Practical guidance for direct oral anticoagulant use in the treatment of venous thromboembolism in primary and metastatic brain tumor patients.

Management of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors (BT) is challenging because of the risk of intracranial hemorrhage (ICH). There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants (DOACs), specifically in patients with BT, but they are widely used for VTE in this population. A group of neuro-oncology experts convened to provide practical clinical guidance for the off-label use of DOACs in treating VTE in patients with BT. We searched PubMed for the following terms: BTs, glioma, glioblastoma (GBM), brain metastasis, VTE, heparin, low-molecular-weight heparin (LWMH), DOACs, and ICH. Although prospective clinical trials are needed, the recommendations presented aim to assist clinicians in making informed decisions regarding DOACs for VTE in patients with BT.

Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.

Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.

Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation.

Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.

Genome-matched treatments and patient outcomes in the Maine Cancer Genomics Initiative (MCGI).

Genomic tumor testing (GTT) is an emerging technology aimed at identifying variants in tumors that can be targeted with genomically matched drugs. Due to limited resources, rural patients receiving care in community oncology settings may be less likely to benefit from GTT. We analyzed GTT results and observational clinical outcomes data from patients enrolled in the Maine Cancer Genomics Initiative (MCGI), which provided access to GTTs; clinician educational resources; and genomic tumor boards in community practices in a predominantly rural state. 1603 adult cancer patients completed enrollment; 1258 had at least one potentially actionable variant identified. 206 (16.4%) patients received a total of 240 genome matched treatments, of those treatments, 64% were FDA-approved in the tumor type, 27% FDA-approved in a different tumor type and 9% were given on a clinical trial. Using Inverse Probability of Treatment Weighting to adjust for baseline characteristics, a Cox proportional hazards model demonstrated that patients who received genome matched treatment were 31% less likely to die within 1 year compared to those who did not receive genome matched treatment (HR: 0.69; 95% CI: 0.52-0.90; p-value: 0.006). Overall, GTT through this initiative resulted in levels of genome matched treatment that were similar to other initiatives, however, clinical trials represented a smaller share of treatments than previously reported, and "off-label" treatments represented a greater share. Although this was an observational study, we found evidence for a potential 1-year survival benefit for patients who received genome matched treatments. These findings suggest that when disseminated and implemented with a supportive infrastructure, GTT may benefit cancer patients in rural community oncology settings, with further work remaining on providing genome-matched clinical trials.

The Maine Cancer Genomics Initiative: Implementing a Community Cancer Genomics Program Across an Entire Rural State.

PURPOSE: The Maine Cancer Genomics Initiative (MCGI) aimed to overcome patient- and provider-level barriers to using genomic tumor testing (GTT) in rural practices by providing genomic tumor boards (GTBs), clinician education, and access to comprehensive large-panel next-generation sequencing to all patients with cancer in Maine. This paper describes the successful implementation of the initiative and three key services made operative between 2016 and 2020. METHODS: A community-inclusive, hub-and-spoke approach was taken to implement the three program components: (1) a centralized GTB program; (2) a modular online education program, designed using an iterative approach with broad clinical stakeholders; and (3) GTT free of charge to clinicians and patients. Implementation timelines, participation metrics, and survey data were used to describe the rollout. RESULTS: The MCGI was launched over an 18-month period at all 19 oncology practices in the State. Seventy-nine physicians (66 medical oncologists, 5 gynecologic oncologists, 1 neuro-oncologist, and 7 pediatric oncologists) enrolled on the study, representing 100% of all practicing oncologists in Maine. Between July 2017 and September 2020, 1610 patients were enrolled. A total of 515 cases were discussed by 47 (73%) clinicians in 196 GTBs. Clinicians who participated in the GTBs enrolled significantly more patients on the study, stayed in Maine, and reported less time spent in clinical patient care. CONCLUSION: The MCGI was able to engage geographically and culturally disparate cancer care practices in a precision oncology program using a hub-and-spoke model. By facilitating access to GTT, structured education, and GTBs, we narrowed the gap in the implementation of precision oncology in one of the most rural states in the country.

Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial.

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.

Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization.

PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780). RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma.

