Leptomeningeal metastases: the future is now.

Leptomeningeal metastases (LM) constitute an involvement of cancer which is associated with marked morbidity and mortality. The contemporary diagnostic and therapeutic management of LM from solid tumors is reviewed. Therapeutic modalities including systemic therapies, cerebrospinal fluid (CSF)-directed therapies, and radiation therapy are discussed. This is to provide context for how the field of LM management may evolve in the near term. The future directions currently undergoing investigation for diagnostic, response assessment, and therapeutic purposes are highlighted. This is done within the context of the pathophysiology of the disease. Specifically the role of CSF circulating tumor cells and cell free circulating tumor DNA in diagnosis and response assement are reviewed. Novel therapeutic approaches across a range of modalities are discussed. Numerous ongoing studies which have the potential to alter the management of LM are referenced.

Acute Neurological Complications of Brain Tumors and Immune Therapies, a Guideline for the Neuro-hospitalist.

PURPOSE OF REVIEW: Patients with brain tumors presenting to the emergency room with acute neurologic complications may warrant urgent investigations and emergent management. As the neuro-hospitalist will likely encounter this complex patient population, an understanding of the acute neurologic issues will have value. RECENT FINDINGS: We discuss updated information and management regarding various acute neurologic complications among neuro-oncology patients and neurologic complications of immunotherapy. Understanding of the acute neurologic complications associated with central nervous system tumors and with common contemporary cancer treatments will facilitate the neuro-hospitalist management of these patient populations. While there are aspects analogous to the diagnosis and management in the non-oncologic population, a number of unique features discussed in this review should be considered.

Bilateral Radiation Optic Neuropathy Following Concurrent Chemotherapy and Radiation in Glioblastoma.

Radiation optic neuropathy (RON) is an iatrogenic complication that causes severe, irreversible vision loss within months to years following radiation to lesions close to the visual pathway. The authors describe a case of RON in glioblastoma after radio-sensitisation with temozolomide with sequential involvement of both optic nerves. This case provides a timeline for clinical and imaging findings with RON and specifically resolution of nerve enhancement. The authors also highlight the potential of an increase in incidence of RON in glioblastoma with advances in survival seen with greater use of second-line chemotherapy and even re-radiation.

Epidemiology of meningiomas post-Public Law 107-206: The Benign Brain Tumor Cancer Registries Amendment Act.

BACKGROUND: The current analysis follows the implementation of Public Law 107-260, the Benign Brain Tumor Cancer Registries Amendment Act, which mandated the collection of nonmalignant brain tumors. METHODS: Meningiomas were selected from the Surveillance, Epidemiology, and End Results (SEER) Program database for the years 2004 to 2011. Demographic and clinical characteristics, initial treatment patterns, and survival outcomes were evaluated using surveillance epidemiology statistical methods. RESULTS: The average annual age-adjusted incidence rate per 100,000 population was 7.62 (95 % confidence interval [CI], 7.55-7.68) for all meningiomas, 7.18 (95% CI, 7.12-7.25) for benign meningiomas, 0.32 (95% CI, 0.31-0.33) for borderline malignant meningiomas, and 0.12 (95% CI, 0.11-0.12) for malignant meningiomas. The annual rates increased for benign and borderline malignant tumors but decreased for malignant tumors. The rates for women exceeded those for men, especially for those with benign meningiomas. Black race was associated with significantly higher rates as was advancing age. Greater than 80% of tumors were located in cerebral meninges. Diagnostic confirmation through pathology occurred for approximately 50% of benign tumors, 90% of borderline malignant tumors, and 80% of malignant tumors. No initial treatment was reported for greater than 60% of benign tumors, 29% of borderline malignant tumors, or 31% of malignant tumors. The 5-year relative survival estimates for benign tumors, borderline malignant tumors, and malignant tumors were 85.6% (95% confidence interval [CI], 85%-86.2%), 82.3% (95% CI, 79.3%-84.8%), and 66% (95% CI, 60.6%-70.9%), respectively. Predictors of poorer survival were advanced age, being male gender, black race, no initial treatment, and malignant tumor behavior. CONCLUSIONS: The current analysis demonstrates that there is an increasing incidence of nonmalignant meningiomas, probably because of reporting learning curves associated with the implementation of Public Law 107-260. The high proportion of cases who receive no initial treatment is a survival outcome concern, especially for patients with malignant meningiomas.

