Glioblastoma (GBM) is the most common primary brain tumor in adults an carries and carries a terrible prognosis. The current regiment of surgical resection, radiation, and chemotherapy has remained ...largely unchanged in recent years as new therapeutic approaches have struggled to demonstrate benefit. One of the most challenging hurdles to overcome in developing novel treatments is the profound immune suppression found in many GBM patients. This limits the utility of all manner of immunotherapeutic agents, which have revolutionized the treatment of a number of cancers in recent years, but have failed to show similar benefit in GBM therapy. Understanding the mechanisms of tumor-mediated immune suppression in GBM is critical to the development of effective novel therapies, and reversal of this effect may prove key to effective immunotherapy for GBM. In this review, we discuss the current understanding of tumor-mediated immune suppression in GBM in both the local tumor microenvironment and systemically. We also discuss the effects of current GBM therapy on the immune system. We specifically explore some of the downstream effectors of tumor-driven immune suppression, particularly myeloid-derived suppressor cells (MDSCs) and other immunosuppressive monocytes, and the manner by which GBM induces their formation, with particular attention to the role of GBM-derived extracellular vesicles (EVs). Lastly, we briefly review the current state of immunotherapy for GBM and discuss additional hurdles to overcome identification and implementation of effective therapeutic strategies.
Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates 10nmol/L, or tumor tissue studies demonstrate CDK inhibition, ...then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The authors sought to investigate the incidence and predictors of venous thromboembolic events (VTEs) after craniotomy for tumor resection, which are not well established, and the efficacy of and ...risks associated with VTE chemoprophylaxis, which remains controversial.
The authors investigated the incidence of VTEs in a consecutive series of patients presenting to the authors' institution for resection of an intracranial lesion between 2012 and 2017. Information on patient and tumor characteristics was collected and independent predictors of VTEs were determined using stepwise multivariate logistic regression analysis. Review of the literature was performed by searching MEDLINE using the keywords "venous thromboembolism," "deep venous thrombosis," "pulmonary embolism," "craniotomy," and "brain neoplasms."
There were 1622 patients included for analysis. A small majority of patients were female (52.6%) and the mean age of the cohort was 52.9 years (SD 15.8 years). A majority of intracranial lesions were intraaxial (59.3%). The incidence of VTEs was 3.0% and the rates of deep venous thromboses and pulmonary emboli were 2.3% and 0.9%, respectively. On multivariate analysis, increasing patient age (unit OR 1.02, 95% CI 1.00-1.05; p = 0.018), history of VTE (OR 7.26, 95% CI 3.24-16.27; p < 0.001), presence of motor deficit (OR 2.64, 95% CI 1.43-4.88; p = 0.002), postoperative intracranial hemorrhage (OR 4.35, 95% CI 1.51-12.55; p < 0.001), and prolonged intubation or reintubation (OR 3.27, 95% CI 1.28-8.32; p < 0.001) were independently associated with increased odds of a VTE. There were 192 patients who received VTE chemoprophylaxis (11.8%); the mean postoperative day of chemoprophylaxis initiation was 4.6 (SD 3.8). The incidence of VTEs was higher in patients receiving chemoprophylaxis than in patients not receiving chemoprophylaxis (8.3% vs 2.2%; p < 0.001). There were 30 instances of clinically significant postoperative hemorrhage (1.9%), with only 1 hemorrhage occurring after initiation of VTE chemoprophylaxis (0.1%).
The study results show the incidence and predictors of VTEs after craniotomy for tumor resection in this patient population. The incidence of VTE within this cohort appears low and comparable to that observed in other institutional series, despite the lack of routine prophylactic anticoagulation in the postoperative setting.
Glioblastoma (GBM) is one of the most aggressive and devastating primary brain tumors, with a median survival of 15 months following diagnosis. Despite the intense treatment regimen which routinely ...includes maximal safe neurosurgical resection followed by adjuvant radio- and chemotherapy, the disease remains uniformly fatal. The poor prognosis associated with GBM is multifactorial owing to factors such as increased proliferation, angiogenesis, and metabolic switching to glycolytic pathways. Critically, GBM-mediated local and systemic immunosuppression result in inadequate immune surveillance and ultimately, tumor-immune escape. Microglia—the resident macrophages of the central nervous system (CNS)—play crucial roles in mediating the local immune response in the brain. Depending on the specific pathological cues, microglia are activated into either a pro-inflammatory, neurotoxic phenotype, known as M1, or an anti-inflammatory, regenerative phenotype, known as M2. In either case, microglia secrete corresponding pro- or anti-inflammatory cytokines and chemokines that either promote or hinder tumor growth. Herein, we review the interplay between GBM cells and resident microglia with a focus on contemporary studies highlighting the effect of GBM on the subtypes of microglia expressed, the associated cytokines/chemokines secreted, and ultimately, their impact on tumor pathogenesis. Finally, we explore how understanding the intricacies of the tumor-immune landscape can inform novel immunotherapeutic strategies against this devastating disease.
