Publications by authors named "Khe Hoang-Xuan"

193 Publications

Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network.

Neurology 2021 Sep;97(13):628-631

From the APHP (C.H., K.H.-X.), Sorbonne Université, IHU, ICM, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris; Service d'Hématologie (C.M.C.), CHU de Clermont-Ferrand, Clermont-Ferrand; Service des Maladies du Sang (M.-P.M.-M.), CHU d'Angers; APHP (L.W.), Hôpital Cochin, Service d'Hématologie, Paris; Service de Neurologie (G.A.), Hôpitaux Civils, Colmar; Service d'Hématologie (A.W.-R.), CHU de Nîmes; Service d'Hématologie (L.-M.F.), Institut de Cancérologie de Strasbourg Europe, Strasbourg; Service d'Hématologie (C.S.), Institut Curie, Site Saint Cloud; INSERM U932 (C.S.), Institut Curie, PSL Research University, Paris.

Background And Objectives: To evaluate the efficacy and tolerance of the association rituximab-lenalidomide-ibrutinib (RI) in relapsed/refractory (R/R) primary CNS lymphoma (PCNSL).

Methods: R/R PCNSL patients treated with RI were retrospectively selected and analyzed from the French LOC database.

Results: Fourteen patients (median age: 63 years, median Karnofsky Performance Status: 75%) received RI, administered after a median of 2 previous lines of chemotherapy, including autologous stem cell transplantation (ASCT) in 5 cases. The best response was complete response in 4/14 patients and partial response in 4/14 patients, achieved in a median of 2.5 months. Three responder patients received consolidation treatment (WBRT: N = 2, ASCT: N = 1) after RI, and RI served as a bridge before CAR-T cell therapy for one patient. RI was discontinued due to toxicity in 3/14 patients. There were no toxicity-related deaths.

Discussion: The RI combination resulted in a high rate of response of rapid-onset in heavily pretreated patients with poor prognosis, with manageable toxicity, and allowed 3 patients to proceed to consolidation. Although preliminary, these results support the use of RI for R/R PCNSL failing conventional chemotherapies.

Classification Of Evidence: This study provides Class IV evidence that combination of rituximab-lenalidomide-ibrutinib induces a high rate of response in heavily pretreated R/R PCNSL.
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http://dx.doi.org/10.1212/WNL.0000000000012515DOI Listing
September 2021

Primary Central Nervous System Lymphoma in Elderly Patients: Management and Perspectives.

Cancers (Basel) 2021 Jul 12;13(14). Epub 2021 Jul 12.

APHP, Groupe Hospitalier Salpêtrière, Sorbonne Université, IHU, ICM, Service de Neurologie 2-Mazarin, 75013 Paris, France.

The management of elderly patients suffering from primary central nervous system (CNS) lymphoma, who represent a rapidly growing population, is challenging. Despite the advances made in PCNSL treatment, the prognosis in older patients remains unsatisfactory. The high risk of systemic and CNS toxicity induced by a high-dose chemotherapy regimen and radiation therapy, respectively, limits the use of consolidation phase treatments in elderly patients and contributes to the poor outcome of these patients. Here, we review the current treatment strategies and ongoing trials proposed for elderly PCNSL patients.
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http://dx.doi.org/10.3390/cancers13143479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303711PMC
July 2021

Primary vitreoretinal lymphoma: short review of the literature, results of a European survey and French guidelines of the LOC network for diagnosis, treatment and follow-up.

Curr Opin Oncol 2021 Sep;33(5):420-431

Member of European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet).

Purpose Of Review: The aim of this study was to highlight the diagnostic and management challenges of primary vitreoretinal lymphoma (PVRL) through a review of the literature and a European survey on real-life practices for PVRL.

Recent Findings: The care of PVRL patients is heterogeneous between specialists and countries. Upfront systemic treatment based on high-dose methotrexate chemotherapy, with or without local treatment, might reduce or delay the risk of brain relapse.Ibrutinib, lenalidomide with or without rituximab, and temozolomide are effective for patients with relapsed/refractory PVRL and should be tested as first-line treatments.

