Prognostic value of cerebrospinal fluid tumor cell count in leptomeningeal disease from solid tumors.

PURPOSE: Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs), such as CNSide assay, improved the sensitivity of LMD diagnosis, but prognostic value is unknown. This study assesses the prognostic value of CSF-TC density in patients with LMD from solid tumors. METHODS: We conducted a retrospective cohort study of patients with newly diagnosed or previously treated LMD from a single institution who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival. RESULTS: Of 31 patients, 29 had CSF-TCs detected on CNSide. Median (interquartile range [IQR]) CSF-TC density was 67.8 (4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median (IQR) survival from time of CSF-TC detection was 176 (89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival. An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively. CONCLUSIONS: CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.

ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.

PURPOSE: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. METHODS: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. RESULTS: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. CONCLUSION: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

Paraneoplastic Neurologic Syndromes.

OBJECTIVE: Progress is ongoing in understanding paraneoplastic neurologic disorders, with new syndromes and antibodies being described and more detailed evidence available to guide workup for diagnosis and treatment to improve outcomes. Many excellent reviews have summarized the molecular features of different antibodies, but this article emphasizes the clinical features of each syndrome that may help guide initial diagnosis and treatment, which often should occur before an antibody or cancer is found to confirm the diagnosis. LATEST DEVELOPMENTS: Recent findings include updated diagnostic criteria with validated sensitivity and specificity, discovery of novel antibodies, and clinical findings that increase the likelihood of an underlying paraneoplastic disorder. Suggestive syndromes that have been recently identified include faciobrachial dystonic seizures and pilomotor auras in anti-leucine-rich glioma inactivated protein 1 encephalitis, extreme delta brush on EEG in N-methyl-d-aspartate (NMDA)-receptor encephalitis, déjà vu aura in anti-glutamic acid decarboxylase 65 (GAD65) encephalitis, and sleep disturbances in several disorders. In addition, there is confirmed utility of brain positron emission tomography (PET) and CSF markers, including carcinoembryonic antigen and oligoclonal bands, as well as improved tests for the presence of leptomeningeal cancer cells in CSF. Associations of cancer immunotherapies with paraneoplastic syndromes and herpes simplex virus encephalitis (and COVID-19) with NMDA-receptor encephalitis have been described. ESSENTIAL POINTS: All neurologists should be aware of advances regarding paraneoplastic neurologic syndromes, as patients can present with a wide variety of neurologic symptoms and earlier diagnosis and treatment can improve outcomes.

Neuro-oncology Treatment Strategies for Primary Glial Tumors.

Primary brain tumors underwent reclassification in the 2021 World Health Organization update, relying on molecular findings (especially isocitrate dehydrogenase mutations and chromosomal changes in 1p, 19q, gain of chromosome 7 and loss of chromosome 10). Newer entities have also been described including histone 3 mutant midline gliomas. These updated pathologic classifications improve prognostication and reliable diagnosis, but may confuse interpretation of prior clinical trials and require reclassification of patients diagnosed in the past. For patients over seventy, multiple studies have now confirmed the utility of shorter courses of radiation, and the risk of post-operative delirium. Ongoing studies are comparing proton to photon radiation. Long term follow up of prior clinical trials have confirmed the roles and length of chemotherapy (mainly temozolomide) in different tumors, as well as the wearable novottf device. New oral isocitrate dehydrogenase inhibitors have also shown efficacy in clinical trials.

Temporalis muscle thickness predicts early relapse and short survival in primary CNS lymphoma.

Background: Most patients with primary CNS lymphoma (PCNSL) achieve durable remission whereas a minority die in the first year. Sarcopenia is a powerful predictor of mortality in the brain and systemic cancers. Temporalis muscle thickness (TMT) is a validated radiographic measure of sarcopenia. We hypothesized that patients with thin TMT at diagnosis would have early progression and short survival. Methods: Two blinded operators retrospectively measured TMT in 99 consecutive brain MRIs from untreated patients with PCNSL. Results: We generated a receiver operator characteristic curve and chose a single threshold defining thin TMT in all patients as <5.65 mm, at which specificity and sensitivity for 1-year progression were 98.4% and 29.7% and for 1-year mortality were 97.4% and 43.5% respectively. Those with thin TMT were both more likely to progress (P < .001) and had higher rates of mortality (P < .001). These effects were independent of the effect of age, sex, and Eastern Cooperative Oncology Group performance status in a cox regression. Memorial Sloan Kettering Cancer Center score did not predict progression-free survival or overall survival as well as TMT. Patients with thin TMT received fewer cycles of high-dose methotrexate and were less likely to receive consolidation but neither variable could be included in the Cox regression due to violation of the proportional hazards assumption. Conclusions: We conclude that PCNSL patients with thin TMT are at high risk for early relapse and short survival. Future trials should stratify patients by TMT to avoid confounding.

