Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas.

Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV+) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. In this study, a comprehensive genetic analysis of 22 EBV+ PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV+ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV- PCNSL. Instead, EBV+ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV+ PCNSL. In addition to novel insights into the pathobiology of EBV+ PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.

Myasthenia Gravis in the Setting of Immune Checkpoint Inhibitor Therapy: Practical Considerations and Opinion-Based Approach to Acute Management.

Use of immune checkpoint inhibitors (ICI) is increasing in patients with oncologic disease. Three classes of checkpoint inhibitors exist: anti-PD1 (nivolumab, pembrolizumab), anti-CTLA4 (ipilimumab), and anti-PDL1 (atezolizumab, avelumab, durvalumab). ICI therapy has been used in multiple malignancies including renal cell cancer, non-small-cell lung cancer, and melanoma. These therapies have led to improved oncologic treatment and outcomes in patients but can lead to immune-related or inflammatory adverse effects. Neuromuscular system side effects, particularly at the neuromuscular junction, have been observed, including myasthenia gravis (MG). This narrative review serves to summarize key available information regarding myasthenia gravis in the setting of immune checkpoint inhibitor use including the molecular targets of checkpoint inhibitors, the clinical manifestations of MG in patients with checkpoint inhibitor therapy, and potential treatment options. Studies have shown that the use of checkpoint inhibitor therapy can trigger MG, and that patients with ICI-related MG can have more severe disease. Recognition and understanding of the range of neurologic complications, including neuromuscular disorders, which can be seen with ICI therapy is a critical step toward developing better treatment algorithms and improved clinical outcomes. Future investigations which include deep mechanistic studies to further our understanding of the immunopathologic triggers and predictive markers of ICI-related MG will be important to address the current knowledge gaps.

Treatment Options for Recurrent Primary CNS Lymphoma.

OPINION STATEMENT: Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m2) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.

Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors.

BACKGROUND: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors. METHODS: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures. RESULTS: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%). CONCLUSION: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes. TRIAL REGISTRATION NUMBER: NCT02335918.

Clinical Reasoning: A 73-Year-Old Woman With Episodic Dysarthria and Horizontal Binocular Diplopia.

A 73-year-old woman presented with transient episodes of dysarthria and horizontal diplopia. She had stereotactic radiosurgery 18 years prior for a retroclival meningioma. Neurologic examination was notable for right-sided tongue deviation, tongue fasciculations, and intermittent impaired abduction of the right eye. MRI ruled out recurrence or progression of the retroclival meningioma. EEG failed to reveal electrographic seizures. EMG showed spontaneous depolarizations in bursts that sounded like "marching soldiers" in the right hemitongue, consistent with myokymia. Focal myokymia is an unusual EMG finding that is usually seen in demyelinating disorders, after radiation, or in neoplastic/inflammatory conditions. The clinical presentation and EMG findings were most consistent with delayed radiation-induced myokymia. Similar cases of transient dysarthria and tongue myokymia from radiation have been infrequently reported in the literature; however, this case uniquely exhibited additional episodes of transient horizontal diplopia, which was possibly from ocular myokymia or neuromyotonia. Although there are limited data, sodium channel inhibitors (e.g., carbamazepine, oxcarbazepine, and lacosamide) have shown some success to provide symptomatic relief, most likely secondary to their ability to inhibit underlying peripheral nerve hyperexcitability. Our patient was started on lacosamide 50 mg twice a day with a notable decrease in symptom frequency. This case illustrates the importance of detailed clinical and electrodiagnostic studies in making the diagnosis of delayed radiation-induced myokymia with episodic dysarthria and provides guidance on potential therapeutics.

Clinical Reasoning: A 64-Year-Old Man With History of Meningitis Presenting With Proximal Weakness of the Arms.

A 64-year-old man presented for evaluation of proximally pronounced weakness of the arms with preserved facial and lower extremity strength. Symptoms slowly developed over the last 2 years, and the patient's history was notable for severe Listeria monocytogenes meningitis 4 years before presentation, which was adequately treated with antibiotics. On examination, symptoms clinically reassembled man-in-the-barrel syndrome and localized to the cervicothoracic central cord. Blood analysis was unremarkable, and CSF analysis showed no recurrent or persistent infection. Spinal MRI revealed pockets of sequestered CSF from C3 to C4 and areas of CSF space effacement from C3 to T12. MRI findings were interpreted as cord tethering suggestive of adhesive arachnoiditis. CT myelogram showed insufficient contrast agent migration above T10 and contour irregularities of the conus medullaris, confirming the postulated pathomechanism of cord tethering. Final diagnosis was therefore cervicothoracic central cord damage due to cord tethering in the setting of postinfectious adhesive arachnoiditis following bacterial meningitis. The patient failed a course of pulsed methylprednisolone therapy, and symptoms progressed. Best supportive care was provided. The clinical presentation of adhesive arachnoiditis is variable, and advanced imaging techniques and invasive studies such as CT myelogram may be required to establish the diagnosis. Timely diagnosis is warranted as early surgical or medical therapy can improve symptoms.

ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody.

The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting of brain tumors with an anti-DNA autoantibody. Deoxymab-1 (DX1) is a DNA-damaging autoantibody that localizes to tumors and is synthetically lethal to cancer cells with defects in the DNA damage response. We found that DX1 penetrated brain endothelial cells and crossed the BBB, and mechanistic studies identify ENT2 as the key transporter. In efficacy studies, DX1 crosses the BBB to suppress orthotopic glioblastoma and breast cancer brain metastases. ENT2-linked transport of autoantibodies across the BBB has potential to be exploited in brain tumor immunotherapy, and its discovery raises hypotheses on actionable mechanisms of CNS penetration by neurotoxic autoantibodies in CNS lupus.

Hemorrhage Into a Subependymal Giant Cell Astrocytoma in an Adult With Tuberous Sclerosis: Case Report.

BACKGROUND: We present an uncommon cause of intracranial hemorrhage in a young adult. Tuberous sclerosis complex is a rare genetic disorder characterized by skin changes, benign systemic or central nervous system tumors [subependymal giant cell astrocytoma (SEGA)], mental retardation, or epilepsy. Hemorrhage into SEGA is exceedingly rare. CASE PRESENTATION: We evaluated a 21-year-old college student with migraine. Biopsy of numerous popular skin lesions on his nose revealed adenoma sebaceum. Magnetic resonance imaging brain showed a subependymal nodule near the foramen of Monro suspected to be SEGA. Genetic analysis identified a tuberous sclerosis complex-1 germ line mutation. Surveillance imaging was recommended for the subependymal tumor. Fourteen months later, he presented with spontaneous hemorrhage into the tumor. Hematoma evacuation and tumor resection revealed SEGA. The college graduate was able to return to full-time work. CONCLUSIONS: We present an unusual cause of intracranial hemorrhage in a young adult. Thorough work-up and recognition of an underlying genetic predisposition can curtails diagnostic delay when life-threatening complications occur.

Neurotoxicities associated with immune checkpoint inhibitor therapy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal complications of ICIs, and clinical experience is limited. The aim of this study is to further define the clinical spectrum and outcome of ICI-mediated neurotoxicities. METHODS: Patients with ICI-associated neurotoxicities were identified from retrospective review of the quality control database at a single institution. Data regarding demographics, medical history, clinical presentation, diagnosis, management and outcome were recorded. RESULTS: We identified 18 patients with neurotoxicity following ICI therapy with pembrolizumab, nivolumab, atezolizumab, or ipilimumab for a diverse set of malignancies. Neurotoxicities comprised central demyelinating disorder (28%), autoimmune encephalitis predominantly affecting the grey matter (17%), aseptic meningitis (6%), myasthenia gravis (MG) (17%) with concurrent myositis (6%), sensorimotor polyneuropathy (11%) and hypophysitis (17%). Median time to onset of neurotoxicities was 5 weeks (range 1-72). All patients discontinued ICIs and received steroids with additional immunomodulation required in 9 patients, resulting in improvement for 16 of 18 patients. Grade 3-4 neurotoxicity developed in 14 patients, of whom 6 had died at database closure. Grade 3-4 severity negatively impacted overall survival (OS) (p = 0.046). CONCLUSIONS: ICI-mediated neurotoxicities present early, are rapidly progressive and include a diverse phenotype affecting the CNS, PNS and neuroendocrine system. A high level of vigilance is warranted, as early diagnosis and targeted treatment can substantially prevent morbidity and mortality. Prospective clinical trials are warranted to assess optimized management of ICI-induced neurotoxicities.

Exome sequencing identifies SLIT2 variants in primary CNS lymphoma.

SLIT2 constitutes a known tumour suppressor gene, which has not yet been implicated in the pathogenesis of primary central nervous system lymphoma (PCNSL). Performing exome sequencing on paired blood and tumour DNA samples from six treatment-naïve PCNSL patients, we identified novel SLIT2 variants (p.N63S, p.T590M, p.T732S) that were associated with shorter progression-free survival in our cohort and shorter overall survival in a large validation cohort of lymphoid malignancies from the cBio Cancer Genomics Portal. WNT- and NF-κB-reporter luciferase assays suggest detected alterations are loss-of-function variants. Given the possible prognostic implications, the role of SLIT2 in PCNSL pathogenesis and progression warrants further investigation.