Summary: The prognosis of PVRL remains dismal. No firm conclusion regarding optimal treatment can yet be drawn. The risk of brain relapse remains high. Diagnostic procedures and assessment of therapeutic responses need to be homogenized. Collaboration between specialists involved in PVRL and multicentric prospective therapeutic studies are strongly needed. The recommendations of the French group for primary oculocerebral lymphoma (LOC network) are provided, as a basis for further European collaborative work.
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http://dx.doi.org/10.1097/CCO.0000000000000776DOI Listing
September 2021

Sustained Tumor Control With MAPK Inhibition in V600-Mutant Adult Glial and Glioneuronal Tumors.

Neurology 2021 08 4;97(7):e673-e683. Epub 2021 Jun 4.

From Sorbonne Université (G.B., L.B., C.D., A.I., J.-Y.D., K.H.-X., F.B., M.S., M.T., A.L.D.S.), Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Épinière, and AP-HP Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France; Radiation Therapy Unit (L.B.), Imaging and Medical Physics Department, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy; Drug Development Department (C.B.), Institut Gustave Roussy and Université Paris-Saclay, Villejuif; Department of Neuroncology (F.D.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron; Department of Neurology (D.G., N.Y., A.L.D.S.), Department of Neurosurgery (S.G.), Service de Pharmacie (C.L.-S.), Department of Oncology (S.S.), Department of Neuroradiology (J.G.), and Department of Pathology (C.V.), Hôpital Foch, Suresnes, France; Neuro-oncology Unit (M.E., A.S.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Service de Neurologie (L.N.T.), Centre Hospitalier Perpignan, France; Radiation Oncology (F.P.), Department of Medicine and Oncology, University Hospital, Pisa, Italy; Clinical Research Unit (P.T.), Institut Curie, Paris; Department of Nuclear Medicine (A.K.), AP-HP GH Pitié-Salpêtrière, Paris; Department of Diagnostic Radiology (S.A.), Institut Gustave Roussy, Villejuif, France; Neuroradiology Unit (E.S., J.S.), Fondation Ophtalmologique Adolphe de Rothschild, Paris; Department of Pathology (D.M.), Eastern Hospital Group, Lyon Civil Hospices; Department of Neuropathology (F.B.), AP-HP, Hôpital de la Pitié-Salpêtrière; and Onconeurotek Tumor Bank (F.B., M.S.), Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France. Dr. Berzero is currently at Neurology Unit (G.B.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and Dr. Gaillard is currently at the Department of Neurosurgery, AP-HP, Groupe hospitalier Pitié-Salpêtrière, Paris.

Objective: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with V600-mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort.

Methods: We performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated V600-mutant GGNTs treated with RAFi/MEKi.

Results: Twenty-eight adults with recurrent or disseminated V600-mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, = 0.047). Responders had better KPS score ( = 0.018) and tended to be younger ( = 0.061) and to be treated earlier ( = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival.

Conclusions: Our study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with V600-mutant GGNTs and encourages rechallenge in responders.

Classification Of Evidence: This study provides Class III evidence that, for adult patients with V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.
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http://dx.doi.org/10.1212/WNL.0000000000012330DOI Listing
August 2021

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors.

Sci Rep 2021 05 13;11(1):10176. Epub 2021 May 13.

Service de Santé des Armées, Hôpital d'Instruction des Armées Percy, Service de Neurologie, 101 boulevard Henri Barbusse, 92140, Clamart, France.

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18-69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.
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http://dx.doi.org/10.1038/s41598-021-89216-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119685PMC
May 2021

Severe acute respiratory syndrome coronavirus 2 vaccination for patients with solid cancer: Review and point of view of a French oncology intergroup (GCO, TNCD, UNICANCER).

Eur J Cancer 2021 06 1;150:232-239. Epub 2021 Apr 1.

Digestive Oncology Department, CHU Reims University Hospital, TNCD, Reims, France.

