Newly Diagnosed Glioblastoma in Elderly Patients.

PURPOSE OF REVIEW: Elderly patients with newly diagnosed glioblastoma (eGBM) carry a worse prognosis compared with their younger counterparts. eGBM garners special attention due to the unique challenges, including increased treatment-associated toxicity, less relative benefit from aggressive therapy, medical comorbidities, and immunosuppression. The pivotal GBM trials excluded patients > 70 years old and the optimal treatment approach remains unsettled for eGBM. In this review, we analyze the historical evidence-based data for treating eGBM and discuss the future direction for managing this vulnerable population. RECENT FINDINGS: Treatment for eGBM continues to evolve. Therapy choice is guided by performance status and presence of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. For eGBM with good performance status, combinatorial hypofractionated radiation therapy (hRT) and temozolomide should be recommended. For those with poor performance status, further stratification based on MGMT promoter methylation test result is recommended. Single-agent temozolomide is a viable treatment option for MGMT methylated tumors (mMGMT); in particular, those classified with receptor tyrosine kinase II methylation. hRT alone can be considered in MGMT unmethylated (uMGMT) eGBM patients. As precision oncology continues to advance, effective targeted and immunotherapy may emerge as new treatment options for eGBM. Management of elderly patients with newly diagnosed GBM carries a unique set of challenges. Progress has been made in defining the optimal therapeutic approach for these patients, but many questions remain to be answered.

Primary Ocular Adnexal Extranodal Marginal Zone Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma Presenting as Orbital Apex Syndrome.

A 75-year-old female with a past medical history significant for prior stroke and atrial fibrillation presented with acute onset of orbital apex syndrome with chemosis and periorbital ecchymosis. Following initial treatment to relieve intraocular pressure, she began spontaneously haemorrhaging retro-orbitally. Preliminary investigation with neuroimaging demonstrated a left orbital mass with extension into the orbital apex. A provisional diagnosis of cavernous haemangioma was made. She was treated with transorbital resection of the orbital mass. Subsequent histopathology revealed a diagnosis of ocular adnexal non-Hodgkin lymphoma of histologic type extranodal marginal zone of mucosa-associated lymphoid tissue (MALT lymphoma). MALT lymphoma should be considered in cases of orbital apex syndrome.

Using the Theories of Joseph Babinski to Manage Functional Vision Loss.

OBJECTIVE: To report our use of persuasion to treat patients with functional vision loss and to place them in the context of both Joseph Babinski's theories on hysteria and the current literature on management of functional vision loss. BACKGROUND: Conversion disorders, such as functional vision loss, can develop in response to a traumatic event. Recent functional imaging studies have found that, rather than being malingerers, patients with conversion disorders show changes within neuromodulatory pathways, suggesting organic dysfunction rather than a purely psychological disorder. METHODS: We conducted a retrospective analysis of 8 consecutive patients (7 female, 1 male; mean age 16 years) who had presented to a university-based neuro-ophthalmology clinic with vision loss from a conversion disorder. The patients had been given a lengthy visual task to perform at home, with the suggestion that their vision would improve by the time they completed the task. RESULTS: All 8 patients had evidence of a dissociation between real and perceived visual acuity and fields. All the patients performed the assigned visual task at home, and all either reported improvement or showed improved visual function at follow-up. CONCLUSIONS: A century after Joseph Babinski proposed using persuasion in managing patients with vision loss from a conversion disorder, we report that his method remains a viable and pathophysiologically sound option. Future case-controlled studies that include functional magnetic resonance imaging, other neurophysiologic imaging, and neuroradiographic evaluation may strengthen the correlation between persuasion therapy and recovery of normal vision.

Pembrolizumab in an HIV-infected patient with glioblastoma.

Persons living with human immunodeficiency virus (PLWH) carry increased risk for developing malignancies, including glioblastoma. Despite extensive investigations, both human immunodeficiency virus (HIV) and glioblastoma are incurable. Treatment for a patient with combined glioblastoma and HIV remains an unexplored need. Preliminary evidence suggests that immunotherapy may be effective for the simultaneous treatment of both HIV and cancer by reversing HIV latency and T cell exhaustion. We present a case of glioblastoma in a PLWH who was treated with pembrolizumab. Treatment was well tolerated and safe with a mixed response. Our patient did not develop any opportunistic infections, immune-related adverse events, or worsening of his immunodeficiency. To our knowledge, this is the first reported case of a PLWH and glioblastoma treated with immunotherapy.

Persons living with human immunodeficiency virus (PLWH) are at increased risk for cancers, including glioblastoma. Despite extensive research, both human immunodeficiency virus (HIV) and glioblastoma are incurable. The optimal treatment for concurrent HIV and glioblastoma is unknown. Early evidence suggests that immunotherapy can deplete residual HIV and restore immune function. We present a case of glioblastoma in a PLWH treated with immunotherapy. Treatment was well tolerated and safe. To our knowledge, this is the first reported case of a PLWH and glioblastoma treated with immunotherapy.

