To evaluate the role of multimodal magnetic resonance imaging radiomics features in predicting early recurrence of primary central nervous system lymphoma (PCNSL) and to investigate their correlation with patient prognosis.

A retrospective analysis was conducted on 145 patients with PCNSL who were treated with high-dose methotrexate-based chemotherapy. Clinical data and MRI images were collected, with tumor regions segmented using ITK-SNAP software. Radiomics features were extracted via Pyradiomics, and predictive models were developed using various machine learning algorithms. The predictive performance of these models was assessed using receiver operating characteristic (ROC) curves. Additionally, Cox regression analysis was employed to identify risk factors associated with progression-free survival (PFS).

In the cohort of 145 PCNSL patients (72 recurrence, 73 non-recurrence), clinical characteristics were comparable between groups except for multiple lesion frequency (61.1% vs. 39.7%, p < 0.05) and not receiving consolidation therapy (44.4% vs. 13.7%, p < 0.05). A total of 2392 radiomics features were extracted from CET1 and T2WI MRI sequence. Combining clinical variables, 10 features were retained after the feature selection process. The logistic regression (LR) model exhibited superior predictive performance in the test set to predict PCNSL early relapse, with an area under the curve (AUC) of 0.887 (95 % confidence interval: 0.785-0.988). Multivariate Cox regression identified the Cli-Rad score as an independent prognostic factor for PFS. Significant difference in PFS was observed between high- and low-risk groups defined by Cli-Rad score (8.24 months vs. 24.17 months, p < 0.001).

The LR model based on multimodal MRI radiomics and clinical features, can effectively predict early recurrence of PCNSL, while the Cli-Rad score could independently forecast PFS among PCNSL patients.

Diagnosing primary or secondary CNS lymphoma (CNSL) is a clinical challenge due to the limitations of standard biopsy and imaging procedures despite established guidelines. Therefore, accurate biomarkers and analytical methods that are convenient for practical routine use are needed to diagnose and manage these aggressive lymphomas effectively. We evaluated the utility of minimally invasive circulating tumor DNA (ctDNA) detection in a prospective real-world scenario, moving this approach closer to clinical practice.

A total of 164 plasma, cerebrospinal fluid (CSF), and tumor samples from 56 CNSL patients were collected to analyze tumor DNA by the diagnostic next-generation sequencing (NGS) panel LYNX, enabling simultaneous analysis of gene variants, chromosomal aberrations, and antigen receptor rearrangements in targeted regions.

The well-known genetic heterogeneity of CNSL was refined with integrative molecular data, showing the most frequent MYD88, PIM1, and KMT2D mutations and a broad spectrum of chromosomal aberrations, reflecting high genomic complexity. The multi-target approach achieved a substantially higher detection rate of CNS infiltration (90%) than tracking a single variant in gene MYD88 (46%). CSF clearly surpasses plasma if applying a routine (non-ultrasensitive) NGS approach and allows for more reliable evidence of CNS involvement than conventional flow cytometry (91% vs. 21%, p < 0.001). Parallel analysis of tumor DNA in both cell-free and cellular DNA from CSF makes the probability of primary or secondary CNS malignancy detection even higher.

Our prospective, tissue-agnostic approach highlights the feasibility of ctDNA sequencing by a commonplace and affordable method, offering higher sensitivity to detect CNS infiltration with lymphoma than standard cell-analyzing techniques. We accentuate the benefit of a multi-target NGS approach and adequate CSF sampling to obtain satisfactory diagnostic yield. Less invasive liquid biopsy testing by comprehensive NGS complements standard procedures in the diagnostics and management of CNSL patients, especially when encountering limitations.

Large B-cell lymphoma of immune-privileged sites (LBCL-IP) is a rare subtype characterized by immune evasion properties. Primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL) are examples of LBCL-IP associated with programmed cell death protein 1 (PD-1). Few studies have investigated the use of PD-1 inhibitors in patients with relapsed PCNSL and PTL.

To conduct a systematic review evaluating the efficacy and safety of PD-1 inhibitors in patients with relapsed PCNSL and PTL.

We searched the PubMed, Embase, and Scopus databases for relevant studies. The inclusion criteria focused on adult patients diagnosed with relapsed PCNSL or PTL who were treated with PD-1 inhibitors. We excluded case reports or series with fewer than five participants, review articles, and animal studies. A random-effects model with the DerSimonian‒Laird method analyzed the pooled complete response rate (CRR), partial response rate (PRR), overall response rate (ORR), and progression-free survival (PFS) rate.

Seven studies comprising 127 patients (124 with relapsed PCNSL and 3 with PTL) were included. All patients were treated with either nivolumab or pembrolizumab. The pooled CRR was 42.8% (95% CI, 25.7%‒60.0%; I2 = 75.25%; p < 0.001), indicating high heterogeneity. The pooled PRR was 17.1% (95% CI, 9.5%‒24.7%; I2 = 18.71%; p = 0.287), with nonsignificant heterogeneity. The pooled ORR was 67.1% (95% CI, 44.9%‒89.4%; I2 = 88.64%; p < 0.001), indicating high heterogeneity. The 6-month PFS rate was 34.8% (95% CI, 18.1%‒51.5%; I2 = 27%; p = 0.242), with low heterogeneity. Thirty-eight adverse events were reported. The most common were skin reactions (14 events; 36.8%), fatigue (11 events; 28.9%), and nausea (6 events; 15.8%).

Our study demonstrates that PD-1 inhibitors show promising efficacy in relapsed PCNSL and PTL, with significant responses observed. The adverse effects were mild, with the most common being skin reactions. Therefore, PD1 inhibitors have the potential to drive advancements in treatment strategies for relapsed PCNSL and PTL.

Primary central nervous system Burkitt lymphoma (PCNSBL) is a rare and aggressive malignancy, particularly challenging to diagnose in immunocompetent individuals due to its nonspecific presentation.

A 38-year-old immunocompetent woman presented with a 1-week history of progressively severe headaches in the left frontotemporal region, without systemic symptoms or significant laboratory abnormalities.

