The role of upfront lenalidomide maintenance for primary central nervous system lymphoma following first-line methotrexate treatment: A retrospective study.

BACKGROUND: Consolidation therapy improves the duration of response among patients with primary central nervous system lymphoma (PCNSL). Lenalidomide maintenance has shown encouraging results in older patients with PCNSL. Herein, we performed a retrospective, single-center analysis to evaluate the effect of lenalidomide maintenance on the duration of response in patients with newly-diagnosed PCNSL. METHODS: Sixty-nine adult patients with PCNSL who achieved complete remission or partial remission (PR) after induction therapy were enrolled. The median age of patients was 58.0 years. The maintenance group (n = 35) received oral lenalidomide (25 mg/day) for 21 days, every 28 days for 24 months; the observation group did not undergo any further treatment. RESULTS: After a median follow-up of 32.6 months, the maintenance group experienced fewer relapse events. However, the median progression-free survival (PFS) was similar between groups (36.1 vs. 30.6 months; hazard ratio, 0.78; 95% confidence interval, 0.446). Lenalidomide maintenance significantly improved PFS and overall survival (OS) only among patients who experienced PR after induction. The median duration of lenalidomide maintenance was 18 months; lenalidomide was well tolerated and minimally impacted the quality of life. CONCLUSIONS: The present study was the first to evaluate lenalidomide maintenance as a frontline treatment among patients with PCNSL, PFS and OS did not improve, although the safety profile was satisfactory.

Real-World Use of Hypofractionated Radiotherapy for Primary CNS Tumors in the Elderly, and Implications on Medicare Spending.

BACKGROUND: For elderly patients with high-grade gliomas, 3-week hypofractionated radiotherapy (HFRT) is noninferior to standard long-course radiotherapy (LCRT). We analyzed real-world utilization of HFRT with and without systemic therapy in Medicare beneficiaries treated with RT for primary central nervous system (CNS) tumors using Centers for Medicare & Medicaid Services data. METHODS: Radiation modality, year, age (65-74, 75-84, or ≥85 years), and site of care (freestanding vs hospital-affiliated) were evaluated. Utilization of HFRT (11-20 fractions) versus LCRT (21-30 or 31-40 fractions) and systemic therapy was evaluated by multivariable logistic regression. Medicare spending over the 90-day episode after RT planning initiation was analyzed using multivariable linear regression. RESULTS: From 2015 to 2019, a total of 10,702 RT courses (ie, episodes) were included (28% HFRT; 65% of patients aged 65-74 years). A considerable minority died within 90 days of RT planning initiation (n=1,251; 12%), and 765 (61%) of those received HFRT. HFRT utilization increased (24% in 2015 to 31% in 2019; odds ratio [OR], 1.2 per year; 95% CI, 1.1-1.2) and was associated with older age (≥85 vs 65-74 years; OR, 6.8; 95% CI, 5.5-8.4), death within 90 days of RT planning initiation (OR, 5.0; 95% CI, 4.4-5.8), hospital-affiliated sites (OR, 1.4; 95% CI, 1.3-1.6), conventional external-beam RT (vs intensity-modulated RT; OR, 2.7; 95% CI, 2.3-3.1), and no systemic therapy (OR, 1.2; 95% CI, 1.1-1.3; P<.001 for all). Increasing use of HFRT was concentrated in hospital-affiliated sites (P=.002 for interaction). Most patients (69%) received systemic therapy with no differences by site of care (P=.12). Systemic therapy utilization increased (67% in 2015 to 71% in 2019; OR, 1.1 per year; 95% CI, 1.0-1.1) and was less likely for older patients, patients who died within 90 days of RT planning initiation, those who received conventional external-beam RT, and those who received HFRT. HFRT significantly reduced spending compared with LCRT (adjusted ß for LCRT = +$8,649; 95% CI, $8,544-$8,755), whereas spending modestly increased with systemic therapy (adjusted ß for systemic therapy = +$270; 95% CI, $176-$365). CONCLUSIONS: Although most Medicare beneficiaries received LCRT for primary brain tumors, HFRT utilization increased in hospital-affiliated centers. Despite high-level evidence for elderly patients, discrepancy in HFRT implementation by site of care persists. Further investigation is needed to understand why patients with short survival may still receive LCRT, because this has major quality-of-life and Medicare spending implications.

Factors Influencing Mortality in Children with Central Nervous System Tumors: A Cohort Study on Clinical Characteristics and Genetic Markers.

