Thus, manipulating the host immune system to minimize antiviral responses and viral clearance while still promoting immune-mediated tumor destruction remains a key challenge facing oncolytic virotherapy. Recent clinical trials have established the safety, tolerability, and efficacy of virotherapies in the treatment of a variety of malignancies. Most notably, talimogene laherparepvec (T-VEC), a genetically engineered oncolytic herpesvirus-expressing granulocyte macrophage colony stimulating factor, was recently approved for the treatment of melanoma, representing the first OV to be approved by the FDA as an anticancer therapy in the US. This review discusses OVs and their antitumor properties, their complex interactions with the immune system, synergy between virotherapy and existing cancer treatments, and emerging strategies to augment the efficacy of OVs as anticancer therapies.
T cell chimeric antigen receptor (CAR) technology has allowed for the introduction of a high degree of tumor selectivity into adoptive cell transfer therapies. Evolution of this technology has ...produced a robust antitumor immunotherapeutic strategy that has resulted in dramatic outcomes in liquid cancers. CAR-expressing T-cells (CARTs) targeting CD19 and CD20 have been successfully used in the treatment of hematologic malignancies, producing sustained tumor regressions in a majority of treated patients. These encouraging results have led to a historic and unprecedented FDA approval of CTL019, Novartis' CAR T-cell therapy for the treatment of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). However, the translation of this technology to solid tumors, like malignant gliomas (MG), has thus far been unsuccessful. This review provides a timely analysis of the factors leading to the success of CART immunotherapy in the setting of hematologic malignancies, barriers limiting its success in the treatment of solid tumors, and approaches to overcome these challenges and allow the application of CART immunotherapy as a treatment modality for refractory tumors, like malignant gliomas, that are in desperate need of effective therapies.
Malignant gliomas (MG), tumors of glial origin, are the most commonly diagnosed primary intracranial malignancies in adults. Currently available treatments have provided only modest improvements in ...overall survival and remain limited by inevitable local recurrence, necessitating exploration of novel therapies. Among approaches being investigated, one of the leading contenders is immunotherapy, which aims to modulate immune pathways to stimulate the selective destruction of malignant cells. Dendritic cells (DCs) are potent initiators of adaptive immune responses and therefore crucial players in the development and success of immunotherapy. Clinical trials of various DC-based vaccinations have demonstrated the induction of anti-tumor immune responses and prolonged survival in the setting of many cancers. In this review, we summarize current literature regarding DCs and their role in the tumor microenvironment, their application and current clinical use in immunotherapy, current challenges limiting their efficacy in anti-cancer therapy, and future avenues for developing successful anti-tumor DC-based vaccines.
Benign Glioma Wu, Peter B; Filley, Anna C; Miller, Michael L ...
Advances in experimental medicine and biology,
2023, Letnik:
1405
Journal Article
Recenzirano
Benign glioma broadly refers to a heterogeneous group of slow-growing glial tumors with low proliferative rates and a more indolent clinical course. These tumors may also be described as "low-grade" ...glioma (LGG) and are classified as WHO grade I or II lesions according to the Classification of Tumors of the Central Nervous System (CNS) (Louis et al. in Acta Neuropathol 114:97-109, 2007). Advances in molecular genetics have improved understanding of glioma tumorigenesis, leading to the identification of common mutation profiles with significant treatment and prognostic implications. The most recent WHO 2016 classification system has introduced several notable changes in the way that gliomas are diagnosed, with a new emphasis on molecular features as key factors in differentiation (Wesseling and Capper in Neuropathol Appl Neurobiol 44:139-150, 2018). Benign gliomas have a predilection for younger patients and are among the most frequently