Publications by authors named "Jorg Dietrich"

98 Publications

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

Intracranial Foreign Body Granuloma Mimicking Brain Tumor Recurrence: A Case Series.

Oncologist 2021 May 11;26(5):e893-e897. Epub 2021 Apr 11.

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

Background: Intracranial foreign body granuloma (FBG) is a rare inflammatory reaction to retained foreign material, manifesting acutely or months to years following neurosurgical procedures. Radiographically, FBG can mimic tumor progression, and tissue biopsy may be required to guide management.

Materials And Methods: In this retrospective case series, we present unique clinico-radiographic and histopathological features of six neuro-oncological patients diagnosed with FBG between 2007 and 2019.

Results: All six patients (4 women and 2 men, aged 29-54 [median, 30.5] years) had undergone surgical resection of a low- (n = 4) or high-grade (n = 2) glioma. FBG manifestation postsurgery ranged from 1 day to 4 years and was predominantly asymptomatic (n = 5/6). Magnetic resonance imaging universally demonstrated one or multiple peripherally enhancing lesion(s) adjacent to the resection cavity. Histopathology in all (n = 4/4) resected specimens demonstrated an inflammatory reaction to foreign material, confirming FBG.

Conclusion: Intracranial FBG constitutes a rare but challenging treatment-related condition effectively managed by surgery, with important therapeutic implications in neuro-oncology.
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http://dx.doi.org/10.1002/onco.13766DOI Listing
May 2021

A Rapid Genotyping Panel for Detection of Primary Central Nervous System Lymphoma.

Blood 2021 Mar 18. Epub 2021 Mar 18.

Massachusetts General Hospital, Boston, Massachusetts, United States.

Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N=1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0-617 days. Permanent histopathology confirmed PCNSL in 142/152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% CI: 44.1-70.4% and 87.2-100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2-74.5% and 83.9-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.
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http://dx.doi.org/10.1182/blood.2020010137DOI Listing
March 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

Application of the theory of planned behavior with agent-based modeling for sustainable management of vegetative filter strips.

J Environ Manage 2021 Apr 5;284:112014. Epub 2021 Feb 5.

University of Concepcion, Chillán, Chile.

This study proposes an innovative socio-hydrological modeling framework for the development of environmental policies that are tailored to farmers' attitudes and economic interests but also optimize environmental criteria. From a farmers' on-site survey, a behavior model is developed based on a modified Theory of Planned Behavior (TPB). The dynamics of the social and environmental system is implemented by coupling an agent-based model (ABM) with an agro-hydrological model for vegetative filter strips (VFS). A case study is conducted with farmers from the Larqui river basin, Chile to understand their standpoint on VFS to reduce soil loss in their agricultural fields and protect water bodies. Partial least square structural equation modeling is used to analyze the survey on farmers' aspiration and attitudes. It showed that the constructs added to TPB (behavioral morality, behavioral willingness, knowledge) had a significant effect on modeling the intention and behavior of farmers to have VFS. Based on the survey, the farmers were categorized into perceptive, proactive, bounded rational and interactive agents. An ABM was developed using the behavioral categorization, related decision rules, and utility functions of agricultural activities including the VFS implementation and management. The results of the ABM corroborate with the survey of the farmers. The survey supports the view that the decision on the width of VFS is not solely dependent on the utility generated and the reduction in soil losses but also on the behavior of farmers. This behavioral sociohydrological modeling framework is capable of supporting policy-makers in developing tailored environmental policies that might improve the acceptance of sustainable agricultural practices by farmers.
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http://dx.doi.org/10.1016/j.jenvman.2021.112014DOI Listing
April 2021

The best matrix for the brain: advances in secondary CNS lymphoma.

Authors:
Jorg Dietrich

Lancet Haematol 2021 02;8(2):e96-e97

Massachusetts General Hospital Cancer Center, Division of Neuro-Oncology, Harvard Medical School, Boston, MA 02114, USA. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(20)30431-2DOI Listing
February 2021

Vascular dysfunction promotes regional hypoxia after bevacizumab therapy in recurrent glioblastoma patients.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa157. Epub 2020 Nov 17.

Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Background: Hypoxia is a driver of treatment resistance in glioblastoma. Antiangiogenic agents may transiently normalize blood vessels and decrease hypoxia before excessive pruning of vessels increases hypoxia. The time window of normalization is dose and time dependent. We sought to determine how VEGF blockade with bevacizumab modulates tumor vasculature and the impact that those vascular changes have on hypoxia in recurrent glioblastoma patients.

Methods: We measured tumor volume, vascular permeability (Ktrans), perfusion parameters (cerebral blood flow/volume, vessel caliber, and mean transit time), and regions of hypoxia in patients with recurrent glioblastoma before and after treatment with bevacizumab alone or with lomustine using [F]FMISO PET-MRI. We also examined serial changes in plasma biomarkers of angiogenesis and inflammation.

Results: Eleven patients were studied. The magnitude of global tumor hypoxia was variable across these 11 patients prior to treatment and it did not significantly change after bevacizumab. The hypoxic regions had an inefficient vasculature characterized by elevated cerebral blood flow/volume and increased vessel caliber. In a subset of patients, there were tumor subregions with decreased mean transit times and a decrease in hypoxia, suggesting heterogeneous improvement in vascular efficiency. Bevacizumab significantly changed known pharmacodynamic biomarkers such as plasma VEGF and PlGF.

Conclusions: The vascular signature in hypoxic tumor regions indicates a disorganized vasculature which, in most tumors, does not significantly change after bevacizumab treatment. While some tumor regions showed improved vascular efficiency following treatment, bevacizumab did not globally alter hypoxia or normalize tumor vasculature in glioblastoma.
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http://dx.doi.org/10.1093/noajnl/vdaa157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764510PMC
November 2020

Fatal neurotoxicity after chimeric antigen receptor T-cell therapy: An unexpected case of fludarabine-associated progressive leukoencephalopathy.

Eur J Cancer 2021 Feb 23;144:178-181. Epub 2020 Dec 23.

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

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http://dx.doi.org/10.1016/j.ejca.2020.11.021DOI Listing
February 2021

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events.

J Immunother Cancer 2020 12;8(2)

Cancer Immunotherapy Program, Division of Oncology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, USA

Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as 'living drugs,' their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients.
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http://dx.doi.org/10.1136/jitc-2020-001511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745688PMC
December 2020

Neurotoxicity of Cancer Therapies.

Authors:
Jorg Dietrich

Continuum (Minneap Minn) 2020 12;26(6):1646-1672

Purpose Of Review: This article reviews neurologic complications associated with chemotherapy, radiation therapy, antiangiogenic therapy, and immunotherapy.

Recent Findings: Cancer therapies can cause a wide range of neurologic adverse effects and may result in significant patient morbidity and mortality. Although some treatment-associated neurologic complications manifest acutely and are often reversible and transient, others occur with delayed onset, can be progressive, and are uniquely challenging to patient management. With an increase in multimodality and combination therapies, including targeted therapies and immunotherapies, and prolonged patient survival, novel and unique patterns of neurologic complications have emerged.

Summary: Both conventional and novel cancer therapies can adversely affect the nervous system, thereby producing a wide range of neurologic complications. Increased awareness among neurologists and early recognition of cancer therapy-induced neurotoxic syndromes is critically important to minimize patient morbidity, prevent permanent injury, and improve patient outcomes.
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http://dx.doi.org/10.1212/CON.0000000000000943DOI Listing
December 2020

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults.

J Neurooncol 2020 Nov 19;150(2):165-213. Epub 2020 Nov 19.

Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA.

Question: What is the role of temozolomide in the management of adult patients (aged 65 and under) with newly diagnosed glioblastoma?

Target Population: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma.

Recommendation: Level I: Concurrent and post-irradiation Temozolomide (TMZ) in combination with radiotherapy and post-radiotherapy as described by Stupp et al. is recommended to improve both PFS and OS in adult patients with newly diagnosed GBM. There is no evidence that alterations in the dosing regimen have additional beneficial effect.