The impacts of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on cancer care are multiple, entailing a high risk of death from coronavirus disease 2019 (COVID-19) in patients with cancer treated by chemotherapy. SARS-CoV-2 vaccines represent an opportunity to decrease the rate of severe COVID-19 cases in patients with cancer and also to restore normal cancer care. Patients with cancer to be targeted for vaccination are difficult to define owing to the limited contribution of these patients in the phase III trials testing the different vaccines. It seems appropriate to vaccinate not only patients with cancer with ongoing treatment or with a treatment having been completed less than 3 years ago but also household and close contacts. High-risk patients with cancer who are candidates for priority access to vaccination are those treated by chemotherapy. The very high-priority population includes patients with curative treatment and palliative first- or second-line chemotherapy, as well as patients requiring surgery or radiotherapy involving a large volume of lung, lymph node and/or haematopoietic tissue. When possible, vaccination should be carried out before cancer treatment begins. SARS-CoV-2 vaccination can be performed during chemotherapy while avoiding periods of neutropenia and lymphopenia. For organisational reasons, vaccination should be performed in cancer care centres with messenger RNA vaccines (or non-replicating adenoviral vaccines in non-immunocompromised patients). Considering the current state of knowledge, the benefit-risk ratio strongly favours SARS-CoV-2 vaccination of all patients with cancer. To obtain more data concerning the safety and effectiveness of vaccines, it is necessary to implement cohorts of vaccinated patients with cancer.
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http://dx.doi.org/10.1016/j.ejca.2021.03.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015403PMC
June 2021

[Vaccination against COVID-19 in patients with solid cancer: Review and point of view from a French oncology inter-group (CGO, TNCD, UNICANCER)].

Bull Cancer 2021 Jun 12;108(6):614-626. Epub 2021 Apr 12.

CHU de Reims, Reims, service d'oncologie digestive, TNCD, Rue du Général Koenig, 51100 Reims, France.

The COVID-19 pandemic has a major impact at all stages of cancer treatment. Risk of death from COVID-19 in patients treated for a cancer is high. COVID-19 vaccines represent a major issue to decrease the rate of severe forms of the COVID-19 cases and to maintain a normal cancer care. It is difficult to define the target population for vaccination due to the limited data available and the lack of vaccine doses available. It appears theoretically important to vaccinate patients with active cancer treatment or treated since less than three years, as well as their family circle. In France, patients actually defined at "high risk" for priority access to vaccination are those with a cancer treated by chemotherapy. A panel of experts recently defined another "very high-priority" population, which includes patients with curative or palliative first or second-line chemotherapy, as well as patients requiring surgery or radiotherapy involving a large lung volume, lymph nodes and/or of hematopoietic tissue. Ideally, it is best to vaccinate before cancer treatment. Despite the lack of published data, COVID-19 vaccines can also be performed during chemotherapy by avoiding periods of bone marrow aplasia and if possible, to do it in cancer care centers. It is necessary to implement cohorts with immunological and clinical monitoring of vaccinated cancer patients. To conclude, considering the current state of knowledge, the benefit-risk ratio strongly favours COVID-19 vaccination of all cancer patients.
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http://dx.doi.org/10.1016/j.bulcan.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041180PMC
June 2021

Intravenous high-dose methotrexate based systemic therapy in the treatment of isolated primary vitreoretinal lymphoma: An LOC network study.

Am J Hematol 2021 07 3;96(7):823-833. Epub 2021 May 3.

Ophthalmology, Centre Hospitalier Universitaire de Brest, Brest, France.

The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high-dose methotrexate (IV HD-MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first-line treatment with HD-MTX between 2011 and 2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL-10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL-10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow-up of 61 months, 42/59 (71%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression-free survival, ocular-free survival and brain-free survival were 75, 18, 29 and 73 months, respectively. IV HD-MTX based systemic therapy as a first-line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL-10.
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http://dx.doi.org/10.1002/ajh.26199DOI Listing
July 2021

TEMOBIC: Phase II Trial of Neoadjuvant Chemotherapy for Unresectable Anaplastic Gliomas: An ANOCEF Study.

