Publications by authors named "Philipp Karschnia"

38 Publications

Extent, pattern, and prognostic value of MGMT promotor methylation: does it differ between glioblastoma and IDH-wildtype/TERT-mutated astrocytoma?

J Neurooncol 2021 Dec 13. Epub 2021 Dec 13.

Department of Neurosurgery, Ludwig-Maximilians-University School of Medicine, Munich, Germany.

Introduction: The cIMPACT-NOW update 6 first introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear.

Methods: We searched the institutional database for patients with: (1) glioblastoma defined by histopathology; and (2) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region.

Results: We identified 224 patients with glioblastoma diagnosed based on histopathology, and 54 patients with IDHwt astrocytoma with pTERTmut (19 astrocytomas WHO grade II and 38 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two cohorts as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two cohorts when treated with radio- or chemotherapy. In both cohorts, higher numbers of methylated CpG sites were associated with favourable outcome.

Conclusions: Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both tumor entities, higher numbers of methylated CpG sites appear associated with more favourable outcome. Evaluation in larger prospective cohorts is warranted.
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http://dx.doi.org/10.1007/s11060-021-03912-6DOI Listing
December 2021

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

Neurology 2021 Nov 19. Epub 2021 Nov 19.

Department of Neurology, Yale School of Medicine, New Haven, CT

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 two years, and the patient's history was notable for severe meningitis four years prior to 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.
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http://dx.doi.org/10.1212/WNL.0000000000013085DOI Listing
November 2021

Subventricular zone involvement is associated with worse outcome in glioma WHO grade 2 depending on molecular markers.

Sci Rep 2021 10 8;11(1):20045. Epub 2021 Oct 8.

Department of Neurosurgery, Ludwig Maximilians University, Marchioninistrasse 15, 81377, Munich, Germany.

Neural stem cells within the subventricular zone were identified as cells of origin driving growth of high-grade gliomas, and anatomical involvement of the subventricular zone has been associated with an inferior clinical outcome. Whether the association between poor outcome and subventricular zone involvement also applies to glioma of lower grades is unclear. We therefore analysed a retrospective cohort of 182 patients with glioma grade 2 (according to the WHO 2016 classification) including 78 individuals (43%) with subventricular zone involvement. Patients with and without subventricular zone involvement did not differ in regard to demographics, histopathology, and molecular markers. Notably, subventricular zone involvement was a negative prognostic marker for malignant progression and overall survival on uni- and multivariate analysis. When patients were stratified according to the cIMPACT-NOW update 6, subventricular zone involvement was negatively associated with outcome in IDH-wildtype astrocytomas and 1p19q-codeleted oligodendrogliomas but not in IDH-mutant astrocytomas. Collectively, subventricular zone involvement may represent a risk factor for worse outcome in glioma WHO grade 2 depending on the molecular tumor signature. The present data confirm the relevance of molecular glioma classifications as proposed by the cIMPACT-NOW update 6. These findings warrant evaluation in prospective cohorts.
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http://dx.doi.org/10.1038/s41598-021-97714-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501091PMC
October 2021

In vivo two-photon characterization of tumor-associated macrophages and microglia (TAM/M) and CX3CR1 during different steps of brain metastasis formation from lung cancer.

Neoplasia 2021 11 26;23(11):1089-1100. Epub 2021 Sep 26.

Department of Neurology, Ludwig-Maximilians-University School of Medicine, Munich, Germany; Department of Neurosurgery, Ludwig-Maximilians-University School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. Electronic address:

Brain metastases frequently occur in lung cancer and dramatically limit prognosis of affected patients. The influence of tumor-associated macrophages and microglia (TAM/M) and their receptor CX3CR1 on different steps of brain metastasis formation from lung cancer is poorly characterized. We established a syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intravital 2-photon laser scanning microscopy. This allowed in vivo tracking of fluorescence-expressing tumor cells and TAM/M on a single-cell level over weeks. Intracarotid injection of red tdTomato-fluorescent Lewis lung carcinoma cell was performed in transgenic mice either proficient or deficient for CX3CR1. After intracarotid cell injection, intravascular tumor cells extravasated into the brain parenchyma and formed micro- and mature macrometastases. We observed potential phagocytosis of extravasated tumor cells by TAM/M. However, during later steps of metastasis formation, these anti-tumor effects diminished and were paralleled by TAM/M accumulation and activation. Although CX3CR1 deficiency resulted in a lower number of extravasated tumor cells, progression of these extravasated cells into micro metastases was more efficient. Overall, this resulted in a comparable number of mature macrometastases in CX3CR1-deficient and -proficient mice. Our findings indicate that unspecific inhibition of CX3CR1 might not be a suitable therapeutic option to prevent dissemination of lung cancer cells to the brain. Given the close interaction between TAM/M and tumor cells during metastasis formation, other therapeutic approaches targeting TAM/M function may warrant further evaluation. The herein established orthotopic mouse model may be a useful tool to evaluate such concepts in vivo.
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http://dx.doi.org/10.1016/j.neo.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479202PMC
November 2021