Advanced magnetic resonance imaging revealed a nodular lesion in the left frontal area, initially diagnosed as meningioma. Postsurgical histopathological analysis confirmed the diagnosis of Burkitt lymphoma, characterized by diffuse infiltration of medium-sized lymphocytes, a high MIB1 proliferation index, and Myc gene rearrangement.

The patient underwent complete surgical resection of the tumor and a 5-cycle chemotherapy regimen based on high-dose methotrexate, without the need for radiotherapy due to the localized nature of the tumor and complete surgical removal.

Postoperatively, the patient's headaches resolved, and no evidence of tumor recurrence was observed on magnetic resonance imaging after 11 months of follow-up. Additional examinations, including fluorodeoxyglucose-18-positron emission computed tomography, bone marrow biopsy, and cerebrospinal fluid cytology, confirmed the absence of systemic involvement.

This case highlights the importance of considering PCNSBL in the differential diagnosis of brain tumors, even in immunocompetent patients. Early diagnosis and a tailored chemotherapy regimen can lead to favorable treatment outcomes, emphasizing the need for a multimodality approach in managing PCNSBL.

Primary pituitary lymphomas are uncommon neoplasms that are typically derived from a B-cell lineage. Extranodal natural killer (NK)/T-cell lymphoma is distinct from B- and T-cell lymphomas and is associated with Epstein-Barr virus infection. Primary central nervous system (CNS) presentations of this neoplasm are exceptionally rare. Here, we report the case of extranodal NK/T-cell lymphoma presenting as a pituitary mass and review the literature related to this rare clinical entity.

A 31-year-old previously healthy male presented with 2 weeks of progressive headaches and ophthalmoplegia. Imaging revealed a large intrasellar mass with retroclival extension and involvement of the sphenoid and cavernous sinuses. An endoscopic biopsy of the sphenoidal mucosa was performed, and pathological examination was consistent with extranodal NK/T-cell lymphoma. Despite treatment with chemo- and radiotherapy, the patient died approximately 8 months after initial presentation due to systemic disease progression with multiorgan failure.

The presentation of extranodal NK/T-cell lymphoma as a pituitary lesion is very rare, having been reported only twice in the previous literature. Patients with primary CNS extranodal NK/T-cell lymphoma typically experience an aggressive clinical course with a poor prognosis, as in our case.

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive form of non-Hodgkin lymphoma, primarily confined to the central nervous system. In recent years, growing evidence has indicated that dysbiosis of the gut microbiota is closely associated with the development of various malignancies. This study aims to systematically explore the potential role of gut microbiota and their metabolic pathways in the pathogenesis of PCNSL by integrating metagenomic and metabolomic approaches.

A total of 33 PCNSL patients and 32 healthy controls were enrolled in this study, and fecal samples were collected from each participant. The fecal samples were analyzed using metagenomic and metabolomic techniques, followed by KEGG pathway enrichment analysis to investigate the biological pathways enriched by the differential gut microbiota and metabolites.

Significant differences were observed in the composition of gut microbiota and metabolites between PCNSL patients and healthy controls. In the gut microbiota of PCNSL patients, the abundance of the phylum Proteobacteria was markedly increased, while the Firmicutes/Bacteroidetes (F/B) ratio was significantly elevated. Metabolomic analysis revealed that the abundance of oleamide was significantly reduced in the PCNSL group, while the relative abundance of deoxycholic acid was significantly elevated. KEGG pathway analysis indicated that the differential gut microbiota and metabolites were primarily involved in key metabolic pathways such as nitrogen metabolism, phenylalanine metabolism, purine metabolism, and pyrimidine metabolism, with these pathways being more active in PCNSL patients.

This study is the first to systematically investigate the differences in gut microbiota and their metabolites between PCNSL patients and healthy individuals, highlighting the potential role of gut microbiota alterations in the pathogenesis of PCNSL.

The usefulness of brain 18 F-FDG PET/CT in primary central nervous system lymphoma (PCNSL) remains underexplored. This study investigated whether early metabolic responses in interim brain FDG PET/CT serve as a prognostic indicator of PCNSL treatment outcomes.

This prospective study included 53 patients with PCNSL who underwent a high-dose methotrexate-based treatment. Brain FDG PET was performed at diagnosis (baseline PET) and after induction chemotherapy (interim PET), assessing interim PET parameters such as the highest maximum standardized uptake value (hSUV max ), sum of SUV max (sumSUV max ), highest tumor-to-normal ratio (hTNR max ), sum of TNR max (sumTNR max ), highest metabolic tumor volume (MTV) (hMTV), and sum of MTV (sumMTV) across all PET-positive lesions.

High interim hTNR max (hazards ratio: 9.76, 95% confidence interval: 1.90-50.11, P = 0.01) was an independently significant predictor of poor progression-free survival in multivariate analysis. Patients with low interim hTNR max (≤1.0) had a significantly longer median progression-free survival than those with high interim hTNR max (>1.0) (25.0 vs 3.6 months, P < 0.001). Incorporating interim MRI-based clinical response assessments and hTNR max allowed the classification of partial response subgroups with markedly different prognoses ( P < 0.001). High interim hTNR max (hazards ratio: 2.76, 95% confidence interval: 1.39-5.48, P = 0.004) was an independently significant predictor of poor overall survival in multivariate analysis.

The hTNR max measurement from interim brain FDG PET scans emerges as an important prognostic marker in PCNSL. These findings underscore the potential of interim FDG PET evaluations to refine response assessments and inform tailored therapeutic strategies.

In primary central nervous system lymphoma (PCNSL), the extent to which post-methotrexate consolidation contributes to neurotoxicity is unclear. Concerns for neurotoxicity from standard dose whole-brain radiation therapy (WBRT) have led to declining use. Cerebral atrophy is an established surrogate for neurotoxicity; however, the relative extent to which modern consolidation (ie, reduced-dose [RD-]WBRT ≤24 Gy, autologous hematopoietic cell transplant) contributes to cerebral atrophy is unclear.

Patients with PCNSL from 2000-2020 who achieved a complete response to consolidation following methotrexate-based induction were included. Inclusion criteria were preconsolidation magnetic resonance imaging (baseline) and ≥1 magnetic resonance imaging showing sustained remission at 1, 3, 5, or 10 years. An expert neuroradiologist longitudinally measured parenchymal volume loss via ventricular volumetric change. Linear mixed-effects models were performed to estimate absolute and annual volumetric change rates.