Oncologist 2021 08 20;26(8):647-e1304. Epub 2021 Apr 20.

APHM, CHU Timone, Service de Neurooncologie, Marseille, France.

Lessons Learned: Treatment with temozolomide and BCNU was associated with substantial response and survival rates for patients with unresectable anaplastic glioma, suggesting potential therapeutic alternative for these patients. The optimal treatment for unresectable large anaplastic gliomas remains debated.

Background: The optimal treatment for unresectable large anaplastic gliomas remains debated.

Methods: Adult patients with histologically proven unresectable anaplastic oligodendroglioma or mixed gliomas (World Health Organization [WHO] 2007) were eligible. Treatment consisted of BCNU (150 mg/m ) and temozolomide (110 mg/m for 5 days) every 6 weeks for six cycles before radiotherapy.

Results: Between December 2005 and December 2009, 55 patients (median age of 53.1 years; range, 20.5-70.2) were included. Forty percent of patients presented with wild-type IDH1 gliomas, and 30% presented with methylated MGMT promoter. Median progression-free survival (PFS), centralized PFS, and overall survival (OS) were 16.6 (95% confidence interval [CI], 12.8-20.3), 15.4 (95% CI, 10.0-20.8), and 25.4 (95% CI, 17.5-33.2) months, respectively. Complete and partial responses under chemotherapy were observed for 28.3% and 17% of patients, respectively. Radiotherapy completion was achieved for 75% of patients. Preservation of functional status and self-care capability (Karnofsky performance status [KPS] ≥70) were preserved until disease progression for 69% of patients. Grade ≥ 3 toxicities were reported for 52% of patients, and three deaths were related to treatment. By multivariate analyses including age and KPS, IDH mutation was associated with better prognostic for both PFS and OS, whereas MGMT promoter methylation was associated with better OS.

Conclusion: The association of BCNU and temozolomide upfront is active for patients with unresectable anaplastic gliomas, but toxicity limits its use.
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http://dx.doi.org/10.1002/onco.13765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342578PMC
August 2021

Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome.

Neurol Neuroimmunol Neuroinflamm 2021 05 3;8(3). Epub 2021 Mar 3.

From the Department of Neurology (G.T., P.L.), CHU Montpellier, Hospital Gui de Chauliac; Pôle de Neurosciences Cliniques (E.K.), CHU Timone, Assistance Publique Hôpitaux de Marseille; Clinical Research and Epidemiology Unit (C.D.), CHU Montpellier, University Montpellier; Unité de recherche clinique côte d'azur UR2CA (URRIS) (C.L.-F.), CRCSEP Nice; Department of Pathology (V.R.), CHU Montpellier, Hospital Gui de Chauliac; Department of Neurology (E.T.), CHU Carémeau, Nîmes; Department of Neurology (E.D.-G.), CH Valenciennes; Department of Neurology (R.L.), Rouen University Hospital; APHP (K.H.-X.), Sorbonne Université, IHU, ICM, Department of Neurology Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris; Department of Neurology (S.C.), CH Gonesse; Department of Neurology (J.C.O.), CHU de Bordeaux; Department of Neuroradiology (N.M.C.), CHU Montpellier, Hospital Gui de Chauliac; Department of Neurology (C.T.), CHU Strasbourg; Université de Paris (C.P., M.F., F.E.S., G.S.B.), Imagine Institute, INSERM U 1163; Centre d'Etude des Déficits Immunitaires (C.P., M.F., G.S.B.), AP-HP, Hôpital Necker-Enfants Malades, Paris; and Centre national de la recherche scientifique (CNRS) (F.E.S.), Paris, France.

Objective: To determine whether adult cases of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) may be related to familial hemophagocytic lymphohistiocytosis (HLH) causes, we have screened patients with adult-onset CLIPPERS for mutations in primary HLH-associated genes.

Methods: In our cohort of 36 patients fulfilling the criteria for probable or definite CLIPPERS according to the CLIPPERS-2017 criteria, we conducted a first study on 12 patients who consented to genetic testing. In these 12 patients, systemic HLH criteria were searched, and genetic analysis of 8 genes involved in primary HLH was performed.