Extent and prognostic value of MGMT promotor methylation in glioma WHO grade II.

MGMT promotor methylation is associated with favourable outcome in high-grade glioma. In glioma WHO grade II, it is unclear whether the extent of MGMT promotor methylation and its prognostic role is independent from other molecular markers. We performed a retrospective analysis of 155 patients with glioma WHO grade II. First, all 155 patients were assigned to three molecular groups according to the 2016 WHO classification system: (1) oligodendroglioma, IDH-mutant and 1p19q co-deleted (n = 81); (2) astrocytoma, IDH-mutant and 1p19q non-codeleted (n = 54); (3) astrocytoma, IDH-wildtype (n = 20). MGMT promotor methylation was quantified using Sanger sequencing of the CpG sites 74-98 within the MGMT promotor region. Highest numbers of methylated CpG sites were found for oligodendroglioma, IDH-mutant and 1p19q co-deleted. When 1p19q co-deletion was absent, numbers of methylated CpG sites were higher in the presence of IDH-mutation. Accordingly, lowest numbers were seen in the IDH-wildtype subpopulation. In the entire cohort, larger numbers of methylated CpG sites were associated with favourable outcome. When analysed separately for the three WHO subgroups, a similar association was only retained in astrocytoma, IDH-wildtype. Collectively, extent of MGMT promotor methylation was strongly associated with other molecular markers and added prognostic information in astrocytoma, IDH-wildtype. Evaluation in prospective cohorts is warranted.

Autoimmune disease-related primary CNS lymphoma: systematic review and meta-analysis.

BACKGROUND: Recent studies suggest a relatively high prevalence of autoimmune disorders (AD) among primary CNS lymphoma (PCNSL) patients, however, the literature is limited to case reports. To gain a better understanding of AD-PCNSL we reviewed and analyzed all cases described in the literature. METHODS: We searched the MEDLINE database using the search terms 'central nervous system lymphoma' or 'CNS lymphoma' along with AD-related terms. We selected 39 records for qualitative synthesis of data and identified 50 AD-PCNSL. Clinical, imaging and outcome data were collected. Overall survival (OS) was analyzed with the Kaplan-Meier method. Univariate and multivariate analyses were performed using log rank test and Cox proportional hazard model. RESULTS: Most common AD were systemic lupus erythematosus (24%), multiple sclerosis (16%), and myasthenia gravis (14%). All patients had received immunosuppressants for their AD. Median interval from AD until PCNSL diagnosis was 108 months (range: 11-420). Male-to-female ratio was 0.42 and AD-PCNSL was diagnosed at a median age of 57 years (range: 2-88). On imaging lesions typically localized to the hemispheres (65%) and displayed peripheral enhancement (74%). Pathological evaluation revealed diffuse large-B-cell lymphoma (DLBCL) subtype (80%) and Epstein-Barr virus positivity (75%) in most AD-PCNSL. Median OS was 31 months. Age > 60 years (p = 0.014) was identified as a significant prognostic factor. CONCLUSIONS: AD requiring immunosuppression appear over-represented in the population of PCNSL patients. Aggressive polychemotherapy can accomplish long term OS in AD-PCNSL comparable to immunocompetent patients. Age > 60 may serve as a prognostic factor.

Laser interstitial thermal therapy (LITT) vs. bevacizumab for radiation necrosis in previously irradiated brain metastases.

PURPOSE: Both laser interstitial thermal therapy (LITT) and bevacizumab have been used successfully to treat radiation necrosis (RN) after radiation for brain metastases. Our purpose is to compare pre-treatment patient characteristics and outcomes between the two treatment options. METHODS: Single-institution retrospective chart review identified brain metastasis patients who developed RN between 2011 and 2018. Pre-treatment factors and treatment responses were compared between those treated with LITT versus bevacizumab. RESULTS: Twenty-five patients underwent LITT and 13 patients were treated with bevacizumab. The LITT cohort had a longer overall survival (median 24.8 vs. 15.2 months for bevacizumab, p = 0.003) and trended to have a longer time to local recurrence (median 12.1 months vs. 2.0 for bevacizumab), although the latter failed to achieve statistical significance (p = 0.091). LITT resulted in an initial increase in lesional volume compared to bevacizumab (p < 0.001). However, this trend reversed in the long term follow-up, with LITT resulting in a median volume decrease at 1 year post-treatment of - 64.7% (range - 96.0% to + > 100%), while bevacizumab patients saw a median volume increase of + > 100% (range - 63.0% to + > 100%), p = 0.010. CONCLUSIONS: Our study suggests that patients undergoing LITT for RN have longer overall survival and better long-term lesional volume reduction than those treated with bevacizumab. However, it remains unclear whether our findings are due only to a difference in efficacy of the treatments or the implications of selection bias.

