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Purpose: Primary central nervous system lymphoma (PCNSL) is a rare malignancy of the central nervous system with high invasiveness. There is little consensus on the treatment of PCNSL. This study retrospectively studied data from PCNSL patients in a single center to summarize treatment experience and explore prognostic factors. Methods: Survival curves were drawn using the Kaplan–Meier method and prognostic factors were analyzed using Cox's hazards model. Results: In multivariate analysis, cerebrospinal fluid lactic acid dehydrogenase (CSF LDH; p = 0.005 and p = 0.002), neutrophil to lymphocyte ratio (NLR; p = 0.014 and p = 0.038), and completion of four cycles of induction therapy (p < 0.001and p < 0.001) were significant and independent predictors of overall survival (OS) and progression-free survival (PFS), respectively. Conclusion: On the basis of this study, we propose that PCNSL patients should receive early induction therapy with sufficient cycles. Subsequent consolidation therapy can prevent relapses and improve survival. In patients with PCNSL, the independent prognostic factors for OS and PFS were CSF LDH level, NLR, and full cycles of induction therapy. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma is a rare form of central nervous system malignancy. It predominantly affects immunocompromised individuals and the elderly population. Diffuse large B-cell lymphoma is the most common type. This case report presents a 35-year-old female patient presented with progressive difficulty maintaining balance, headaches, seizures, and blurry vision for 2 months. Physical examination was unremarkable except for sluggish bilateral pupillary reaction and lower extremity weakness. MRI revealed multiple bilateral intraaxial masses. Biopsy and immunohistochemistry confirmed diffuse large B-cell lymphoma, nongerminal center B-cell type. However, the diagnosis was delayed for 4 months. The delay in the diagnosis was caused by its atypical presentation, a surgical site infection, and limited resources, which led the patient to disregard the recommended treatment and leave the hospital against medical advice. Even in the absence of risk factors of primary central nervous system lymphoma, it should be considered as a differential in a young patient with neurologic symptoms and intraaxial mass. Minimally invasive biopsy techniques and readily available immunohistochemistry are essential for prompt diagnosis and guiding treatment.

Abstract Background Despite recent advances, optimal therapeutic approaches applicable to subpopulations with primary central nervous system (CNS) lymphoma outside of clinical trials remain to be determined. Methods We performed a retrospective study of immunocompetent, adult patients with histologically confirmed diffuse large B‐cell lymphoma of the CNS (PCNSL). 190/204 (93%) patients (median age: 65) received one of five high‐dose methotrexate (HD‐MTX) containing chemotherapy regimens: MPV/Ara‐C (HD‐MTX, procarbazine, and vincristine, followed by cytarabine [Ara‐C]) (n = 94, 50%), MATRix (HD‐MTX, Ara‐C, thiotepa, and rituximab) (n = 19, 10%), HD‐MTX/Ara‐C (n = 31, 16%), HD‐MTX monotherapy (n = 35, 18%) and MBVP (HD‐MTX, carmustine, teniposide, prednisolone) (n = 11, 6%). Results Cumulative median HD‐MTX and Ara‐C doses were 17 g/m2 (range: 1–64 g/m2) and 12 g/m2 (0–32 g/m2) respectively. Using 14 g/m2 as the reference dose, the median HD‐MTX relative dose intensity (HD‐MTX‐RDI) was 1.25 (0.27‐4.57) with 84% receiving > 0.75. The overall response rate (ORR) was 72% (complete response: 50%) after completing HD‐MTX. At a median follow‐up of 3.41 years (0.06–9.42), progression‐free survival (PFS) and overall survival (OS) were different between chemotherapy cohorts, with the best outcomes achieved in the MPV/Ara‐C cohort (2‐year PFS 74%, 2‐year OS 82%; p = 0.0001 and p = 0.0024 respectively). On multivariate analysis, MPV/Ara‐C administration and HD‐MTX‐RDI > 0.75 were associated with longer PFS and OS. Conclusion Sequential, response‐adapted approaches can improve outcomes, even in older patients who are ineligible for a high‐intensity concurrent chemotherapy approach and do not undergo traditional consolidative strategies.

Abstract Background Diagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy. Case presentations. The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3. Conclusions Taken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment.

A key limitation in treatment initiation in primary central nervous system lymphoma (PCNSL) is the diagnostic delay caused by lack of recognition of a lesion as a possible lymphoma, steroid initiation, and lesion involution, often resulting in an inconclusive biopsy result. We highlight the importance of multiparametric magnetic resonance imaging (MRI), which incorporates diffusion-weighted imaging, dynamic susceptibility contrast-enhanced perfusion-weighted imaging, and proton magnetic resonance spectroscopy in addition to standard MRI sequences in resolving diagnostic uncertainty for PCNSL. At our center, a consecutive series of 10 patients with histology-proven PCNSL (specifically, diffuse large B-cell lymphoma of the central nervous system) underwent multiparametric MRI. We retrospectively analyzed qualitative and semiquantitative parameters and assessed their radiological concordance for this diagnosis. We noted overall low apparent diffusion coefficient on diffusion-weighted imaging (mean minimum apparent diffusion coefficient of 0.74), high percentage signal recovery on perfusion-weighted imaging (mean 170%), a high choline-to-creatine ratio, and a high-grade lipid peak on proton magnetic resonance spectroscopy giving an appearance of twin towers. Of 10 patients, 9 had MRI findings concordant for PCNSL, defined as at least 3 of 4 parameters being consistent for PCNSL. Concordance between these imaging multiparametric modalities could be used as a radiological predictor of PCNSL, reducing diagnostic delays, providing a more accurate biopsy target, and resulting in quicker treatment initiation. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive lymphoma entirely localized in the central nervous system or vitreoretinal space. PCNSL generally initially responds to methotrexate-containing chemotherapy regimens, but progressive or relapsing disease is common, and the prognosis is poor for relapsed or refractory (R/R) patients. PCNSL is often characterized by activation of nuclear factor kappa B (NF-κB) due to mutations in the B-cell receptor (BCR) or toll-like receptor (TLR) pathways, as well as immune evasion. Targeted treatments that inhibit key PCNSL mechanisms and pathways are being evaluated; inhibition of Bruton's tyrosine kinase (BTK) downstream of BCR activation has demonstrated promising results in treating R/R disease. This review will summarize the evidence and potential for targeted therapeutic agents to improve treatment outcomes in PCNSL. This includes immunotherapeutic and immunomodulatory approaches and inhibitors of the key pathways driving PCNSL, such as aberrant BCR and TLR signaling. [ABSTRACT FROM AUTHOR]