diagnosed tumors in children and young adults (Ostrom et al. in Neuro Oncol 22:iv1-iv96, 2020). These tumors can be separated into two clinically distinct subgroups. The first group is of focal, well-circumscribed lesions that notably are not associated with an increased risk of malignant transformation. Primarily diagnosed in pediatric patients, these WHO grade I tumors may be cured with surgical resection alone (Sturm et al. in J Clin Oncol 35:2370-2377, 2017). Recurrence rates are low, and the prognosis for these patients is excellent (Ostrom et al. in Neuro Oncol 22:iv1-iv96, 2020). Diffuse gliomas are WHO grade II lesions with a more infiltrative pattern of growth and high propensity for recurrence. These tumors are primarily diagnosed in young adult patients, and classically present with seizures (Pallud et al. Brain 137:449-462, 2014). The term "benign" is a misnomer in many cases, as the natural history of these tumors is with malignant transformation and recurrence as grade III or grade IV tumors (Jooma et al. in J Neurosurg 14:356-363, 2019). For all LGG, surgery with maximal safe resection is the treatment of choice for both primary and recurrent tumors. The goal of surgery should be for gross total resection (GTR), as complete tumor removal is associated with higher rates of tumor control and seizure freedom. Chemotherapy and radiation therapy (RT), while not typically a component of first-line treatment in most cases, may be employed as adjunctive therapy in high-risk or recurrent tumors and in some select cases. The prognosis of benign gliomas varies widely; non-infiltrative tumor subtypes generally have an excellent prognosis, while diffusely infiltrative tumors, although slow-growing, are eventually fatal (Sturm et al. in J Clin Oncol 35:2370-2377, 2017). This chapter reviews the shared and unique individual features of the benign glioma including diffuse glioma, pilocytic astrocytoma and pilomyxoid astrocytoma (PMA), subependymal giant cell astrocytoma (SEGA), pleomorphic xanthoastrocytoma (PXA), subependymoma (SE), angiocentric glioma (AG), and chordoid glioma (CG). Also discussed is ganglioglioma (GG), a mixed neuronal-glial tumor that represents a notable diagnosis in the differential for other LGG (Wesseling and Capper 2018). Ependymomas of the brain and spinal cord, including major histologic subtypes, are discussed in other chapters.
The natural history and long-term durability of Guglielmi detachable coil (GDC) embolization is still unknown. We hypothesize a stepwise decrease in durability of embolized cerebral aneurysms as ...stratified by the Modified Raymond-Roy Classification (MRRC).
First-time GDC-embolized cerebral aneurysms were retrospectively reviewed from 2004 to 2015. Loss of durability (LOD) was defined by change in aneurysm size or patency seen on serial radiographic follow-up. Kaplan-Meier survival analysis was performed to evaluate embolization durability. Multivariate Cox regression modeling was used to assess baseline aneurysm and patient characteristics for their effect on LOD.
A total of 427 patients with 443 aneurysms met the inclusion criteria. Overall, 89 (21%) aneurysms met LOD criteria. Grade 1 aneurysms had statistically significantly greater durability than did all other MRRC grades. Grade 3b aneurysms had significantly worse durability than did all other aneurysm grades. There was no difference in durability between grade 2 and 3a aneurysms. Of aneurysms with LOD, 26 (29%) experienced worsening of MRRC grade. Thirty-five (24%) initial MRRC grade 2, 72 (45%) initial MRRC grade 3a, and 6 (22%) initial MRRC grade 3b aneurysms progressed to MRRC grade 1 without retreatment. In our multivariate analysis, only initial MRRC grade was statistically significantly associated with treatment durability (P < 0.001).
MRRC grade is independently associated with first-time GDC-embolized cerebral aneurysm durability. Achieving MRRC grade 1 occlusion outcome is significantly associated with greater long-term GDC durability. Although few aneurysms experience further growth and/or recanalization, most incompletely obliterated aneurysms tend to remain stable over time or even progress to occlusion. Grading scales such as the MRRC are useful for characterizing aneurysm occlusion but may lack sensitivity and specificity for characterizing changes in aneurysm morphology over time.