Distinct imaging patterns of pseudoprogression in glioma patients following proton versus photon radiation therapy.

PURPOSE: Criteria by the Radiologic Assessment in Neuro-Oncology (RANO) group outline the diagnosis of pseudoprogression (Ps) after photon therapy for gliomas based on timing and location. We noted that patients receiving proton therapy manifested radiographic changes that appear different than Ps after photon therapy, which could be interpreted as tumor progression. In this study, we retrospectively reviewed MR imaging after proton or photon radiation for gliomas. We propose criteria to characterize proton pseudoprogression (ProPs) as distinct from Ps seen after photons. METHODS: Post-treatment MR imaging, clinical and pathological data of low grade glioma patients were reviewed. Overall, 57 patients receiving protons were reviewed for the presence of ProPs, and 43 patients receiving photons were reviewed for any equivalent imaging changes. Data collected included the location and timing of the new enhancement, tumor grade, molecular subtype, chemotherapy received, and clinical symptoms. RESULTS: Fourteen patients (24.6%) had new enhancement following radiation therapy that was unique to treatment with protons. The mean time to development of the ProPs was 15.4 months (7-27 months). We established the following criteria to characterize ProPs: located at the distal end of the proton beam; resolves without tumor-directed therapy; and subjectively multifocal, patchy, and small (< 1 cm). In the group receiving photons, none had changes that met our criteria for ProPs. CONCLUSION: Patients who receive protons have unique imaging changes after radiation therapy. ProPs could be mistaken for tumor progression, but typically resolves on follow up. Further studies are needed to understand the radiobiology and pathophysiology underlying these imaging changes.

A single-center retrospective analysis of outcome measures and consolidation strategies for relapsed and refractory primary CNS lymphoma.

BACKGROUND: Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management. METHODS: We present a retrospective cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded. RESULTS: During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2-88.5) months and median PFS was 11.0 (0.2-73.9) months. At diagnosis (r2 = 0.85, p < 0.001), first relapse (r2 = 0.69, p < 0.001), multiple relapses (r2 = 0.97, p < 0.001) PFS was highly correlated with OS. In contrast, there was no correlation between the duration of subsequent progression-free intervals. No difference in PFS or OS was seen between CSF or intraocular relapse and parenchymal relapse. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7%. Consolidation with autologous stem cell transplant (ASCT) was associated with longer PFS compared to either no consolidation (p = 0.01) and trended to longer PFS when compared to other consolidation strategies (p = 0.06). OS was similarly improved in patients consolidated with ASCT compared with no consolidation (p = 0.04), but not compared with other consolidation (p = 0.22). Although patients receiving ASCT were younger, KPS, sex, and number of recurrences were similar between consolidation groups. A multivariate analysis confirmed an independent effect of consolidation group on PFS (p = 0.01), but not OS. CONCLUSIONS: PFS may be a useful surrogate endpoint which predicts OS in PCNSL. Consolidation with ASCT was associated with improved PFS in rrPCNSL.

Distinguishing and treating depression, anxiety, adjustment, and post-traumatic stress disorders in brain tumor patients.

Cancer patients often suffer from psychiatric disorders as a result of their disease and its treatment. Rates of depression, anxiety, adjustment, and post-traumatic stress disorders are particularly high for individuals with cancer and differentiating between these conditions is important for providing both appropriate and high-quality care. Patients with primary and metastatic brain tumors are particularly susceptible to psychiatric morbidities as a result of direct neuropsychiatric effects from the tumor itself, as well as psychological distress stemming from their diagnosis, prognosis, or treatment. However, these morbidities are often underdiagnosed, misdiagnosed, and undertreated. Many tools exist for screening, diagnosing, and treating psychiatric disorders in brain tumor patients, and palliative care settings are well suited to both identify and treat psychiatric disorders in brain tumor patients. This review summarizes our current knowledge of psychiatric disorders in patients in patients with brain tumors, highlights the susceptibility of brain tumor patients to psychiatric conditions, provides recommendations for differentiating and treating these conditions, and emphasizes the need for further research. The goal of this review is to inform healthcare providers of the opportunities to address psychiatric morbidities in patients with primary and metastatic brain tumors, particularly in palliative care settings, and identify areas in need of additional research.