Background: Diagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy. Case presentations. The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3. Conclusions: Taken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma is a kind of extranodal lymphoma with high degree of malignancy, hidden onset and strong invasion. It is a special type of non-Hodgkin's lymphoma and very rare in clinic. Due to little understanding of the pathogenesis and high risk factors of the disease, there are great differences in the prevention, staging and treatment plan of the disease, and there is no strict standard. In this review, we aim to comprehensively summarize the clinical characteristics of PCNSL and the promising clinical treatment strategies for PCNSL to date. [ABSTRACT FROM AUTHOR]

Primary Angiitis of the Central Nervous System (PACNS) is a rare disease and its diagnosis is a challenge for several reasons, including the lack of specificity of the main findings highlighted in the current diagnostic criteria. Among the neuroimaging pattern of PACNS, a tumefactive form (t-PACNS) is a rare subtype and its differential diagnosis mainly relies on neuroimaging. Tumor-like mass lesions in the brain are a heterogeneous category including tumors (in particular, primary brain tumors such as glial tumors and lymphoma), inflammatory (e.g., t-PACNS, tumefactive demyelinating lesions, and neurosarcoidosis), and infectious diseases (e.g., neurotoxoplasmosis). In this review, the main features of t-PACNS are addressed and the main differential diagnoses from a neuroimaging perspective (mainly Magnetic Resonance Imaging—MRI—techniques) are described, including conventional and advanced MRI. [ABSTRACT FROM AUTHOR]

Background and Purpose: Dynamic susceptibility contrast‐enhanced (DSC) MR perfusion is a valuable technique for distinguishing brain tumors. Diagnostic potential of measurable parameters derived from preload leakage‐corrected‐DSC‐MRI remains somewhat underexplored. This study aimed to evaluate these parameters for differentiating primary CNS lymphoma (PCNSL), glioblastoma, and metastasis. Methods: Thirty‐nine patients with pathologically proven PCNSL (n = 14), glioblastoma (n = 14), and metastasis (n = 11) were analyzed. Five DSC parameters—relative CBV (rCBV), percentage of signal recovery (PSR), downward slope (DS), upward slope (US), and first‐pass slope ratio—were derived from tumor‐enhancing areas. Diagnostic performance was assessed using receiver operating characteristic curve analysis. Results: RCBV was higher in metastasis (4.58; interquartile range [IQR]: 2.54) and glioblastoma (3.98; IQR: 1.87), compared with PCNSL (1.46; IQR: 0.29; p =.00006 for both). rCBV better distinguished metastasis and glioblastoma from PCNSL, with an area under the curve (AUC) of 0.97 and 0.99, respectively. PSR was higher in PCNSL (88.11; IQR: 21.21) than metastases (58.30; IQR: 22.28; p =.0002), while glioblastoma (74.54; IQR: 21.23) presented almost significant trend‐level differences compared to the others (p≈.05). AUCs were 0.79 (PCNSL vs. glioblastoma), 0.91 (PCNSL vs. metastasis), and 0.78 (glioblastoma vs. metastasis). DS and US parameters were statistically significant between glioblastoma (−109.92; IQR: 152.71 and 59.06; IQR: 52.87) and PCNSL (−47.36; IQR: 44.30 and 21.68; IQR: 16.85), presenting AUCs of 0.86 and 0.87. Conclusion: Metastasis and glioblastoma can be better differentiated from PCNSL through rCBV. PSR demonstrated higher differential performance compared to the other parameters and seemed useful, allowing a proper distinction among all, particularly between metastasis and glioblastoma, where rCBV failed. Finally, DS and US were only helpful in differentiating glioblastoma from PCNSL. [ABSTRACT FROM AUTHOR]

Background: Neurological manifestations are one of the major concerns for patients with human immunodeficiency virus (HIV). The secondary spectrum includes space-occupying lesions (SOL), including tuberculoma, cryptococcosis, candidiasis, toxoplasmosis, primary central nervous system lymphoma (PCNSL), and progressive multifocal leukoencephalopathy (PML). Aim: To assess the neurological manifestations, disease outcome, and their associations with cluster of differentiation 4 (CD4) counts in patients with HIV. Materials and Methods: This single-center, prospective, observational study was performed in the Department of General Medicine of a tertiary care institute, over a period of 2 years (January 2017 to December 2018). The study included 150 known or newly diagnosed HIV patients with CNS SOL. The physical examination, laboratory investigations, and imaging were conducted on every patient, and the findings were noted. Results: The patients mainly presented with hemiparesis (52%), had involvement of the frontal region (38.7%), and were diagnosed with tuberculoma (29.3%). Other diagnoses were toxoplasmosis (22.7%), PML (17.3%), PCNSL (15.3%), brain abscess (10%), and neurocysticercosis (5.3%). Of 150 patients, 136 (90.7%) were survivors, while 14 (9.3%) were non-survivors. The mean CD4 count was significantly less in patients with toxoplasmosis (P < 0.0001) and PCNSL (P = 0.02), and significantly higher in patients with tuberculoma (P < 0.0001) and brain abscess (P = 0.0009) relative to other causes of SOL. Moreover, the mean CD4 count was not significantly associated with survivors and non-survivors (P = 0.28). Conclusion: In patients with HIV, CD4 count was significantly low in toxoplasmosis and PCNSL, and high in tuberculoma and brain abscess. [ABSTRACT FROM AUTHOR]

Background: Neurological manifestations are one of the major concerns for patients with human immunodeficiency virus (HIV). The secondary spectrum includes space-occupying lesions (SOL), including tuberculoma, cryptococcosis, candidiasis, toxoplasmosis, primary central nervous system lymphoma (PCNSL), and progressive multifocal leukoencephalopathy (PML). Aim: To assess the neurological manifestations, disease outcome, and their associations with cluster of differentiation 4 (CD4) counts in patients with HIV. Materials and Methods: This single-center, prospective, observational study was performed in the Department of General Medicine of a tertiary care institute, over a period of 2 years (January 2017 to December 2018). The study included 150 known or newly diagnosed HIV patients with CNS SOL. The physical examination, laboratory investigations, and imaging were conducted on every patient, and the findings were noted. Results: The patients mainly presented with hemiparesis (52%), had involvement of the frontal region (38.7%), and were diagnosed with tuberculoma (29.3%). Other diagnoses were toxoplasmosis (22.7%), PML (17.3%), PCNSL (15.3%), brain abscess (10%), and neurocysticercosis (5.3%). Of 150 patients, 136 (90.7%) were survivors, while 14 (9.3%) were non-survivors. The mean CD4 count was significantly less in patients with toxoplasmosis (P < 0.0001) and PCNSL (P = 0.02), and significantly higher in patients with tuberculoma (P < 0.0001) and brain abscess (P = 0.0009) relative to other causes of SOL. Moreover, the mean CD4 count was not significantly associated with survivors and non-survivors (P = 0.28). Conclusion: In patients with HIV, CD4 count was significantly low in toxoplasmosis and PCNSL, and high in tuberculoma and brain abscess.