Question: Is there benefit to adjuvant temozolomide treatment in elderly patients (> 65 years old?).

Target Population: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma.

Recommendation: Level III: Adjuvant TMZ treatment is suggested as a treatment option to improve PFS and OS in adult patients (over 70 years of age) with newly diagnosed GBM.

Question: What is the role of local regional chemotherapy with BCNU biodegradable polymeric wafers in adult patients with newly diagnosed glioblastoma?

Target Population: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma.

Recommendation: Level III: There is insufficient evidence for the use of BCNU wafers following resection in patients with newly diagnosed glioblastoma who undergo the Stupp protocol after surgery. Further studies of higher quality are suggested to understand the role of BCNU wafer and other locoregional therapy in the setting of Stupp Protocol.

Question: What is the role of bevacizumab in the adult patient with newly diagnosed glioblastoma?

Target Population: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma.

Recommendation: Level I: Bevacizumab in general is not recommended in the initial treatment of adult patients with newly diagnosed GBM. It continues to be strongly recommended that patients with newly diagnosed GBM be enrolled in properly designed clinical trials to assess the benefit of novel chemotherapeutic agents compared to standard therapy.
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http://dx.doi.org/10.1007/s11060-020-03601-wDOI Listing
November 2020

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

Perceptions of prognosis and goal of treatment in patients with malignant gliomas and their caregivers.

Neurooncol Pract 2020 Oct 17;7(5):490-497. Epub 2020 Apr 17.

Department of Medicine, Division of Hematology & Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Background: Patients with malignant gliomas have a poor prognosis. However, little is known about patients' and caregivers' understanding of the prognosis and the primary treatment goal.

Methods: We conducted a prospective study in patients with newly diagnosed malignant gliomas (N = 72) and their caregivers (N = 55). At 12 weeks after diagnosis, we administered the Prognosis and Treatment Perceptions Questionnaire to assess understanding of prognosis and the Hospital Anxiety and Depression Scale to evaluate mood. We used multivariable regression analyses to explore associations between prognostic understanding and mood and McNemar tests to compare prognostic perceptions among patient-caregiver dyads (N = 48).

Results: A total of 87.1% (61/70) of patients and 79.6% (43/54) of caregivers reported that it was "very" or "extremely" important to know about the patient's prognosis. The majority of patients (72.7%, [48/66]) reported that their cancer was curable. Patients who reported that their illness was incurable had greater depressive symptoms (B = 3.01, 95% CI, 0.89-5.14, = .01). There was no association between caregivers' prognostic understanding and mood. Among patient-caregiver dyads, patients were more likely than caregivers to report that their primary treatment goal was cure (43.8% [21/48] vs 25.0% [12/48], = .04) and that the oncologist's primary goal was cure (29.2% [14/48] vs 8.3% [4/48], = .02).

Conclusions: Patients with malignant gliomas frequently hold inaccurate perceptions of the prognosis and treatment goal. Although caregivers more often report an accurate assessment of these metrics, many still report an overly optimistic perception of prognosis. Interventions are needed to enhance prognostic communication and to help patients cope with the associated distress.
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http://dx.doi.org/10.1093/nop/npaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516113PMC
October 2020

Ipilimumab: an investigational immunotherapy for glioblastoma.

Expert Opin Investig Drugs 2020 Nov 6;29(11):1187-1193. Epub 2020 Oct 6.

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

Introduction: Glioblastoma (GBM) is the most common primary malignant central nervous system tumor and has a poor overall outcome despite an aggressive standard-of-care treatment. Hence, better therapeutic modalities are necessary. Immunotherapy is a novel modality that has an indirect action against the tumor cells through activation of an anti-tumor immune response.