Legal assistance in dying for people with brain tumors.

The number of countries and states that have legalized assistance in dying under various names (Medical Assistance in Dying, Death with Dignity, etc.) has continued to grow in recent years, allowing this option for more patients. Most of these laws include restrictions for eligibility based on a terminal diagnosis and estimated prognosis, as well as asking certifying providers to attest to the cognitive and psychiatric competence and capacity of patients requesting access. Some laws also require that patients must be able to 'self-administer' the regimen, though details vary. Such determinations can be vague and difficult to clearly apply to patients with neurologic conditions and primary or metastatic brain tumors. There is currently a lack of rigorous studies guiding providers on how to apply these important legal criteria to this special and common patient population. As access to legal assistance in dying expands, more research is needed on how to ethically apply the laws and guide patients, families and providers through the process.

Overview of prognostic factors in adult gliomas.

Gliomas represent the majority of malignant central nervous system tumors, with the most aggressive subtype, glioblastoma, accounting for almost 57% of this entity. Type of glioma and its incidence can vary depending on the age of presentation. In turn, outcomes can vary significantly based on the actual type of glioma (histologically and molecularly) and age of the patient, as well as various tumor specific factors such as size, location, comorbidities, etc. In the last decade we have been able to identify key molecular features that have provided us with greater insight into the behavior of these tumors, but the spectrum of treatment options remains limited. In addition, ultimate causes of death in patients with gliomas are variable and stochastic in nature. Given these complicated factors, prognostication for gliomas remains extremely difficult. This review aims to discuss prognostication in low grade versus high grade gliomas, variability in treatment of these tumors, clinical features of poor prognosis, and differences in prognostic understanding between patients, caregivers, and providers. We will also make some general recommendations where appropriate on how to approach this subject from a palliative care perspective.

Seasonal variation in the incidence of primary CNS lymphoma.

BACKGROUND: Primary CNS lymphoma is a rare and aggressive cancer that can develop in immunocompetent individuals, but little is known about risk factors and causes of disease. Previous studies have demonstrated seasonal patterns for lymphomas and brain tumors. This study examined the seasonal incidence pattern for primary CNSlymphoma. METHODS: A retrospective review was performed for patients diagnosed with primary CNS lymphoma from 2000 through 2018 at our tertiary referral center. A total of 156 patients were categorized based on month of symptom onset, month of diagnosis, and month of recurrence if they experienced a relapse of their disease. The distributions were then analyzed for seasonal patterns. RESULTS: There was a significant, bimodal seasonal incidence pattern based on month of symptom onset (P < .001), with peaks in July (n = 19) and December (n = 23) and troughs in March (n = 4) and September (n = 5). There were no significant differences in patients' sex, age at presentation, length of follow-up, and progression-free survival across months. There were no seasonal patterns based on month of diagnosis (P = .450) or month of disease recurrence (P = .572). CONCLUSION: The incidence of primary CNS lymphoma has bimodal peaks in midsummer and early winter, which could provide insight into causative agents and mechanisms of disease.

T2-FLAIR mismatch in isocitrate dehydrogenase mutant astrocytomas: Variability and evolution.