Of 139 patients (median follow-up, 4.5 years), most were Memorial Sloan Kettering Cancer Center (MSK) recursive partitioning analysis (RPA) class 2 (age ≤50 years, Karnofsky performance score (KPS) ≥70). Consolidation therapies included nonmyeloablative chemotherapy (n = 57; 41%), high-dose myeloablative chemotherapy with autologous hematopoietic cell transplant (n = 50; 36%), and RD-WBRT (n = 28; 20%). A higher MSK RPA class was associated with greater baseline ventricular volume (P < .001). Overall adjusted annual ventricular volume change rates were greater than those published in healthy controls (4.3% vs 1.8%) and generally increased by age/decade at diagnosis: 40 to 49-year-olds 1.8% (95% CI, -1.4% to 5.0%), 50 to 59-year-olds 3.1% (95% CI, 0.7%-5.5%), 60 to 69-year-olds 4.8% (95% CI, 2.4%-7.3%), 70 to 79-year-olds 7.2% (95% CI, 4.3%-10.2%), and 80 to 89-year-olds 4.2% (95% CI, -1.1% to 9.6%). There were no significant associations between consolidation strategy and ventricular volume change rates accounting for age, KPS, gender, baseline ventricular volume, or interaction between age and consolidation.

These findings demonstrate accelerated cerebral atrophy in PCNSL after consolidation compared with healthy adults. However, atrophy did not differ by consolidation strategy. These long-term results suggest acceptable neurotoxicity following RD-WBRT.

The paradigm of isocitrate dehydrogenase (IDH)-wildtype glioblastoma is rapidly evolving, reflecting clinical, pathological, and imaging advancements. Thus, it remains challenging for radiologists, even those who are dedicated to neuro-oncology imaging, to keep pace with this rapidly progressing field and provide useful and updated information to clinicians. Based on current knowledge, radiologists can play a significant role in managing patients with IDH-wildtype glioblastoma by providing accurate preoperative diagnosis as well as preoperative and postoperative treatment planning including accurate delineation of the residual tumor. Through active communication with clinicians, extending far beyond the confines of the radiology reading room, radiologists can impact clinical decision making. This Part 1 review provides an overview about the neuropathological diagnosis of glioblastoma to understand the past, present, and upcoming revisions of the World Health Organization classification. The imaging findings that are noteworthy for radiologists while communicating with clinicians on preoperative and immediate postoperative imaging of IDH-wildtype glioblastomas will be summarized.

Primary central nervous system lymphomas (PCNSLs) are relatively infrequent tumors and are usually high-grade and aggressive neoplasms. A small portion of PCNSLs are low-grade lymphomas and can involve the dura. Mucosa-associated lymphoid tissue (MALT) lymphoma of the dura is an extremely rare subtype with only case reports and series documented in the literature.

A 65-year-old woman presented with a history of headaches followed by progressive left hemiparesis. Imaging studies showed an extra-axial dural-based tumor causing midline shift. Gross total resection was achieved, and the patient was discharged without postoperative complications. Histopathological examination confirmed the diagnosis of MALT lymphoma of the dura. The patient was evaluated by the oncologist and received adjuvant chemotherapy. At the 10-month follow-up, the patient experienced remission of her symptoms, and the last magnetic resonance imaging showed no evidence of tumor recurrence.

MALT lymphoma of the dura diagnosis requires a high level of suspicion because it can often mimic meningioma. Given its rarity, there is no consensus on the standard treatment strategy. Gross total resection followed by adjuvant therapy is an accepted treatment to manage these cases.

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma involving the brain, cerebrospinal fluid, or retina/vitreous without systemic involvement. Induction with high-dose methotrexate (HD-MTX) followed by consolidation with autologous stem cell transplant (auto-SCT) has become the standard treatment paradigm for most patients. However, limited data are available regarding the efficacy of a maintenance approach with HD-MTX. Herein, we retrospectively reviewed the characteristics and outcomes of 148 patients diagnosed with PCNSL between October 2010 and June 2022, who underwent HD-MTX-based induction therapy followed by either auto-SCT consolidation (n = 70) or HD-MTX maintenance therapy (n = 37). At a median follow-up time of 4.5 years, the progression-free survival (PFS) was 8.3 years and the overall survival (OS) was not reached. Compared to patients who underwent auto-SCT, patients who received maintenance HD-MTX had a higher median age at diagnosis of 72 vs 62 years and a trend toward higher proportion of patients being Eastern Cooperative Oncology Group 2 or higher (41% vs 29%). At 5-years postinduction treatment initiation, the PFS rates in the auto-SCT cohort and HD-MTX maintenance cohort were 74.6% and 72.6%, respectively, and the OS rates were 76.0% and 82.4%, respectively. Overall, there was no significant difference in PFS or OS based on postinduction management strategy. Our data suggest that maintenance HD-MTX may be a reasonable, time-limited treatment strategy for patients with PCNSL responding to initial induction therapy.

Primary central nervous system lymphoma (PCNSL) is non-Hodgkin's lymphoma (NHL) confined to the central nervous system. Most of the patients eventually develop relapsed/refractory (R/R) PCNSL, and the overall prognosis for PCNSL remains dismal. Recently, gene sequencing, transcriptome sequencing, and single-cell sequencing platforms have provided a large amount of data revealing the mechanisms underlying the pathogenesis and drug resistance in PCNSL, including the activation of the NF-κB signaling pathway in tumor cells, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Advances in molecular pathology studies for PCNSL have led to identifying new therapeutic targets and developing novel drugs. New therapeutic strategies, such as creating small molecule targeted agents, immunomodulatory drugs, immune checkpoint inhibitors, and chimeric antigen receptor T (CAR-T) cell therapy, have brought new hope for patients with PCNSL, especially for R/R PCNSL. This review presents recent advances in the treatment of PCNSL, reviews and discusses the efficacy and challenges of targeted therapy and immunotherapy, and provides an outlook on the future development of PCNSL treatment strategies.