Leptomeningeal dissemination of low-grade neuroepithelial CNS tumors in adults: a 15-year experience.

BACKGROUND: Leptomeningeal dissemination (LD) in adults is an exceedingly rare complication of low-grade neuroepithelial CNS tumors (LGNs). We aimed to determine relative incidence, clinical presentation, and predictors of outcome. METHODS: We searched the quality control database of the Section of Neuro-Oncology, Yale Cancer Center, for patients with LGN (WHO grade I/II) seen between 2002 and 2017. For cases complicated by LD, we recorded demographics, clinical signs, histopathological diagnosis, and imaging findings. A comprehensive literature review was performed. RESULTS: Eleven consecutive patients with LD were identified, representing 2.3% of individuals with LGN seen at our institution between 2002 and 2017 (n = 475). Ependymoma was the predominant histological entity. Mean time interval from diagnosis of LGN to LD was 38.6 ± 10 months. Symptoms were mostly attributed to communicating hydrocephalus. Tumor deposits of LD were either nodular or linear with variable enhancement (nonenhancing lesions in 4 of 11 patients). Localized (surgery, radiosurgery, involved-field, or craniospinal radiation therapy) or systemic treatments (chemotherapy) were provided. All patients progressed radiographically. Median overall survival after LD was 102 months. Survival was prolonged when a combination of localized and systemic therapies was administered (188.5 vs 25.5 months; P = .03). Demographics and tumor spectrum reported in the literature were similar to our cohort. CONCLUSIONS: LD is a rare complication of LGNs. A high level of suspicion is required for timely diagnosis as early symptoms are nonspecific and commonly do not occur until years after initial tumor diagnosis. Repeated aggressive treatment appears to be beneficial in improving survival.

Primary dural lymphomas: Clinical presentation, management, and outcome.

BACKGROUND: Clinical experience is limited for primary central nervous system (CNS) lymphoma that arises from the dura mater, which is denoted with the term primary dural lymphoma (PDL). This study was aimed at determining the relative incidence, presentation, and outcomes of PDL. METHODS: The institutional databases of the Divisions of Neuro-Oncology at the Massachusetts General Hospital and the Yale School of Medicine were retrospectively searched for patients with primary CNS lymphoma. Patients with pathologically confirmed dural lymphoma and no evidence of primary cerebral or systemic involvement were identified. Clinical data, diagnostic findings, treatments, and outcomes were recorded. RESULTS: A total of 20 patients with PDL were identified, and they represented 6.3% of the individuals with primary CNS lymphomas (20 of 316). Histopathological examination of PDL revealed the following underlying subtypes: diffuse large B-cell lymphoma (10 of 20 patients), marginal zone lymphoma (6 of 20), follicular lymphoma (2 of 20), undefined B-cell non-Hodgkin lymphoma (1 of 20), and T-cell non-Hodgkin lymphoma (1 of 20). On imaging, all tumors appeared as extra-axial masses with avid contrast enhancement and mostly mimicked meningioma. The median apparent diffusion coefficient value was 667 ± 26 mm2 /s. Cerebrospinal fluid analyses and symptoms were nonspecific, and the diagnosis rested on tissue analysis. Therapeutic approaches included surgery, radiotherapy, and chemotherapy. The median overall survival was not reached after 5 years. Three patients were deceased at database closure because of tumor progression. The extent of tumor resection correlated positively with overall survival (P = .044). CONCLUSIONS: PDL is a rare variant of primary CNS lymphoma that can be radiographically mistaken for meningioma. The outcome is excellent with multimodality treatment, and aggressive surgery may convey a survival advantage in select cases.

Somatic PRKAR1A mutation in sporadic atrial myxoma with cerebral parenchymal metastases: a case report.

