Lymphoma of the central nervous system originating from the septum pellucidum region: Two case reports with literature review.

RATIONALE: Central nervous system lymphoma (CNSL) originating from the septum pellucidum is exceptionally rare, presenting unique diagnostic and therapeutic complexities. This case report aims to elucidate the diagnostic challenges, treatment strategies, and outcomes of this rare manifestation. By documenting this case, we seek to enhance understanding within the medical community and contribute valuable insights to the management of CNSL, particularly in atypical locations. PATIENT CONCERNS: A 45-year-old female presented with persistent headaches, blurred vision, and motor weakness, prompting a thorough neurological evaluation. Imaging revealed an enhancing mass in the septum pellucidum, leading to the diagnosis of CNSL. The patient's concerns encompassed not only the physical symptoms but also the emotional impact of her diagnosis and treatment journey. DIAGNOSES: Diagnostic confirmation of CNSL involved cerebrospinal fluid analysis and imaging findings, highlighting the challenge of distinguishing lymphoma from other intracranial pathologies. The case underscores the importance of comprehensive diagnostic evaluation in rare CNSL presentations. INTERVENTIONS: Multidisciplinary management included high-dose methotrexate-based chemotherapy and corticosteroids, with consideration for neurosurgical intervention. Psychosocial support and self-care strategies were integrated into the treatment plan to address holistic patient needs. OUTCOMES: Monitoring revealed a positive treatment response, with a reduction observed in the septum pellucidum mass. Regular assessments ensured adherence to interventions and management of treatment-related side effects, contributing to favorable outcomes and improved quality of life for the patient. LESSONS: This case emphasizes the significance of meticulous diagnostic evaluation and personalized treatment approaches in managing rare CNSL presentations. Collaboration among specialists and comprehensive patient support is paramount in optimizing outcomes and addressing the multifaceted challenges posed by CNSL in unique anatomical locations.

Comparative analysis of bevacizumab and LITT for treating radiation necrosis in previously radiated CNS neoplasms: a systematic review and meta-analysis.

PURPOSE: Radiation necrosis (RN) is a local inflammatory reaction that arises in response to radiation injury and may cause significant morbidity. This study aims to evaluate and compare the efficacy of bevacizumab and laser interstitial thermal therapy (LITT) in treating RN in patients with previously radiated central nervous system (CNS) neoplasms. METHODS: PubMed, Cochrane, Scopus, and EMBASE databases were screened. Studies of patients with radiation necrosis from primary or secondary brain tumors were included. Indirect meta-analysis with random-effect modeling was performed to compare clinical and radiological outcomes. RESULTS: Twenty-four studies were included with 210 patients in the bevacizumab group and 337 patients in the LITT group. Bevacizumab demonstrated symptomatic improvement/stability in 87.7% of cases, radiological improvement/stability in 86.2%, and steroid wean-off in 45%. LITT exhibited symptomatic improvement/stability in 71.2%, radiological improvement/stability in 64.7%, and steroid wean-off in 62.4%. Comparative analysis revealed statistically significant differences favoring bevacizumab in symptomatic improvement/stability (p = 0.02), while no significant differences were observed in radiological improvement/stability (p = 0.27) or steroid wean-off (p = 0.90). The rates of adverse reactions were 11.2% for bevacizumab and 14.9% for LITT (p = 0.66), with the majority being grade 2 or lower (72.2% for bevacizumab and 62.5% for LITT). CONCLUSION: Both bevacizumab and LITT exhibited favorable clinical and radiological outcomes in managing RN. Bevacizumab was found to be associated with better symptomatic control compared to LITT. Patient-, diagnosis- and lesion-related factors should be considered when choosing the ideal treatment modality for RN to enhance overall patient outcomes.

Virtual multi-institutional tumor board: a strategy for personalized diagnoses and management of rare CNS tumors.

PURPOSE: Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers. METHODS: We retrospectively reviewed records from virtual MTBs held between 04/2020-03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions. RESULTS: During 25 meetings, 32 presenters discussed 44 cases. Approximately half (n = 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (n = 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (n = 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (n = 13), enrollment in the observational NCI Natural History Study to 21% (n = 9), neuropathology review and molecular testing at the NIH to 17% (n = 7), and all received management suggestions. CONCLUSION: Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management.