Multidrug resistance (MDR) commonly leads to cancer treatment failure because cancer cells often expel chemotherapeutic drugs using ATP-binding cassette (ABC) transporters, which reduce drug levels within the cells. This study investigated the clinical characteristics and single nucleotide variant (SNV) in ABCB1, ABCC1, ABCC2, ABCC4, and ABCG2, and their association with mortality in pediatric patients with central nervous system tumors (CNST). Using TaqMan probes, a real-time polymerase chain reaction genotyped 15 SNPs in 111 samples. Patients were followed up until death or the last follow-up day using the Cox proportional hazards model. An association was found between the rs1045642 (ABCB1) in the recessive model (HR = 2.433, 95% CI 1.098-5.392, p = 0.029), and the ICE scheme in the codominant model (HR = 9.810, 95% CI 2.74-35.06, p ≤ 0.001), dominant model (HR = 6.807, 95% CI 2.87-16.103, p ≤ 0.001), and recessive model (HR = 6.903, 95% CI 2.915-16.544, p = 0.038) significantly increased mortality in this cohort of patients. An association was also observed between the variant rs3114020 (ABCG2) and mortality in the codominant model (HR = 5.35, 95% CI 1.83-15.39, p = 0.002) and the dominant model (HR = 4.421, 95% CI 1.747-11.185, p = 0.002). A significant association between the ICE treatment schedule and increased mortality risk in the codominant model (HR = 6.351, 95% CI 1.831-22.02, p = 0.004, HR = 9.571, 95% CI 2.856-32.07, p ≤ 0.001), dominant model (HR = 6.592, 95% CI 2.669-16.280, p ≤ 0.001), and recessive model (HR = 5.798, 95% CI 2.411-13.940, p ≤ 0.001). The genetic variants rs3114020 in the ABCG2 gene and rs1045642 in the ABCB1 gene and the ICE chemotherapy schedule were associated with an increased mortality risk in this cohort of pediatric patients with CNST.

Registration, incidence patterns, and survival trends of central nervous system tumors among children in Germany 1980-2019: An analysis of 40 years based on data from the German Childhood Cancer Registry.

BACKGROUND: Tumors of the central nervous system (CNS) are the second most common type of pediatric cancer in Germany. We aimed to describe registration practice, incidence, and survival patterns for childhood CNS tumors in Germany for the past 40 years. PROCEDURE: Including all CNS tumor cases in children diagnosed at ages 0-14 years registered at the German Childhood Cancer Registry (GCCR) in 1980-2019 (for survival analysis 1980-2016), we calculated age-specific and age-standardized incidence rates (ASIR) over time, average annual percentage changes (AAPC), and 1- and 5-year overall survival. RESULTS: While we observed a pronounced increase in ASIR after the establishment of the GCCR during the 1980s, ASIR for all pediatric CNS tumors combined continued to increase markedly from 28.6 per million in 1990-1999 to 43.3 in 2010-2019 (AAPC = 2.7% in 1991-2010, AAPC = 0.3% in 2010-2019). The 5-year overall survival from CNS tumors improved from 63% in the 1980s, 70% in the 1990s to 79% in 2010-2016. These improvements have occurred across all age groups. Children diagnosed with ependymomas and choroid plexus tumors experienced the strongest increase (from 54% to 81%). CONCLUSIONS: Observed increases in incidence rates for pediatric CNS tumors are likely only partially caused by actual increasing case numbers. The majority is a function of improved registration and, to a minor extent, improvements in diagnostics. Survival from pediatric CNS tumors has, by and large, improved consistently, leading to a growing population of childhood cancer survivors with diverse health biographies and risk of lifelong adverse impact on health and wellbeing.

Patterns and prognostic impact of CNS infiltration in adults with newly diagnosed acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is highly associated with central nervous system (CNS) infiltration and can be associated with higher risk of relapse. Conventional cytology (CC) is the traditional method for diagnosing CNS infiltration, although the use of immunophenotyping by flow cytometry (FC) has gained prominence in recent years due to its higher sensitivity. Also, some authors have proposed that CSF contamination by a traumatic lumbar puncture (TLP) could have a clinical impact. This retrospective study accessed the impact of CNS infiltration by CC or FC on overall survival, event-free survival, and relapse rate. In a cohort of 105 newly diagnosed ALL patients, CNS1, CNS2, and CNS3 status were found in 84%, 14%, and 2%, respectively. We found that extramedullary disease at the diagnosis, higher leukocyte counts, and higher blast percentage were associated with a positive CC. Sensitivity and specificity of CC were 53% and 98%, respectively. Three-year overall survival was 42.5%. Conversely, TLP was not associated with a positive CC nor had an impact on relapse rates. In multivariate analysis, a positive CC was associated with an increased relapse rate (HR 2.074, p = 0.037), while its detection by FC did not associate with this endpoint. Survival rates seem to be increasing over the last years by the adoption of a stratified CNS prophylaxis risk strategy. CSF contamination does not represent a major concern according to our report, as it did not increase CNS involvement or relapse rates.