To examine the correlation of apparent diffusion coefficient (ADC), diffusion weighted imaging (DWI), and T1 contrast enhanced (T1-CE) with Ki-67 in primary central nervous system lymphomas (PCNSL). And to assess the diagnostic performance of MRI radiomics-based machine-learning algorithms in differentiating the high proliferation and low proliferation groups of PCNSL.

83 patients with PCNSL were included in this retrospective study. ADC, DWI and T1-CE sequences were collected and their correlation with Ki-67 was examined using Spearman's correlation analysis. The Kaplan-Meier method and log-rank test were used to compare the survival rates of the high proliferation and low proliferation groups. The radiomics features were extracted respectively, and the features were screened by machine learning algorithm and statistical method. Radiomics models of seven different sequence permutations were constructed. The area under the receiver operating characteristic curve (ROC AUC) was used to evaluate the predictive performance of all models. DeLong test was utilized to compare the differences of models.

Relative mean apparent diffusion coefficient (rADCmean) (ρ=-0.354, p = 0.019), relative mean diffusion weighted imaging (rDWImean) (b = 1000) (ρ = 0.273, p = 0.013) and relative mean T1 contrast enhancement (rT1-CEmean) (ρ = 0.385, p = 0.001) was significantly correlated with Ki-67. Interobserver agreements between the two radiologists were almost perfect for all parameters (rADCmean ICC = 0.978, 95%CI 0.966-0.986; rDWImean (b = 1000) ICC = 0.931, 95% CI 0.895-0.955; rT1-CEmean ICC = 0.969, 95% CI 0.953-0.980). The differences in PFS (p = 0.016) and OS (p = 0.014) between the low and high proliferation groups were statistically significant. The best prediction model in our study used a combination of ADC, DWI, and T1-CE achieving the highest AUC of 0.869, while the second ranked model used ADC and DWI, achieving an AUC of 0.828.

rDWImean, rADCmean and rT1-CEmean were correlated with Ki-67. The radiomics model based on MRI sequences combined is promising to distinguish low proliferation PCNSL from high proliferation PCNSL.

Introduction: Treatment for primary central nervous system lymphoma (PCNSL) includes high-dose methotrexate (HD-MTX)-based systemic therapy. Multiple regimens exist with no clear standard of care. We evaluated the impact of different therapies on PCNSL outcomes at a single institution. Materials and Methods: A total of 95 consecutive patients with PCNSL from 2002 to 2021 were retrospectively reviewed. The overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. The log-rank test and univariate and multivariable Cox regression analysis were used to evaluate the relationship between clinicopathologic and treatment variables with outcomes. Results: Among the 62 patients treated with definitive systemic therapy, the median age was 58; 71% had a Karnofsky performance status > 70, 49% had a single lesion, 31% received HD-MTX alone, and 61% had HD-MTX + rituximab. The two-year OS and PFS were 64% (95% CI: 49.8-75.0%) and 49% (95% CI: 35.0-60.9%), respectively. On multivariable analysis, the completion of > six cycles of HD-MTX (HR 0.40; 95% CI: 0.21-0.76; p = 0.01) was associated with superior OS, while the use of rituximab was associated with inferior OS (HR 2.82; 95% CI: 1.37-5.83; p = 0.01). There were no significant associations between the OS and PFS with temozolomide, the extent of surgical resection, radiation, or the size or number of initial lesions (all p > 0.05). Discussion: Innovation is needed to improve the outcomes for patients with PCNSL.

Primary central nervous system diffused large B-cell lymphoma (PCNS-DLBCL) is a rare type of non-Hodgkin lymphoma restricted to the central nervous system (CNS). To explore its specific pathogenesis and therapeutic targets, we performed multi-omics sequencing on tumor samples from patients diagnosed with PCNS-DLBCL, secondary CNS-DLBCL or extracranial (ec) DLBCL.By single-cell RNA sequencing, highly proliferated and dark zone (DZ)-related B cell subclusters, MKI67_B1, PTTG1_B2 and BTG1_B3, were predominant significantly in PCNS-DLBCL. Compared to SCNS-DLBCL and ecDLBCL, an immune-suppressive tumor microenvironment was observed in PCNS-DLBCL by analysis of immune-stimulating/inhibitory ligand‒receptor (L-R) pairs. By performing whole-exome sequencing in 93 patients, mutations enriched in BCR-NFkB and TLR pathways and the cooperation of these two pathways were found to be predominant in PCNS-DLBCL comparing to nonGCB-ecDLBCL. In summary, our study provides comprehensive insights into the transcriptomic and genetic characteristics of PCNS-DLBCL in contrast to ecDLBCL and will help dissect the oncogenic mechanism of this disease.

Marginal zone lymphomas (MZL) are low-grade B-cell neoplasms with indolent clinical behavior and a favorable prognosis. Central nervous system (CNS) involvement is extremely rare in MZL, as in other low-grade lymphomas where some presented with primary CNS disease without involvement elsewhere, and only a few cases were secondary to MZL. The dura mater is the most common site of involvement, while cavernous sinus involvement is extremely rare. There are no specific treatment recommendations for patients with secondary CNS-MZL exhibiting an indolent course. Therapeutic trials and recommendations typically focus on aggressive lymphomas with a poor prognosis, where induction with intensive chemotherapy, including high-dose methotrexate and/or cytarabine, followed by autologous stem cell transplantation, is standard. We present the case of a 50-year-old man with MZL involving the cavernous sinus, who initially presented with neurological and ophthalmological symptoms and was successfully treated with high-dose methotrexate and the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen.

The nervous system plays a vital role throughout the entire lifecycle and it may regulate the formation, development and metastasis of tumors. Small cell lung cancer is a typical neuroendocrine tumor, and it is naturally equipped with neurotropism. In this review, we firstly summarize current preclinical and clinical evidence to demonstrate the reciprocal crosstalk among the nervous system, tumor, and tumor microenvironment in various ways, including neurotransmitter-receptor pathways, innervations of nerve fibers, different types of synapse formation by neurons, astrocytes, and cancer cells, neoneurogenesis. Futherly, we emphasize how the nervous system interacts with small cell lung cancer and discuss the limitations of current research methods for examining the interactions. We propose that integrating neuroscience, development biology, and tumor biology can be a promising direction to provide new insights into development and metastasis of small cell lung cancer and raise some novel treatment strategies.