Treatment of secondary CNS lymphoma using CD19-targeted chimeric antigen receptor (CAR) T cells.

BACKGROUND: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported. METHODS: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity. RESULTS: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4+ central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient's CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells. CONCLUSIONS: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS.

Central Nervous System Metastases in Pediatric Patients With Ewing Sarcoma.

Metastatic central nervous system (CNS) involvement is rare in pediatric primary extracranial Ewing sarcoma (ES). We describe the incidence and course of 6 patients with extracranial ES who developed metastatic CNS lesions treated at a single institution. The median time to CNS disease detection was 16.3 months (10.0-28.3 months). Event-free and overall survival after CNS disease detection were 1.9 months (0.4 to 10.3 months) and 4.6 months (1.1 to 50.9 months), respectively. One patient was alive at the time of analysis. Clinical status and ability to obtain disease control should be considered when making decisions regarding aggressive interventions in these patients with poor prognosis.

Central nervous system tumours in neonates: what should the neonatologist know?

Central nervous system (CNS) tumours in neonates are relatively rare and present differently when compared with those occurring later in childhood in terms of aetiology, clinical features, location, histology and prognosis. The clinical presentation is extremely variable. Even if the most frequent clinical sign is a macrocephaly, there are many other non-specific symptoms associated. The prognosis is usually poor with overall survival of less than 30%. Surgery continues to be the primary treatment for neonatal CNS tumours, aiming for a gross total resection, directly correlated with prognosis and the overall outcome. The chemotherapy is the only adjuvant therapy whereas the radiotherapy is avoided under three years of age because of the severe sequelae. Hence the importance of molecular characterization of these neoplasms in order to improve the accuracy of the diagnosis and identify new therapeutic targets. The aim of this review is to describe the main characteristics of these tumours and the recent advances in their treatment in order to recognize these pathologies in the prenatal period and create a multidisciplinary team providing the best possible treatment while minimising the risk of long-term complications. Neonatologists play a key role in the early detection, diagnostic evaluation, management and supportive care of these neonates.  Conclusion: The aim of this review is to describe the main characteristics of these tumours and the recent advances in their treatment in order to ensure the essential knowledge that will help the neonatologist identify them and create a multidisciplinary team providing the best possible treatment while minimising the risk of long-term complications. What is Known: • Neonatal CNS tumours are relatively rare and their early identification is important to identify the best diagnostic-therapeutic management. • Surgery is the main treatment of neonatal CNS tumours. The extent of surgical resection directly correlates with prognosis and outcome. What is New: • Predisposing conditions such as Cancer Predisposition Syndromes must be considered. • Targeted drugs and other therapeutic strategies can be identified through molecular characterization.

Relevance of different prognostic scores in primary CNS lymphoma in the era of intensified treatment regimens: A retrospective, multicenter analysis of 174 patients.

OBJECTIVES: Treatment intensification (including consolidative high-dose chemotherapy with autologous stem cell transplantation [HDT-ASCT]) significantly improved outcome in primary central nervous system lymphoma (PCNSL) patients. METHODS: We conducted a multicenter, retrospective analysis of newly diagnosed PCNSL patients, treated with intensified treatment regimens. The following scores were evaluated in terms of overall survival (OS) and progression-free survival (PFS): Memorial Sloan-Kettering Cancer Center (MSKCC), International Extranodal Lymphoma Study Group (IELSG), and three-factor (3F) prognostic score. Further, all scores were comparatively investigated for model quality and concordance. RESULTS: Altogether, 174 PCNSL patients were included. One hundred and five patients (60.3%) underwent HDT-ASCT. Two-year OS and 2-year PFS for the entire population were 73.3% and 48.5%, respectively. The MSKCC (p = .003) and 3F score (p < .001), but not the IELSG score (p = .06), had the discriminatory power to identify different risk groups for OS. In regard to concordance, the 3F score (C-index [0.71]) outperformed both the MSKCC (C-index [0.64]) and IELSG (C-index [0.53]) score. Moreover, the superiority of the 3F score was shown for PFS, successfully stratifying patients in three risk groups, which also resulted in the highest C-index (0.66). CONCLUSION: The comparative analysis of established PCNSL risk scores affirm the clinical utility of the 3F score stratifying the widest prognostic spectrum among PCNSL patients treated with intensified treatment approaches.