Areas Covered: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) belongs to a class of molecules called immune checkpoints that are inherently expressed on immune cells and lead to attenuation of the immune response. Inhibition of such molecules has been approved for the treatment of melanoma, and prolonged survival and complete responses have been reported in preclinical GBM mouse models. Ipilimumab inhibits CTLA-4 and is being investigated for the treatment of GBM, alone or in combination with other treatment modalities, in various preclinical and clinical studies, the results of the most relevant of which are discussed in this review.

Expert Opinion: Combining ipilimumab with other immunotherapy modalities and using it in specific conditions may increase the rate of objective responses in patients with GBM.
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http://dx.doi.org/10.1080/13543784.2020.1826436DOI Listing
November 2020

Central nervous system injury from novel cancer immunotherapies.

Curr Opin Neurol 2020 Dec;33(6):723-735

MGH Cancer Center.

Purpose Of Review: Neurotoxicity from antineoplastic treatment remains a challenge in oncology. Cancer treatment-induced central nervous system (CNS) injury can be therapy-limiting, severely disabling, and even fatal. While emerging cancer immunotherapies have revolutionized oncology during the past decade, their immunomodulatory properties can cause immune-related adverse effects (IRAE) across organ systems, including the nervous system. Central neurologic IRAEs from chimeric antigen receptor T cells (CAR-T) and immune checkpoint inhibitors (ICPI) are challenging complications of such therapies.We aim to provide clinicians with a comprehensive review of the relevant forms of CAR-T and ICPI-associated CNS toxicity, focusing on clinical features of such complications, diagnostic workup, predictive biomarkers, and management considerations in affected patients.

Recent Findings: Unique forms of CAR-T and ICPI-related CNS toxicity have been characterized in the recent literature. CAR-T-related neurotoxicity is common and clinically well delineated. ICPI-related CNS toxicity is relatively rare but includes a heterogenous spectrum of severe and diagnostically challenging conditions. While putative risk factors, neurotoxicity biomarkers, imaging correlates and treatment strategies have been put forward, development of tailored diagnostic and management consensus guidelines awaits further clinical investigation.

Summary: As CAR-T and ICPI become more widely adopted, early recognition, documentation, and management of immunotherapy-related CNS toxicity are of paramount importance in the clinical setting.
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http://dx.doi.org/10.1097/WCO.0000000000000867DOI Listing
December 2020

An integrated RF-receive/B-shim array coil boosts performance of whole-brain MR spectroscopic imaging at 7 T.

Sci Rep 2020 09 14;10(1):15029. Epub 2020 Sep 14.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Metabolic imaging of the human brain by in-vivo magnetic resonance spectroscopic imaging (MRSI) can non-invasively probe neurochemistry in healthy and disease conditions. MRSI at ultra-high field (≥ 7 T) provides increased sensitivity for fast high-resolution metabolic imaging, but comes with technical challenges due to non-uniform B field. Here, we show that an integrated RF-receive/B-shim (AC/DC) array coil can be used to mitigate 7 T B inhomogeneity, which improves spectral quality and metabolite quantification over a whole-brain slab. Our results from simulations, phantoms, healthy and brain tumor human subjects indicate improvements of global B homogeneity by 55%, narrower spectral linewidth by 29%, higher signal-to-noise ratio by 31%, more precise metabolite quantification by 22%, and an increase by 21% of the brain volume that can be reliably analyzed. AC/DC shimming provide the highest correlation (R = 0.98, P = 0.001) with ground-truth values for metabolite concentration. Clinical translation of AC/DC and MRSI is demonstrated in a patient with mutant-IDH1 glioma where it enables imaging of D-2-hydroxyglutarate oncometabolite with a 2.8-fold increase in contrast-to-noise ratio at higher resolution and more brain coverage compared to previous 7 T studies. Hence, AC/DC technology may help ultra-high field MRSI become more feasible to take advantage of higher signal/contrast-to-noise in clinical applications.
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http://dx.doi.org/10.1038/s41598-020-71623-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490394PMC
September 2020

Exploring Predictors of Response to Dacomitinib in -Amplified Recurrent Glioblastoma.

JCO Precis Oncol 2020 8;4. Epub 2020 Jun 8.

Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Purpose: Despite the high frequency of genetic alterations in glioblastoma (GBM), EGFR-targeted therapies have not had success in this disease. To improve the likelihood of efficacy, we targeted adult patients with recurrent GBM enriched for gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that penetrates the blood-brain barrier, in a multicenter phase II trial.

Patients And Methods: We retrospectively explored whether previously described extracellular domain (ECD)-sensitizing mutations in the context of gene amplification could predict response to dacomitinib, and in a predefined subset of patients, we measured post-treatment intratumoral dacomitinib levels to verify tumor penetration.

Results: We found that dacomitinib effectively penetrates contrast-enhancing GBM tumors. Among all 56 treated patients, 8 (14.3%) had a clinical benefit as defined by a duration of treatment of at least 6 months, of whom 5 (8.9%) remained progression free for at least 1 year. Presence of or ECD missense mutation was not associated with clinical benefit. We evaluated the pretreatment transcriptome in circulating extracellular vesicles (EVs) by RNA sequencing in a subset of patients and identified a signature that distinguished patients who had durable benefit versus those with rapid progression.

Conclusion: While dacomitinib was not effective in most patients with -amplified GBM, a subset experienced a durable, clinically meaningful benefit. Moreover, and ECD mutation status in archival tumors did not predict clinical benefit. RNA signatures in circulating EVs may warrant investigation as biomarkers of dacomitinib efficacy in GBM.
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http://dx.doi.org/10.1200/PO.19.00295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446412PMC
June 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

Eosinophil and lymphocyte counts predict bevacizumab response and survival in recurrent glioblastoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa031. Epub 2020 Mar 11.

Harvard Medical School, Boston, Massachusetts, USA.

Background: There is a lack of biomarkers to identify glioblastoma (GBM) patients who may benefit from specific salvage therapies, such as the anti-angiogenic agent bevacizumab. We hypothesized that circulating blood counts may serve as biomarkers for treatment response and clinical outcomes.

Methods: Complete blood counts, clinical data, and radiographic information were collected retrospectively from 84 recurrent GBM patients receiving bevacizumab (10 mg/kg every 2 weeks). Significant biomarkers were categorized into quartiles and the association with clinical outcomes was assessed using the Kaplan-Meier method.

Results: The median treatment duration and survival on bevacizumab (OS-A) was 88 and 192 days, respectively. On multivariate analysis, promoter methylation (hazard ratio [HR] 0.504, = .031), increases in red blood cells (HR 0.496, = .035), and increases in eosinophils (HR 0.048, = .054) during treatment predicted improved OS-A. Patients in the first and fourth quartiles of eosinophil changes had a 12-month survival probability of 5.6% and 41.2% ( < .0001), respectively. Treatment response was associated with increases in eosinophil counts ( = .009) and improved progression-free survival ( = .013). On multivariate analysis, increases in lymphocyte counts among responders predicted improved OS-A (HR 0.389, = .044). Responders in the first and fourth quartiles of lymphocyte changes had a 12-month survival probability of 0% and 44.4% ( = .019), respectively. Changes in platelet counts differed before and after radiographic response ( = .014).

Conclusions: Changes in circulating eosinophil, lymphocyte, and platelet counts may predict treatment response and clinical outcomes in patients with recurrent GBM receiving bevacizumab.
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http://dx.doi.org/10.1093/noajnl/vdaa031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212859PMC
March 2020

Pemetrexed in Recurrent or Progressive Central Nervous System Lymphoma: A Phase I Multicenter Clinical Trial.

Oncologist 2020 09 1;25(9):747-e1273. Epub 2020 Jul 1.

Massachusetts General Hospital, Boston, Massachusetts, USA.

Lessons Learned: The findings from this study using monotherapy with pemetrexed in a pretreated patient population are, overall, encouraging. Unlike high-dose methotrexate, which requires several days of inpatient hospitalization, pemetrexed is relatively easy to administer in the outpatient setting and remains a viable treatment option in this patient population. The maximum tolerated dose of pemetrexed administered (900 mg/m every 2 weeks) was generally well tolerated and showed activity in patients with relapsed or refractory CNSL.