Metastatic glioblastoma to the lungs: a case report and literature review.

Glioblastoma is the most common malignant primary brain tumor. Despite its infiltrative nature, extra-cranial glioblastoma metastases are rare. We present a case of a 63-year-old woman with metastatic glioblastoma in the lungs. Sarcomatous histology, a reported risk factor for disseminated disease, was found. Genomic alterations of TP53 mutation, TERT mutation, PTEN mutation, and +7/-10 were also uncovered. Early evidence suggests these molecular aberrations are common in metastatic glioblastoma. Treatment with third-line lenvatinib resulted in a mixed response. This case contributes to the growing body of evidence for the role of genomic alterations in predictive risk in metastatic glioblastoma. There remains an unmet need for treatment of metastatic glioblastoma.

Glioblastoma is the most common malignant primary brain tumor. Glioblastoma can spread into healthy tissue, but metastases beyond the brain are rare. We present a case of a 63-year-old woman with metastatic glioblastoma in the lungs. We identified risk factors associated with spread beyond the brain, including factors related to tissue structure and specific molecular alterations. Treatment with third-line lenvatinib resulted in a mixed response. This case adds to the limited existing data for the use of molecular alterations to serve as risk factors for metastatic glioblastoma. Treatment options are needed for this devastating disease.

Dabrafenib and steroids for the treatment of Erdheim-Chester disease with extensive CNS involvement: a case report.

Erdheim-Chester disease (ECD) is an exceedingly rare non-Langerhans cell CD68+ CD1a- S100- histiocytic multi-organ disease. Diagnosis of ECD is often delayed due to non-specific radiographic findings and heterogeneous lesional tissue. Increasingly, the role of genomic alterations is being recognized for both diagnosis and treatment of ECD. More than half of ECD patients harbor the BRAFV600E mutation. Evaluation for this mutation be can falsely negative on immunohistochemical staining and confirmation with molecular analyses is recommended. We present a case of the 44 year-old male with BRAFV600E-positive ECD treated successfully with steroids followed by single-agent dabrafenib.

Erdheim-Chester disease (ECD) is an exceedingly rare type of histiocytosis (a disorder of white blood cells). The diagnosis of ECD can be challenging because tissue biopsy may not provide a definitive diagnosis. Currently, genetic mutations can be used to support both diagnosis and treatment. We present a case of the 44 year-old male with BRAF V600E -positive ECD who was treated successfully with steroids followed by dabrafenib.

Axicabtagene Ciloleucel in Patients Ineligible for ZUMA-1 Because of CNS Involvement and/or HIV: A Multicenter Experience.

Secondary central nervous system lymphoma (SCNSL) is associated with poor prognosis and new therapeutic approaches are needed. The pivotal trial that led to US Food and Drug Administration (FDA) approval of axicabtagene ciloleucel excluded patients with SCNSL and human immunodeficiency virus. In this multi-institutional retrospective study, 14 SCNSL patients treated with axicabtagene ciloleucel, 3 of whom had human immunodeficiency virus, experienced rates of severe neurotoxicity and complete response of 32% and 58%, respectively. This is similar to rates observed in the pivotal ZUMA-1 trial that led to the approval of axi-cel at median follow-up of 5.9 months. Chimeric antigen receptor T-cell therapy is potentially a life-saving therapy for SCNSL patients and should not be withheld.

Asymptomatic brainstem lesions and pachymeningeal enhancement after anti-PD-1 therapy.

Neurological immune-related adverse events (irAEs) are rare toxicities that occur following immune checkpoint inhibitor therapy. We propose that patients with thymic malignancies and graft-versus-host disease (GVHD) are predisposed to irAEs. We present two asymptomatic patients, one with thymoma and another with GVHD, who developed abnormal brain MRIs after treatment with programmed cell death protein 1 inhibitors. The first patient, with thymic cancer and thymoma, developed pontine enhancing MRI lesions following treatment with pembrolizumab. The second patient, with prior GVHD, developed pachymeningeal enhancement following treatment with nivolumab. IrAEs with abnormal MRI studies, despite asymptomatology, have significant impact on the treatment strategy for these patients.

Severity of Downgaze Palsy in the Context of Disease Duration Could Estimate Survival Duration in Patients With Progressive Supranuclear Palsy.

It is an unmet need to estimate survival duration for patients with progressive supranuclear palsy (PSP). The objective of this study was to identify factors associated with the survival duration in patients with PSP. We followed up 23 patients with probable PSP-RS (Richardson syndrome) or PSP-P (parkinsonism) in our PSP center until death from 2011 to 2019. We prospectively and quantitatively rated their downgaze palsy whenever first noticed in our clinic. This was utilized along with the disease duration, motor function, medication use for parkinsonism, sex, age at onset of PSP, comorbid pulmonary and cardiovascular diseases, and the total survival duration from the onset of PSP to death for prediction analysis. A well-fitted linear regression model and a multivariant Cox model were applied to identify predicting factors for total survival duration. All patients had the specific hummingbird sign on brain MRI for PSP when downgaze palsy was documented. We found that the severity of downgaze palsy and the disease duration at the assessment were consistently correlated with the total survival duration in both models. The total survival duration could be further estimated by a formed regression equation. We conclude that severity and time to develop downgaze palsy could help to estimate the total survival duration in patients with probable PSP-RS and PSP-P, the major forms of PSP, which has significant clinical applications in clinical counseling and trial enrollment.