A novel lactate dehydrogenase-based risk score model to predict the prognosis of primary central nervous system germ cell tumor treated with chemoradiotherapy.

BACKGROUND: The prognostic role of lactate dehydrogenase (LDH) has been confirmed in many malignant tumors, but the role of serum LDH in primary central nervous system germ cell tumor (GCT) remains unknown. This study aimed to assess the prognostic value of LDH in GCT patients and develop a nomogram to predict prognosis in patients undergoing chemoradiotherapy. METHODS: A total of 161 patients with GCT were included in this study. Using a restricted cubic spline (RCS) model, the optimal cutoff point for LDH was determined to be 217 U/L. The survival of GCT patients was evaluated using the Kaplan-Meier method and log-rank test to analyze the effects of LDH levels. Univariate Cox regression, multivariate Cox regression, and LASSO Cox regression were conducted to identify prognostic factors, which were incorporated into a nomogram for predicting overall survival (OS). The predictive accuracy of the nomogram was assessed using the C-index, calibration curve, area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and risk group stratification. The net benefits of the nomogram at different threshold probabilities were quantified using decision curve analysis (DCA). RESULTS: The high-LDH group had significantly shorter OS compared to the low-LDH group (P = 0.016). Based on the SYSUCC cohort, three variables were shown to be significant factors for OS and were incorporated in the nomogram: LDH, histopathology, and dissemination. It showed good discrimination ability, with C-index of 0.789 (95% CI, 0.671-0.907). Additionally, the clinical usefulness of the nomogram was confirmed by calibration curves and time-dependent AUC. DCA further highlighted the potential of the nomogram to guide clinical treatment strategies for patients. Moreover, there was a significant difference in OS among patients categorized into different risk groups (P < 0.001). CONCLUSION: LDH levels may serve as a reliable predictor for assessing the therapeutic effect of chemoradiotherapy in GCT. The developed nomogram exhibits high accuracy in predicting survival outcomes, aiding in the classification of prognostic groups, and supporting informed clinical decision-making.

Adolescents and Young Adults With Cancer: CNS Tumors.

Tumors of CNS are common in adolescents and young adults (AYAs). As the second leading cause of cancer-related death, CNS tumors in AYAs require improved clinical management. In this review, we discussed the current diagnostic approaches and recommended management strategies for malignant tumors in adult-type (IDH-mutant gliomas) and pediatric-type gliomas (pediatric high-grade gliomas), ependymoma and medulloblastoma, which commonly occur in AYAs. The impact of advanced molecular diagnostic approaches on the understanding of tumor biology of AYA CNS tumors is emphasized. To enhance participation in clinical trials, which poses a unique challenge in AYAs with CNS tumors, we propose encouraging referrals to neuro-oncology specialty care and improving collaboration between oncologists who care for both pediatric and adult patients. This will ensure better representation of AYA patients in research studies. Finally, we discussed the importance of considering neurocognitive and psychological function in AYAs with CNS tumor.

Diagnostic, Pathologic, and Therapeutic Considerations for Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) is a rare lymphoma representing 3% of CNS malignancies. The diagnosis is complicated by the unique risks associated with brain biopsy, and the treatment is similarly complicated by the restriction of effective therapeutics able to cross the blood-brain barrier. Currently, the majority of individuals diagnosed with this disease are immunocompetent although immune deficiency related to HIV or immunosuppressive therapy remains an important risk factor. Improvements in both frontline therapy and consolidation options, including the use of hematopoietic stem-cell transplantation, have translated to improved survival. Unfortunately, patients experiencing relapsed or refractory disease often fare poorly. Here, we review key clinical, pathologic, and therapeutic aspects of PCNSL and highlight challenging clinical scenarios that may be encountered by the treating oncologist.

Entirely noninvasive outcome prediction in central nervous system lymphomas using circulating tumor DNA.

ABSTRACT: State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD after treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in patients with CNSL (failure-free survival hazard ratio per risk group of 6.60; 95% confidence interval, 3.12-13.97; P < .0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way toward individualized treatment.