Background: There is currently no standard salvage treatment for patients with relapsed/refractory central nervous system (CNS) lymphoma (CNSL). We report the results of a phase I study of pemetrexed, an antifolate drug with broader activity than methotrexate (MTX). We provide the safety, tolerability, and maximum tolerated dose (MTD) of pemetrexed in patients with recurrent CNSL.

Methods: Through October 2015, 17 patients with relapsed/refractory CNSL received pemetrexed every 2 weeks with the first cohort receiving 600 mg/m and dose escalation in increments of 300 mg/m to a maximum of 1,200 mg/m . Three patients were to enroll at each dose level with expansion to six patients in the event of dose-limiting toxicity. Patients with both primary CNS lymphoma (PCNSL) and secondary CNS lymphoma (SCNSL) could be enrolled.

Results: Seventeen patients were evaluable with a median age of 63.7 years. Main adverse events included fatigue (82.4%), anemia (82.4%), and neutropenia (70.6%). The MTD was established at 900 mg/m . Dose-limiting toxicities were recorded in one patient in the 600 mg/m cohort and in two patients in the 1,200 mg/m cohort. Fourteen patients were evaluable for response assessment; 21.4% achieved a complete response, 35.7% had a partial response, 14.3% had stable disease, and 28.6% had progressive disease. The median progression-free survival was 4.2 months. The median overall survival was 44.5 months. In the original study protocol, the plan was to add an expansion cohort of six patients at MTD level. However, the first phase of the study was characterized by slow recruitment. Therefore, after achieving the primary objective of the study and establishing the MTD, the investigators decided to amend the protocol and to close the study.

Conclusion: Pemetrexed administered at 900 mg/m every 2 weeks exhibits single-agent activity in patients with recurrent CNSL; it is well tolerated, and side effects are manageable.
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http://dx.doi.org/10.1634/theoncologist.2020-0489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485351PMC
September 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

Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis.

Nat Med 2020 08 2;26(8):1280-1284. Epub 2020 Jun 2.

Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients-17 with breast cancer, two with lung cancer and one with ovarian cancer-were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39-0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab.
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http://dx.doi.org/10.1038/s41591-020-0918-0DOI Listing
August 2020

Strategies to Prevent or Remediate Cancer and Treatment-Related Aging.

J Natl Cancer Inst 2021 Feb;113(2):112-122

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.

Up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with an accumulation of chronic conditions, frailty, and/or cognitive impairments resulting from cancer and its treatment. Thus, survivors often show an accelerated development of multiple geriatric syndromes and need therapeutic interventions. To advance progress in this area, the National Cancer Institute convened the second of 2 think tanks under the auspices of the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Experts assembled to share evidence of promising strategies to prevent, slow, or reverse the aging consequences of cancer and its treatment. The meeting identified research and resource needs, including geroscience-guided clinical trials; comprehensive assessments of functional, cognitive, and psychosocial vulnerabilities to assess and predict age-related outcomes; preclinical and clinical research to determine the optimal dosing for behavioral (eg, diet, exercise) and pharmacologic (eg, senolytic) therapies; health-care delivery research to evaluate the efficacy of integrated cancer care delivery models; optimization of intervention implementation, delivery, and uptake; and patient and provider education on cancer and treatment-related late and long-term adverse effects. Addressing these needs will expand knowledge of aging-related consequences of cancer and cancer treatment and inform strategies to promote healthy aging of cancer survivors.
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http://dx.doi.org/10.1093/jnci/djaa060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850536PMC
February 2021

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

Super-Resolution Whole-Brain 3D MR Spectroscopic Imaging for Mapping D-2-Hydroxyglutarate and Tumor Metabolism in Isocitrate Dehydrogenase 1-mutated Human Gliomas.

Radiology 2020 03 7;294(3):589-597. Epub 2020 Jan 7.