Background. Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma which may affect brain parenchyma. Hyponatremia can be present as one of the complications, either due to neuronal injury arising from in-situ tumor and/or surgical resection (resulting in cerebral salt wasting syndrome/CSWS) or indolent, slowly progressing and often asymptomatic one as a consequence of ongoing chronic illness (so-called syndrome of inappropriate antidiuretic hormone/SIADH). Differentiating between the two is critical, since each diagnosis has a starkly different treatment approach which may exacerbate one another. Case presentation. Herein, we reported a case of a 48-year-old immunocompetent male who presented with diplopia, hallucination, imbalance, and dizziness, later to be diagnosed with PCNSL on multiple brain regions. He suffered from symptomatic hyponatremia post-surgically as a result of CSWS which in turn responding well to intensive dose of desmopressin acetate and fluid replenishment. However, as the disease progressed, hyponatremia also relapsed but was refractory to the same treatment approach. After subsequent investigations, patient was known to have SIADH. Treatments tailored to SIADH including fluid restriction and administration of hypertonic saline as well as tolvaptan lead to stabilization of sodium levels and significant clinical improvements. Conclusion. Post-operative hyponatremia in the setting of a PCNSL continues to be a complex issue. It underscores the importance of careful clinical assessment, monitoring, and the need for flexibility in diagnosis and management strategies. Furthermore, it highlights the challenges of distinguishing between CSWS and SIADH, two conditions with similar laboratory findings but divergent management approaches. Recognizing the subtleties in clinical presentation and responding appropriately can greatly influence patient outcomes. The rising incidence of PCNSL in immunocompetent individuals also needs a heightened awareness and understanding of its presentations and potential post-operative complications among clinicians.

Simple Summary: Malignant lymphomata originating from the central nervous system are rare entities and usually are characterized by rapid growth, requiring intensified treatment. In contrast, low-grade lymphoma variants may be treated using radiotherapy alone. As the majority of cases arise from the dura, only very few cases of parenchymal low-grade lymphoma have been reported in the literature. We present a retrospective analysis of two patients treated with involved-site radiotherapy at our institution and discuss the available literature. Overall, these patients have a good prognosis and may be treated using primary radiation therapy. Background: Primary lymphoma of the central nervous system (PCNSL) encompasses a variety of lymphoma subtypes, with the majority being diffuse large B-cell lymphomas, which require aggressive systemic treatment. In contrast, low-grade lymphomas are reported infrequently and are mostly limited to dural manifestations. Very rarely, parenchymal low-grade PCNSL is diagnosed, and the cases documented in the literature show a wide variety of treatment approaches. Methods: We screened all cases of PCNSL treated at our department (a tertiary hematooncology and neurooncology center) in the last 15 years and conducted a comprehensive literature research in the PubMed database. Results: Overall, two cases of low-grade primary parenchymal PCNSL treated with irradiation were identified. The dose prescriptions ranged from 30.6 to 36 Gy for the involved site, with sparing of the hippocampal structures. Both patients had an excellent response to the treatment with a mean follow-up of 20 months. No clinical or radiological signs of treatment toxicity were detected. Conclusions: Our analysis corroborates the results from the literature and demonstrates that parenchymal low-grade PCNSL shows a good response to localized radiation treatment, enabling a favorable outcome while avoiding long-term treatment toxicity. [ABSTRACT FROM AUTHOR]

The role of surgery in the management of primary central nervous system lymphomas (PCNSL) is currently confined to diagnosis. However, over recent years, an increasing number of papers have suggested a possible positive prognostic impact of surgery in selected cases. The present work aims to perform a meta-analysis of the available literature evidence. A meta-analysis with meta-regression on the role of surgical resection compared to biopsy in the management of PCNSL was conducted according to the PRISMA statement, searching MEDLINE via PubMed and Embase. The random effect model was used. The quality of evidence was assessed using the GRADE framework. After screening 1395 records, we included 11 papers in our analysis. Patients who underwent surgical resection harbored superficial and single-lesion tumors. At 1-, 2-, and 5-year follow-up, progression-free survival did not differ between the two groups, while overall survival favored resection, even if in a non-significant fashion. Meta-regression analysis showed that the overall survival rate at 2 years, but not at 1 or 5 years, was significantly influenced by tumor location. There were no differences in terms of age, sex, Karnofsky performance status, adjuvant therapy, or procedure-related complications. Overall, the quality of evidence is low. The results of the present meta-analysis do not change the current standard of care for PCNSL. However, surgery could be non-inferior to biopsy with an acceptable risk profile in selected patients harboring single and superficial lesions. The low quality of evidence prompts future randomized studies. [ABSTRACT FROM AUTHOR]

Abstract Purpose One of the main limiting factors of whole-brain radiation therapy (WBRT) for primary central nervous system lymphoma (PCNSL) is the impairment of neurocognitive functions (NCFs), which is mainly caused by radiation-induced injury to the hippocampus. With a view to preventing NCF impairment and personalizing treatment, we explored the feasibility of sparing the hippocampus during WBRT by correlating the sites of PCNSL lesions with the hippocampus. Methods and materials Pre-treatment MR images from patients who underwent WBRT between 2010 and January 2020—and post-radiotherapy images in cases of relapse—were imported into the Varian Eclipse treatment-planning system and registered with the simulation CT. We constructed three 3-dimensional envelopes around the hippocampus at distances of 5, 10 and 15 mm and also contoured primary lesions and recurrences. Results We analyzed 43 patients with 66 primary lesions: 9/66 (13.6%) involved the hippocampus and 11/66 (16.7%) were located within 5 mm of it. Thirty-six lesions (54.5%) were situated more than 15 mm from the hippocampus, while 10/66 (15.2%) were between 5 and 15 mm from it. The most common location was in deep brain structures (31%). Thirty-five of the 66 lesions relapsed: in field in 14/35 (40%) and outfield in 21/35 (60%) in different sites. Globally, 16/35 recurrences (45.7%) were located in the hippocampus or within 5 mm of it. Conclusion These data show that routinely sparing the hippocampus is not feasible. This approach could be considered in selected patients, when the lesion is more than 15 mm from the hippocampus.