The PI3K/AKT/mTOR signaling pathway is aberrantly activated in primary central nervous system lymphoma and correlated with a poor prognosis.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a specific subtype of non-Hodgkin lymphoma that is highly invasive and confined to the central nervous system (CNS). The vast majority of PCNSLs are diffuse large B-cell lymphomas (DLBCLs). PCNSL is a highly heterogeneous disease, and its pathogenesis has not yet been fully elucidated. Further studies are needed to guide individualized therapy and improve the prognosis. METHODS: In this study, we detected 1) the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 by immunohistochemistry (IHC) and Western blotting, 2) the mRNA expression by real-time qPCR and 3) the deletion of PTEN gene by immunofluorescence in situ hybridization (FISH) in order to investigate the activation status of the PI3K/AKT/mTOR signaling pathway in PCNSL. Samples of reactive hyperplasia lymphnods were used as the control group. The correlations between the clinical characteristics and prognosis of PCNSL patients and the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 and the deletion of PTEN were assessed. RESULTS: The IHC results showed that the positive expression rates of p-AKT, p-mTOR, p-S6 and p-4E-BP1 in PCNSL were significantly higher in the PCNSL group than in the control group (P < 0.05). The relative mRNA expression level of MTOR in PCNSL samples was significantly increased (P = 0.013). Correlation analysis revealed that the expression of p-mTOR was correlated with that of p-AKT, p-S6, p-4E-BP1. PTEN deletion was found in 18.9% of PCNSL samples and was correlated with the expression of p-AKT (P = 0.031). Correlation analysis revealed that the PCNSL relapse rate in the p-mTOR-positive group was 64.5%, significantly higher than that in the negative group (P = 0.001). Kaplan-Meier survival analysis showed inferior progression-free survival (PFS) in the p-mTOR- and p-S6-positive groups (P = 0.002 and 0.009, respectively), and PTEN deletion tended to be related to shorter overall survival (OS) (P = 0.072). Cox regression analysis revealed p-mTOR expression as an independent prognostic factor for a shorter PFS (hazard ratio (HR) =7.849, P = 0.046). CONCLUSIONS: Our results suggest that the PI3K/AKT/mTOR signaling pathway is aberrantly activated in PCNSL and associated with a poor prognosis, which might indicate new therapeutic targets and prognostic factors.

The epidemiology series of brain-related disorders in Mongolia: nationwide registry-based epidemiological study on CNS tumours in Mongolia, 2015-2019.

No epidemiological study on central nervous system tumours is available for Mongolia. The aim of this study was to determine the incidence, mortality and survival of people diagnosed with central nervous system tumours in Mongolia. It reports cancer data for the entire population (3.3 million) during the period between 2015 and 2019. Data was obtained from the National Cancer Registry of Mongolia. Diagnosis of tumours was established according to the diagnostic criteria of the International Classification of Diseases-10 (ICD-10). Incidence and mortality rates were calculated as mean annual numbers per 100,000 population. Age-standardized incidence and age-standardized mortality rates were calculated from age-specific rates by weighting directly from the World Standard Population. The three-year survival from 2015 through 2017 was calculated between treatment types by the Kaplan-Meier survival analysis. It found 515 (adults: 83 %; children: 17%) newly diagnosed central nervous system tumour cases over the five year period. The national age-standardized incidence of central nervous system tumours for the entire population was 3.7 per 100,000. The rate was higher for males than females (4.2 versus 3.4 per 100,000, respectively). Only 23% of the diagnosed cases were confirmed histologically. The most common tumour was glioma (57.6% of histologically verified tumours). In children (age 0-19 years) the age-specified incidence rate of tumours was 1.4 per 100,000. Geographically, the age-standardized incidences of the Eastern region were higher than the country average rates for both genders. During the period, 381 deaths were registered with an age-standardized mortality rate of 3.0 per 100,000 population. Furthermore, the overall three-year survival rate was 40.6% (out of 283 patients, 115 survived). The five-year prevalence of tumours was 183 and the mean per 100,000 population was 5.5. In conclusion, the data from the National Cancer Registry indicate that the incidence and survival rates of central nervous system tumours in Mongolia are relatively low. The most common location of central nervous system tumours was the brain. Glioma was the most common tumour among histologically confirmed cases. Despite the limitations, data from this study should provide information for national health policy and health care assessment. To improve the diagnosis, prognosis and treatment of central nervous system tumours, expansion of the cancer registry through collecting data on non-malignant tumours, increasing the rate of histological verification, conducting studies on cancer epidemiology and the introduction of advanced treatment technologies for central nervous system tumours are recommended.