The goal of this study is to show using 5 illustrative cases that the transcortical route for resection of mediobasal temporal region (MBTR) lesions is safe and effective when performed with awake ...functional mapping and knowledge of the relevant subcortical anatomy. Although several have been proposed, there is a paucity of reports on transcorticosubcortical approaches to these lesions, particularly in patients with posterior-superior extension. We present a case series of 5 patients with left posterior MBTR gliomas and summarize the relevant subcortical anatomy knowledge of what is a prerequisite for safe resection.
Five patients with left posterior MBTR gliomas underwent awake resection with functional corticosubcortical electric mapping. Details of the approach are presented with a review of relevant anatomy.
Gross total resection was achieved in 4 patients. One patient who had previously undergone radiation therapy had a subtotal resection. There were 4 cases of World Health Organization grade II glioma and 1 case of World Health Organization grade IV glioma. All patients underwent preoperative and postoperative neurologic and neuropsychological assessment and there were no new or worsening sensorimotor, visual, language, or cognitive deficits.
The transcorticosubcortical approach is a safe and effective approach to lesions of the posterior MBTR. The approach is safe and effective even in patients with superior extension, if the surgical approach is predicated on knowledge of individual functional anatomy. Awake resection with cortical and axonal mapping with well-selected paradigms is invaluable in maximizing extent of resection and ensuring patient safety.
Almost one third of cancer patients in the United States will develop brain metastases on an annual basis. Surgical resection is indicated in the setting of brain metastases for reasons, such as ...maximizing local control in select patients, decompression of mass effect, and/or tissue diagnosis. The current standard of care following resection of a brain metastasis has shifted from whole brain radiation therapy to post-operative stereotactic radiosurgery (SRS). However, there is a significant rate of local recurrence within one year of postoperative SRS. Emerging retrospective and prospective data suggest pre-operative SRS is a safe and potentially effective treatment paradigm for surgical brain metastases. This trial intends to determine, for patients with an indication for resection of a brain metastasis, whether there is an increase in the time to a composite endpoint of adverse outcomes; including the first occurrence of either: local recurrence, leptomeningeal disease, or symptomatic radiation brain necrosis - in patients who receive pre-operative SRS as compared to patients who receive post-operative SRS.
This randomized phase III clinical trial compares pre-operative with post-operative SRS for brain metastases. A dynamic random allocation procedure will allocate an equal number of patients to each arm: pre-operative SRS followed by surgery or surgery followed by post-operative SRS.
If pre-operative SRS improves outcomes relative to post-operative SRS, this will establish pre-operative SRS as superior. If post-operative SRS proves superior to pre-operative SRS, it will remain a standard of care and halt the increasing utilization of pre-operative SRS. If there is no difference in pre- versus post-operative SRS, then pre-operative SRS may still be preferred, given patient convenience and the potential for a condensed timeline.
Emerging retrospective and prospective data have demonstrated some benefits of pre-op SRS vs. post-op SRS. This study will show whether there is an increase in the time to the composite endpoint. Additionally, the study will compare overall survival; patient-reported outcomes; morbidity; completion of planned therapies; time to systemic therapy; time to regional progression; time to CNS progression; time to subsequent treatment; rate of radiation necrosis; rate of local recurrence; and rate of leptomeningeal disease.
NCT03750227 (Registration date: 21/11/2018).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The objective of this review was to describe the immunological changes that take place in the dura mater in response to metastatic disease that seeds the CNS. The authors hypothesized that the dura's ...anatomy and resident immune cell population play a role in enabling metastasis to the brain and leptomeninges.
An extensive literature search was conducted to identify evidence that supports the dura's participation in metastasis to the CNS. The authors' hypothesis was informed by a recent upsurge in studies that have investigated the dura's role in metastatic development, CNS infections, and autoimmunity. They reviewed this literature as well as the use of immunotherapy in treating brain metastases and how these therapies change the meningeal immune landscape to overcome and reverse tumor-promoting immunosuppression.
Evidence suggests that the unique architecture and immune cell profile of the dura, compared with other immune compartments within the CNS, facilitate entry of metastatic tumor cells into the brain. Once these tumor cells penetrate the dural barrier, they propagate an immunosuppressive tumor microenvironment. Therefore, immunotherapy may serve to overcome this immunosuppressive environment and liberate proinflammatory immune cells in an effort to combat metastatic disease.
Within the next few years, the authors expect the addition of several more scientific studies into the literature that further underscore the dura as a chief participant and neuroanatomical barrier in neuro-oncology.
The efficacy of laser interstitial thermal therapy (LITT) in recurrent glioblastoma (rGBM) is unknown. The goal of this study was to conduct a systematic review and pooled analysis of the literature ...for outcomes on patients with rGBM undergoing LITT.
A literature search was performed to retrieve all studies investigating overall survival, postprocedure survival, and progression-free survival outcomes of patients with rGBM undergoing LITT. Statistics were pooled together by meta-analysis of mean using a weighted random-effects or fixed-effect model.