From the A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149 13th St, Suite 2301, Charlestown, MA 02129 (X.L., B.S., B.T., O.C.A.); iCAD, Nashua, NH (K.J.); Departments of Neurosurgery (J.S., D.P.C.) and Neurology (J.D.), Massachusetts General Hospital, Boston, Mass; Department of Neurology, Brigham and Women's Hospital, Boston, Mass (T.T.B.); and Dana-Farber Cancer Institute, Boston, Mass (T.T.B.).

Background Isocitrate dehydrogenase (IDH) mutations are highly frequent in glioma, producing high levels of the oncometabolite D-2-hydroxyglutarate (D-2HG). Hence, D-2HG represents a valuable imaging marker for IDH-mutated human glioma. Purpose To develop and evaluate a super-resolution three-dimensional (3D) MR spectroscopic imaging strategy to map D-2HG and tumor metabolism in IDH-mutated human glioma. Materials and Methods Between March and September 2018, participants with IDH1-mutated gliomas and healthy participants were prospectively scanned with a 3-T whole-brain 3D MR spectroscopic imaging protocol optimized for D-2HG. The acquired D-2HG maps with a voxel size of 5.2 × 5.2 × 12 mm were upsampled to a voxel size of 1.7 × 1.7 × 3 mm using a super-resolution method that combined weighted total variation, feature-based nonlocal means, and high-spatial-resolution anatomic imaging priors. Validation with simulated healthy and patient data and phantom measurements was also performed. The Mann-Whitney test was used to check that the proposed super-resolution technique yields the highest peak signal-to-noise ratio and structural similarity index. Results Three participants with IDH1-mutated gliomas (mean age, 50 years ± 21 [standard deviation]; two men) and three healthy participants (mean age, 32 years ± 3; two men) were scanned. Twenty healthy participants (mean age, 33 years ± 5; 16 men) underwent a simulation of upsampled MR spectroscopic imaging. Super-resolution upsampling improved peak signal-to-noise ratio and structural similarity index by 62% ( < .05) and 7.3% ( < .05), respectively, for simulated data when compared with spline interpolation. Correspondingly, the proposed method significantly improved tissue contrast and structural information for the acquired 3D MR spectroscopic imaging data. Conclusion High-spatial-resolution whole-brain D-2-hydroxyglutarate imaging is possible in isocitrate dehydrogenase 1-mutated human glioma by using a super-resolution framework to upsample three-dimensional MR spectroscopic images acquired at lower resolution. © RSNA, 2020 See also the editorial by Huang and Lin in this issue.
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http://dx.doi.org/10.1148/radiol.2020191529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053225PMC
March 2020

Cognitive Performance and Psychological Distress in Breast Cancer Patients at Disease Onset.

Front Psychol 2019 15;10:2584. Epub 2019 Nov 15.

Institute of Medical Psychology, Goethe University Frankfurt, Frankfurt am Main, Germany.

Objective: Many cancer patients complain about cognitive dysfunction. While cognitive deficits have been attributed to the side effects of chemotherapy, there is evidence for impairment at disease onset, prior to cancer-directed therapy. Further debated issues concern the relationship between self-reported complaints and objective test performance and the role of psychological distress.

Method: We assessed performance on neuropsychological tests of attention and memory and obtained estimates of subjective distress and quality of life in 27 breast cancer patients and 20 healthy controls. Testing in patients took place shortly after the initial diagnosis, but prior to subsequent therapy.

Results: While patients showed elevated distress, cognitive performance differed on a few subtests only. Patients showed slower processing speed and poorer verbal memory than controls. Objective and self-reported cognitive function were unrelated, and psychological distress correlated more strongly with subjective complaints than with neuropsychological test performance.

Conclusion: This study provides further evidence of limited cognitive deficits in cancer patients prior to the onset of adjuvant therapy. Self-reported cognitive deficits seem more closely related to psychological distress than to objective test performance.
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http://dx.doi.org/10.3389/fpsyg.2019.02584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873390PMC
November 2019

Radiation and chemotherapy for high-risk lower grade gliomas: Choosing between temozolomide and PCV.