Routine use of low-dose glucarpidase following high-dose methotrexate in adult patients with CNS lymphoma: an open-label, multi-center phase I study.

BACKGROUND: High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL). METHODS: Eight CNSL patients received HD-MTX 3 or 6 g/m2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles. RESULTS: Fifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy. CONCLUSIONS: This study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS. CLINICAL TRIAL REGISTRATION: NCT03684980 (Registration date 26/09/2018).

Incidence and survival of childhood central nervous system tumors in Denmark, 1997-2019.

BACKGROUND: Incidence rates in Denmark of central nervous system (CNS) tumors remain among the highest in the world. Survival rates, however, have improved in the past decades in high-income countries. METHODS: We analyzed incidence and survival of childhood CNS tumors in Denmark diagnosed from 1997 to 2019 based on data from the Danish Childhood Cancer Registry and information on histological types, tumor localization, and treatment from medical records. RESULTS: From 1997 to 2019, 949 children<15 years were diagnosed with a CNS tumor. Age-standardized incidence was 42.1 (95% CI, 39.4-44.6) per million person-years and stable during this period. Age-specific incidence for children aged 0-4 years was 47.7 per million. More than one-third (n = 374, 39.4%) were treated with surgery alone. Overall survival rates 5 and 10 years after diagnosis were 77.6% (95% CI, 74.7-80.2) and 74.7% (95% CI, 71.7-77.5). Five-year overall survival improved from 73.0% (95% CI, 68.9-76.7) in 1997-2008 to 83.2% (95% CI, 79.2-86.4) in 2009-2019 (p-value < 0.0001) in children aged 0-4 years (p = 0.0006). CONCLUSION: Incidence rates are stable but remain among the highest in the world. Despite improved survival rates in recent years in younger children, some subtypes still have a poor prognosis.

Distribuição da Mortalidade Infantojuvenil por Tumores do Sistema Nervoso Central no Estado do Ceará / Distribution of Children and Adolescent Mortality by Central Nervous System Tumors in the State of Ceará / Distribución de la Mortalidad Infantil y Juvenil por Tumores del Sistema Nervioso Central en el Estado de Ceará

Introdução: Os tumores do sistema nervoso central (SNC) são um dos tipos mais comuns de tumores sólidos que acometem crianças. Apresentam heterogeneidade por compreender mais de 100 tipos histológicos definidos com base na origem da célula e outras características histopatológicas. Objetivo: Analisar a distribuição espacial da mortalidade por tumores do SNC em crianças e adolescentes no Estado do Ceará, no período de 2008-2018. Método: Estudo ecológico realizado com dados de fontes secundárias de 2008-2018 disponíveis no Sistema de Informação sobre Mortalidade (SIM). Foram calculadas as taxas brutas, o Índice de Moran Global e Local e o risco relativo para todos os óbitos. Resultados: Dos 378 óbitos, 197 eram do sexo masculino (52%), 116 apresentavam a faixa etária entre 5-9 anos (30,7%), 193 eram pardos (51%) e 354 morreram no hospital (93,6%). Os municípios que apresentaram as maiores taxas (49,94 e 99,88 óbitos/1 milhão de habitantes) foram Aracati, Barreira, Catunda, Coreaú e Fortaleza. Pelo Índice de Moran, observou-se a formação de um cluster com padrão alto-alto e significância estatística de distribuição na Mesorregião do Metropolitana de Fortaleza. O município de Pacujá apresentou o maior risco relativo (7,32) seguido do município de Catunda (6,94). Conclusão: As Regiões Norte e Noroeste do Ceará possuem taxas mais elevadas e risco maior para mortalidade por tumores do SNC

Introduction: Central nervous system (CNS) tumors are one of the most common types of solid tumors that affect children. Due to their heterogeneity, they comprise more than 100 defined histological types of cell origin-based and other histopathological characteristics. Objective: To analyze the spatial distribution of mortality by CNS tumors in children and adolescents in the State of Ceará in the period 2008-2018. Method: Ecological study, with secondary data of the period selected available in the Mortality Information System (SIM). Crude rates, Moran Global and Local index, and relative risk for all deaths were calculated. Results: Of the 378 deaths, 197 were males (52%) mostly, 116 aged between 5-9 years (30.7%), 193 brown (51%) and 354 died in the hospital (93.6%). The municipalities with the highest rates (49.94 and 99.88 deaths/1 million inhabitants) were Aracati, Barreira, Catunda, Coreaú and Fortaleza. The Moran Index showed the formation of a cluster with a high-high standard and statistical significance of distribution in the Metropolitana Fortaleza Mesoregion. The municipality of Pacujá had the highest relative risk (7.32) followed by the municipality of Catunda (6.94). Conclusion: The North and Northwest Regions of Ceará presented the higher mortality and risk rates by CNS tumors