BACKGROUND: Atrial myxomas are generally considered benign neoplasms. The majority of tumors are sporadic and less than 10% are associated with an autosomal dominant condition known as the Carney complex, which is most often caused by germline mutation in the gene PRKAR1A. Whether this gene plays a role in the development of sporadic myxomas has been an area of debate, although recent studies have suggested that some fraction of sporadic tumors also carry mutations in PRKARIA. Extra-cardiac complications of atrial myxoma include dissemination of tumor to the brain; however, the dissemination of viable invasive tumor cells is exceedingly rare. CASE PRESENTATION: We present here a 48-year-old white woman who developed multiple intracranial hemorrhagic lesions secondary to tumor embolism that progressed to 'false' aneurysm formation and invasion through the vascular wall into brain parenchyma 7 months after resection of an atrial myxoma. Whole exome sequencing of her tumor revealed multiple mutations in PRKAR1A not found in her germline deoxyribonucleic acid (DNA), suggesting that the myxoma in this patient was sporadic. CONCLUSIONS: Our patient illustrates that mutations in PRKAR1A may be found in sporadic lesions. Whether the presence of this mutation affects the clinical behavior of sporadic tumors and increases risk for metastasis is not clear. Regardless, the protein kinase A pathway which is regulated by PRKAR1A represents a possible target for treatment in patients with metastatic cardiac myxomas harboring mutations in the PRKARIA gene.

Prognostic markers for immunodeficiency-associated primary central nervous system lymphoma.

BACKGROUND: Immunodeficiency is a major risk factor for primary central nervous system lymphoma (PCNSL), but data on the disease in immunocompromised hosts are scarce. We aimed to define clinical and imaging features and determine prognostic factors for immunodeficiency-associated PCNSL. METHODS: All PCNSL cases seen at Yale-New Haven Hospital between 2002 and 2017 were retrospectively screened for immunodeficiency. For patients with immunosuppression, biopsies were evaluated and clinical data were collected. Predictors of survival were identified using Kaplan-Meier survival analysis and log-rank test. p values < 0.05 were considered significant. RESULTS: 23 patients with immunodeficiencies were identified: eleven on immunosuppressants after solid organ transplantation, seven with human immunodeficiency virus infection, and five on immunosuppressive treatment due to various autoimmune disorders. PCNSL cases were largely Epstein-Barr-Virus positive (78%), histologically classified as diffuse large B cell lymphomas (87%), and showed peripheral contrast enhancement (81%) and corresponding heterogeneous diffusion-weighted imaging patterns (DWI) on magnetic resonance imaging (MRI) (71%). Median overall survival was 31 months. Age > 60 years at diagnosis (p < 0.01), peripheral enhancement of the mass on MRI (p = 0.04), heterogeneous DWI patterns (p = 0.04), and clonal immunoglobulin heavy chain gene rearrangement (IgHR) (p = 0.03) were found to be negative prognostic markers. CONCLUSIONS: Immunodeficiency-associated PCNSL presents with similar clinical, pathological and imaging features. Age > 60 years, clonal IgHR, heterogeneous DWI pattern and peripheral enhancement on MRI may serve as predictors of less favorable outcome.

Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells.

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein-directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient's outcome when compared with <7 days of steroids. Management of CAR T cell-mediated neurotoxicity warrants evaluation in prospective clinical trials.

Paraneoplastic neurological syndromes: a single institution 10-year case series.

BACKGROUND: Given its rare incidence, there are few epidemiological case series on paraneoplastic neurologic syndromes (PNS). METHODS: We present a 10-year series compiled in the Section of Neuro-Oncology, Yale Cancer Center between 2002 and 2012. RESULTS: Twenty-five cases met the PNS Euro-network criteria for definitive PNS. Most (64%; 16/25) had no known neoplasm. Cerebrospinal fluid pleocytosis declined logarithmically over time. Neuroimaging abnormalities were seen in 88% of cases (15/17), but with delayed onset. Therapeutic benefit correlated strongly to pre-treatment modified Rankin Scale (mRS) (p < 0.01), but not with time elapsed between syndrome onset to treatment (p = 0.8), first immunotherapy modality (corticosteroids: n = 10; IVIG: n = 10; PLEX: n = 3; p = 0.37), or number of immunotherapy modalities provided (p = 0.17). PNS-related mortality was high (24%; 6/25). Nonetheless, 16% (3/18; 7 living patients censored) survived over 6 times the anticipated median expected by tumor type and stage. CONCLUSIONS: PNS are rare, at an estimated incidence of 3.1 cases per million-person-years. Detection of CSF pleocytosis and MRI abnormalities depend on time of analysis. While PNS-related mortality was high, immunotherapy benefit correlated strongly with pre-treatment mRS and long-term survival is possible.