Results: Four definite and 8 probable CLIPPERS were enrolled (n = 12). Mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS (4/12). Three of them had biallelic mutations with reduced perforin expression in natural killer cells. The remaining patient had biallelic mutations with cytotoxic lymphocyte impaired degranulation. None of the mutated patients reached the criteria for systemic HLH. During follow-up, 3 of them displayed atypical findings for CLIPPERS, including emergence of systemic non-Hodgkin lymphoma (1/3) and confluent gadolinium-enhancing lesions on brain MRI (3/3).

Conclusions: In our patients presenting with adult-onset CLIPPERS, one-third have HLH gene mutations. This genetic treatable condition should be searched in patients with CLIPPERS, especially in those presenting with atypical findings.
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http://dx.doi.org/10.1212/NXI.0000000000000970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963436PMC
May 2021

Clinical features and outcome of patients with primary central nervous system lymphoma admitted to the intensive care unit: a French national expert center experience.

J Neurol 2021 Jun 16;268(6):2141-2150. Epub 2021 Jan 16.

Service de Pneumologie, Médecine Intensive et Réanimation (Département R3S), AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site Pitié-Salpêtrière, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.

Introduction: To describe the reasons for intensive care unit (ICU) admission and to evaluate the outcomes and prognostic factors of patients with primary central nervous system lymphoma (PCNSL) admitted to the ICU.

Patients And Methods: Retrospective observational cohort study of 101 PCNSL patients admitted to 3 ICUs over a two-decade period.

Results: Acute respiratory failure, mainly secondary to aspiration pneumonia and Pneumocystis jirovecii pneumonia, was the leading reason for ICU admission (33%). Aspiration pneumonia was more common in patients with brainstem tumor (67% vs. 0%, p < 0.001), whereas patients with intracranial hypertension were more frequently admitted for coma without seizures (61% vs. 9%, p = 0.004). Hospital and 6-month mortality were 47% and 53%, respectively. In multivariate analysis, admission for coma without seizures (OR 7.28), cancer progression (OR 3.47), mechanical ventilation (OR 6.58) and vasopressors (OR 4.07) were associated with higher 6-month mortality. Karnofsky performance status prior to ICU admission was independently associated with lower 6-month mortality (OR 0.96).

Discussion: Six-month survival of PCNSL patients admitted to the ICU appears to be relatively favorable (around 50%) and the presence of PCNSL alone is not a relevant criterion for ICU refusal. Predictive factors of mortality may help clinicians to make optimal triage decisions.
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http://dx.doi.org/10.1007/s00415-021-10396-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810601PMC
June 2021

Leptomeningeal Spread in Glioblastoma: Diagnostic and Therapeutic Challenges.

Oncologist 2020 11 31;25(11):e1763-e1776. Epub 2020 Aug 31.

Sorbonne Université, INSERM, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix Service de Neurologie 2-Mazarin, Paris, France.

Background: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Leptomeningeal spread (LMS) is a severe complication of GBM, raising diagnostic and therapeutic challenges in clinical routine.

Methods: We performed a review of the literature focused on LMS in GBM. MEDLINE and EMBASE databases were queried from 1989 to 2019 for articles describing diagnosis and therapeutic options in GBM LMS, as well as risk factors and pathogenic mechanisms.

Results: We retrieved 155 articles, including retrospective series, case reports, and early phase clinical trials, as well as preclinical studies. These articles confirmed that LMS in GBM remains (a) a diagnostic challenge with cytological proof of LMS obtained in only 35% of cases and (b) a therapeutic challenge with a median overall survival below 2 months with best supportive care alone. For patients faced with suggestive clinical symptoms, whole neuroaxis magnetic resonance imaging and cerebrospinal fluid analysis are both recommended. Liquid biopsies are under investigation and may help prompt a reliable diagnosis. Based on the literature, a multimodal and personalized therapeutic approach of LMS, including surgery, radiotherapy, systemic cytotoxic chemotherapy, and intrathecal chemotherapies, may provide benefits to selected patients. Interestingly, molecular targeted therapies appear promising in case of actionable molecular target and should be considered.