The evolving role of neurosurgery for central nervous system metastases in the era of personalized cancer therapy.

Eur J Cancer 2021 10 20;156:93-108. Epub 2021 Aug 20.

Department of Neurosurgery, Ludwig-Maximilians-University School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. Electronic address:

Recent therapeutic advances involving the use of systemic targeted treatments and immunotherapeutic agents in patients with advanced cancers have translated into improved survival rates. Despite the emergence of such promising pharmacological therapies and extended survival, the frequency of metastases in the central nervous system has steadily increased. Effective medical and surgical therapies are available for many patients with brain metastases and need to be incorporated into multi-disciplinary care protocols. The role of neurosurgeons is evolving within these multi-disciplinary care teams. Surgical resection of brain metastases can provide immediate relief from neurological symptoms due to large lesions and provides the histopathological diagnosis in cases of no known primary malignancy. In situations where immunotherapy is part of the oncological treatment plan, surgery may be proposed for expeditious relief of edema to remove the need for steroids. In patients with multiple brain metastases and mixed response to therapeutics or radiosurgery, tumour resampling allows tissue analysis for druggable targets or to distinguish radiation effects from progression. Ventriculo-peritoneal shunting may improve quality of life in patients with hydrocephalus associated with leptomeningeal tumour dissemination and may allow for time to administer more therapy thus prolonging overall survival. Addressing the limited efficacy of many oncological drugs for brain metastases due to insufficient blood-brain barrier penetrance, clinical trial protocols in which surgical specimens are analysed after pre-surgical administration of therapeutics offer pharmacodynamic insights. Comprehensive neurosurgical assessment remains an integral element of multi-disciplinary oncological care of patients with brain metastases and is integral to tumour biology research and therapeutic advancement.
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http://dx.doi.org/10.1016/j.ejca.2021.07.032DOI Listing
October 2021

CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma.

Blood 2021 12;138(24):2499-2513

Department of Medicine III, University Hospital, Ludwig Maximilian University (LMU) Munich, Munich, Germany.

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell-related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (absolute neutrophil count [ANC] <100 cells per µL) neutropenia in 72% of patients and prolonged (21 days or longer) neutropenia in 64% of patients. The median duration of severe neutropenia (ANC < 500 cells per µL) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary end point. In the training cohort (n = 58), we observed a significant correlation with baseline thrombocytopenia (r = -0.43; P = .001) and hyperferritinemia (r = 0.54; P < .0001) on univariate and multivariate analysis. Incidence and severity of cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, and peak cytokine levels were not associated with the primary end point. We created the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (eg, platelet count, hemoglobin, and ANC) and baseline inflammation (eg, C-reactive protein and ferritin). This model was validated in independent cohorts, one from Europe (n = 91) and one from the United States (n = 109) and discriminated patients with severe neutropenia ≥14 days to <14 days (pooled validation: area under the curve, 0.89; sensitivity, 89%; specificity, 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs 5.5 days; P < .001) and a higher incidence of severe thrombocytopenia (87% vs 34%; P < .001) and anemia (96% vs 40%; P < .001). The score implicates bone marrow reserve and inflammation prior to CAR T-cell therapy as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.
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http://dx.doi.org/10.1182/blood.2020010543DOI Listing
December 2021

CAR T-Cells for CNS Lymphoma: Driving into New Terrain?

Cancers (Basel) 2021 May 20;13(10). Epub 2021 May 20.

Department of Neurosurgery, Division of Neuro-Oncology, Ludwig Maximilians University School of Medicine, Marchioninistrasse, 1581377 Munich, Germany.

Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma.
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http://dx.doi.org/10.3390/cancers13102503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161128PMC
May 2021

Chimeric Antigen Receptor T Cells for Glioblastoma: Current Concepts, Challenges, and Future Perspectives.