Background. Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma which may affect brain parenchyma. Hyponatremia can be present as one of the complications, either due to neuronal injury arising from in-situ tumor and/or surgical resection (resulting in cerebral salt wasting syndrome/CSWS) or indolent, slowly progressing and often asymptomatic one as a consequence of ongoing chronic illness (so-called syndrome of inappropriate antidiuretic hormone/SIADH). Differentiating between the two is critical, since each diagnosis has a starkly different treatment approach which may exacerbate one another. Case presentation. Herein, we reported a case of a 48-year-old immunocompetent male who presented with diplopia, hallucination, imbalance, and dizziness, later to be diagnosed with PCNSL on multiple brain regions. He suffered from symptomatic hyponatremia post-surgically as a result of CSWS which in turn responding well to intensive dose of desmopressin acetate and fluid replenishment. However, as the disease progressed, hyponatremia also relapsed but was refractory to the same treatment approach. After subsequent investigations, patient was known to have SIADH. Treatments tailored to SIADH including fluid restriction and administration of hypertonic saline as well as tolvaptan lead to stabilization of sodium levels and significant clinical improvements. Conclusion. Post-operative hyponatremia in the setting of a PCNSL continues to be a complex issue. It underscores the importance of careful clinical assessment, monitoring, and the need for flexibility in diagnosis and management strategies. Furthermore, it highlights the challenges of distinguishing between CSWS and SIADH, two conditions with similar laboratory findings but divergent management approaches. Recognizing the subtleties in clinical presentation and responding appropriately can greatly influence patient outcomes. The rising incidence of PCNSL in immunocompetent individuals also needs a heightened awareness and understanding of its presentations and potential post-operative complications among clinicians. [ABSTRACT FROM AUTHOR]

Purpose: One of the main limiting factors of whole-brain radiation therapy (WBRT) for primary central nervous system lymphoma (PCNSL) is the impairment of neurocognitive functions (NCFs), which is mainly caused by radiation-induced injury to the hippocampus. With a view to preventing NCF impairment and personalizing treatment, we explored the feasibility of sparing the hippocampus during WBRT by correlating the sites of PCNSL lesions with the hippocampus. Methods and materials: Pre-treatment MR images from patients who underwent WBRT between 2010 and January 2020—and post-radiotherapy images in cases of relapse—were imported into the Varian Eclipse treatment-planning system and registered with the simulation CT. We constructed three 3-dimensional envelopes around the hippocampus at distances of 5, 10 and 15 mm and also contoured primary lesions and recurrences. Results: We analyzed 43 patients with 66 primary lesions: 9/66 (13.6%) involved the hippocampus and 11/66 (16.7%) were located within 5 mm of it. Thirty-six lesions (54.5%) were situated more than 15 mm from the hippocampus, while 10/66 (15.2%) were between 5 and 15 mm from it. The most common location was in deep brain structures (31%). Thirty-five of the 66 lesions relapsed: in field in 14/35 (40%) and outfield in 21/35 (60%) in different sites. Globally, 16/35 recurrences (45.7%) were located in the hippocampus or within 5 mm of it. Conclusion: These data show that routinely sparing the hippocampus is not feasible. This approach could be considered in selected patients, when the lesion is more than 15 mm from the hippocampus. [ABSTRACT FROM AUTHOR]

Purpose: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive form of extranodal non-Hodgkin lymphoma. To predict the overall survival (OS) in advance is of utmost importance as it has the potential to aid clinical decision-making. Though radiomics-based machine learning (ML) has demonstrated the promising performance in PCNSL, it demands large amounts of manual feature extraction efforts from magnetic resonance images beforehand. deep learning (DL) overcomes this limitation. Methods: In this paper, we tailored the 3D ResNet to predict the OS of patients with PCNSL. To overcome the limitation of data sparsity, we introduced data augmentation and transfer learning, and we evaluated the results using r stratified k-fold cross-validation. To explain the results of our model, gradient-weighted class activation mapping was applied. Results: We obtained the best performance (the standard error) on post-contrast T1-weighted (T1Gd)—area under curve = 0.81 (0.03) , accuracy = 0.87 (0.07) , precision = 0.88 (0.07) , recall = 0.88 (0.07) and F1-score = 0.87 (0.07) , while compared with ML-based models on clinical data and radiomics data, respectively, further confirming the stability of our model. Also, we observed that PCNSL is a whole-brain disease and in the cases where the OS is less than 1 year, it is more difficult to distinguish the tumor boundary from the normal part of the brain, which is consistent with the clinical outcome. Conclusions: All these findings indicate that T1Gd can improve prognosis predictions of patients with PCNSL. To the best of our knowledge, this is the first time to use DL to explain model patterns in OS classification of patients with PCNSL. Future work would involve collecting more data of patients with PCNSL, or additional retrospective studies on different patient populations with rare diseases, to further promote the clinical role of our model. [ABSTRACT FROM AUTHOR]

Central Nervous System (CNS) Lymphomas are aggressive brain tumors with limited treatment options. Targeting the phosphoinositide 3-kinase (PI3K) pathway yields promising responses across B-cell malignancies, but its therapeutic potential in CNS lymphomas remains unexplored. We present pre-clinical and clinical data on the pan-PI3K inhibitor Buparlisib in CNS lymphomas. In a primary CNS lymphoma-patient-derived cell line, we define the EC50. Four patients with recurrent CNS lymphoma were enrolled in a prospective trial. We evaluated Buparlisib plasma and cerebrospinal fluid pharmacokinetics, clinical outcomes, and adverse events. Treatment was well tolerated. Common toxicities include hyperglycemia, thrombocytopenia, and lymphopenia. The presence of Buparlisib in plasma and CSF was confirmed 2h post-treatment with a median CSF concentration below the EC50 defined in the cell line All four patients were evaluated for response and the median time to progression was 39 days. Buparlisib monotherapy did not lead to meaningful responses and the trial was prematurely stopped.Clinical Trial Registration: NCT02301364 [ABSTRACT FROM AUTHOR]

Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both "ideal" and "minimum standard" protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.

Primary Angiitis of the Central Nervous System (PACNS) is a rare disease and its diagnosis is a challenge for several reasons, including the lack of specificity of the main findings highlighted in the current diagnostic criteria. Among the neuroimaging pattern of PACNS, a tumefactive form (t-PACNS) is a rare subtype and its differential diagnosis mainly relies on neuroimaging. Tumor-like mass lesions in the brain are a heterogeneous category including tumors (in particular, primary brain tumors such as glial tumors and lymphoma), inflammatory (e.g., t-PACNS, tumefactive demyelinating lesions, and neurosarcoidosis), and infectious diseases (e.g., neurotoxoplasmosis). In this review, the main features of t-PACNS are addressed and the main differential diagnoses from a neuroimaging perspective (mainly Magnetic Resonance Imaging—MRI—techniques) are described, including conventional and advanced MRI.

Primary central nervous system lymphoma (PCNSL) is a malignant neoplasm of the central nervous system that is refractory to treatment and has extremely poor prognosis. One factor hindering the development of therapeutic options for PCNSL is its molecular heterogeneity and the extreme difficulty in establishing in vitro cell lines that permit intensive research on this disease. In the present study, we developed a method to propagate PCNSL cells in vitro using a contacting transwell cell culture system involving brain vascular pericytes. The co-culture system was found to recapitulate the tumor microenvironment that is influenced by the biological activity of adjacent pericytes, and to sustain the survival and proliferation of PCNSL cells in vitro. We further delineated the underlying molecular mechanisms and found that the HGF–c-Met axis may be involved in the long-term in vitro culture of PCNSL cells. Moreover, the peptidylprolyl isomerase Pin1 was found to play a key role in PCNSL cell survival and it sustained proliferation through interactions with key transcription factors related to B-cell lymphomagenesis. These results suggest that our in vitro co-culture system is well suited to analyzing the biological and molecular characteristics of PCNSL, and may contribute to the discovery of new therapeutic interventions.