In the immunocompromised setting, there are distinct radiologic findings of primary central nervous system lymphoma (PCNSL), including necrotic ring-enhancing lesions, increased propensity for intralesional haemorrhage, and multiplicity. In this clinical context, advanced imaging with MR perfusion, spectroscopy, and diffusion-weighted imaging can be used to increase accuracy in the diagnosis of lymphoma over mimics such as high-grade glioma, metastases, or infection. This review summarizes the histology and pathophysiology of PCNSL in immunodeficient hosts, which provide a basis for its imaging appearances, prognosis, and treatment. This discussion is important for the general radiologist as the incidence of immunodeficiency-related PCNSL may be increasing.

This study investigated the effect of surgery on the prognosis of patients with primary central nervous system lymphoma (PCNSL) using data from the surveillance, epidemiology, and end results (SEER) database. A cohort of 5932 patients was analyzed, with 1466 undergoing surgical intervention (780 subtotal resection (STR), 686 gross total resection (GTR)) and 4466 receiving no surgery or biopsy only. The median age of the study population was 61.5 years. The median survival was 24.0 months for STR, 30.0 months for GTR, and 18.0 months for non-surgical patients (P < 0.001). Multivariate Cox regression analyses showed that the adjusted hazard ratio (HR) for STR was 0.77 (95% CI 0.70-0.85, P < 0.001) for overall survival (OS) and 0.74 (95% CI 0.66-0.83, P < 0.001) for cancer-specific survival (CSS). For GTR, the adjusted HR was 0.73 (95% CI 0.65-0.80, P < 0.001) for OS and 0.73 (95% CI 0.65-0.82, P < 0.001) for CSS. These results remained robust even after subgroup analyses, sensitivity analyses and propensity score matching (PSM). No significant interactions were observed in any subgroup. These findings indicate that surgery may improve the survival of patients with PCNSL, though further research is needed to confirm these findings. A key limitation is the inability to stratify patients by performance status and lesion number, critical for assessing resective surgery suitability.

The contemporary landscape of systemic therapy options for hematologic malignancies involving the central nervous system (CNS-HM) is rapidly evolving; a key question is how radiotherapy (RT) can be optimally integrated to improve patient outcomes. Historically, use of RT to treat CNS-HM was defined by broad fields and high doses. While effective, this approach raised concerns of potential neurotoxicity which significantly decreased RT utilization. RT was replaced by high-dose, CNS-penetrant, systemic therapies that offered durable control with lower perceived neurotoxic risk. But, as the therapeutic toolbox for CNS-HM expands, so too does the complexity and diversity of potential clinical scenarios where RT should be considered. In this review, we describe both well-established and emerging opportunities for RT integration, emphasizing how dose selection and field design could balance neurotoxicity risk and disease control. We propose an anatomical framework that captures the diverse utilization of RT for CNS-HM and serves as a practical guide for RT volume and dose design.

7-Hydroxymethotrexate (7-OHMTX) is the main metabolite in plasma following high-dose MTX (HD-MTX), which may result in activity and toxicity of the MTX. Moreover, 7-OHMTX could produce crystalline-like deposits within the renal tubules under acidic conditions or induce renal inflammation, oxidative stress, and cell apoptosis through various signaling pathways, ultimately leading to kidney damage. The objectives of this study were thus to explore the exposure-safety relationship of two compounds and search the most reliable marker for predicting HDMTX nephrotoxicity.

A total of 280 plasma concentration data (140 for MTX and 140 for 7-OHMTX) for 60 pediatric patients with non-Hodgkin lymphoma (NHL) were prospectively collected. Plasma MTX and 7-OHMTX concentrations were determined using a high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method. A nonlinear mixed effect model approach was used to build a joint population pharmacokinetic (PopPK) model. After validation, the model estimated the peak concentration (Cmax) and area under the curve within the initial 48 h (AUC0-48h) of the patients after drug administration by Bayesian feedback. The receiver operating characteristic (ROC) curves were generated to identify an exposure threshold associated with nephrotoxicity.

A three-compartment chain model (central and peripheral compartments for MTX and central compartment 7-OHMTX) with the first-order elimination adequately characterized the in vivo process of MTX and 7-OHMTX. The covariate analysis identified that the aspartate aminotransferase (AST) was strongly associated with the peripheral volume of distribution of MTX. Moreover, the Cmax of MTX and 7-OHMTX showed significant differences (p < 0.0001, p = 0.0472, respectively) among patients with or without nephrotoxicity. Similarly, individuals with nephrotoxicity also exhibited substantially higher ratio of 7-OHMTX to MTX peak concentration and the sum of MTX + 2.25 times the concentration of 7-OHMTX (p < 0.0001, p = 0.0426, respectively). By ROC analysis, the Cmax of MTX and 7-OHMTX had the greatest area under the curve (AUC) values (0.769 and 0.771, respectively). A Cmax threshold of 9.26 μmol/L for MTX or a Cmax threshold of 0.66 μmol/L for 7-OHMTX was associated with the best sensitivity/specificity for toxicity events (MTX: sensitivity = 0.886; specificity = 0.70; 7-OHMTX: sensitivity = 0.886; specificity = 0.70).

We demonstrated that the Cmax of MTX and 7-OHMTX were the most reliable markers associated with nephrotoxicity and proposed a Cmax threshold of 9.26 μmol/L for MTX and 0.66 μmol/L for 7-OHMTX as the point with a high risk of nephrotoxicity. Altogether, this study may contribute to crucial insights for ensuring the safe administration of drugs in pediatric clinical practice.

Differentiating primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM) is crucial because their prognosis and treatment differ substantially. Manual examination of their histological characteristics is considered the golden standard in clinical diagnosis. However, this process is tedious and time-consuming and might lead to misdiagnosis caused by morphological similarity between their histology and tumor heterogeneity. Existing research focuses on radiological differentiation, which mostly uses multi-parametric magnetic resonance imaging. By contrast, we investigate the pathological differentiation between the two types of tumors using whole slide images (WSIs) of postoperative formalin-fixed paraffin-embedded samples.