Neurology 2021 08 13;97(5):218-230. Epub 2021 May 13.

From the Department of Neurosurgery (P.K., N. Teske, N. Thon, J.C.T., L.v.B.), Department of Medicine, Hematology & Oncology Division (M.S.), Cellular Immunotherapy Program (M.S.), and Department of Neurology (L.v.B.), Ludwig-Maximilians-University School of Medicine, Munich, Germany; Department of Neurology (P.K., J.D.), Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; and German Cancer Consortium (DKTK) (P.K., N. Teske, N. Thon, J.C.T., L.v.B.), Partner Site Munich, Germany.

Glioblastoma is the most common malignant primary brain tumor and is associated with a poor prognosis even after multimodal therapy. Chimeric antigen receptor (CAR) T cells have emerged as a promising therapeutic avenue in glioblastoma. CARs incorporate antigen-recognition moieties that endow autologous T cells with specificity against antigens expressed on glioblastoma (e.g., interleukin [IL]-13Rα2, epidermal growth factor receptor variant III [EGFRvIII], and human epidermal growth factor receptor 2 [HER2]). Compelling antitumor effects of such therapy have been shown in murine glioblastoma models. In humans, 5 phase I/II studies on IL-13Rα2-, EGFRvIII-, and HER2-directed CAR T cells for the treatment of glioblastoma have been published suggesting an acceptable safety profile. However, antitumor effects fell short of expectations in these initial clinical studies. Tumor heterogeneity, antigen loss, and the immunosuppressive tumor microenvironment are among the most important factors to limit the efficacy of CAR T-cell therapy in glioblastoma. Novel target antigens, modification of CAR T-cell design, the combination of CAR T-cell therapy with other therapeutic approaches, but also the use of CAR natural killer cells or CAR macrophages may optimize antitumor effects. Numerous clinical trials studying such approaches are ongoing, as well as several preclinical studies. With an increasing understanding of immune-escape mechanisms of glioblastoma and novel manufacturing techniques for CARs, CAR T cells may provide clinically relevant activity in glioblastoma. This review focuses on the use of CAR T cells in glioblastoma, but also introduces the basic structure, mechanisms of action, and relevant side effects of CAR T cells.
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http://dx.doi.org/10.1212/WNL.0000000000012193DOI Listing
August 2021

Clinical Presentation and Management of SMART Syndrome.

Neurology 2021 May 4. Epub 2021 May 4.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

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http://dx.doi.org/10.1212/WNL.0000000000012150DOI Listing
May 2021

PCV chemotherapy alone for WHO grade 2 oligodendroglioma: prolonged disease control with low risk of malignant progression.

J Neurooncol 2021 Jun 1;153(2):283-291. Epub 2021 May 1.

Department of Neurosurgery, Medical Center of the University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.

Introduction: The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy.

Methods: Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed.

Results: PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS.

Conclusions: PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression.
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http://dx.doi.org/10.1007/s11060-021-03765-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211617PMC
June 2021

Evidence-based recommendations on categories for extent of resection in diffuse glioma.

Eur J Cancer 2021 05 2;149:23-33. Epub 2021 Apr 2.

Department of Neurosurgery, Ludwig-Maximilians-University School of Medicine, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. Electronic address:

Surgical resection represents the standard of care in diffuse glioma, and more extensive tumour resection appears to be associated with favourable outcome. Up to now, terminology to describe extent of resection has been inconsistently applied across clinical trials which hampers comparative analysis of cohorts between different studies. Based on a comprehensive literature review, we developed evidence-based expert recommendations on categories for extent of resection. Recommendations are formulated for the categories 'biopsy', 'partial resection', 'subtotal resection', 'near total resection', 'complete resection' and 'supramaximal resection'. Definitions rest on reduction of contrast- and non-contrast-enhancing tumour in glioblastoma, and on reduction of T2/FLAIR-hyperintense tumour in gliomas WHO grade 2 or 3. Both relative reduction of tumour volume (in percentage) as a measurement of surgical efficacy and absolute residual tumour volume (in cm) as a measurement of remaining tumour burden are incorporated into the categories for extent of resection. Class of evidence for the proposed categories ranges from class IIB to IV. Limitations of the suggested categories are discussed. The proposed categories on extent of resection offer a framework to standardize nomenclature based on previous studies, and will need to be evaluated in prospective, molecularly well-defined cohorts. Our categories may eventually help as a stratification factor for future clinical trials.
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http://dx.doi.org/10.1016/j.ejca.2021.03.002DOI Listing
May 2021

Language dysfunction-associated EEG findings in patients with CAR-T related neurotoxicity.