Background: Due to the poor prognosis and rising occurrence, there is a crucial need to improve the diagnosis of Primary Central Nervous System Lymphoma (PCNSL), which is a rare type of non-Hodgkin’s lymphoma. This study utilized targeted metabolomics of cerebrospinal fluid (CSF) to identify biomarker panels for the improved diagnosis or differential diagnosis of primary central nervous system lymphoma (PCNSL).Methods: In this study, a cohort of 68 individuals, including patients with primary central nervous system lymphoma (PCNSL), non-malignant disease controls, and patients with other brain tumors, was recruited. Their cerebrospinal fluid samples were analyzed using the Ultra-high performance liquid chromatography - tandem mass spectrometer (UHPLC-MS/MS) technique for targeted metabolomics analysis. Multivariate statistical analysis and logistic regression modeling were employed to identify biomarkers for both diagnosis (Dx) and differential diagnosis (Diff) purposes. The Dx and Diff models were further validated using a separate cohort of 34 subjects through logistic regression modeling.Results: A targeted analysis of 45 metabolites was conducted using UHPLC-MS/MS on cerebrospinal fluid (CSF) samples from a cohort of 68 individuals, including PCNSL patients, non-malignant disease controls, and patients with other brain tumors. Five metabolic features were identified as biomarkers for PCNSL diagnosis, while nine metabolic features were found to be biomarkers for differential diagnosis. Logistic regression modeling was employed to validate the Dx and Diff models using an independent cohort of 34 subjects. The logistic model demonstrated excellent performance, with an AUC of 0.83 for PCNSL vs. non-malignant disease controls and 0.86 for PCNSL vs. other brain tumor patients.Conclusion: Our study has successfully developed two logistic regression models utilizing metabolic markers in cerebrospinal fluid (CSF) for the diagnosis and differential diagnosis of PCNSL. These models provide valuable insights and hold promise for the future development of a non-invasive and reliable diagnostic tool for PCNSL.

Primary T-cell CNS lymphoma is a rare and aggressive malignancy. High-dose methotrexate (MTX) based chemotherapy regimens are used as standard first-line treatment, followed by consolidative strategies to improve the duration of response. Although MTX-based therapy has been shown to be efficacious, treatment options for MTX-refractory disease are not well-defined. Here, we report a case of a 38-year-old man with refractory primary T-cell CNS lymphoma who demonstrated a complete response to pemetrexed treatment. He subsequently received conditioning chemotherapy consisting of thiotepa, busulfan and cyclophosphamide followed by autologous stem cell transplantation. The patient continues to remain recurrence-free to date at 9 years post-treatment.

Intracranial tumors are rare in persons with Down syndrome. Although germ cell tumors and gliomas have been reported in Down syndrome, primary central nervous system lymphoma (PCNSL) has not. We report a case of PCNSL in a 48-year-old man with Down syndrome and no history of malignant tumors. He visited our hospital for evaluation of left hemiparesis and gait disturbance. A thorough examination revealed brain tumors, and analysis of a biopsy specimen of the tumor confirmed a diagnosis of PCNSL. The final pathological diagnosis was diffuse large B-cell lymphoma of the central nervous system. Chemotherapy with rituximab, methotrexate, procarbazine, and vincristine was administered, and whole-brain irradiation was planned in conjunction with chemotherapy. It is unclear whether chromosomal abnormalities related to Down syndrome were involved in the development of PCNSL. Further molecular biological analysis may clarify the mechanism of combined Down syndrome and PCNSL. [ABSTRACT FROM AUTHOR]

In the treatment of primary central nervous system lymphoma (PCNSL), intraoperative rapid pathological diagnosis can dramatically change the surgical strategy, and more accurate diagnostic methods are required. In April 2020, we adopted intraoperative rapid immunohistochemistry (IHC) in addition to conventional rapid intraoperative diagnosis based on morphological assessment, mainly for patients with PCNSL. Here, we investigate the usefulness and significance of intraoperative rapid IHC based on our initial experience. We performed intraoperative rapid IHC using antibodies for cluster of differentiation (CD)20, CD3, leukocyte common antigen (LCA) and glial fibrillary acidic protein (GFAP) using enzyme‐labeled antibody methods in 25 patients, including PCNSL patients, from April 2020 to July 2022. We examined the utility of this approach in determining treatment strategies for brain tumors. Postoperative final pathological diagnoses from paraffin‐embedded sections were as follows: diffuse large B‐cell lymphoma, 16 cases; glioblastoma, six cases; pilocytic astrocytoma, one case; adenocarcinoma, one case; and inflammatory disorder, one case. The entire process took 32 min and staining for CD20, CD3, LCA, and GFAP was comparable to that using paraffin‐embedded sections. In all cases, the results of intraoperative rapid IHC were consistent with final pathological diagnoses from paraffin‐embedded sections. In addition, in two cases, the results of conventional intraoperative rapid pathological diagnosis based on morphological assessments using frozen sections were drastically changed by adding intraoperative rapid IHC. Intraoperative rapid IHC contributes to deciding appropriate treatment strategies and facilitating early initiation of chemotherapy for PCNSL. This may allow new therapeutic strategies not only for PCNSL but also for other brain tumors. [ABSTRACT FROM AUTHOR]

BackgroundHigh-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results.Patients and methodsA retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1).ResultsThe 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL.ConclusionHDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.

Objectives To analyse the clinical characteristics and therapeutic response of Chinese patients with primary extranodal diffuse large B-cell lymphoma DLBCL (PE-DLBCL).Methods We analysed the clinical features and outcomes of 197 patients who were newly diagnosed with PE-DLBCL between January 2015 and December 2020.Results The gastrointestinal tract showed the highest rate of involvement (34%), followed by the central nervous system (CNS) and intraocular system (31.5%). The 3-year overall survival (OS) rate was 81% for the entire group and 79% for those with CNS and vitreoretinal involvement. Ann Arbour stage, lactate dehydrogenase level, International Prognostic Index > 2, and complete remission (CR) were significantly related to the survival of patients with PE-DLBCL. The lack of CR was the only independent adverse prognostic factor for OS.Conclusion The clinical outcomes of patients with PE-DLBCL at our centre were encouraging, especially for patients with CNS and vitreoretinal involvement.

