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.

Clinical outcomes of etoposide and cytarabine as consolidation in elderly patients with primary CNS lymphoma.

BACKGROUND: A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy. MATERIALS AND METHODS: Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy. RESULTS: Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications. CONCLUSION: EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.

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.

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.

Pre-treatment systemic inflammation response index and systemic immune inflammation in patients with primary central nerve system lymphoma as a useful prognostic indicator.

PURPOSE: The systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII) are based on neutrophil, monocyte, platelet, and lymphocyte counts. The SIRI and SII are used to predict the survival of patients with malignant tumors. It is well known that the inflammatory immune response is closely related to cancer occurrence and progression. In the present study, we evaluated the potential prognostic significance of SIRI and SII in patients with primary central nervous system lymphoma (PCNSL). METHODS: Fifty-eight consecutive patients were enrolled in this study between November 2006 and May 2022. Among the 58 patients, 47 patients with sufficient blood test data and follow-up were analyzed. The patients with steroid intake at the time point of the blood test and higher C-reactive protein were excluded. RESULTS: The median follow-up and survival times were 31 and 36 months, respectively. The optimal cutoff SIRI value was based on the receiver operating characteristic curve (ROC) for overall survival (OS) and stratified patients into low (< 1.43 × 109/L, n = 22) and high (≥ 1.43 × 109/L, n = 25) SIRI groups. The optimal cutoff SII value based on the ROC for OS stratified patients into low (< 694.9, n = 28) and high (≥ 694.9, n = 19) SII groups. A low SIRI value was associated with longer OS (p = 0.006). Furthermore, a low SII value was associated with longer OS (p = 0.044). The prognostic factors associated with prolonged survival in univariate analysis using the Cox proportional hazard model were age < 65 years, low SIRI, and low SII. The multivariate analysis demonstrated that age < 65 years and low SIRI independently predicted longer OS. CONCLUSION: Simple, less expensive, and routinely ordered preoperative blood count assessments such as SIRI and SII predict the OS of patients with PCNSL. This study demonstrated that PCNSL is associated with pre-treatment systemic immune-inflammation states.

Machine learning-based pathomics signature of histology slides as a novel prognostic indicator in primary central nervous system lymphoma.

PURPOSE: To develop and validate a pathomics signature for predicting the outcomes of Primary Central Nervous System Lymphoma (PCNSL). METHODS: In this study, 132 whole-slide images (WSIs) of 114 patients with PCNSL were enrolled. Quantitative features of hematoxylin and eosin (H&E) stained slides were extracted using CellProfiler. A pathomics signature was established and validated. Cox regression analysis, receiver operating characteristic (ROC) curves, Calibration, decision curve analysis (DCA), and net reclassification improvement (NRI) were performed to assess the significance and performance. RESULTS: In total, 802 features were extracted using a fully automated pipeline. Six machine-learning classifiers demonstrated high accuracy in distinguishing malignant neoplasms. The pathomics signature remained a significant factor of overall survival (OS) and progression-free survival (PFS) in the training cohort (OS: HR 7.423, p < 0.001; PFS: HR 2.143, p = 0.022) and independent validation cohort (OS: HR 4.204, p = 0.017; PFS: HR 3.243, p = 0.005). A significantly lower response rate to initial treatment was found in high Path-score group (19/35, 54.29%) as compared to patients in the low Path-score group (16/70, 22.86%; p < 0.001). The DCA and NRI analyses confirmed that the nomogram showed incremental performance compared with existing models. The ROC curve demonstrated a relatively sensitive and specific profile for the nomogram (1-, 2-, and 3-year AUC = 0.862, 0.932, and 0.927, respectively). CONCLUSION: As a novel, non-invasive, and convenient approach, the newly developed pathomics signature is a powerful predictor of OS and PFS in PCNSL and might be a potential predictive indicator for therapeutic response.

CAR T-cell therapy induces a high rate of prolonged remission in relapsed primary CNS lymphoma: Real-life results of the LOC network.

The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T-cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR-T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty-seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T-cells (tisa-cel: N = 16, axi-cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow-up after leukapheresis was 20.8 months. The best response after CAR-T cells was complete response in 16 patients (64%). One-year progression-free survival from leukapheresis was 43% with a plateau afterward. One-year relapse-free survival was 79% for patients in complete or partial response at CAR T-cell infusion. The median overall survival was 21.2 months. Twenty-three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T-cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T-cells reported worldwide. CAR T-cells are effective in relapsed PCNSL, with a high rate of long-term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting.

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.

Prognostic factors for CNS control in children with acute lymphoblastic leukemia treated without cranial irradiation.

To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).

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.

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).

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.

Temporal trends in childhood cancer survival in Egypt, 2007 to 2017: A large retrospective study of 14 808 children with cancer from the Children's Cancer Hospital Egypt.