BMJ Neurol Open 2020 18;2(1):e000054. Epub 2020 Jun 18.

Neuro-oncology/Neurology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Chimeric antigen receptor-modified T cells (CAR-T) have emerged as a promising immunotherapeutic approach in relapsed/refractory haematolgical malignancies. Broader application is limited by unique toxicities, notably, neurotoxicity (NTX). Language dysfunction is among the most frequent symptoms of NTX, the underlying mechanisms of which remain to be elucidated. Electroencephalogram (EEG) is an important tool to monitor for NTX and may provide insights into language dysfunction.

Aim: We aimed to characterise language dysfunction and define electroencephalographic signatures after CAR-T cell therapy.

Methods: We reviewed the clinical presentation and EEG findings of 20 adult patients presenting with language dysfunction after CAR-T cell infusion. The cohort included a subset of patients treated with investigational CD19-directed CAR-T cells for non-Hodgkin's lymphoma (n=17), acute lymphoblastic leukaemia (n=1), follicular lymphoma (n=1) and chronic lymphocytic leukaemia (n=1).

Results: Language dysfunction presented within 14 days of CAR-T cell infusion in 16 (84%) patients. Ten (50%) patients had mild word-finding difficulties and 10 (50%) had marked dysphasia with profound word-finding difficulties; the latter were all associated with generalised rhythmic delta activity or generalised periodic discharges on EEG.

Conclusions: Language dysfunction after CAR-T cell therapy is associated with generalised EEG abnormalities.
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http://dx.doi.org/10.1136/bmjno-2020-000054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871716PMC
June 2020

Past medical history of tumors other than meningioma is a negative prognostic factor for tumor recurrence in meningiomas WHO grade I.

Acta Neurochir (Wien) 2021 10 5;163(10):2853-2859. Epub 2021 Mar 5.

Department of Neurosurgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany.

Background: Prognostic markers for meningioma recurrence are needed to guide patient management. Apart from rare hereditary syndromes, the impact of a previous unrelated tumor disease on meningioma recurrence has not been described before.

Methods: We retrospectively searched our database for patients with meningioma WHO grade I and complete resection provided between 2002 and 2016. Demographical, clinical, pathological, and outcome data were recorded. The following covariates were included in the statistical model: age, sex, clinical history of unrelated tumor disease, and localization (skull base vs. convexity). Particular interest was paid to the patients' past medical history. The study endpoint was date of tumor recurrence on imaging. Prognostic factors were obtained from multivariate proportional hazards models.

Results: Out of 976 meningioma patients diagnosed with a meningioma WHO grade I, 416 patients fulfilled our inclusion criteria. We encountered 305 women and 111 men with a median age of 57 years (range: 21-89 years). Forty-six patients suffered from a tumor other than meningioma, and no TERT mutation was detected in these patients. There were no differences between patients with and without a positive oncological history in terms of age, tumor localization, or mitotic cell count. Clinical history of prior tumors other than meningioma showed the strongest association with meningioma recurrence (p = 0.004, HR = 3.113, CI = 1.431-6.771) both on uni- and multivariate analysis.

Conclusion: Past medical history of tumors other than meningioma might be associated with an increased risk of meningioma recurrence. A detailed pre-surgical history might help to identify patients at risk for early recurrence.
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http://dx.doi.org/10.1007/s00701-021-04780-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437882PMC
October 2021

The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents.

Acta Neuropathol Commun 2021 03 4;9(1):35. Epub 2021 Mar 4.

Department of Neurosurgery, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany.