Anti-aquaporin-4 immunoglobulin G/anti-myelin oligodendrocyte glycoprotein immunoglobulin G double-positive paraneoplastic neurological syndrome in a patient with triple-negative breast cancer.

We report a rare case of paraneoplastic neurological syndrome with dual seropositivity of anti-aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in a 40 year-old woman with metastatic triple-negative breast cancer. She received multiple lines of anti-neoplastic treatment, including immunotherapy with pembrolizumab, as well as cytotoxic chemotherapy. Paraneoplastic meningoencephalomyelitis developed 2 years after diagnosis of breast cancer and 1 year after discontinuation of immunotherapy with pembrolizumab. She first developed longitudinally extending transverse myelitis followed by left optic neuritis and meningoencephalitis with new enhancing lesions in the brain and spinal leptomeninges. Cerebrospinal fluid analysis during both episodes showed normal glucose and protein, and elevated white blood cell count. Cytology was negative for malignancy. Cerebrospinal fluid was positive for neuromyelitis optica immunoglobulin G antibody anti-aquaporin-4, and autoimmune myelopathy panel was positive for myelin oligodendrocyte glycoprotein antibody. The patient had significant clinical and radiographic improvement after completion of five cycles of plasmapheresis followed by intravenous immunoglobulin. She did not have recurrence of paraneoplastic syndrome with maintenance rituximab every 6 months and daily low-dose prednisone. She succumbed to progressive systemic metastatic disease 4.5 years after her breast cancer diagnosis. This case shows that these antibodies can occur concurrently and cause clinical features, such as both neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody disease, in a patient with a singular type of cancer. We highlight the importance of testing for paraneoplastic etiology in cancer patients with radiographic menigoencephalomyelitis or meningitis with atypical symptoms of meningeal carcinomatosis and/or cerebrospinal fluid profile negative for leptomeningeal carcinomatosis.

National Trends and Factors Associated with Voluntary Refusal of Glioblastoma Treatment: A Retrospective Review of the National Cancer Database.

OBJECTIVE: Adherence to combinatorial treatments are important predictors of improved long-term outcomes for patients with glioblastoma (GB); however, factors associated with refusal of surgery, chemotherapy, or radiotherapy (RT) by patients with GB have not been studied. METHODS: The National Cancer Database was queried from 2004 to 2018 to identify patients with a primary diagnosis of GB who underwent surgical resection alone or followed by either RT or chemotherapy. Adult patients who voluntarily rejected a physician's recommendations for 1 or more treatment were selected. Multivariable regression was used to identify factors associated with rejection of surgical resection, chemotherapy, and RT. Patients receiving treatment were 3:1 propensity score matched to those rejecting treatment and median overall survival (OS) was compared. RESULTS: 58,788 patients were included in the analysis. Factors associated with voluntary refusal of GB treatment included: old age, nonprivate insurance, female sex, Black race, comorbidities, treatment at a nonacademic facility, and living 55+ miles away from a treatment facility (P < 0.05). On propensity matched analysis, refusal of surgery conferred a 4 month decrease in OS (P < 0.001), RT an 8 month decrease in OS (P < 0.001), and chemotherapy a 7 month decrease in OS (P < 0.001). CONCLUSIONS: In patients with GB, age, sex, race, nonprivate insurance, medical comorbidities, distance from treatment facility, and geographic location were associated with refusal of surgery, postsurgical RT, and chemotherapy. In addition, treatment refusal had a significant impact on OS length.

Age-stratified comorbid and pharmacologic analysis of patients with glioblastoma.