Introducción: Los tumores del sistema nervioso central (SNC) son uno de los tipos más comunes de tumores sólidos que afectan a los niños. Presentan heterogeneidad al comprender más de 100 tipos histológicos definidos y basados en el origen celular y otras características histopatológicas. Objetivo: Analizar la distribución espacial de la mortalidad por tumores del SNC en niños y adolescentes en el Estado de Ceará en el período 2008-2018. Método: Estudio ecológico realizado con datos de fuentes secundarias de 2008-2018 disponibles en el Sistema de Información de Mortalidad (SIM). Se calcularon las tasas brutas, el Índice de Moran Global y Local y el riesgo relativo de todas las muertes. Resultados: De los 378 fallecidos, 197 eran varones (52%), 116 presentaban el grupo de edad entre 5-9 años (30,7%), 193 eran morenos (51%) y 354 murieron en el hospital (93,6%). Los municipios con mayores tasas (49,94 y 99,88 defunciones/1 millón de habitantes) fueron Aracati, Barreira, Catunda, Coreaú y Fortaleza. El Índice de Moran observó la formación de un cluster con un patrón alto-alto y significación estadística de distribución en la Mesoregión de Fortaleza Metropolitana. El municipio de Pacujá presentó el mayor riesgo relativo (7,32) seguido del municipio de Catunda (6,94). Conclusión: Las regiones del Norte y Noroeste de Ceará tienen tasas más elevadas y un mayor riesgo de mortalidad por tumores del SNC

Primary central nervous system lymphomas express immunohistochemical factors of autophagy.

Primary central nervous system lymphoma (PCNSL) is an aggressive and rare disease. Autophagy is a catabolic mechanism boosting various tumors, including lymphomas; its inhibition is thus a promising therapeutic target. Its presence has never been studied in PCNSLs. We conducted a retrospective immunohistochemical study of 25 PCNSLs for LC3B, p62, and M6PR, comparing it with clinicopathological characteristics. Fourteen (56%) and eleven (44%) PCNSLs were of low and high LC3B expression, respectively. p62 expression was present in most tumors (n = 21, 84%). M6PR was present in all tumors, with 14 (56%) and 11 (44%) cases being of low and high M6PR expression, respectively. LC3B expression was correlated with the performance status (PS) (p = 0.04). No association was found with other clinical parameters, such as deep structure invasion, multiple lesions, complete response, and recurrence after response. p62 showed a strong positive association with MUM1 expression (p = 0.0005). M6PR expression showed a positive correlation (p = 0.04) with PD-L1 expression. No association was found with p53, Ki67, CD8, BCL2, BCL6, or double MYC/BLC2 co-expressors. No association of LC3B, p62, and M6PR expression with survival was found. Our findings provide evidence for the possible presence of autophagic markers in PCNSLs and, thus, for possible treatment targets.

Neighborhood Socioeconomic Deprivation and Mortality in Children with Central Nervous System Tumors.

BACKGROUND: Although there is evidence of socioeconomic disparities in survival of children diagnosed with central nervous system (CNS) tumors, the impact of neighborhood socioeconomic deprivation on the survival of these malignancies has not been adequately studied. We investigated the association between area deprivation index (ADI), a measure of neighborhood socioeconomic disadvantage, and pediatric CNS tumor survival. METHODS: Demographic and clinical characteristics, geocoded addresses at diagnosis, and vital status of pediatric CNS tumor cases (n = 5,477) for the period 1995 to 2017 were obtained from the Texas Cancer Registry. ADI scores were computed for census tracts in Texas using the U.S. Census Bureau 2010 geography. Tracts were classified into quartiles as least, third-most, second-most, and most disadvantaged. Children were mapped to quartiles based on residency at diagnosis. The adjusted hazard ratio (HR) and 95% confidence interval (CI) were calculated. RESULTS: The results showed a significantly increased HR for death among children in the most (HR, 1.29; 95% CI, 1.09-1.51), second-most (HR, 1.18; 95% CI, 1.01-1.38), and third-most disadvantaged census tracts (HR, 1.18; 95% CI, 1.02-1.37) compared with children in the least disadvantaged tracts. CONCLUSIONS: Children living in the most disadvantaged neighborhoods experienced a significantly higher risk of mortality, indicating the important role of socioeconomic disparities in the survival of pediatric CNS tumors. IMPACT: The demographic and socioeconomic disparities identified by this study should be considered when planning treatment strategies for these susceptible groups and thus, lead to a better outcome in socioeconomically disadvantaged children diagnosed with CNS tumors.