Eleven studies were included in the final cohort, representing a total of 134 patients with rGBM. The pooled mean age of the cohort at the time of recurrence was 56.7 ± 4.56 years; 41% of the cohort were female. For delivery of LITT, 2 studies used neodymium-yttrium aluminum-garnet laser (Nd:YAG laser), 3 studies used the Visualase system, 5 studies used the NeuroBlate system, and 1 study used both the NeuroBlate and the Visualase system. A total of 8 studies with 107 patients had available data for overall median survival. The pooled overall survival was found to be 18.6 months (95% confidence interval CI 16.2–21.1). A total of 6 studies with 93 patients had available data for post-LITT survival. The pooled post-LITT survival was found to be 10.1 months (95% CI 8.8–11.6). A total of 8 studies with 119 patients had available data for progression-free survival. Pooled progression free survival was found to be 6 months (95% CI 5.3–6.7).
LITT is a novel minimally invasive procedure which, when used with optimal adjuvant therapy, may confer survival benefit for patients with rGBM.
Although it has been shown that surgery for glioblastoma (GBM) at high-volume facilities (HVFs) may be associated with better postoperative outcomes, the use of such hospitals may not be equally ...distributed. The authors aimed to evaluate racial and socioeconomic differences in access to surgery for GBM at high-volume Commission on Cancer (CoC)-accredited hospitals.
The National Cancer Database was queried for patients with GBM that was newly diagnosed between 2004 and 2015. Patients who received no surgical intervention or those who received surgical intervention at a site other than the reporting facility were excluded. Annual surgical case volume was calculated for each hospital, with volume ≥ 90th percentile defined as an HVF. Multivariable logistic regression was performed to identify patient-level predictors for undergoing surgery at an HVF. Furthermore, multiple subgroup analyses were performed to determine the adjusted odds ratio of the likelihood of undergoing surgery at an HVF in 2016 as compared to 2004 for each patient subpopulation (by age, race, sex, educational group, etc.).
A total of 51,859 patients were included, with 10.7% (n = 5562) undergoing surgery at an HVF. On multivariable analysis, Hispanic White patients (OR 0.58, 95% CI 0.49-0.69, p < 0.001) were found to have significantly lower odds of undergoing surgery at an HVF (reference = non-Hispanic White). In addition, patients from a rural residential location (OR 0.55, 95% CI 0.41-0.72, p < 0.001; reference = metropolitan); patients with nonprivate insurance status (Medicare OR 0.78, 95% CI 0.71-0.86, p < 0.001, Medicaid OR 0.68, 95% CI 0.60-0.78, p < 0001, other government insurance OR 0.68, 95% CI 0.52-0.86, p = 0.002, or who were uninsured OR 0.61, 95% CI 0.51-0.72, p < 0.001); and lower-income patients ($50,354-$63,332 OR 0.68, 95% CI 0.63-0.74, p < 0.001, $40,227-$50,353 OR 0.84, 95% CI 0.76-0.92, p < 0.001; reference = ≥ $63,333) were also found to be significantly associated with a lower likelihood of surgery at an HVF. Subgroup analyses revealed that elderly patients (age ≥ 65 years), both male and female patients and non-Hispanic White patients, and those with private insurance, Medicare, metropolitan residential location, median zip code-level household income in the first and second quartiles, and educational attainment in the first and third quartiles had increased odds of undergoing surgery at an HVF in 2016 compared to 2004 (all p ≤ 0.05). On the other hand, patients with other governmental insurance, patients with a rural residence, and those from a non-White racial category did not show a significant difference in odds of surgery at an HVF over time (all p > 0.05).
The present analysis from the National Cancer Database revealed significant disparities in access to surgery at an HVF for GBM within the United States. Furthermore, there was evidence that these racial and socioeconomic disparities may have widened between 2004 and 2016. The findings should assist health policy makers in the development of strategies for improving access to HVFs for racially and socioeconomically disadvantaged populations.
Glioblastoma is the most common primary malignant brain neoplasm with dismal 10-year survival rates of < 1%. Despite promising preliminary results from several novel therapeutic agents, clinical ...responses have been modest due to several factors, including tumor heterogeneity, immunosuppressive tumor microenvironment, and treatment resistance. Novel immunotherapeutics have been developed to reverse tumor-induced immunosuppression in patients with glioblastomas. In order to recapitulate the tumor microenvironment, reliable in vivo syngeneic murine models are critical for the development of new targeted agents as these models demonstrate rapid tumor induction and reliable tumor growth over multiple generations. Despite the clear advantages of murine models, choosing an appropriate model from an immunological perspective can be difficult and have significant ramifications on the translatability of the results from murine to human trials. Herein, the authors reviewed the 4 most commonly used immunocompetent syngeneic murine glioma models (GL261 C57BL/6, SB28 C57BL/6, CT-2A C57BL/6, and SMA-560 VM/Dk) and compared their strengths and weaknesses from an immunological standpoint.
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