To learn the specific and intrinsic histological feature representations from the WSI patches, a self-supervised feature extractor is trained. Then, the patch representations are fused by feeding into a weakly supervised multiple-instance learning model for the WSI classification. We validate our approach on 134 PCNSL and 526 GBM cases collected from three hospitals. We also investigate the effect of feature extraction on the final prediction by comparing the performance of applying the feature extractors trained on the PCNSL/GBM slides from specific institutions, multi-site PCNSL/GBM slides, and large-scale histopathological images.

Different feature extractors perform comparably with the overall area under the receiver operating characteristic curve value exceeding 85% for each dataset and close to 95% for the combined multi-site dataset. Using the institution-specific feature extractors generally obtains the best overall prediction with both of the PCNSL and GBM classification accuracies reaching 80% for each dataset.

The excellent classification performance suggests that our approach can be used as an assistant tool to reduce the pathologists' workload by providing an accurate and objective second diagnosis. Moreover, the discriminant regions indicated by the generated attention heatmap improve the model interpretability and provide additional diagnostic information.

Primary central nervous system lymphoma (PCNSL) is a very rare extranodal non-Hodgkin's lymphoma confined to the brain, eyes, spinal cord, and cerebrospinal fluid (CSF). This disease is highly aggressive. For decades, high-dose methotrexate-based induction regimens have been the standard treatment for PCNSL and have significantly improved patient overall survival (OS). However, some patients still experience disease recurrence or develop drug resistance. With a deeper understanding of the pathophysiology of PCNSL, various therapies, including CD20 monoclonal antibodies, Bruton's tyrosine kinase (BTK) inhibitors, immunomodulatory drugs, immune checkpoint inhibitors, phosphoinositide 3-kinase (PI3 K)/mammalian target of rapamycin(mTOR) inhibitors, and chimeric antigen receptor (CAR) -T cells are increasingly being applied and have demonstrated considerable efficacy. These therapies have paved the way for novel treatment strategies in PCNSL, representing a highly promising field. Investigating the mechanisms, specific targets, and signaling pathways, as well as interactions with the tumor microenvironment (TME), can provide a solid foundation for further exploration and potentially enhance the optimization of treatment approaches for PCNSL. This review seeks to explore the characteristics of the TME in PCNSL, elucidate the molecular mechanisms of various immunotherapies and targeted therapies, examine their interactions with the TME, and summarize the advancements in the research of PCNSL immunotherapy and targeted therapy.

Primary central nervous system lymphoma (PCNSL) is one of the rare lymphomas limited to the central nervous system. With the availability of immunotherapy, the tumor microenvironment (TME) attracts much attention nowadays. However, the systematic studies on the TME of PCNSL are lacking. By reviewing the existing research, we found that the TME of PCNSL is infiltrated with abundant TAMs and TILs, among which cytotoxic T cells (CTLs) and M2-polarized macrophages are principal. However, the counts of immune cells infiltrated in the TME of PCNSL are significantly lower than systemic diffuse large B-cell lymphoma (DLBCL). In addition, PCNSL can attract the infiltration of immunosuppressive cells and the loss of HLA I/II expression, overexpress inhibitory immune checkpoints, and release immunosuppressive cytokines to form an immunosuppressive TME. The immunosuppressive effect of TME in PCNSL is significantly stronger than that in systemic DLBCL. These characteristics of TME highlight the immunosuppression of PCNSL.

The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in the prognostication and response evaluation of primary central nervous system lymphoma (PCNSL) remains inadequately defined.

We conducted a retrospective analysis of 268 consecutive newly diagnosed patients with PCNSL between 2006 and 2020. Of these patients, 105 and 110 patients were included to evaluate the prognostic value of baseline and post-treatment 18F-FDG-PET/CT scans, respectively. Tumor uptake was considered positive when it exceeded that of the contralateral brain upon visual assessment. Quantitative analysis of baseline 18F-FDG-PET/CT included measurement of the maximal standardized uptake value (SUVmax), total metabolic tumor volume (TMTV), and total lesion glycolysis (TLG).

The median age of the 268 patients was 62 years (range: 17-85), with 55% being male. The median progression-free survival (PFS) was 24.5 months (95% CI: 19.9-29.1), and the median overall survival (OS) was 34.5 months (95% CI: 22.9-46.1). The average SUVmax was 15.3 ± 5.7 and the mean TMTV and TLG were 12.6 ± 13.9 cm3 and 135.0 ± 152.7 g, respectively. Patients with a baseline TMTV ≥ 17.0 cm3 had significantly shorter OS (12.5 vs 74.0 months, P = .011). Post-treatment metabolic response by 18F-FDG-PET/CT significantly predicted PFS (median: 10.5 vs 46.0 months, P = .001) and OS (median: 21.0 vs 62.0 months, P = .002), whereas anatomic response by contrast-enhanced MRI showed no statistically significant differences in PFS (P = .130) or OS (P = .540).

Baseline TMTV and post-treatment metabolic response, as assessed by 18F-FDG-PET/CT, are significant prognostic factors in patients with PCNSL.

In this study, we compare outcomes of older patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) undergoing autologous hematopoietic cell transplantation (autoHCT) with either thiotepa/carmustine (BCNU/Thio) or thiotepa/busulfan/cyclophosphamide (TBC) conditioning. We used a postpublication dataset made available by the Center for International Blood and Marrow Transplantation Research including patients who were ≥65 years in age with PCNSL and underwent autoHCT as consolidation with TBC or BCNU/Thio conditioning. Out of 147 patients; n = 84 received BCNU/Thio and n = 63 received TBC. The 1-year NRM in the BCNU/Thio group was 10% versus 22% in the TBC group (P = .05) and the 2-year relapse rate was 5% versus 5%, respectively (P = 1.00). The 2-year progression-free survival (PFS) in the BCNU/Thio group was 85% versus 71% in the TBC group (P = .05) and 2-year overall survival (OS) was 86% versus 74% (P = .08). In a multivariable regression model, BCNU/Thio was associated with a lower risk for NRM (hazard ratio [HR], 0.33, P = .009), improved PFS (HR, 0.41, P = .008) and OS (HR, 0.37, P = .007), but there was no association with relapse risk. We found that in older adults with PCNSL undergoing consolidation with autoHCT, BCNU/Thio conditioning is associated with lower NRM and improved OS compared to TBC.