Treatment of glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains a significant unmet need in oncology. Historically, cytotoxic treatments provided little durable benefit, and tumors recurred within several months. This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM. In this context, antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors. In particular, GBMs overexpress vascular endothelial growth factor (VEGF), a proangiogenic cytokine. Indeed, many studies have demonstrated promising radiographic response rates, delayed tumor progression, and a relatively safe profile for anti-VEGF agents. However, randomized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy. These results indicate that antiangiogenic agents may not be beneficial in unselected populations of patients with GBM. Unfortunately, biomarker development has lagged behind in the process of drug development, and no validated biomarker exists for patient stratification. However, hypothesis-generating data from phase II trials that reveal an association between increased perfusion and/or oxygenation (ie, consequences of vascular normalization) and survival suggest that early imaging biomarkers could help identify the subset of patients who most likely will benefit from anti-VEGF agents. In this article, we discuss the lessons learned from the trials conducted to date and how we could potentially use recent advances in GBM biology and imaging to improve outcomes of patients with GBM who receive antiangiogenic therapy.

Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma.

Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas, but tumors invariably recur. Because tumor-associated macrophages have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of macrophages in patients with recurrent glioblastoma. We compared autopsy brain specimens from 20 patients with recurrent glioblastoma who received antiangiogenic treatment and chemoradiation with 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy or no treatment. Tumor-associated macrophages were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in macrophages in the antiangiogenic-treated patients. Immunohistochemical analysis demonstrated an increase in CD68+ macrophages in the tumor bulk (P < .01) and infiltrative areas (P = .02) in antiangiogenic-treated patients. We also observed an increase in CD11b+ cells in the tumor bulk (P < .01) and an increase in CD163+ macrophages in infiltrative tumor (P = .02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumors (P = .05 and P = .05, respectively) correlated with poor overall survival among patients who first received antiangiogenic therapy at recurrence. In summary, recurrent glioblastomas showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after antiangiogenic therapy. Higher numbers of CD11b+ cells correlated with poor survival among these patients. These data suggest that tumor-associated macrophages may participate in escape from antiangiogenic therapy and may represent a potential biomarker of resistance and a potential therapeutic target in recurrent glioblastoma.

Brain metastases.

PURPOSE OF REVIEW: Brain metastases are the most common neurologic complication related to systemic cancer. With continued improvements in systemic treatment, the incidence is expected to increase. This article reviews the clinical presentation, pathophysiology, prognostic factors, and treatment of metastatic brain tumors. RECENT FINDINGS: Brain metastases from systemic cancer are up to 10 times more common than primary malignant brain tumors and are a significant burden in the management of patients with advanced cancer. Common presenting symptoms include headache, focal weakness or numbness, mental status change, and seizure. Management and treatment of metastatic brain tumors is complex and dependent on several factors, including age, performance status, number of metastases at presentation, and status of systemic disease. At the time of diagnosis, most patients have more than one brain metastasis, and treatment has traditionally consisted of whole-brain radiation therapy (WBRT). For those patients with single brain metastases, aggressive local treatment with surgery or stereotactic radiosurgery (SRS) combined with WBRT has been shown to improve survival and neurologic outcomes compared with WBRT alone. In patients with a limited number of brain metastases, SRS alone is being increasingly explored as a treatment option that spares the upfront toxicity of WBRT. Currently, the role of chemotherapy is limited to experimental settings and salvage after radiation therapy. SUMMARY: Patients with brain metastases have complex needs and require a multidisciplinary approach in order to optimize intracranial disease control while maximizing neurologic function and quality of life. Patients with multiple metastases, uncontrolled systemic disease, and poor functional status are typically treated with WBRT alone, whereas surgery and SRS may be used for additional local control in a subset of patients with fewer tumors and good functional status. The incorporation of neuropsychological outcomes, neurologic function, and quality of life as end points in future studies will offer further guidance for providing comprehensive care to patients with metastatic brain tumors.

Neurological sequelae of hypoxic-ischemic brain injury.

Hypoxic-ischemic brain injury (HI-BI) after cardiac arrest commonly results in neurological injury and long term dysfunction, with outcomes ranging from coma and vegetative states to functional disability with various degrees of dependence. Increased rates of bystander CPR and cardiac defibrillation has led to a rapid increase in successful resuscitations. Patients who reach the hospital after cardiac arrest may develop various neurological deficits or clinical syndromes that may preclude recovery to their premorbid baseline. Consequently, clinicians are faced with not only predicting outcome regarding wakefulness and independence but also with long term therapeutic management. Several neurological syndromes have been reported as consequences of HI-BI. This review will describe some of the more common syndromes seen after HI-BI, including the various levels of arousal, seizures, myoclonus, movement disorders, cognitive impairments, and other specific neurological abnormalities.

Management of ischemic stroke: Part 2. The inpatient stay.