Background: Increased age is a strong and unfavorable prognostic factor for patients with glioblastoma (GBM). However, the relationships between stratified patient age, comorbidities, and medications have yet to be explored in GBM patient survival analyses. Objective: To evaluate co-morbid conditions, tumor-related symptoms, medication prescriptions, and subject age for patients with GBM and to establish potential targets for prospective studies. Methods: Electronic health records for 565 patients with IDHwt GBM were evaluated at a single center between January 1, 2000 and August 9, 2021 were retrospectively assessed. Data were stratified by MGMT promoter methylation status when available and were used to construct multivariable time-dependent cox models and intra-cohort hazards. Results: Younger (<65 years of age) but not older (≥65 years) GBM patients demonstrated a worse prognosis with movement related disabilities (P < 0.0001), gait/balance difficulty (P = 0.04) and weakness (P = 0.007), as well as psychiatric conditions, mental health disorders (P = 0.002) and anxiety (P = 0.001). In contrast, older but not younger GBM patients demonstrated a worse prognosis with epilepsy (P = 0.039). Both groups had worse survival with confusion/altered mental status (P = 0.023 vs < 0.000) and an improved survival with a Temozolomide prescription. Older but not younger GBM patients experienced an improved hazard with a prescription of ace-inhibitor medications (P = 0.048). Conclusion: Age-dependent novel associations between clinical symptoms and medications prescribed for co-morbid conditions were demonstrated in patients with GBM. The results of the current work support future mechanistic studies that investigate the negative relationship(s) between increased age, comorbidities, and drug therapies for differential clinical decision-making across the lifespan of patients with GBM.

MGMT Methylated High Grade Glioma with Distant Recurrence and Stable Original Tumor Site: Case Series.

We present three cases of O6-Methylguanine-DNA Methyl-transferase (MGMT) methylated high grade gliomas with distant recurrence. All three patients had a radiographic stability of original tumor site at time of distant recurrence indicating impressive local control with Stupp protocol in patients with a MGMT methylated tumors. All patients had a poor outcome after distant recurrence. For one patient Next Generation Sequencing (NGS) was available for both original and recurrent tumor and did not reveal any difference other than high tumor mutational burden in the distant recurrent tumor. Understanding risk factors of distant recurrence in MGMT methylated tumors and investigating correlations between recurrences will help plan therapeutic strategies to prevent distant recurrence and improve survival of these patients.

A review of an unfavorable subset of breast cancer: estrogen receptor positive progesterone receptor negative.

Estrogen receptor (ER)(+) progesterone receptor (PR)(-) tumors are a distinct subset of breast cancers characterized by aggressive behavior and tamoxifen resistance in spite of being ER(+). They are categorized as luminal B tumors and have greater genomic instability and a higher proliferation rate. High growth factor (GF) signaling and membranous ER activity contribute to the aggressive behavior of these tumors. The absence of PR is attributable to low serum estrogen, low levels of nuclear ER, and features of molecular crosstalk between GFs and membranous ER. PR expression is also downregulated by expression of mutated epidermal growth factor receptor (EGFRvIII). This subset of patients has greater expression of human epidermal growth factor receptor (HER)-1 and HER-2 and active GF signaling mediated by the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin pathway. Currently, aromatase inhibitors, fulvestrant, and chemotherapy may be the favored treatment approaches for this subset of patients. Overcoming tamoxifen resistance with targeted therapies such as gefitinib is being evaluated and strategies involving short courses of tamoxifen have been postulated for prevention of recurrence of this subtype. Understanding the interplay between molecular endocrinology and tumor biology has provided experimental therapeutic insights, and continued work in this area holds the promise of future advances in prognosis.

What is New in Neuro-oncology?

Neuro-oncology is a rapidly developing field. A continuous evolution in the understanding of the molecular underpinnings of central nervous system tumors has helped reconfigure the classification of brain tumors. More importantly, it has laid the path forward for the development and investigation of new therapeutics. The authors discuss the classification of brain tumors and novel therapies in brain tumors as well as promising treatments underway.

Socioeconomic Disparities in Non-Small Cell Lung Cancer With Brain Metastases at Presentation: A Population-Based Study.