Conclusion: As the prognosis of glioblastoma is improving over time, LMS becomes a more common complication. Our review highlights the need for translational studies and clinical trials dedicated to this challenging condition in order to improve diagnostic and therapeutic strategies.

Implications For Practice: This review summarizes the diagnostic tools and applied treatments for leptomeningeal spread, a complication of glioblastoma, as well as their outcomes. The importance of exhaustive molecular testing for molecular targeted therapies is discussed. New diagnostic and therapeutic strategies are outlined, and the need for translational studies and clinical trials dedicated to this challenging condition is highlighted.
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http://dx.doi.org/10.1634/theoncologist.2020-0258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648332PMC
November 2020

SARS-CoV-2 infection in patients with primary central nervous system lymphoma.

J Neurol 2021 Sep 2;268(9):3072-3080. Epub 2021 Jan 2.

Service de Neurologie 2-Mazarin, Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau Et de La Moelle Épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, 47-83 boulevard de l'Hôpital, 75013, Paris, France.

Background: Cancer patients may be at higher risk for severe coronavirus infectious disease-19 (COVID-19); however, the outcome of Primary Central Nervous System Lymphoma (PCNSL) patients with SARS-CoV-2 infection has not been described yet.

Methods: We conducted a retrospective study within the Lymphomes Oculo-Cérébraux national network (LOC) to assess the clinical characteristics and outcome of SARS-CoV-2 infection in PCNSL patients (positive real-time polymerase chain reaction of nasopharyngeal swab or evocative lung computed tomography scan). We compared clinical characteristics between patients with severe (death and/or intensive care unit admission) and mild disease.

Results: Between March and May 2020, 13 PCNSL patients were diagnosed with SARS-CoV-2 infection, 11 (85%) of whom were undergoing chemotherapy at the time of infection. The mortality rate was 23% (3/13), and two additional patients (15%) required mechanical ventilation. Two patients (15%) had no COVID-19 symptoms. History of diabetes mellitus was more common in severe patients (3/5 vs 0/8, p = 0.03). Two patients recovered from COVID-19 after mechanical ventilation during more than two weeks and resumed chemotherapy. In all, chemotherapy was resumed after COVID-19 recovery in nine patients (69%) after a median delay of 16 days (range 3-32), none of whom developed unusual chemotherapy complication nor SARS-Cov2 reactivation.

Conclusion: This preliminary analysis suggests that, while being at higher risk be for severe illness, PCNSL patients with COVID-19 might be treated maximally especially if they achieved oncological response at the time of SARS-CoV-2 infection. Chemotherapy might be resumed without prolonged delay in PCNSL patients with COVID-19.
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http://dx.doi.org/10.1007/s00415-020-10311-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776286PMC
September 2021

Tracking the Genetic Susceptibility Background of B-Cell Non-Hodgkin's Lymphomas from Genome-Wide Association Studies.

Int J Mol Sci 2020 Dec 24;22(1). Epub 2020 Dec 24.

Faculté de Médecine, Sorbonne Université, 75013 Paris, France.

B-cell non-Hodgkin's lymphoma (NHL) risk associations had been mainly attributed to family history of the disease, inflammation, and immune components including human leukocyte antigen (HLA) genetic variations. Nevertheless, a broad range of genome-wide association studies (GWAS) have shed light into the identification of several genetic variants presumptively associated with B-cell NHL etiologies, survival or shared genetic risk with other diseases. The present review aims to overview HLA structure and diversity and summarize the evidence of genetic variations, by GWAS, on five NHL subtypes (diffuse large B-cell lymphoma DLBCL, follicular lymphoma FL, chronic lymphocytic leukemia CLL, marginal zone lymphoma MZL, and primary central nervous system lymphoma PCNSL). Evidence indicates that the HLA zygosity status in B-cell NHL might promote immune escape and that genome-wide significance variants can give biological insight but also potential therapeutic markers such as WEE1 in DLBCL. However, additional studies are needed, especially for non-DLBCL, to replicate the associations found to date.
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http://dx.doi.org/10.3390/ijms22010122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795678PMC
December 2020

IDH-wildtype lower-grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification.