Incidence and survival for childhood central nervous system tumours in Australia, 1983-2016.

PURPOSE: To investigate incidence and survival of childhood tumours of the central nervous system (CNS) by histological subtype, tumour behaviour and tumour grade. METHODS: National, population-based data on all children under 15 years old diagnosed with a CNS tumour between 1983 and 2016 were sourced from the Australian Childhood Cancer Registry. Incidence rate trends were calculated using Joinpoint regression. Relative survival was calculated using the cohort method, with changes in survival over time by cancer type and tumour grade assessed by multivariable flexible parametric survival modelling. RESULTS: The study cohort included 4914 patients, with astrocytoma (n = 2181, 44%) and embryonal tumours (n = 931, 19%) the most common diagnostic subgroups. Almost half (n = 2181, 44%) of all tumours were classified as high grade (III or IV). Incidence rates increased by 29% between 1983 and 2016, with high grade tumours rising by an annual average of + 1.1% (95% CI = + 0.7%, + 1.5%, p < 0.001). 5-year survival for all patients combined was 72% (95% CI = 71-74%), ranging from 50% (46-54%) for those with other gliomas to 81% (79-83%) for astrocytoma (p < 0.001). Survival improved over time for grade II and III ependymomas but not for patients with astrocytoma irrespective of grade. CONCLUSION: Improvements in diagnostic technology leading to more precise tumour classification are likely to explain some of the differences in incidence rate trends by histological type and grade. While improvements in survival over time were noted for some tumours, outcomes remained poor among patients with high-grade astrocytoma.

Combined tumor-associated macrophages biomarker predicting extremely poor outcome of patients with primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is an aggressive and rare malignancy with poor prognosis. However, there are no reliable prognostic biomarkers for PCNSL in clinical practice. Here, we aimed to identify a reliable prognostic biomarker for predicting the survival of PCNSL patients. In this study, multiplex immunofluorescence and digital imaging analysis were used to characterize tumor-associated macrophages (TAMs) immunophenotypes and the expression of programmed cell death ligand 1 on TAMs, with regard to prognosis from diagnostic tumor tissue samples of 59 PCNSL patients. We found that the M2-to-M1 ratio was a more reliable prognostic biomarker for PCNSL than M1-like or M2-like macrophage infiltration. In addition, the combination of programmed death-ligand 1 (PD-L1) expression on TAMs and the M2-to-M1 ratio in PCNSL demonstrated improved performance in prognostic discrimination than PD-L1-positive TAMs or M2-to-M1 ratio. To validate the prognostic significance of the combined TAMs associated biomarkers, they were integrated into the International Extranodal Lymphoma Study Group (IELSG) index and termed as IELSG-M index. Kaplan-Meier plots showed that the IELSG-M index could discriminate patients into low-, intermediate- or high-risk subgroups, better than IELSG, in terms of prognosis. The areas under the receiver operating characteristic curves of IELSG-M was 0.844 for overall survival; superior to the IELSG model (0.580). Taken together, this study's findings showed that the combination of PD-L1 on TAMs and the M2-to-M1 ratio could be strong prognostic predictive biomarkers for PCNSL and the IELSG-M index had improved prognostic significance than the IELSG index.

Significant improvement in survival of advanced stage childhood and young adolescent cancer in the Netherlands since the 1990s.