Cancer Med 2020 01 7;9(1):3-11. Epub 2019 Nov 7.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.

Purpose: The majority of patients with high-risk lower grade gliomas (LGG) are treated with single-agent temozolomide (TMZ) and radiotherapy despite three randomized trials showing a striking overall survival benefit with adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy and radiotherapy. This article aims to evaluate the evidence and rationale for the widespread use of TMZ instead of PCV for high-risk LGG.

Methods And Materials: We conducted a literature search utilizing PubMed for articles investigating the combination of radiotherapy and chemotherapy for high-risk LGG and analyzed the results of these studies.

Results: For patients with IDH mutant 1p/19q codeleted LGG tumors, there is limited evidence to support the use of TMZ. In medically fit patients with codeleted disease, existing data demonstrate a large survival benefit for PCV as compared to adjuvant radiation therapy alone. For patients with non-1p/19q codeleted LGG, early data from the CATNON study supports inclusion of adjuvant TMZ for 12 months. Subset analyses of the RTOG 9402 and EORTC 26951 do not demonstrate a survival benefit for adjuvant PCV for non-1p/19q codeleted gliomas, however secondary analyses of RTOG 9802 and RTOG 9402 demonstrated survival benefit in any IDH mutant lower grade gliomas, regardless of 1p/19q codeletion status.

Conclusions: At present, we conclude that current evidence does not support the widespread use of TMZ over PCV for all patients with high-risk LGG, and we instead recommend tailoring chemotherapy recommendation based on IDH status, favoring adjuvant PCV for patients with any IDH mutant tumors, both those that harbor 1p/19q codeletion and those non-1p/19q codeleted. Given the critical role radiation plays in the treatment of LGG, radiation oncologists should be actively involved in discussions regarding chemotherapy choice in order to optimize treatment for their patients.
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http://dx.doi.org/10.1002/cam4.2686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943166PMC
January 2020

Bevacizumab Reduces Permeability and Concurrent Temozolomide Delivery in a Subset of Patients with Recurrent Glioblastoma.

Clin Cancer Res 2020 01 26;26(1):206-212. Epub 2019 Sep 26.

Harvard Medical School, Boston, Massachusetts.

Purpose: Targeting tumor blood vessels is an attractive therapy in glioblastoma (GBM), but the mechanism of action of these agents and how they modulate delivery of concomitant chemotherapy are not clear in humans. We sought to elucidate how bevacizumab modulates tumor vasculature and the impact those vascular changes have on drug delivery in patients with recurrent GBM.

Experimental Design: Temozolomide was labeled with [11C], and serial PET-MRI scans were performed in patients with recurrent GBM treated with bevacizumab and daily temozolomide. PET-MRI scans were performed prior to the first bevacizumab dose, 1 day after the first dose, and prior to the third dose of bevacizumab. We calculated tumor volume, vascular permeability (), perfusion (cerebral blood flow), and the standardized uptake values (SUV) of [11C] temozolomide within the tumor.

Results: Twelve patients were enrolled, resulting in 23 evaluable scans. Within the entire contrast-enhancing tumor volume, both temozolomide uptake and vascular permeability decreased after initiation of bevacizumab in most patients, whereas change in perfusion was more variable. In subregions of the tumor where permeability was low and the blood-brain barrier not compromised, increased perfusion correlated with increased temozolomide uptake.

Conclusions: Bevacizumab led to a decrease in permeability and concomitant delivery of temozolomide. However, in subregions of the tumor where permeability was low, increased perfusion improved delivery of temozolomide, suggesting that perfusion may modulate the delivery of chemotherapy in certain settings. These results support exploring whether lower doses of bevacizumab improve perfusion and concomitant drug delivery.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139851PMC
January 2020

Successful anti-CD19 CAR T-cell therapy in HIV-infected patients with refractory high-grade B-cell lymphoma.

Cancer 2019 Nov 10;125(21):3692-3698. Epub 2019 Sep 10.

Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1002/cncr.32411DOI Listing
November 2019