Measurement Properties of Patient-Reported Outcome Measures for Adolescent and Young Adult Survivors of a Central Nervous System Tumor: A Systematic Review.

Purpose: To identify and evaluate patient-reported outcome measures (PROMs) for assessing survivorship-related concepts for adolescent and young adult (AYA) survivors of central nervous system (CNS) tumors. Methods: We searched five electronic databases. Two researchers independently screened all titles for inclusion and used consensus-based standards for the selection of health measurement instruments (COSMIN) guidance to grade the quality of evidence for each measurement property. Results: Four studies met eligibility criteria: single-item pain thermometer; single-item fatigue thermometer; 37-item pediatric functional assessment of cancer therapy-brain tumor survivors, measuring quality of life; and 12-item Perceived Barriers Scale to assess barriers to employment. The Perceived Barrier Scale showed high-quality evidence for internal consistency and moderate quality evidence for construct and structural validity. Evidence for the measurement properties of the other PROMs was low-to-moderate quality. Conclusion: We found one PROM with sufficient evidence for good measurement properties to support its use. This warrants development and evaluation of further PROMs to inform ongoing supportive care for this population. Implications for Cancer Survivors: The Perceived Barriers Scale is sufficiently validated and could be considered to guide support for AYA survivors of CNS tumors to achieve their employment goals.

Acute Lymphoblastic Leukemia with Central Nervous System Involvement-Challenges in Management.

The survival of patients with acute lymphoblastic leukemia (ALL) has dramatically improved during the last six decades. This improvement is secondary to improved diagnostics, risk stratification of treatment by biological features and response to treatment, improved supportive care, and the introduction of new treatment modalities such as immunotherapy and molecular targeted therapy. However, many questions remain concerning the involvement of the central nervous system (CNS) in leukemia, including ones pertaining to the risk factors for CNS involvement and relapse, the optimal treatment strategy to prevent relapse, and the role of newer therapies. This review discusses these questions by addressing the diagnosis of CNS leukemia, the current clinical trial data for treatment regimens with CNS activity, and issues specific to treatment in low- and middle-income countries (LMICs).

Preclinical pediatric brain tumor models for immunotherapy: Hurdles and a way forward.

Brain tumors are the most common solid tumor in children and the leading cause of cancer-related deaths. Over the last few years, improvements have been made in the diagnosis and treatment of children with Central Nervous System tumors. Unfortunately, for many patients with high-grade tumors, the overall prognosis remains poor. Lower survival rates are partly attributed to the lack of efficacious therapies. The advent and success of immune checkpoint inhibitors (ICIs) in adults have sparked interest in investigating the utility of these therapies alone or in combination with other drug treatments in pediatric patients. However, to achieve improved clinical outcomes, the establishment and selection of relevant and robust preclinical pediatric high-grade brain tumor models is imperative. Here, we review the information that influenced our model selection as we embarked on an international collaborative study to test ICIs in combination with epigenetic modifying agents to enhance adaptive immunity to treat pediatric brain tumors. We also share challenges that we faced and potential solutions.

Molecular neuropathology: an essential and evolving toolbox for the diagnosis and clinical management of central nervous system tumors.

Molecular profiling has transformed the diagnostic workflow of CNS tumors during the last years. The latest WHO classification of CNS tumors (5th edition), published in 2021, pushed forward the integration between histopathological features and molecular hallmarks to achieve reproducible and clinically relevant diagnoses. To address these demands, pathologists have to appropriately deal with multiple molecular assays mainly including DNA methylation profiling and DNA/RNA next generation sequencing. Tumor classification by DNA methylation profiling is now a critical tool for many diagnostic tasks in neuropathology including the assessment of complex cases, to evaluate novel tumor types and to perform tumor subgrouping in hetereogenous entities like medulloblastoma or ependymoma. DNA/RNA NGS allow the detection of multiple molecular alterations including single nucleotide variations, small insertions/deletions (InDel), and gene fusions. These molecular markers can provide key insights for diagnosis, for example, if a tumor-specific mutation is detected, but also for treatment since targeted therapies are progressively entering the clinical practice. In the present review, a brief, but comprehensive overview of these tools will be provided, discussing their technical specifications, diagnostic value, and potential limitations. Moreover, the importance of molecular profiling will be shown in a representative series of CNS neoplasms including both the most frequent tumor types and other selected entities for which molecular characterization plays a critical role.