•Patients with degenerative spinal disease often have underlying osteoporosis.•Osteoporosis is an important risk factor for mechanical complications after lumbar fusion.•Routine preoperative ...screening allows interventions that can reduce complication risk.•Alternative screening recommendations may be necessary for surgical spine patients.•Standardized methods of bone health evaluation and complication reporting are needed.
Adults undergoing spine surgery often have underlying osteoporosis, which may be a risk factor for postoperative complications. Although these associations have been described, osteoporosis remains profoundly underdiagnosed and undertreated in the spine surgery population. A thorough, comprehensive systematic review summarizing the relationships between bone mineral density (BMD) and specific complications of lumbar fusion surgery could be a valuable resource for raising awareness and supporting clinical practice changes.
PubMed, Embase, and Web of Science databases were searched for original clinical research articles reporting on BMD, or surrogate measure, as a predictor of complications in adults undergoing elective lumbar fusion for degenerative disease or deformity. Endpoints included cage subsidence, screw loosening, pseudarthrosis, vertebral fracture, junctional complications, and reoperation.
A total of 71 studies comprising 12,278 patients were included. Overall, considerable heterogeneity in study populations, methods of bone health assessment, and definition and evaluation of clinical endpoints precluded meta-analysis. Nevertheless, low BMD was associated with higher rates of implant failures like cage subsidence and screw loosening, which were often diagnosed with concomitant pseudarthrosis. Osteoporosis was also a significant risk factor for proximal junctional kyphosis, particularly due to fracture. Many studies found surgical site-specific BMD to best predict focal complications. Functional outcomes were inconsistently addressed.
Our findings suggest osteoporosis is a significant risk factor for mechanical complications of lumbar fusion. These results emphasize the importance of preoperative osteoporosis screening, which allows for medical and surgical optimization of high-risk patients. This review also highlights current practical challenges facing bone health evaluation in patients undergoing elective surgery. Future prospective studies using standardized methods are necessary to strengthen existing evidence, identify optimal predictive thresholds, and establish specialty-specific practice guidelines. In the meantime, an awareness of the surgical implications of osteoporosis and utility of preoperative screening can provide for more informed, effective patient care.
Hospital length of stay (LOS), discharge disposition, and subsequent completion of outpatient follow-up are important components of a patient's postoperative clinical course. Understanding the major ...determinants of these outcomes can inform a more accurate, comprehensive determination of an individual's unique postoperative needs. These evaluations are fundamental for optimal allocation of resources and ensuring that each patient has the tools that he or she needs to achieve a successful recovery. However, the determinants of these outcomes are incompletely understood.
The purpose of this study was to examine factors that predict hospital LOS, discharge disposition, and completion of postoperative follow-up after elective lumbar spine surgery in patients with degenerative spondylolisthesis.
A retrospective cohort analysis.
A total of 351 consecutive patients who underwent elective surgical treatment of symptomatic L4/5 degenerative spondylolisthesis at our institution between January 2016 and June 2020 were reviewed.
Multivariate analysis was performed to identify factors independently predictive of LOS, discharge disposition, and completion of postoperative follow-up. Sociodemographic variables, health-related behaviors, baseline medical comorbidities, and surgical characteristics were analyzed as possible contributors.
Data was collected on a total of 351 patients (56% female, mean age 67.9 years). The mean postoperative LOS was 3.5 days. A total of 43% of patients were discharged home, an additional 41% home with services, 8% to acute rehab, and 8% to a subacute nursing facility. Median follow-up duration was 16 months, and 41% of patients ultimately failed to return for a scheduled clinic visit. LOS was significantly longer for non-English-speakers (5.3 vs 4.4 days, p=0.05), current smokers (5.9 vs 4.2 days, p=0.005), and those with underlying psychiatric disorder (5.1 vs 4.7 days, p=0.05). Compared to patients who were actively working, LOS was longer for those who reported being unemployed (p=0.01) or disabled (p=0.08), but not retired (p=0.99). LOS was also incrementally higher per unit increase in CCI (0.3 days, p<0.0001) and surgical invasiveness (0.1 days, p=0.0002), and per 500mL increase in EBL (0.6 days, p=0.0008). In terms of discharge disposition, patients who were not partnered (single, divorced, or widowed) were significantly more likely to be discharged to an acute rehab (adjusted odds ratio, aOR 2.9; 95% CI 1.2-7.0, p=0.01) or subacute nursing facility (aOR 3.8;95% CI 1.6-9.1, p=0.002) postoperatively. The risk of a nonhome discharge increased by approximately 2-fold for each unit increase in CCI (p<0.0001). Patients with an underlying psychiatric disorder were nearly twice as likely not to return for a scheduled postoperative appointment, and psychiatric comorbidity was the only independent predictor of loss to follow-up on multivariate analysis (aOR 1.9; 95% CI 1.2-3.2, p=0.005).