BACKGROUND: This is the first national study on trends in cancer survival and mortality for children and young adolescents in the Netherlands including unique information on stage at diagnosis. METHODS: All neoplasms in patients <18 years, diagnosed between 1990 and 2015 (N = 14,060), were derived from the Netherlands Cancer Registry. Cohort and period survival analyses were used to estimate observed survival (OS). Time trends in OS and mortality rates were evaluated by parametric survival models and average annual percentage change, respectively. RESULTS: Between 1990 and 2015, 5-year OS and 10-year OS of childhood and young adolescent cancer have improved significantly by 9 percent points, reaching 81% and 78%, respectively. Favourable trends in survival were observed for all age groups and most diagnostic (sub)groups, being particularly pronounced for advanced disease. Non-Hodgkin lymphomas Ann Arbor stage III, metastatic neuroblastomas (age ≥18 months) and Ewing bone sarcomas showed significant improvements in 5-year OS. Compared with 1990-99, the risk of dying within five years of diagnosis was decreased significantly during 2000-09 (hazard ratio [HR] = 0.8) and 2010-15 (HR = 0.6), after adjustment for age, gender and follow-up time. Nonetheless, the prognosis of young patients suffering from central nervous system tumours, neuroblastoma and osteosarcomas remained modest, with 5-year OS <70% and 10-year OS <65%. Childhood and young adolescent cancer mortality decreased by an average of 2.0% annually between 1990 and 2018. CONCLUSIONS: Significant progress has been realised in the prognosis of childhood and young adolescent cancer in the Netherlands since the 1990s. Survival improvements were especially evident for patients with advanced stages and were also reflected in the declining mortality rates.

Improved survival outcomes despite older age at diagnosis: an era-by-era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom.

Observational studies with long-term follow-up of patients with primary central nervous system lymphoma (PCNSL) are scarce. Patient data over a period of four decades were retrospectively analysed from databases at Nottingham University Hospitals Trust, UK. The cohort was delineated by two distinct therapeutic eras; the first from 01/01/1982 to 31/12/2010 (n = 147) and the second 01/01/2011 to 31/07/2020 (n = 125). The median age at diagnosis was significantly older in the second era compared to the first (69 and 65 years respectively, P = 0·003). The 3-, 6- and 12-month overall survival (OS) rates in the second era were significantly higher compared to the first, at 85%, 77%, 62% versus 56%, 49%, 38% respectively (log-rank test P < 0·0001). On multivariate analysis, high-dose methotrexate (HD-MTX)-based induction protocols employed in the second era were associated with improved OS compared to those used in the first [hazard ratio (HR) 0·40, 95% confidence interval (CI) 0·28-0·57]. Within the second era, superior OS rates were seen with the use of intensive HD-MTX protocols (including consolidation with high-dose chemotherapy and autologous stem cell transplantation) compared to non-intensive HD-MTX schedules (HR 0·47, 95% CI 0·22-0·99). Initiating chemotherapy within 14 days of biopsy and use of rituximab were independently associated with improved OS and progression-free survival during the second era. These data suggest that prompt treatment initiation and use of intensive HD-MTX- and rituximab-based protocols have resulted in improved survival outcomes for patients.

MYC, BCL2, and BCL6 expression as prognostic indicators in primary central nervous system lymphoma: A systematic review and meta-analysis.

BACKGROUND: We conducted a meta-analysis to comprehensively assess the predictive role of MYC, BCL2, and BCL6 genetic alterations and protein expression in PCNSL for clinical application. METHODS: A systematic retrieval was performed on PubMed, Embase, the Cochrane library, Web of Science, Scopus, and 2 Chinese databases. Cohort studies discussing the prognostic impact of MYC, BCl2, or BCL6 genetic alterations or gene expression in PCNSL were selected. The pooled hazard ratio (HR) and median survival ratio (MSR) were calculated. RESULTS: 31 studies involving 1739 patients fulfilled our inclusion criteria. MYC expression was significantly associated with short median OS (MSR = 0.62; 95%CI, 0.44-0.88) and PFS (HR = 1.53; 95%CI, 1.06-2.20). No significant association was found between BCL2 expression and OS or PFS (P > 0.05). BCL6 protein positivity was significantly associated with extended median OS (MSR = 1.62; 95%CI, 1.10-2.40). MYC and BCL2 coexpression was significantly associated with short median OS (MSR = 0.61; 95%CI, 0.45-0.84). Subgroup analysis demonstrated that MYC protein positivity remained as a significant indicator for short median OS in studies whose sample size ≥ 45, treatment without WBRT, quality scale score ≥ 7, and positivity threshold set at 40% stratum (MSR < 1 and P < 0.05), but failed to reach a statistically significant difference in the other stratum. CONCLUSIONS: MYC expression predicts inferior median OS and PFS in PCNSL. BCL6 protein positivity is associated with a favorable prognosis. The sample size, average age of subjects, WBRT treatment, study quality, and cut-off values for discriminating positive and negative protein expression in IHC may be origins of heterogeneity.

Brain and other central nervous system tumor statistics, 2021.