The prognosis of patients with relapsed and refractory primary central nervous system diffuse large B cell lymphoma (PCNSL) is poor and there is no standard salvage treatment currently available. Gene expression profiling and next-generation sequencing have provided massive amounts of data, revealing the pathogenic mechanism of PCNSL and identifying potential mechanisms for therapeutic exploration. Here, we review targeted drugs that may change the current treatment model of PCNSL.

Central nervous system lymphoma (CNSL) represents one of the most aggressive forms of extranodal lymphoma. The gold standard for CNSL diagnosis remains the stereotactic biopsy, with a limited role for cytoreductive surgery that has not been supported by historical data. Our study aims to provide a comprehensive overview of neurosurgery's role in the diagnosis of systemic relapsed and primary CNSL, with an emphasis on the impact on management and survival. This is a single center retrospective cohort study with data collected between August 2012 and August 2020, including patients referred with a potential diagnosis of CNSL to the local Neuro-oncology Multidisciplinary Team (MDT). The concordance between the MDT outcome and histopathological confirmation was assessed using diagnostic statistics. A Cox regression is used for overall survival (OS) risk factor analysis, and Kaplan–Meier statistics are performed for three prognostic models. The diagnosis of lymphoma is confirmed in all cases of relapsed CNSL, and in all but two patients who underwent neurosurgery. For the relapsed CNSL group, the highest positive predictive value (PPV) is found for an MDT outcome when lymphoma had been considered as single or topmost probable diagnosis. Neuro-oncology MDT has an important role in establishing the diagnosis in CNSL, not only to plan tissue diagnosis but also to stratify the surgical candidates. The MDT outcome based on history and imaging has good predictive value for cases where lymphoma is considered the most probable diagnosis, with the best prediction for cases of relapsed CNSL, questioning the need for invasive tissue diagnosis in the latter group. [ABSTRACT FROM AUTHOR]

Background Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. Methods We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Results Natalizumab was associated with EBV negative tumors (P  = .023), and EBV positive tumors were associated with improved outcomes (P  = .016). Surgical resection was associated with improved outcomes (P  = .032), although limited by potential confounding effect. Antiviral treatment (P  = .095), rituximab (P  = .111), and stem cell transplant (SCT) (P  = .198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. Conclusion We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted. [ABSTRACT FROM AUTHOR]

High-dose methotrexate (HD-MTX)–based regimens are the standard treatment for patients with primary central nervous system lymphoma (PCNSL); however, MTX has extensive interpatient variability in pharmacokinetics and clinical outcomes, with genetic variation an important factor involved in the variability in drug response. 123 PCNSL patients who received 524 courses of chemotherapy were genotyped for 42 single nucleotide polymorphisms in MTX pathway. The relationship between these polymorphisms and the pharmacokinetics, clinical outcomes, and toxicity of MTX was explored using both univariate and multivariate analyses. We found ABCB1 rs2032582 and GGH rs2305558 were substantially associated with the pharmacokinetics of MTX. Patients with GGH rs2305558 T and ABCB1 rs2032582 non-G allele had a higher Cmax increased by 20.5%, area under the concentration-time curve (AUC0-48h) increased by 19.6% and lower clearance decreased by 19.6%. ABCB1 rs1045642 and rs2032582 might be independent predictors of progression-free survival. Patients with ABCB1 rs1045642 non-A and rs2032582 G allele correlated with higher progression risk of the disease. Furthermore, ATIC rs3821353 was associated with MTX-induced hepatotoxicity (Grade ≥ 2). These variants may serve as biomarkers to predict the pharmacokinetics, clinical outcomes, and hepatotoxicity of MTX and contribute to personalized therapy for PCNSL patients. [ABSTRACT FROM AUTHOR]

Background: Primary central nervous system lymphoma (PCNSL) is a type of extranodal non-Hodgkin lymphoma. Although there are widely used prognostic scores, their accuracy and practicality are insufficient. Thus, a novel prognostic prediction model was developed for risk stratification of PCNSL patients in our research. Methods: We retrospectively collected 122 patients with PCNSL from two medical centers in China from January 2010 to June 2022. Among them, 72 patients were used as the development cohort to construct a new model, and 50 patients were used for the validation. Then, by using univariate and multivariate Cox regression analsis and Lasso analysis, the Xijing model was developed and composed of four variables, including lesion number, β2-microglobulin (β2-MG), systemic inflammation response index (SIRI) and Karnofsky performance status (KPS). Finally, we evaluated the Xijing model through internal and external validation. Results: Compared with the original prognostic scores, the Xijing model has an overall improvement in predicting the prognosis of PCNSL according to the timedependent area under the curve (AUC), Harrell's concordance index (C-index), decision curve analysis (DCA), integrated discrimination improvement (IDI) and continuous net reclassification index (NRI). For overall survival (OS) and progression-free survival (PFS), the Xijing model can divide PCNSL patients into three groups, and shows more accurate stratification ability. In addition, the Xijing model can still stratify and predict prognosis similarly better in the elderlywith PCNSL and subgroups received high-dose methotrexate (HD-MTX) or Bruton's tyrosine kinase inhibitors (BTKi). Finally, external validation confirmed the above results. Conclusions: Integrating four prognostic factors, including imaging findings, tumor burden, systemic inflammation response index, and comprehensive physical condition, we provided a novel prognostic model for PCNSL based on real-world data and evaluated its predictive capacity. [ABSTRACT FROM AUTHOR]