Childhood cancer is a priority in Egypt due to large numbers of children with cancer, suboptimal care and insufficient resources. It is difficult to evaluate progress in survival because of paucity of data in National Cancer Registry. In this study, we studied survival rates and trends in survival of the largest available cohort of children with cancer (n = 15 779, aged 0-18 years) from Egypt between 2007 and 2017, treated at Children's Cancer Hospital Egypt-(CCHE), representing 40% to 50% of all childhood cancers across Egypt. We estimated 5-year overall survival (OS) for 14 808 eligible patients using Kaplan-Meier method, and determined survival trends using Cox regression by single year of diagnosis and by diagnosis periods. We compared age-standardized rates to international benchmarks in England and the United States, identified cancers with inferior survival and provided recommendations for improvement. Five-year OS was 72.1% (95% CI 71.3-72.9) for all cancers combined, and survival trends increased significantly by single year of diagnosis (P < .001) and by calendar periods from 69.6% to 74.2% (P < .0001) between 2007-2012 and 2013-2017. Survival trends improved significantly for leukemias, lymphomas, CNS tumors, neuroblastoma, hepatoblastoma and Ewing Sarcoma. Survival was significantly lower by 9% and 11.2% (P < .001) than England and the United States, respectively. Significantly inferior survival was observed for the majority of cancers. Although survival trends are improving for childhood cancers in Egypt/CCHE, survival is still inferior in high-income countries. We provide evidence-based recommendations to improve survival in Egypt by reflecting on current obstacles in care, with further implications on practice and policy.

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience.

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.

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.

R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma.

Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor necrosis factor-α coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 µg/m2) afterward. This trial included 2 phases: an "explorative phase" addressing the effect of NGR-hTNF on drug pharmacokinetic parameters and on vessel permeability, assessed by dynamic contrast-enhanced magnetic resonance imaging and 99mTc-diethylene-triamine-pentacetic acid-single-photon emission computed tomography, and the expression of CD13 on tumor tissue; and an "expansion phase" with overall response rate as the primary end point, in which the 2-stage Simon Minimax design was used. At the first stage, if ≥4 responses were observed among 12 patients, the study accrual would have continued (sample size, 28). Herein, we report results of the explorative phase and the first-stage analysis (n = 12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/cerebrospinal fluid concentrations. The NGR-hTNF/R-CHOP combination was well tolerated: there were only 2 serious adverse events, and grade 4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with 9 confirmed responses (75%; 95% confidence interval, 51-99), 8 of which were complete. In conclusion, NGR-hTNF/R-CHOP was safe in these heavily pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral/peritumoral areas, which resulted in fast and sustained responses.

A retrospective study of alectinib versus ceritinib in patients with advanced non-small-cell lung cancer of anaplastic lymphoma kinase fusion in whom crizotinib treatment failed.

BACKGROUND: Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking. METHODS: Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy. RESULTS: Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib. CONCLUSION: Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

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.

Prognosis and risk factors for central nervous system relapse after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia.

We performed a nested case-control study to investigate the incidence, treatment, and prognosis of central nervous system (CNS) relapse after allogenic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) and compared the outcomes of patients with CNS relapse following haploidentical donor (HID) HSCT versus identical sibling donor (ISD) HSCT. A total of 37 patients (HID-HSCT, 24; ISD-HSCT, 13) developed CNS relapse after transplantation between January 2009 and January 2019, with an incidence of 1.81%. The median time from transplantation to CNS relapse was 239 days. Pre-HSCT CNS involvement (HR 6.940, 95% CI 3.146-15.306, p < .001) was an independent risk factor for CNS relapse after allo-HSCT for AML. The 3-year overall survival (OS) for patients with CNS relapse was 60.3 ± 8.8%, which was significantly lower than that in the controls (81.5 ± 4.5%, p = .003). The incidence of CNS relapse was 1.64% for patients who received HID-HSCT and 2.55% for those who received ISD-HSCT (p = .193). There was no significant difference in OS between the HID-HSCT and ISD-HSCT subgroups among the patients with CNS relapse. In conclusion, CNS relapse is a rare but serious complication after allo-HSCT for AML, and the incidence and outcomes of patients with CNS relapse are comparable following HID-HSCT and ISD-HSCT.

Motor deficits at presentation and predictors of overall survival in central nervous system lymphomas.

PURPOSE: Central nervous system lymphomas (CNSL) can present with motor and non-motor symptoms. In many central nervous system tumors, motor deficits are associated with significant morbidity and functional impairment, and correlate with worse prognosis. CNSLs however, often exhibit remarkable response to chemotherapy and radiotherapy with corresponding symptom improvement. We investigate the survival outcomes and trajectories of motor and functional recovery in a cohort of patients presenting with and without initial motor deficits. METHODS: Patients who underwent biopsy and with a histologically confirmed CNSL between 2008 and 2019 were retrospectively identified. Baseline demographic variables, comorbidities, presenting symptoms, histological type, neuroimaging features (location and number of lesions), and treatment administered (pre- and post-operative steroid use and chemotherapy regime) were recorded. Dates of death were obtained from the National Registry of Births and Deaths. Motor power and performance status at admission, 1 month and 6 months were determined. RESULTS: We identified 119 patients, of whom 34% presented with focal motor deficits. The median overall survival (OS) was 26.6 months. Those with focal motor deficits had longer OS (median 42.4 months) than those without (median 23.3 months; p = 0.047). In multivariate Cox analysis, age (HR 1.04 per year; p = 0.003), CCI (HR 1.31 per point; p < 0.001), leptomeningeal/ependymal involvement (HR 2.53; p = 0.016), thalamus involvement (HR 0.34; p = 0.019), neutrophil:lymphocyte ratio (HR 1.06 per point; p = 0.034), positive HIV status (HR 5.31; p = 0.003), preoperative steroids use (HR 0.49; p = 0.018), postoperative high-dose steroids (HR 0.26; p < 0.001) and postoperative low-dose steroids (HR 0.28; p = 0.010) were significant predictors of OS. By one month, 43% of surviving patients had full power, increasing to 61% by six months. CONCLUSION: A significant proportion of patients with initial motor deficits recovered in motor strength by six months. In our population, those presenting with motor deficits had paradoxically better overall survival.