MGMT-promoter methylation is associated with favorable outcome in glioblastoma. The aim of this study was to determine whether the absolute number of methylated Cytosine-Guanine-dinucleotide-(CpG-)sites within the DMR-2 island of the MGMT-promoter may correlate with outcome in a qualitative or quantitative fashion. In a cohort of newly diagnosed glioblastoma patients treated with stereotactic biopsy or open tumor resection plus concomitant chemoradiotherapy, we assessed MGMT-promoter methylation by methylation-specific polymerase-chain-reaction (MSP). Methylation of the CpG-sites 74-98 within the MGMT-promoter region was additionally analysed by Sanger sequencing, and the total number of methylated CpG-sites was correlated with outcome using proportional hazards models. 215 patients with glioblastoma were identified and stratified per MSP (positive: 53%, negative: 47%). Among MSP-positive tumors, hierarchical clustering identified three subgroups with different methylation rates (median: 80% vs. 52% vs. 47%), indicating a site-dependent methylation propagation. The methylation status of a given CpG-site indicated a neighborhood-dependent methylation propagation. Survival was linearly associated with the cumulative number of methylated CpG-sites. This was particularly true in patients who received at least one adjuvant cycle of temozolomide. Notably, all CpG-sites analyzed contributed similarly to effect size; this enabled a further predictive substratification of MSP-positive tumors with median OS ranging from as low as 17.1 months (< 18 methylated CpG-sites) to as high as 26.2 months (≥ 18 methylated CpG-sites) in the overall cohort. All in all, total number of methylated CpG-sites may correlate with outcome in a linear fashion. Such analysis may therefore add further predictive value to conventional methods of determining the MGMT-promoter status.
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http://dx.doi.org/10.1186/s40478-021-01134-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934240PMC
March 2021

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy - a case report.

BMC Infect Dis 2021 Jan 28;21(1):121. Epub 2021 Jan 28.

Department of Hematology and Oncology, University Hospital, LMU Munich, Munich, Germany.

Background: Prolonged myelosuppression following CD19-directed CAR T-cell transfusion represents an important, yet underreported, adverse event. The resulting neutropenia and multifactorial immunosuppression can facilitate severe infectious complications.

Case Presentation: We describe the clinical course of a 59-year-old patient with relapsed/refractory DLBCL who received Axicabtagene-Ciloleucel (Axi-cel). The patient developed ASTCT grade I CRS and grade IV ICANS, necessitating admission to the neurological ICU and prolonged application of high-dose corticosteroids and other immunosuppressive agents. Importantly, neutropenia was profound (ANC < 100/μl), G-CSF-refractory, and prolonged, lasting more than 50 days. The patient developed severe septic shock 3 weeks after CAR transfusion while receiving anti-fungal prophylaxis with micafungin. His clinical status stabilized with broad anti-infective treatment and intensive supportive measures. An autologous stem cell backup was employed on day 46 to support hematopoietic recovery. Although the counts of the patient eventually started to recover, he developed an invasive pulmonary aspergillosis, which ultimately lead to respiratory failure and death. Postmortem examination revealed signs of Candida glabrata pancolitis.

Conclusions: This case highlights the increased risk for fatal infectious complications in patients who present with profound and prolonged cytopenia after CAR T-cell therapy. We describe a rare case of C. glabrata pancolitis associated with multifactorial immunosuppression. Although our patient succumbed to a fatal fungal infection, autologous stem cell boost was able to spur hematopoiesis and may represent an important therapeutic strategy for DLBCL patients with CAR T-cell associated bone marrow aplasia who have underwent prior stem cell harvest.
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http://dx.doi.org/10.1186/s12879-020-05755-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841988PMC
January 2021

Exome sequencing identifies SLIT2 variants in primary CNS lymphoma.

Br J Haematol 2021 04 22;193(2):375-379. Epub 2021 Jan 22.

Department of Neurology, Yale School of Medicine, New Haven, USA.

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.
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http://dx.doi.org/10.1111/bjh.17319DOI Listing
April 2021

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

Sci Rep 2020 11 12;10(1):19758. Epub 2020 Nov 12.

Division of Neuro-Oncology, Department of Neurosurgery, Ludwig Maximilians University School of Medicine, Marchioninistrasse 15, 81377, Munich, Germany.

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.
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http://dx.doi.org/10.1038/s41598-020-76312-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661705PMC
November 2020

Disproportionate decline in admissions for exacerbated COPD during the COVID-19 pandemic.

Respir Med 2020 Aug 14:106120. Epub 2020 Aug 14.

Department of Cardiology, Respiratory Medicine and Intensive Care, University Hospital Augsburg, Augsburg University, Germany; Ludwig-Maximilians-University Munich, Germany.

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http://dx.doi.org/10.1016/j.rmed.2020.106120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427552PMC
August 2020

Genomic alterations in Turcot syndrome: Insights from whole exome sequencing.

J Neurol Sci 2020 10 25;417:117056. Epub 2020 Jul 25.