BACKGROUND: Acute ischemic stroke is commonly encountered by the hospitalist. There have been dramatic changes in our ability to care for these patients both acutely and in secondary prevention. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) primary stroke center certification has become progressively more important to institutions nationally and emphasizes many elements of the inpatient stay and discharge process. PURPOSE: After admission, the focus changes to avoidance of complications and the appropriate initiation of allied therapies and secondary prevention. DATA SOURCES: Primary trials, current guidelines. CONCLUSIONS: The hospitalist is well-positioned to play a major role in the treatment of stroke patients as well as the systems work that aids in the management of this population.

Management of ischemic stroke: Part 1. Emergency room management.

BACKGROUND: Acute ischemic stroke is commonly encountered by the hospitalist. There have been dramatic changes in our ability to care for these patients acutely. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) primary stroke center certification has become progressively more important to institutions nationally and includes many aspects of initial evaluation and treatment. PURPOSE: Acute treatment involves the rapid assimilation of patient characteristics, laboratory results, and imaging results. There are a growing number of potential acute therapies with a range of risk, benefit, necessary time windows, and specific eligibility criteria. DATA SOURCES: Primary trials, current guidelines. CONCLUSIONS: The hospitalist is well-positioned to play a major role in the treatment of stroke patients as well as the systems work that aids in the management of this population.

Lethal giant cell arteritis with multiple ischemic strokes despite aggressive immunosuppressive therapy.

Two patients with giant cell arteritis (GCA) had a malignant course despite aggressive immunosuppressive therapy. A 63-year-old woman presented with symptoms of headache, jaw claudication, scalp paresthesia, and visual disturbances. A temporal artery biopsy showed GCA. While on prednisone, she suffered ischemic strokes, and serial cerebral angiograms demonstrated bilateral, severe and progressive narrowing of distal vertebral and internal carotid arteries. Despite escalating immunosuppressive therapies, she suffered more infarcts and eventually died. Postmortem examination of arteries showed no active inflammation. A 65-year-old man presented with extrapyramidal symptoms though no symptoms typical of GCA. Imaging showed multiple ischemic strokes. Because serial angiograms demonstrated findings similar to the first patient, he underwent temporal artery biopsy that showed GCA. He died 7 months after his presentation with complications of aggressive immunosuppressive therapy. These two patients confirm that GCA can follow a lethal course despite escalating immunosuppressive therapies. Our two patients were unique in that eventually both anterior and posterior circulations were involved bilaterally in a characteristic location where the arteries penetrate the dura. This pattern should always raise the possibility of GCA and, if confirmed, should prompt aggressive immunosuppressive therapy. The dismal outcomes despite this approach may suggest a non-inflammatory arteriopathy, as seen on necropsy in one of our patients. Such an arteriopathy may require novel therapies to be considered for this severe variant of GCA.

The Neurofibromatoses. Part 1: NF1.

The neurofibromatoses, including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, comprise a group of genetically distinct disorders of the nervous system unified by the predisposition to nerve sheath tumors. NF1 is the most common neurogenetic disorder, with a birth incidence of 1 in 3000. NF1 is inherited in auto-somal dominant fashion with full penetrance and variable expressivity. The hallmark lesion of NF1 is the neurofibroma, a benign tumor derived from the nerve sheath and composed of a mixture of proliferating Schwann cells, fibroblasts, mast cells, and pericytes. Other findings include gliomas, learning disability, vasculopathy, and bony abnormalities. Café au lait macules are typically the initial clinical manifestation of NF1 and tend to increase in size and number throughout childhood and puberty. Current treatment of patients with NF1 remains primarily surgical. Genetic counseling is essential for adult patients because molecular diagnostic testing can minimize the risk of transmission to children.

The neurofibromatoses. Part 2: NF2 and schwannomatosis.

The neurofibromatoses, including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, comprise a group of genetically distinct disorders of the nervous system that are unified by the predisposition to nerve sheath tumors. All 3 types of NF have tumor manifestations (consistent with tumor-suppressor status) and nontumor manifestations. In the second part of this 2-part series, the manifestations of NF2 and schwannomatosis are reviewed. NF2 is characterized by bilateral vestibular schwannomas, meningiomas, ependymomas, cataracts, and epiretinal membranes. The combination of complete hearing loss from vestibular schwannomas and blindness from bifacial weakness is a devastating potential outcome of NF2. Schwannomatosis is characterized by multiple nonvestibular, nonintradermal schwannomas and chronic pain. Recently, germline alterations in the SMARCB1/INI1 gene have been implicated in both familial and sporadic forms of this disorder. Neurologists play an important role in the diagnosis and management of the neurofibromatoses.