OBJECTIVE/BACKGROUND: The purpose of this study was to characterize the impact of household income disparities in the survival of patients with non-small cell lung cancer (NSCLC) presenting with brain metastasis on a population-based level. METHODS: This is a population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from 2010-2016 including 15,808 NSCLC patients presenting with brain metastasis. RESULTS: This study comprises 15,808 adult patients with NSCLC presenting with brain metastases having an age range 64 ± 10 years with 51% male, 76% white, 52% married, 61% insured, and with 85% of lung adenocarcinoma histopathology. The 1-, 2- and 5-year survival rates for living in the lower household income quartile were 21%, 10%, and 3%, respectively, for the second quartile 24%, 10%, and 3%; for the third quartile 28%, 14%, and 4%; and for the top quartile 31%, 17%, and 4%, respectively. Multivariate Cox proportional hazard analysis showed that living in a higher quartile household income county is associated with increased survival (P < 0.0001), hazard ratio 0.87, 95% confidence interval (0.82-0.92). CONCLUSIONS: This population-based study suggests that living in higher median household income counties is associated with increased survival time and reduced risk of mortality for patients with NSCLC who have brain metastases present at diagnosis, independent of other factors. These findings underscore the importance of ensuring adequate and easy access to care for all patients, irrespective of their economic background.

Leptomeningeal metastasis from solid tumors.

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges (pia, subarachnoid space and arachnoid mater), and dura. Leptomeningeal metastases (LM), also known by different terms including neoplastic meningitis and carcinomatous meningitis, occur in both solid tumors and hematologic malignancies. This review will focus exclusively on LM arising from solid tumors with a goal of providing the reader an understanding of the epidemiology, pathophysiology, clinical presentation, prognostication, current management and future directions.

National cancer database analysis of outcomes in pediatric glioblastoma.

Glioblastoma in children is an aggressive disease with no defined standard therapy. We evaluated hospital-based demographic and survival patterns obtained through the National Cancer Database to better characterize children with glioblastoma. Our study identified 1173 patients from 0 to 19 years of age between 1998 and 2011. Comparisons were made among demographics, clinical characteristics, treatment, and survival variables. Fifty-four percent of patients were over 10 years of age. Approximately 80% of patients underwent either partial or complete resection. Adjuvant therapy was used variably, and its use increased with patient age. Forty-eight percent of patients received the combination of surgery, radiation, and chemotherapy, and 4% did not receive any treatment. As expected, patients ≤5 years of age had better 5-year survival than those ages 6-10 (P = 0.01) or 11-19 years (P = 0.0077). Other factors associated with poor survival included black race and central tumor location. Better outcomes were associated with treatment that included surgery, radiotherapy, and chemotherapy compared to any other treatment combinations. Radiotherapy had no impact on survival in the 0 to 10-year-old age group, but was associated with improved survival for patients 11-19 years. We report an extensive demographic and survival analysis of pediatric glioblastoma. The observed differences likely reflect variances in tumor biology and likelihood of treatment receipt. Improved survival was associated with the use of surgery, radiotherapy, and chemotherapy. Radiation therapy was not associated with survival in patients younger than 10 years of age.

Incidence of brain metastasis at initial presentation of lung cancer.

BACKGROUND: No reliable estimates are available on the incidence of brain metastasis (BM) in cancer patients. This information is valuable for planning patient care and developing measures that may prevent or decrease the likelihood of metastatic brain disease. METHODS: We report the first population-based analysis on BM incidence at cancer diagnosis using the Kentucky Cancer Registry (KCR) and Alberta Cancer Registry (ACR). All cancer cases with BM were identified from KCR and ACR, with subsequent focus on metastases from lung primaries; the annual number of BMs at initial presentation was derived. Comparisons were made between Kentucky and Alberta for the stage and site of organ involvement of lung cancer. RESULTS: Low incidence of BM was observed in the United States until mandatory reporting began in 2010. Both the KCR and ACR recorded the highest incidence of BM from lung cancer, with total BM cases at initial presentation occurring at 88% and 77%, respectively. For lung cancer, stage IV was the most common stage at presentation for both registries and ranged from 45.9% to 57.2%. When BM from lung was identified, the most common synchronous organ site of metastasis was osseous, occurring at 28.4%. CONCLUSION: Our analysis from the Kentucky and Alberta cancer registries similarly demonstrated the aggressive nature of lung cancer and its propensity for BM at initial presentation. Besides widespread organ involvement, no synchronous organ site predicted BM in lung cancer. BM is a common and important clinical outcome, and use of registry data is becoming more available.

Age-specific cancer incidence rates increase through the oldest age groups.