Department of Neurology, Yale School of Medicine, New Haven, CT, United States of America; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.117056DOI Listing
October 2020

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

J Neurooncol 2020 Aug 18;149(1):153-159. Epub 2020 Jul 18.

Department of Neurology, Yale School of Medicine, 15 York Street, New Haven, CT, 06510, USA.

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.
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http://dx.doi.org/10.1007/s11060-020-03583-9DOI Listing
August 2020

Defining Treatment-Related Adverse Effects in Patients with Glioma: Distinctive Features of Pseudoprogression and Treatment-Induced Necrosis.

Oncologist 2020 08 18;25(8):e1221-e1232. Epub 2020 Jun 18.

Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: Pseudoprogression (PP) and treatment-induced brain tissue necrosis (TN) are challenging cancer treatment-related effects. Both phenomena remain insufficiently defined; differentiation from recurrent disease frequently necessitates tissue biopsy. We here characterize distinctive features of PP and TN to facilitate noninvasive diagnosis and clinical management.

Materials And Methods: Patients with glioma and confirmed PP (defined as appearance <5 months after radiotherapy [RT] completion) or TN (>5 months after RT) were retrospectively compared using clinical, radiographic, and histopathological data. Each imaging event/lesion (region of interest [ROI]) diagnosed as PP or TN was longitudinally evaluated by serial imaging.

Results: We identified 64 cases of mostly (80%) biopsy-confirmed PP (n = 27) and TN (n = 37), comprising 137 ROIs in total. Median time of onset for PP and TN was 1 and 11 months after RT, respectively. Clinically, PP occurred more frequently during active antineoplastic treatment, necessitated more steroid-based interventions, and was associated with glioblastoma (81 vs. 40%), fewer IDH1 mutations, and shorter median overall survival. Radiographically, TN lesions often initially manifested periventricularly (n = 22/37; 60%), were more numerous (median, 2 vs. 1 ROIs), and contained fewer malignant elements upon biopsy. By contrast, PP predominantly developed around the tumor resection cavity as a non-nodular, ring-like enhancing structure. Both PP and TN lesions almost exclusively developed in the main prior radiation field. Presence of either condition appeared to be associated with above-average overall survival.

Conclusion: PP and TN occur in clinically distinct patient populations and exhibit differences in spatial radiographic pattern. Increased familiarity with both conditions and their unique features will improve patient management and may avoid unnecessary surgical procedures.

Implications For Practice: Pseudoprogression (PP) and treatment-induced brain tissue necrosis (TN) are challenging treatment-related effects mimicking tumor progression in patients with brain cancer. Affected patients frequently require surgery to guide management. PP and TN remain arbitrarily defined and insufficiently characterized. Lack of clear diagnostic criteria compromises treatment and may adversely affect outcome interpretation in clinical trials. The present findings in a cohort of patients with glioma with PP/TN suggest that both phenomena exhibit unique clinical and imaging characteristics, manifest in different patient populations, and should be classified as distinct clinical conditions. Increased familiarity with PP and TN key features may guide clinicians toward timely noninvasive diagnosis, circumvent potentially unnecessary surgical procedures, and improve response assessment in neuro-oncology.
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http://dx.doi.org/10.1634/theoncologist.2020-0085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418360PMC
August 2020

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

Neurooncol Pract 2020 Jan 6;7(1):118-126. Epub 2019 Jul 6.

Department of Neurology, Yale School of Medicine, New Haven, CT, USA.

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; = .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.
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http://dx.doi.org/10.1093/nop/npz020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104875PMC
January 2020

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

Cancer 2020 06 16;126(12):2811-2820. Epub 2020 Mar 16.

Department of Neurology, Yale School of Medicine, New Haven, Connecticut.

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 mm /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.
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http://dx.doi.org/10.1002/cncr.32834DOI Listing
June 2020

Insulin-like growth factor 1 stimulates the angiogenic activity of adipose tissue-derived microvascular fragments.

J Tissue Eng 2019 Jan-Dec;10:2041731419879837. Epub 2019 Sep 27.

Institute for Clinical & Experimental Surgery, Saarland University, Homburg/Saar, Germany.