Brain and other central nervous system (CNS) tumors are among the most fatal cancers and account for substantial morbidity and mortality in the United States. Population-based data from the Central Brain Tumor Registry of the United States (a combined data set of the National Program of Cancer Registries [NPCR] and Surveillance, Epidemiology, and End Results [SEER] registries), NPCR, National Vital Statistics System and SEER program were analyzed to assess the contemporary burden of malignant and nonmalignant brain and other CNS tumors (hereafter brain) by histology, anatomic site, age, sex, and race/ethnicity. Malignant brain tumor incidence rates declined by 0.8% annually from 2008 to 2017 for all ages combined but increased 0.5% to 0.7% per year among children and adolescents. Malignant brain tumor incidence is highest in males and non-Hispanic White individuals, whereas the rates for nonmalignant tumors are highest in females and non-Hispanic Black individuals. Five-year relative survival for all malignant brain tumors combined increased between 1975 to 1977 and 2009 to 2015 from 23% to 36%, with larger gains among younger age groups. Less improvement among older age groups largely reflects a higher burden of glioblastoma, for which there have been few major advances in prevention, early detection, and treatment the past 4 decades. Specifically, 5-year glioblastoma survival only increased from 4% to 7% during the same time period. In addition, important survival disparities by race/ethnicity remain for childhood tumors, with the largest Black-White disparities for diffuse astrocytomas (75% vs 86% for patients diagnosed during 2009-2015) and embryonal tumors (59% vs 67%). Increased resources for the collection and reporting of timely consistent data are critical for advancing research to elucidate the causes of sex, age, and racial/ethnic differences in brain tumor occurrence, especially for rarer subtypes and among understudied populations.

Efficacy and Safety of Axicabtagene Ciloleucel and Tisagenlecleucel Administration in Lymphoma Patients With Secondary CNS Involvement: A Systematic Review.

Background: The efficacy and safety of chimeric antigen receptor T (CAR-T) cell therapy in the treatment of non-Hodgkin's lymphoma has already been demonstrated. However, patients with a history of/active secondary central nervous system (CNS) lymphoma were excluded from the licensing trials conducted on two widely used CAR-T cell products, Axicabtagene ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel). Hence, the objective of the present review was to assess whether secondary CNS lymphoma patients would derive a benefit from Axi-cel or Tisa-cel therapy, while maintaining controllable safety. Method: Two reviewers searched PubMed, Embase, Web of Science, and Cochrane library independently in order to identify all records associated with Axi-cel and Tisa-cel published prior to February 15, 2021. Studies that included secondary CNS lymphoma patients treated with Axi-cel and Tisa-cel and reported or could be inferred efficacy and safety endpoints of secondary CNS lymphoma patients were included. A tool designed specifically to evaluate the risk of bias in case series and reports and the ROBINS-I tool applied for cohort studies were used. Results: Ten studies involving forty-four patients were included. Of these, seven were case reports or series. The other three reports were cohort studies involving twenty-five patients. Current evidence indicates that secondary CNS lymphoma patients could achieve long-term remission following Axi-cel and Tisa-cel treatment. Compared with the non-CNS cohort, however, progression-free survival and overall survival tended to be shorter. This was possibly due to the relatively small size of the CNS cohort. The incidence and grades of adverse effects in secondary CNS lymphoma patients resembled those in the non-CNS cohort. No incidences of CAR-T cell-related deaths were reported. Nevertheless, the small sample size introduced a high risk of bias and prevented the identification of specific patients who could benefit more from CAR-T cell therapy. Conclusion: Secondary CNS lymphoma patients could seem to benefit from both Axi-cel and Tisa-cel treatment, with controllable risks. Thus, CAR-T cell therapy has potential as a candidate treatment for lymphoma patients with CNS involvement. Further prospective studies with larger samples and longer follow-up periods are warranted and recommended.

Sequencing of a central nervous system tumor demonstrates cancer transmission in an organ transplant.

Four organ transplant recipients from an organ donor diagnosed with anaplastic pleomorphic xanthoastrocytoma developed fatal malignancies for which the origin could not be confirmed by standard methods. We identified the somatic mutational profiles of the neoplasms using next-generation sequencing technologies and tracked the relationship between the different samples. The data were consistent with the presence of an aggressive clonal entity in the donor and the subsequent proliferation of descendent tumors in each recipient. Deleterious mutations in BRAF, PIK3CA, SDHC, DDR2, and FANCD2, and a chromosomal deletion spanning the CDKN2A/B genes, were shared between the recipients' lesions. In addition to demonstrating that DNA sequencing tracked a donor/recipient cancer transmission, this study established that the genetic profile of a donor tumor and its potential aggressive phenotype could have been determined before transplantation was considered. As the genetic correlates of tumor invasion and metastases become better known, adding genetic profiling by DNA sequencing to the data considered for transplant safety should be considered.