BACKGROUND: In the United States, from 2005 to 2009, nearly 8% of all cancers diagnosed and 15% of cancer deaths occurred in individuals aged 85 years and older (85+ age group). With the aging of the U.S. population, an analysis of incidence of cancer in the elderly population may provide information for clinical care and resource allocation. MATERIALS AND METHODS: Previously reported data were retrieved from the Surveillance Epidemiology and End Results (SEER) 18 Registry for years 2000 to 2010 and Central Brain Tumor Registry of the United States (CBTRUS) for years 2004 to 2008. Cancers included invasive cases only, except for nonmalignant meningiomas, and rates were per 100,000. RESULTS: The age-specific cancer incidence rate (IR) increases with age until a decrease in the 85+ age group. IR for all cancers combined for this age group was 2,317 per 100,000. Statistically, males had significantly higher IR compared with females (3,194 versus 1,911 [P≤0.0001]). Blacks had an IR similar to whites (2,255 versus 2,340 [P=0.12]). Despite a drop in the overall IR in this oldest age group, IR for certain cancers continued to increase. Among these cancers, gastrointestinal cancers like colorectal, pancreatic and stomach had the highest incidence and mortality rates. CONCLUSIONS: This study contributes to measuring cancer burden in the oldest old population. In certain cancers, including meningiomas, the IR continues to rise with advancing age. Management of cancer in elderly is challenging and screening persons in the 85+ age group for frailty very thoroughly may help guide decisions of palliative versus aggressive therapies.

Epidemiologic and molecular prognostic review of glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system malignancy with a median survival of 15 months. The average incidence rate of GBM is 3.19/100,000 population, and the median age of diagnosis is 64 years. Incidence is higher in men and individuals of white race and non-Hispanic ethnicity. Many genetic and environmental factors have been studied in GBM, but the majority are sporadic, and no risk factor accounting for a large proportion of GBMs has been identified. However, several favorable clinical prognostic factors are identified, including younger age at diagnosis, cerebellar location, high performance status, and maximal tumor resection. GBMs comprise of primary and secondary subtypes, which evolve through different genetic pathways, affect patients at different ages, and have differences in outcomes. We report the current epidemiology of GBM with new data from the Central Brain Tumor Registry of the United States 2006 to 2010 as well as demonstrate and discuss trends in incidence and survival. We also provide a concise review on molecular markers in GBM that have helped distinguish biologically similar subtypes of GBM and have prognostic and predictive value.

Primary CNS germ cell tumors: current epidemiology and update on treatment.

Primary central nervous system (CNS) germ cell tumors (GCTs) are a heterogeneous group of lesions that account for 0.5 % of all primary brain and CNS tumors, occurring at an incidence rate of 0.10 per 100,000 person-years in the United States with approximately 90 % of the cases before the age of 20 years. Primary CNS GCTs demonstrate a remarkable difference in incidence based on gender and location within the brain with males having a 15:1 incidence in the pineal region while the gender incidence is nearly 1:1 in the rest of the brain. Also, historically the incidence was noted to be significantly higher in Japan and East Asia, but recent studies in Japan demonstrate similar incidence as in the United States. They are broadly classified as germinomas and non-germinomatous germ cell tumors (NGGCTs) based on clinicopathologic features. Germinomas are sensitive to treatment with radiotherapy and chemotherapy with high cure rates and carry an excellent prognosis, while NGGCTs display various forms of differentiation, have a poorer prognosis and are refractory to therapy. Standard management of CNS GTCs remains unsettled and ongoing research aims to achieve best possible survival rates and post-treatment quality of life by reduction in treatment intensity.

Intra-CSF administration of chemotherapy medications.

Leptomeningeal carcinomatosis is a devastating complication of cancer and is likely increasing in incidence. The combination of widespread neuro-axial spread based on CSF flow and the blood-brain barrier (BBB) has favored immediate local delivery of antineoplastic agents. With the BBB, the leptomeninges can be a sanctuary site to systemic cancers and goal of therapy includes preventing involvement in this space. Current therapies with U.S. Food and Drug Administration (FDA) approval are limited to treat hematologic cancers. Although lacking FDA guidance, a wider array of therapies is available to treat solid tumors. We provide an updated examination on both well-established intra-CSF chemotherapies as well as agents having limited data, but reports of therapeutic benefit.