OBJECTIVE: To assess the predictive value of T2 appearance as a defining criterion of T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign (T2FM), further characterize tumors that display the marker, and describe its radiographic evolution. METHODS: Records from 64 patients with astrocytomas were assessed for age at diagnosis, sex, tumor characteristics on pretreatment CT, MRI, and pathology, documentation of T2FM, treatment course, and temporal changes in tumor appearance. Cases were divided into those meeting classic criteria (homogenous T2, hyperintense FLAIR rim), those considered geographic (heterogeneous T2, hyperintense FLAIR rim), and those that were negative (no FLAIR rim). Groups were compared using χ2, estimate of effect, and qualitative analyses. RESULTS: Including geographic tumors increased T2FM sensitivity 30% among astrocytomas without decreased specificity for IDH mutation. Tumors with T2FM characteristics were more cystic, less enhancing, and affected younger patients. T2FM persisted in residual tumors following subtotal resection and disappeared with radiotherapy, persisted in 5/8 recurrent tumors that were originally T2FM-positive, and was identified in tumors with high-grade characteristics. T2FM was able to predict IDH mutation status on sequencing when antibody testing was negative. CONCLUSIONS: The presence of a hyperintense FLAIR rim, regardless of T2 appearance, is a reliable indicator of IDH mutation among astrocytomas. Tumors with a FLAIR rim are more cystic and this may lend to their characteristic appearance on MRI. T2FM demonstrates distinctive temporal radiographic changes, may be seen in high-grade gliomas, and may be used in combination with other variables to strengthen prediction of IDH status.

Stereotactic radiosurgery in the treatment of adults with metastatic brain tumors.

Brain metastasis is the most common type of intracranial tumor affecting a significant proportion of advanced cancer patients. In recent years, stereotactic radiosurgery (SRS) has become commonly utilized. It has contributed significantly to decreased toxicity, prolonged quality of life and general improvement in outcomes of patients with brain metastases. Frequent imaging and advanced treatment techniques have allowed for the treatment of more patients with large and numerous metastases extending their overall survival. The addition of targeted therapy and immunotherapy to SRS has introduced novel treatment paradigms and has further improved our ability to effectively treat brain lesions. In this review, we examined in detail the available evidence for the use of SRS alone or in combination with surgery and systemic therapies. Given our developing understanding of the importance of primary tumor histology, the use of different treatment strategies for different metastasis is evolving. Combining SRS with immunotherapy and targeted therapy in breast cancer, lung cancer and melanoma as well as the use of preoperative SRS have shown significant promise in recent years and are investigated in multiple ongoing prospective trials. Further research is needed to guide the optimal sequence of therapies and to identify specific patient subgroups that may benefit the most from aggressive, combined treatment approaches.

Clinical Imaging for Diagnostic Challenges in the Management of Gliomas: A Review.

Neuroimaging plays a critical role in the management of patients with gliomas. While conventional magnetic resonance imaging (MRI) remains the standard imaging modality, it is frequently insufficient to inform clinical decision-making. There is a need for noninvasive strategies for reliably distinguishing low-grade from high-grade gliomas, identifying important molecular features of glioma, choosing an appropriate target for biopsy, delineating target area for surgery or radiosurgery, and distinguishing tumor progression (TP) from pseudoprogression (PsP). One recent advance is the identification of the T2/fluid-attenuated inversion recovery mismatch sign on standard MRI to identify isocitrate dehydrogenase mutant astrocytomas. However, to meet other challenges, neuro-oncologists are increasingly turning to advanced imaging modalities. Diffusion-weighted imaging modalities including diffusion tensor imaging and diffusion kurtosis imaging can be helpful in delineating tumor margins and better visualization of tissue architecture. Perfusion imaging including dynamic contrast-enhanced MRI using gadolinium or ferumoxytol contrast agents can be helpful for grading as well as distinguishing TP from PsP. Positron emission tomography is useful for measuring tumor metabolism, which correlates with grade and can distinguish TP/PsP in the right setting. Magnetic resonance spectroscopy can identify tissue by its chemical composition, can distinguish TP/PsP, and can identify molecular features like 2-hydroxyglutarate. Finally, amide proton transfer imaging measures intracellular protein content, which can be used to identify tumor grade/progression and distinguish TP/PsP.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Use of Stereotactic Radiosurgery in the Treatment of Adults With Metastatic Brain Tumors.