Primary Central Nervous System Lymphoma (PCNSL) is an aggressive neoplasm with a poor prognosis. Although therapeutic progresses have significantly improved Overall Survival (OS), a number of patients do not respond to HD–MTX-based chemotherapy (15–25%) or experience relapse (25–50%) after an initial response. The reasons underlying this poor response to therapy are unknown. Thus, there is an urgent need to develop improved predictive models for PCNSL. In this study, we investigated whether radiomics features can improve outcome prediction in patients with PCNSL. A total of 80 patients diagnosed with PCNSL were enrolled. A patient sub-group, with complete Magnetic Resonance Imaging (MRI) series, were selected for the stratification analysis. Following radiomics feature extraction and selection, different Machine Learning (ML) models were tested for OS and Progression-free Survival (PFS) prediction. To assess the stability of the selected features, images from 23 patients scanned at three different time points were used to compute the Interclass Correlation Coefficient (ICC) and to evaluate the reproducibility of each feature for both original and normalized images. Features extracted from Z-score normalized images were significantly more stable than those extracted from non-normalized images with an improvement of about 38% on average (p-value < 10 − 12 ). The area under the ROC curve (AUC) showed that radiomics-based prediction overcame prediction based on current clinical prognostic factors with an improvement of 23% for OS and 50% for PFS, respectively. These results indicate that radiomics features extracted from normalized MR images can improve prognosis stratification of PCNSL patients and pave the way for further study on its potential role to drive treatment choice. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphomas (PCNSLs) are extranodal variant forms of non-Hodgkin lymphoma arising within the brain parenchyma, leptomeninges, or spinal cord. PCNSL can present with varied neurological symptoms and imaging findings, making diagnosis without biopsy difficult. PCNSLs are highly aggressive, causing rapid deterioration, but are responsive to chemotherapy and radiotherapy making early diagnosis important. Crossed cerebellar diaschisis (CCD) is mostly seen with cerebral cortex vascular insults and is rarely reported with thalamic lesions and even rarer with thalamic lymphoma. However, CCD has also been described in other brain tumors (including primary glioma), chronic subdural hematoma, congenital insults, intracranial infections, and various dementia subtypes. We present a rare case of thalamic lymphoma evaluated with positron emission tomography/computed tomography that showed hypermetabolism of thalamus and associated hypometabolism in ipsilateral cerebral cortex and contralateral cerebellum representing CCD. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma that affects the brain parenchyma, spinal cord, eyes, and cerebrospinal fluid without evidence of systemic, non-CNS involvement. PCNSL is uncommon and only a few randomized trials have been completed in the first-line setting. Over the past decades, the prognosis of PCNSL has improved, mainly due to the introduction and widespread use of high-dose methotrexate, which is now the backbone of all first-line treatment polychemotherapy regimens. Despite this progress, durable remission is recorded in only 50% of patients, and therapy can be associated with significant late neurotoxicity. Here, we overview the epidemiology, clinical presentation, staging evaluation, prognosis, and current up-to-date treatment of immunocompetent PCNSL patients.

Haiyan Bian,1 Lisheng Wang,2 Chengwen Gao,3 Zhihe Liu,1 Yang Sun,2 Minghui Hu,4 Yujing Xiao,5 Fengyun Hao,5 Yushuo Ma,1 Xia Zhao1 1Department of Hematology, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Laboratory of Molecular Diagnosis and Regenerative Medicine, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3Laboratory of Medical Biology, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 4Clinical Laboratory, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 5Department of Pathology, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of ChinaCorrespondence: Xia Zhao, Department of Hematology, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, 266000, People’s Republic of China, Email zhaoxia@qdu.edu.cnPurpose: Primary central nervous system lymphoma (PCNSL) responds favorably to radiation, chemotherapy and targeted drug therapy. However survival is usually worse, the treatment-related drug resistance and recurrence are still clinical problems to be solved urgently. Studies have shown that cytokines are expressed in varying degrees in patients with lymphoma, which is significantly related to the progression, poor prognosis and drug resistance of lymphoma. We explore the expression and clinical significance of Th1/Th2/Th17 cytokines and lymphocyte subsets in patients with PCNSL to provide a more sufficient theoretical basis for its diagnosis and treatment.Patients and Methods: We measured and analysed the levels of Th1/Th2/Th17 cytokines and the distribution of lymphocyte subsets (including Treg cells, CD3+, CD4+, CD8+, CD19+, and CD4+/CD8+) in 39 patients with PCNSL and 96 patients with diffuse large B-cell lymphoma (DLBCL) without central nervous system involvement. The cytokines of 13 healthy people and the lymphocyte subsets of 27 healthy people were measured as the control group.Results: We found a significant difference in the level of Th1/Th2/Th17 cytokines and lymphocyte subsets between PCNSL and healthy controls, especially IL-2, after treatment, which was significantly higher than before treatment (p< 0.01). However, the level of CD19+ and CD4+/CD8+ decreased while CD8+ and CD3+ increased after treatment (regardless of whether the treatment was effective), and the difference was statistically significant. In addition, our analysis of different prognostic factors found that HD-MTX-based chemotherapy appears to have a longer progression-free survival and overall survival than osimertinib-based chemotherapy.Conclusion: There are significant differences in Th1/Th2/Th17 cytokines and lymphocyte subsets among PCNSL, DLBCL, and healthy controls, and their detection is helpful for the diagnosis, treatment, and prognosis of PCNSL. HD-MTX-based chemotherapy may still be the first choice for PCNSL.Keywords: PCNSL, Th1/Th2/Th17 cytokines, lymphocyte subsets, HD-MTX, osimertinib

Earlier, prior to the development of effective systemic therapy, monotherapy with whole-brain radiotherapy (WBRT) was widely used to treat primary central nervous system lymphoma (PCNSL). Recently, chemotherapy, especially with high dose methotrexate (HDMTX), has largely replaced WBRT as upfront treatment, and the most accepted standard of care is induction with a combination drug therapy followed by consolidation therapy with either autologous stem-cell transplantation (ASCT) or radiation. Whilst WBRT is an effective component of treatment, it is occasionally associated with risk of permanent, irreversible neurotoxicity when doses of more than 30 Gy are used. Hence, there has been a strong focus on the optimization of radiotherapy (RT) which includes dose reduction in the consolidation phase. In this comprehensive review, we have summarized the progress on clinical results and evidence considering the role and use of radiation including combined treatment modalities, low-dose radiotherapy, and neurotoxicity. Finally, we present a practical approach to low-dose WBRT and boosting higher doses to the gross tumor that can be integrated into clinical practice.

Simple Summary: We present the results of a prospective trial of systemic chemoimmunotherapy for primary CNS lymphoma including the intra-arterial administration of methotrexate and carboplatin with blood–brain barrier disruption. The safety, response rates, and survival outcomes were favorable. Previous reports of the intra-arterial administration of therapy with blood–brain barrier disruption for this disease have also demonstrated safety and favorable outcomes, but there has been a slow uptake of this approach, partially out of concern that the technique may be difficult to implement across centers. Our data provide further prospective evidence that this approach can be implemented elsewhere with safety and confirm the effectiveness previously reported in a single institution study. These data motivate further study of this approach not only for PCNSL but also for other diseases that exist behind the blood–brain barrier. Primary central nervous system lymphoma is a rare but aggressive brain malignancy. It is associated with poor prognosis even with the current standard of care. The aim of this study was to evaluate the effect and tolerability of blood–brain barrier disruption treatment combined with high-dose treatment with autologous stem cell transplantation as consolidation on primary central nervous system lymphoma patients. We performed a prospective phase II study for 25 patients with previously untreated primary central nervous system lymphoma. The blood–brain barrier disruption treatment was initiated 3–4 weeks after the MATRix regimen using the previously optimized therapy protocol. Briefly, each chemotherapy cycle included two subsequent intra-arterial blood–brain barrier disruption treatments on days 1 and 2 via either one of the internal carotid arteries or vertebral arteries. Patients received the therapy in 3-week intervals. The treatment was continued for two more courses after achieving a maximal radiological response to the maximum of six courses. The complete treatment response was observed in 88.0% of the patients. At the median follow-up time of 30 months, median progression-free and overall survivals were not reached. The 2-year overall and progression-free survival rates were 67.1% and 70.3%, respectively. Blood–brain barrier disruption treatment is a promising option for primary central nervous system lymphoma with an acceptable toxicity profile. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma with poor prognosis. In recent years, the emergence of genetic subtypes of systematic diffuse large B-cell lymphoma has highlighted the importance of molecular genetics, but large-scale research on the molecular genetics of PCNSL is lacking. Herein, we summarize the frequent gene mutations and discuss the possible pathogenesis of PCNSL. Myeloid differentiation primary response gene 88 (MYD88) and CD79B mutations, which cause abnormal activation of noncanonical nuclear factor-κB, are prominent genetic abnormalities in PCNSL. They are considered to play a major role in the pathogenesis of PCNSL. Other genes, such as caspase recruitment domain family member 11 (CARD11), tumor necrosis factor alpha induced protein 3 (TNFAIP3), transducin (β)-like 1 X-linked receptor 1, cyclin dependent kinase inhibitor 2A, PR domain zinc finger protein 1, and proviral insertion in murine malignancies 1, are also frequently mutated. Notably, the pathogenesis of immune insufficiency-associated PCNSL is related to Epstein-Barr virus infection, and its progression may be affected by different signaling pathways. The different mutational patterns in different studies highlight the heterogeneity of PCNSL. However, existing research on the molecular genetics of PCNSL is still limited, and further research into PCNSL is required to clarify the genetic characteristics of PCNSL. [ABSTRACT FROM AUTHOR]