An atypical presentation of primary central nervous system lymphoma: A case report.

RATIONALE: Primary central nervous system lymphoma (PCNSL) involving the choroid plexus is exceedingly rare. The differential diagnosis for choroid plexus enhancing lesions in addition to lymphoma includes infections, sarcoidosis, tuberculosis, papilloma, meningioma, subependymoma, and metastatic lesions. PATIENT CONCERNS: A 71-year-old man presented with 3 days of episodic memory loss and gait disturbance. Brain magnetic resonance imaging showed homogenously enhancing lesions with mildly restricted diffusion and T2 hypointensity in the lateral ventricles, as well as T2 hyperintensity and enhancement in the right hippocampus. His episodic memory loss was thought to be secondary to subclinical focal seizures, supported by EEG revealing right temporal lobe epileptiform discharges. DIAGNOSES: Large B-cell lymphoma, nongerminal center type was revealed on pathological examination. INTERVENTIONS: Stereotactic biopsy of his right thalamic lesion was performed. OUTCOMES: The patient underwent induction therapy with high-dose methotrexate, temozolomide, and rituximab, which resulted in complete resolution of the enhancing lesions. He then underwent conditioning chemotherapy with carmustine and thiotepa, followed by autologous stem cell transplantation. His PCNSL remains in remission 42 weeks after the onset of symptoms. LESSONS: We report a patient with multifocal PCNSL involving the choroid plexus, who presented with abnormal gait and episodic confusion and memory loss. PCNSL should be considered in the differential diagnosis of acute encephalopathy among immunocompetent older individuals who have choroid plexus enhancing lesions.

Eyes and stroke: the visual aspects of cerebrovascular disease.

A large portion of the central nervous system is dedicated to vision and therefore strokes have a high likelihood of involving vision in some way. Vision loss can be the most disabling residual effect after a cerebral infarction. Transient vision problems can likewise be a harbinger of stroke and prompt evaluation after recognition of visual symptoms can prevent future vascular injury. In this review, we discuss the visual aspects of stroke. First, anatomy and the vascular supply of the visual system are considered. Then, the different stroke syndromes which involve vision are discussed. Finally, topics involving the assessment, prognosis, treatment and therapeutic intervention of vision-specific stroke topics are reviewed.

Update on the evaluation of transient vision loss.

Transient vision loss may indicate underlying vascular disease, including carotid occlusion and thromboembolism, or it may have a more benign etiology, such as migraine or vasospasm. This review focuses on the differential diagnosis and workup of patients presenting with transient vision loss, focusing on several key areas: the relationship to thromboembolic vascular disease, hypercoagulable testing, retinal migraine, and bilateral vision loss. The objective is to provide the ophthalmologist with information on how to best manage these patients. Thromboembolic etiologies for transient vision loss are sometimes managed with medications, but when carotid surgery is indicated, earlier intervention may prevent future stroke. This need for early treatment places the ophthalmologist in the important role of expediting the management process. Hospital admission is recommended in patients presenting with transient symptoms within 72 hours who meet certain high-risk criteria. When the cause is giant cell arteritis, ocular ischemic syndrome, or a cardioembolic source, early management of the underlying condition is equally important. For nonthromboembolic causes of transient vision loss such as retinal migraine or retinal vasospasm, the ophthalmologist can provide reassurance as well as potentially give medications to decrease the frequency of vision loss episodes.

Cancer stem cell molecular reprogramming of the Warburg effect in glioblastomas: a new target gleaned from an old concept.

Prior targeted treatment for glioblastoma multiforme (GBM) with anti-angiogenic agents, such as bevacizumab, has been met with limited success potentially owing to GBM tumor's ability to develop a hypoxia-induced escape mechanism--a glycolytic switch from oxidative phosphorylation to glycolysis, an old concept known as the Warburg effect. New studies points to a subpopulation of cells as a source for treatment-resistance, cancer stem cells (CSCs). Taken together, the induction of the Warburg effect leads to the promotion of CSC self-renewal and undifferentiation. In response to hypoxia, hypoxia-inducible transcription factor is upregulated and is the central driver in setting off the cascade of events in CSC metabolic reprogramming. Hypoxia-inducible transcription factor upregulates GLUT1 to increase glucose uptake into the cell, upregulates HK2 and PK during glycolysis, upregulates LDHA in the termination of glycolysis, and downregulates PDH to redirect energy production toward glycolysis. This review aims to unite these old and new concepts simultaneously and examine potential enzyme targets driven by hypoxia in the glycolytic phenotype of CSCs to reverse the metabolic shift induced by the Warburg effect.