Angiogenesis in adipose tissue is promoted by insulin-like growth factor 1 signaling. We analyzed whether this regulatory mechanism also improves the angiogenic activity of adipose tissue-derived microvascular fragments. Murine adipose tissue-derived microvascular fragments were cultivated for 24 h in the University of Wisconsin (UW) solution supplemented with vehicle, insulin-like growth factor 1, or a combination of insulin-like growth factor 1 and insulin-like growth factor-binding protein 4. Subsequently, we assessed their cellular composition, viability, proliferation, and growth factor expression. Moreover, cultivated adipose tissue-derived microvascular fragments were seeded onto collagen-glycosaminoglycan scaffolds, which were implanted into dorsal skinfold chambers to study their vascularization and incorporation. Insulin-like growth factor 1 increased the viability and growth factor expression of adipose tissue-derived microvascular fragments without affecting their cellular composition and proliferation. Accordingly, scaffolds containing insulin-like growth factor 1-stimulated adipose tissue-derived microvascular fragments exhibited an enhanced in vivo vascularization and incorporation. These positive insulin-like growth factor 1 effects were reversed by additional exposure of adipose tissue-derived microvascular fragments to insulin-like growth factor-binding protein 4. Our findings indicate that insulin-like growth factor 1 stimulation of adipose tissue-derived microvascular fragments is suitable to improve their vascularization capacity.
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http://dx.doi.org/10.1177/2041731419879837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767710PMC
September 2019

University of Wisconsin solution for the xeno-free storage of adipose tissue-derived microvascular fragments.

Regen Med 2019 07 17;14(7):681-691. Epub 2019 Jul 17.

Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany.

Adipose tissue-derived microvascular fragments (ad-MVF) are vascularization units for regenerative medicine. We investigated whether University of Wisconsin (UW) solution is suitable for their xeno-free storage. Murine ad-MVF were cultivated for 24 h in 4°C or 20°C UW solution and 20°C endothelial cell growth medium (control). The ad-MVF were seeded onto collagen-glycosaminoglycan scaffolds, which were analyzed in dorsal skinfold chambers by intravital fluorescence microscopy and histology. All implants exhibited microvascular networks on day 14 with the highest functional microvessel density in controls. Ad-MVF cultivation in UW solution at 4°C resulted in an improved scaffold vascularization compared with cultivation at 20°C. UW solution is suitable for the hypothermic storage of ad-MVF.
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http://dx.doi.org/10.2217/rme-2018-0164DOI Listing
July 2019

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

J Neurooncol 2019 Aug 13;144(1):107-115. Epub 2019 Jun 13.

Department of Neurology, Yale School of Medicine, New Haven, USA.

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.
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http://dx.doi.org/10.1007/s11060-019-03208-wDOI Listing
August 2019

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

Blood 2019 05 26;133(20):2212-2221. Epub 2019 Feb 26.

Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.

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 ( = .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) ( = .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 ( = .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.
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http://dx.doi.org/10.1182/blood-2018-12-893396DOI Listing
May 2019

Pharmacologic management of cognitive impairment induced by cancer therapy.

Lancet Oncol 2019 02;20(2):e92-e102

Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA USA. Electronic address:

Cognitive dysfunction is a challenging adverse effect of chemotherapy and radiotherapy that has limited treatment options. Clinical trials for proposed pharmacotherapeutic interventions to help manage these cognitive symptoms have had conflicting results and no standard of care has yet been established. Pharmacotherapeutic approaches for cancer therapy-induced cognitive symptoms include CNS stimulants (eg, methylphenidate and modafinil), medications used in patients with memory impairment (eg, donepezil, memantine, and ginkgo biloba), and bone marrow supporting agents (eg, erythropoietin). Whilst the beneficial effects of CNS stimulants have been mainly reported in children, efficacy in adults has been varied. Antidementia drugs have emerged as promising compounds in the management of cognitive dysfunction, but clinical experience of their use remains limited. Therefore, large clinical trials for these putative memory-enhancing drugs are needed to establish their clinical value in an oncology setting. Several clinical trials testing novel pharmacotherapeutic interventions for the management of cognitive dysfunction are ongoing, as well as numerous preclinical studies. With an increasing understanding of the molecular and cellular mechanisms underlying cognitive deficits in patients with cancer, novel treatment strategies are emerging.
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http://dx.doi.org/10.1016/S1470-2045(18)30938-0DOI Listing
February 2019

MRI findings in trigeminal neuropathy: bilateral Meckel's cave lesions.

Acta Neurol Belg 2020 Feb 2;120(1):171-173. Epub 2019 Feb 2.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.

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http://dx.doi.org/10.1007/s13760-019-01091-wDOI Listing
February 2020
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