TARGET POPULATION: These recommendations apply to adult patients with new or recurrent solitary or multiple brain metastases from solid tumors as detailed in each section. QUESTION 1: Should patients with newly diagnosed metastatic brain tumors undergo stereotactic radiosurgery (SRS) compared with other treatment modalities? RECOMMENDATIONS: Level 3: SRS is recommended as an alternative to surgical resection in solitary metastases when surgical resection is likely to induce new neurological deficits, and tumor volume and location are not likely to be associated with radiation-induced injury to surrounding structures. Level 3: SRS should be considered as a valid adjunctive therapy to supportive palliative care for some patients with brain metastases when it might be reasonably expected to relieve focal symptoms and improve functional quality of life in the short term if this is consistent with the overall goals of the patient. QUESTION 2: What is the role of SRS after open surgical resection of brain metastasis? RECOMMENDATION: Level 3: After open surgical resection of a solitary brain metastasis, SRS should be used to decrease local recurrence rates. QUESTION 3: What is the role of SRS alone in the management of patients with 1 to 4 brain metastases? RECOMMENDATIONS: Level 3: For patients with solitary brain metastasis, SRS should be given to decrease the risk of local progression. Level 3: For patients with 2 to 4 brain metastases, SRS is recommended for local tumor control, instead of whole brain radiotherapy, when their cumulative volume is < 7 mL. QUESTION 4: What is the role of SRS alone in the management of patients with more than 4 brain metastases? RECOMMENDATION: Level 3: The use of stereotactic radiosurgery alone is recommended to improve median overall survival for patients with more than 4 metastases having a cumulative volume < 7 mL. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_4.

Leptomeningeal Metastases.

OPINION STATEMENT: Treatment options for leptomeningeal metastases are expanding with greater tolerability and efficacy than in the past. Improved knowledge of molecular subtypes of some cancers can guide in choosing more effective therapeutic options; however, physicians should be mindful that these molecular types can be different in the central nervous system compared to the rest of the body. This is particularly true in breast and lung cancer, in which some patients now can live for many months or even years after diagnosis of leptomeningeal metastases. Options for intrathecal therapies are expanding, but physicians should be mindful that this is a passive delivery system that relies on normal CSF flow, so therapies will not penetrate bulky or parenchymal disease sites, especially in the presence of abnormal CSF flow. When chemotherapeutic options are lacking or unsuccessful, focal radiosurgery which can provide symptomatic relief and proton craniospinal radiation remain effective options. Hopefully more formal studies will be conducted in the future to verify which treatments are indeed most effective for particular types of cancer.

Association between malignancy and non-alcoholic Wernicke's encephalopathy: a case report and literature review.

BACKGROUND: Wernicke's encephalopathy is a serious medical condition associated with high morbidity and mortality caused by deficiency of thiamine. This disease is classically associated with alcoholism, but is underappreciated in the nonalcoholic population. There is growing acknowledgement of the development of Wernicke's encephalopathy in patients with malignancies. METHODS: We conducted a literature review in PubMed for cases of Wernicke's encephalopathy occurring in patients with malignancy. We also present the case of a 47-year-old woman with recurrent laryngeal cancer and multiple hospital admissions for malnutrition. Neurological examination was notable for pendular nystagmus, severe gait ataxia, confusion, and poor memory consolidation. MRI of the brain was significant for T2-weighted fluid-attenuated inversion recovery hyperintensities in periaqueductal regions, medial thalami, and the tectal plate, typical for Wernicke's encephalopathy. She was treated with thiamine repletion, and had marked improvement in her mental status and some improvement in her vision problems and ataxia, although some nystagmus and significant short-term memory impairment persisted. RESULTS: The literature review yielded dozens of case reports of Wernicke's encephalopathy in patients with malignancy, dominated by cases of patients with malignancies of the gastrointestinal system, followed by those with hematologic malignancies. CONCLUSIONS: Malignancy is an important risk factor for the development of Wernicke's encephalopathy. This diagnosis is underappreciated and difficult for the clinician to discern from multifactorial delirium. Clinicians should be aware to treat at-risk patients with thiamine immediately, especially if multiple risk factors are present.

ILAE type 3 hippocampal sclerosis in patients with anti-GAD-related epilepsy.

OBJECTIVE: To describe the neuropathologic findings and clinical course of 2 patients who underwent temporal lobectomy for medically refractive epilepsy and were later found to have high anti-glutamic acid decarboxylase (GAD) concentrations. METHODS: Small case series. RESULTS: Neuropathologic examination of both patients revealed International League Against Epilepsy (ILAE) type 3 hippocampal sclerosis. Following surgery, both developed signs and symptoms of stiff person syndrome and later cerebellar ataxia. Laboratory studies demonstrated high concentrations of anti-GAD antibodies in both patients. CONCLUSIONS: These cases suggest that ILAE type 3 hippocampal sclerosis may be immunologically related to and may exist as part of a broader anti-GAD-related neurologic syndrome in some instances.