This is an unusual case of primary central nervous system lymphoma (PCNSL) with isolated third cranial nerve palsy as the initial manifestation. Neurolymphomatosis (NL) is a rare manifestation of PCNSL. While NL is a rare manifestation of PCNSL, primary vitreoretinal lymphoma (PVRL) can be the presenting feature or a later-involved manifestation. We present an unusual case of PCNSL with the isolated third cranial nerve palsy as the initial manifestation, which mimics the surgical third cranial nerve palsy. The patient developed PVRL subsequently and succumbed to the disease not long after the presentation.

The present study reports a single-center experience conducted at Józef Struś Multispecialty City Hospital in Poznań, Poland, in diagnosing and treating two patients with primary central nervous system lymphoma (PCNSL), one immunocompetent and one immunodeficient (AIDS). PCNSL is an extremely rare neoplasm with a poor prognosis and non-specific treatment on the basis of immunocompetency. Standard treatment consists of high-dose methotrexate (HD-MTX) being the background of a multimodal therapy, including other chemotherapeutic agents with and without radiation. To our knowledge, no alteration in management exists in immunocompromised individuals and so patients are subject to standard treatment options. Differences in patient management due to immunocompetency may necessitate separate protocols. The immunocompetent patient followed a more typical course, while the immunodeficient patient required balancing lymphoma treatment with the risks of opportunistic infections and drug interactions. These cases underscore the importance of tailored therapeutic approaches based on immune competency, aiming to improve outcomes for PCNSL.

The corpus callosum can reveal a "butterfly" pattern on imaging in various conditions, including glioblastoma, primary central nervous system lymphoma, tumefactive multiple sclerosis, and toxoplasmosis. Early differentiation among these conditions is crucial to avoid aggressive treatments. In one case, a 70-year-old woman with a history of multiple sclerosis experienced a neurological decline. While imaging suggested a high-grade glioma, a biopsy ultimately confirmed the diagnosis of tumefactive multiple sclerosis. The patient showed improvement with steroid therapy. It is essential to distinguish between high-grade gliomas and tumefactive multiple sclerosis, as gliomas typically present acutely while tumefactive multiple sclerosis progresses more slowly. Utilizing advanced imaging techniques and biopsy aids in achieving an accurate diagnosis, thus preventing unnecessary interventions. Additionally, a multidisciplinary approach is vital for optimal management of these conditions.

Primary Central Nervous System Lymphoma (PCNSL) is an aggressive form of lymphoma that can involve the brain, spinal cord, leptomeninges and eyes. PCNSL prognosis continues to be poor, with 5-year survival rates of 30-40%. Therapeutic options are especially limited for relapsed/refractory (r/r) PCNSL. In recent years, studies shed light on the pathogenesis and oncogenic pathways driving PCNSL, leading to the development of novel therapeutics. In this review, we discuss the evidence supporting these novel agents and present ongoing clinical studies.

Key oncogenic drivers of PCNSL include activation of the NFkB pathway, cell cycle dysregulation, somatic hypermutation and immune evasion, leading to the investigation of targeted therapeutics and immunotherapeutics to inhibit these pathways. Such approaches include BTK inhibitors, mTOR/PI3K inhibitors, immunomodulatory agents (IMIDs), immune checkpoint inhibitors and CD19-based CAR T-cells. The therapeutic repertoire for PCNSL is rapidly evolving, and a multi-modality approach including intensive chemotherapy regimens and novel therapies will likely be utilized in the future.

Contemporary outcomes and relapse patterns in primary CNS lymphoma (PCNSL) are lacking. We analyzed factors associated with relapse in a large cohort with extensive follow-up.

T1-post-contrast-enhancing disease was characterized in immunocompetent PCNSL (diffuse large B-cell) patients from 1983 to 2020. Patients were stratified by response to induction and consolidation (complete/unconfirmed [CR/CRu], partial, stable, progression [POD]). Refractory was POD during (or relapse ≤3 months of) induction. Initial relapse site was categorized as local (involving/adjacent to baseline), distant intraparenchymal, leptomeningeal, or other. Progression-free (PFS) and overall survival (OS) were assessed with proportional hazards. Cumulative incidence with competing risks was used to assess local relapse.

Median follow-up was 7.4 years (N = 559). Most (321, 57%) were recursive partitioning analysis class 2 (age ≥50, Karnosfky Performance Status [KPS] ≥70). Most had supratentorial (420, 81%), multifocal (274, 53%), bilateral (224, 43%), and deep structure involvement (314, 56%). Nearly all received methotrexate-based induction (532, 95%). There was no difference in PFS or OS from consolidation based on initial response to induction (CR/CRu vs PR) in patients who ultimately achieved a CR/CRu to consolidation. PFS at 1-, 5 years for 351 patients with CR/CRu to consolidation was 80% (95% confidence interval [95% CI]: 76%-84%) and 46% (95% CI: 41%-53%), respectively; 1-year cumulative incidence of local versus nonlocal relapse was 1.8% versus 15%, respectively. For 97 refractory patients, 1-year cumulative incidence of local versus nonlocal relapse was 57% versus 42%, respectively. Deep structure involvement (HR 1.89, 95% CI: 1.10%-3.27%) was associated with local relapse in refractory patients.

We report the first comprehensive relapse patterns in a large PCNSL cohort. While relapses post-CR to consolidation are typically distant and unpredictable, refractory patients had a relatively high incidence of local relapse. These findings can help optimize multimodality therapy for this highest-risk population.

Cerebrospinal fluid (CSF) cytology of primary central nervous system lymphoma arising in the immune deficiency/dysregulation setting (IDD-PCNSL) has not been described. This study presented a case of IDD-PCNSL-DLBCL, a GCB phenotype who was successfully diagnosed by CSF cytology in conjunction with ICC, ISH, FCM and clinical information.