Patient factors such as language, employment status, current smoking, underlying psychiatric illness, and burden of medical comorbidities may predict longer postoperative hospitalization after surgical treatment of degenerative lumbar spondylolisthesis. Discharge to a facility with skilled nursing or rehabilitation specialists may be more appropriate for patients who are more medically complex and those without significant support or a caregiver at home. Attention to these factors may assist with early discharge planning and identification of patients who may need additional assistance postoperatively, thereby facilitating a safe, efficient discharge. As patients with underlying psychiatric illness may be less likely to complete prescribed postoperative follow-up, targeted intervention strategies may be helpful to ensure continued care.
This abstract does not discuss or include any applicable devices or drugs.
Degenerative spondylolisthesis (DS), is one of the most common causes of back pain and disability worldwide. Recent data has supported the role of surgical intervention for improving outcomes in ...symptomatic DS. As we study DS treatment efficacy, it is important to look at populations’ access to surgical care.
The purpose of this study was to investigate the relationship between social determinants of health (SDoH) and the clinical presentation of patients with operative DS in order to better understand factors influencing patient access to surgical care.
Retrospective study at a single academic center.
A total of 184 consecutive adult (18 and over) patients that underwent operative management of symptomatic degenerative spondylolisthesis at UCSF January 2016-2020.
Primary outcomes were duration of baseline, worsening, and severity symptoms at first consultation, time from referral to surgical consultation and time from consultation to surgical procedure.
A retrospective chart review was performed using the electronic medical record. Baseline patient demographics, zip code data, and above outcome data were collected. Zip codes from the electronic medical record were used to link patients to US Census tracts. The distance traveled was mapped using the shortest driving distance between the patient's listed home address and the spine clinic. Patient income was estimated using median income census data. Univariate analysis was used to assess the influence of SDoH on these outcomes.
Patients with estimated median income in the lowest two quartiles had a significantly longer duration of baseline (112.4 vs 54.5 months, p=0.00139) and worsening symptoms (17.4 vs 9 months, p=0.0262) and waited longer for surgical consultation after initial referral (52 vs 35 days, p=0.0143) than those in the top two quartiles. Patients living >50 miles from UCSF had a significantly longer duration of baseline symptoms (104 vs 61 months p=0.018) and waited longer for surgical consultation after initial referral (53 vs 34 days, p=0.0086). Following surgical consultation, patients with public insurance waited longer for procedures than those with private insurance (440 vs 251 days; p=0.046).
Low income was a risk factor for worse preoperative presentation. To ensure equitable access to appropriate surgical care, SDoH must be considered as these are modifiable risk factors to improve patient outcomes. By understanding factors that may predispose patients to presenting in a worse clinical state prior to surgery, we can not only increase access, but also improve surgical outcomes. Social determinants of health (SDoH) have been recognized as non-medical factors that affect patients’ health. Little work has been done within the orthopedic field. As studies support the efficacy of surgical management for common and debilitating spine conditions, such as degenerative, it is important to see how SDoH can impact access to this new standard of care. In this retrospective study we found that lower income and further distance from referral center resulted in worse access to surgical care.
This abstract does not discuss or include any applicable devices or drugs.
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