Palliative care for children with central nervous system tumors: results of a Spanish multicenter study.

BACKGROUND: Brain tumors represent the most common cause of cancer-related death in children. Few studies concerning the palliative phase in children with brain tumors are available. OBJECTIVES: (i) To describe the palliative phase in children with brain tumors; (ii) to determine whether the use of palliative sedation (PS) depends on the place of death, the age of the patient, or if they received specific palliative care (PC). METHODS: Retrospective multicenter study between 2010 and 2021, including children from one month to 18 years, who had died of a brain tumor. RESULTS: 228 patients (59.2% male) from 10 Spanish institutions were included. Median age at diagnosis was 5 years (IQR 2-9) and median age at death was 7 years (IQR 4-11). The most frequent tumors were medulloblastoma (25.4%) and diffuse intrinsic pontine glioma (DIPG) (24.1%). Median number of antineoplastic regimens were 2 (range 0-5 regimens). During palliative phase, 52.2% of the patients were attended by PC teams, while 47.8% were cared exclusively by pediatric oncology teams. Most common concerns included motor deficit (93.4%) and asthenia (87.5%) and communication disorders (89.8%). Most frequently prescribed supportive drugs were antiemetics (83.6%), opioids (81.6%), and dexamethasone (78.5%). PS was administered to 48.7% patients. Most of them died in the hospital (85.6%), while patients who died at home required PS less frequently (14.4%) (p = .01). CONCLUSION: Children dying from CNS tumors have specific needs during palliative phase. The optimal indication of PS depended on the center experience although, in our series, it was also influenced by the place of death.

Trends in pediatric CNS tumors in Armenia: a multicenter retrospective study.

PURPOSE: Central nervous system (CNS) tumors are the most common solid malignancies in children worldwide, including in Armenia. The current study aims to analyze epidemiological data, treatment, and outcomes of children and young adults (≤25 years) with CNS tumors in Armenia during the last 26 years. METHODS: We collected data from pediatric and young adult patients treated in selected sites in Armenia from 1st January 1995 to 31st December 2020. Incidence by sex, age at diagnosis, time from first complaints to diagnosis, histopathology results, treatment strategies, complications, and overall survival (OS) rates were calculated. RESULTS: The multicenter data analysis revealed 149 patients with diagnosed primary CNS tumors over 26 years. Among them, 84 (56.4%) were male. The median age at diagnosis was 7 years (range, 3 months to 25 years), and the median time from the first complaints to diagnosis was 2 months (range, 1 week to 70 months). Medulloblastomas and other embryonal tumors (47), low-grade gliomas (32), and high-grade gliomas (22) were the most commonly diagnosed malignancies. Ependymomas, craniopharyngiomas, germ cell tumors, and other malignancies were observed in 22 patients. For 26 patients, no histopathological or radiological diagnosis was available. Follow-up information was available for 98 (65.8%) patients. The 5-year OS rate for the whole study group was 67.7%. CONCLUSION: Consistent with international data, embryonal tumors, and gliomas were the most commonly diagnosed CNS malignancies in Armenia. Multimodal treatment was often not available in Armenia during the study period, especially for early cases.

Primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma (NHL) manifesting in the brain, spinal cord, cerebrospinal fluid and/or eyes, in the absence of systemic manifestations. With an increasing incidence and a 30% 5-year overall survival if promptly treated, timely diagnosis and subsequent treatment is paramount. The typical MRI appearance for PCNSL is a solitary or multiple T2-hypointense, homogeneous gadolinium-enhancing lesion with restricted diffusion. Dexamethasone treatment might compromise and delay the diagnosis. Hallmark of treatment is induction with intravenous high-dose methotrexate consisting polychemotherapy followed by consolidation treatment. Consolidation treatment consists of either whole brain radiotherapy (WBRT) or autologous stem cell transplantation (ASCT). Given the (cognitive) side effects of WBRT, ASCT is increasingly being used as the first choice of treatment.