Primary central nervous system (CNS) lymphoma (PCNSL) is a rare and aggressive lymphoma that affects the CNS without other systemic involvement. High-dose methotrexate (HDMTX)-based regimens are recommended frontline treatment, followed by consolidation with either high-dose chemotherapy, whole brain radiation (WBRT) +/- sequential temozolomide (TMZ), or autologous stem cell transplant (autoSCT). Despite advancements with HDMTX and rituximab, up to half of patients will relapse. Treatment for relapsed or refractory (R/R) disease varies widely as preferred regimens are not well-established. Our study aimed to provide real-world characterization of R/R PCNSL therapies. The secondary objective was characterization of consolidation methods after frontline treatment. This retrospective, descriptive analysis included 54 adult PCNSL patients that received a HDMTX-based frontline regimen between 4/1/2016 and 7/1/2022. Patients receiving HDMTX for the purpose of secondary CNS lymphoma, non-B cell origin PCNSL, and intraocular lymphoma were excluded. Thirty-one patients (57%) received consolidation therapy with rituximab and high-dose cytarabine (R-HDAC), WBRT, or both. Thirteen patients (24%) proceeded with autoSCT. Twenty-five patients had disease progression, with 17 patients receiving second line treatment. The second line treatments were WBRT (24%), clinical trial (18%), rituximab with lenalidomide (R2; 18%), re-induction with HDMTX-based regimens (18%), ibrutinib with rituximab (12%) and R-HDAC (12%). Seven patients progressed, and all received third line treatment. Treatments varied, including R2; ibrutinib +/- HDMTX; rituximab, methotrexate, and cytarabine; R-HDAC; R-nivolumab; and WBRT. Five patients received a fourth line regimen of R +/- lenalidomide, R-HDMTX, or nivolumab monotherapy. Regimens used for the three patients who received fifth line treatment and beyond included R-TMZ and pembrolizumab monotherapy in addition to previously described regimens. Regimen selection is varied and highly dependent on physician preference and patient factors, including clinical trial eligibility, prior therapies, performance status, organ function, and treatment intent. Prospective clinical trials are needed to guide optimal management.

Research into the effectiveness and applicability of deep learning, radiomics, and their integrated models based on Magnetic Resonance Imaging (MRI) for preoperative differentiation between Primary Central Nervous System Lymphoma (PCNSL) and Glioblastoma (GBM), along with an exploration of the interpretability of these models.

A retrospective analysis was performed on MRI images and clinical data from 261 patients across two medical centers. The data were split into a training set (n = 153, medical center 1) and an external test set (n = 108, medical center 2). Radiomic features were extracted using Pyradiomics to build the Radiomics Model. Deep learning networks, including the transformer-based MobileVIT Model and Convolutional Neural Networks (CNN) based ConvNeXt Model, were trained separately. By applying the "late fusion" theory, the radiomics model and deep learning model were fused to produce the optimal Max-Fusion Model. Additionally, Shapley Additive exPlanations (SHAP) and Grad-CAM were employed for interpretability analysis.

In the external test set, the Radiomics Model achieved an Area under the receiver operating characteristic curve (AUC) of 0.86, the MobileVIT Model had an AUC of 0.91, the ConvNeXt Model demonstrated an AUC of 0.89, and the Max-Fusion Model showed an AUC of 0.92. The Delong test revealed a significant difference in AUC between the Max-Fusion Model and the Radiomics Model (P = 0.02).

The Max-Fusion Model, combining different models, presents superior performance in distinguishing PCNSL and GBM, highlighting the effectiveness of model fusion for enhanced decision-making in medical applications.

The preoperative non-invasive differentiation between PCNSL and GBM assists clinicians in selecting appropriate treatment regimens and clinical management strategies.

A portion of individuals diagnosed with primary central nervous system lymphomas (PCNSL) may experience early relapse or refractory (R/R) disease following treatment. This research explored the potential of MRI-based radiomics in forecasting R/R cases in PCNSL. Forty-six patients with pathologically confirmed PCNSL diagnosed between January 2008 and December 2020 were included in this study. Only patients who underwent pretreatment brain MRIs and complete postoperative follow-up MRIs were included. Pretreatment contrast-enhanced T1WI, T2WI, and T2 FLAIR imaging were analyzed. A total of 107 radiomic features, including 14 shape-based, 18 first-order statistical, and 75 texture features, were extracted from each sequence. Predictive models were then built using five different machine learning algorithms to predict R/R in PCNSL. Of the included 46 PCNSL patients, 20 (20/46, 43.5%) patients were found to have R/R. In the R/R group, the median scores in predictive models such as support vector machine, k-nearest neighbors, linear discriminant analysis, naïve Bayes, and decision trees were significantly higher, while the apparent diffusion coefficient values were notably lower compared to those without R/R (p < 0.05). The support vector machine model exhibited the highest performance, achieving an overall prediction accuracy of 83%, a precision rate of 80%, and an AUC of 0.78. Additionally, when analyzing tumor progression, patients with elevated support vector machine and naïve Bayes scores demonstrated a significantly reduced progression-free survival (p < 0.05). These findings suggest that preoperative MRI-based radiomics may provide critical insights for treatment strategies in PCNSL.

Central nervous system lymphoma (CNSL) is a devastating disease with a poor prognosis. Early diagnosis, monitoring of the treatment response, and outcome prediction carry the utmost importance in the management of patients with CNSL. Surgical biopsy is the gold standard for tissue diagnosis, however, this procedure has potential complications. Therefore, there is a need for a method that provides information about diagnosis and patient monitoring to avoid surgical risks. The study aimed to investigate potential diagnostic biomarkers for patients with CNSL.

Patients with secondary CNSL were included in this study. Serum and cerebrospinal fluid (CSF) samples were collected before treatment and after completion of the treatment. Cell-free DNA (cfDNA), exosomes, free and exosomal microRNA (miR)-15a, miR-21, miR-155, miR-210, and miR-19b in both serum and CSF were examined, and they were compared with the controls. Also, their levels before and after treatment were compared. Nine patients with the diagnosis of secondary CNSL were reviewed. cfDNA, miR-15a, and miR-155 in serum, and exosome in CSF were found to be significantly higher in CNSL patients compared to the controls. Exosomal miR-15a, miR-21, miR-155, miR-210, and miR-19b in CSF were found to be significantly higher in CNSL patients compared to controls, whereas their levels in serum were not significantly high.

Our findings suggested that exosomes and exosomal miR-15a, miR-21, miR-155, miR-210 and miR-19b in CSF would be promising biomarkers for the diagnosis of patients with CNSL. Further studies are needed to confirm our findings.