Simple Summary: Although primary central nervous system lymphoma (PCNSL) is sometimes indistinguishable from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype, the role of operation on them is very different; therefore, accurate preoperative diagnosis is crucial. In this study, we evaluated whether amide proton transfer-weighted (APTw) imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. The mean APTw signal value did not significantly differ between them; however, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width1–100 APTw signals between the two diseases were significantly different. The area under the curve, sensitivity, and specificity were 0.796, 64.3%, and 88.9%, respectively, using the width1–100 APTw signal values. APTw imaging was useful to differentiate between PCNSL and glioblastoma, IDH-wildtype. Performing APTw imaging is recommended in cases in which PCNSL is one of the differential diagnoses. Distinguishing primary central nervous system lymphoma (PCNSL) from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype is sometimes hard. Because the role of operation on them varies, accurate preoperative diagnosis is crucial. In this study, we evaluated whether a specific kind of chemical exchange saturation transfer imaging, i.e., amide proton transfer-weighted (APTw) imaging, was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. A total of 14 PCNSL and 27 glioblastoma, IDH-wildtype cases were evaluated. There was no significant difference in the mean APTw signal values between the two groups. However, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width1–100 APTw signals significantly differed. The highest area under the curve was 0.796, which was obtained from the width1–100 APTw signal values. The sensitivity and specificity values were 64.3% and 88.9%, respectively. APTw imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. To avoid unnecessary aggressive surgical resection, APTw imaging is recommended for cases in which PCNSL is one of the differential diagnoses. [ABSTRACT FROM AUTHOR]

Simple Summary: Primary central nervous system lymphomas are rare, but the incidence in the elderly population increases constantly. Consequently, more and more elderly patients are treated with high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT). However, data on the recovery after this demanding therapy are scarce, especially concerning quality of life (QoL)-focused patient-reported outcome parameters. Seeing even better QoL results in the elderly compared to the younger population after HDC/ASCT this single-center analysis challenges the assumption of an insufficient recovery by seeing even better QoL results in the elderly compared to the younger population after HDC/ASCT. Moreover, no significant age-dependent differences were observed regarding overall and progression free survival as well as ECOG performance status and mini-mental state examination. Together, our data indicate that HDC/ASCT is an effective therapy with respect to disease control and global health status. Primary central nervous system lymphomas (PCNSL) are rare and associated with an adverse prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT) improves progression free (PFS) and overall survival (OS) but neurocognition, performance status and quality of life (QoL) in patient-reported outcome (PRO) after HDC/ASCT remains underexplored. Especially elderly patients may insufficiently recover from this demanding therapy. Therefore, this single-center analysis investigated all PCNSL patients who received HDC/ASCT at the University Hospital Tübingen from 2006–2021 (n = 40, median age 60.5 years) in a retrospective manner. The 2-year PFS/OS was 78.7%/77.3%, respectively, without significant differences between the tested age-groups (≤60 vs. >60 years, p = 0.531/p = 0.334). Higher Thiotepa dosage was an independent predictor for better OS (p = 0.018). Additionally, a one-time prospective, cross-sectional analysis after HDC/ASCT in the same cohort was performed (n = 31; median follow-up 45 months). Here, the median ECOG improved by HDC/ASCT from 1 to 0 and mini-mental state examinations revealed unimpaired neurocognitive functioning (median 28 pts.). PRO data collected by EORTC QLQ-C30 showed a good QoL in both age groups with an average global health status (GHS) of 68.82% (≤60y: 64.72%, >60y: 74.14%). Together, our data indicate that HDC/ASCT is an effective therapy with respect to disease control, overall health status and quality of life, irrespective of patient age. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions. • Multi-omic data consensus clustering reveals four molecular subtypes of PCNSL with prognostic relevance. • RNA-seq data alone and a publicly accessible algorithm can be used to assign the multi-omic defined PCNSL subtypes. • PCNSL molecular subtyping can improve future clinical stratification and suggest rational subtype-based targeted therapies. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a rare form and aggressive type of diffuse large B-cell lymphoma (DLBCL) that occurs in both immunocompetent and immunocompromised adults. While adding rituximab to chemotherapeutic regimens resulted in dramatic improvement in both progression-free survival and overall survival in patients with non-central nervous system (CNS) DLBCL, the outcomes of PCNSL are generally poor due to the immune-privileged tumor microenvironment or suboptimal delivery of systemic agents into tumor tissues. Therefore, more effective therapy for PCNSL generally requires systemic therapy with sufficient CNS penetration, including high-dose intravenous methotrexate with rituximab or high-dose chemotherapy followed by autologous stem cell transplantation. However, overall survival is usually inferior in comparison to non-CNS lymphomas, and treatment options are limited for elderly patients or patients with relapsed/ refractory disease. Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a cutting-edge cancer therapy, which led to recent FDA approvals for patients with B-cell malignancies and multiple myeloma. Although CAR-T cell therapy in patients with PCNSL demonstrated promising results without significant toxicities in some small cohorts, most cases of PCNSL are excluded from the pivotal CAR-T cell trials due to the concerns of neurotoxicity after CAR-T cell infusion. In this review, we will provide an overview of PCNSL and highlight current approaches, resistance mechanisms, and future perspectives of CAR-T cell therapy in patients with PCNSL. [ABSTRACT FROM AUTHOR]