Neuro Oncol 2021 06;23(6):955-966

Sorbonne University, Brain and Spinal Cord Institute, Paris, France.

Background: Isocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined.

Methods: We searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989-2020).

Results: Out of 517 grade II gliomas, 47 were "diffuse astrocytomas, IDHwt." Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%).

Conclusions: Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.
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http://dx.doi.org/10.1093/neuonc/noaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168809PMC
June 2021

Memory in low-grade glioma patients treated with radiotherapy or temozolomide: a correlative analysis of EORTC study 22033-26033.

Neuro Oncol 2021 05;23(5):803-811

Department of Radiation Oncology (MAASTRO), GROW‒School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: EORTC study 22033-26033 showed no difference in progression-free survival between high-risk low-grade glioma receiving either radiotherapy (RT) or temozolomide (TMZ) chemotherapy alone as primary treatment. Considering the potential long-term deleterious impact of RT on memory functioning, this study aims to determine whether TMZ is associated with less impaired memory functioning.

Methods: Using the Visual Verbal Learning Test (VVLT), memory functioning was evaluated at baseline and subsequently every 6 months. Minimal compliance for statistical analyses was set at 60%. Conventional indices of memory performance (VVLT Immediate Recall, Total Recall, Learning Capacity, and Delayed Recall) were used as outcome measures. Using a mixed linear model, memory functioning was compared between treatment arms and over time.

Results: Neuropsychological assessment was performed in 98 patients (53 RT, 46 TMZ). At 12 months, compliance had dropped to 66%, restricting analyses to baseline, 6 months, and 12 months. At baseline, patients in either treatment arm did not differ in memory functioning, sex, age, or educational level. Over time, patients in both arms showed improvement in Immediate Recall (P = 0.017) and total number of words recalled (Total Recall; P < 0.001, albeit with delayed improvement in RT patients (group by time; P = 0.011). Memory functioning was not associated with RT gross, clinical, or planned target volumes.

Conclusion: In patients with high-risk low-grade glioma there is no indication that in the first year after treatment, RT has a deleterious effect on memory function compared with TMZ chemotherapy.
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http://dx.doi.org/10.1093/neuonc/noaa252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099470PMC
May 2021

Central nervous system involvement in Erdheim-Chester disease: An observational cohort study.

Neurology 2020 11 4;95(20):e2746-e2754. Epub 2020 Sep 4.

From Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares et Histiocytoses (F.C.A., Z.A., J.H.), Service de Neuroradiologie (D.G., B.L.-Y.), Service d'Anatomopathologie (F.C.), Service de Médecine Nucléaire (P.M.), Service de Neuropathologie (D.S.), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université; Service de Neurologie 2-Mazarin (A.I., K.H.-Z.), Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Sorbonne Université, Paris; Département de Pathologie (J.-F.E.), EA4340, Université Versailles-Saint Quentin, Assistance Publique Hôpitaux de Paris, Hôpital Ambroise Paré, Boulogne; and Service d'Hématologie Pédiatrique, Centre de Référence National Histiocytoses (J.D.), Hôpital Trousseau, Sorbonne Université, Paris, France.

Objective: CNS involvement in Erdheim-Chester disease (ECD) leads to substantial morbidity and mortality. To assess CNS manifestations in a French cohort of 253 patients with ECD, we determined clinical characteristics and outcomes, including those under targeted therapies.

Methods: This was a retrospective longitudinal study. CNS manifestations were determined by clinical examination and brain or spine MRI. Targeted therapy efficacy was assessed using global assessment from a physician and a radiologist. The study was approved by the ethics committee Comité de Protection des Personnes Ile de France III.

Results: Ninety-seven of 253 patients (38%) with ECD had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptom onset (mean 50.5 years), as well as with the presence of the mutation (in 77% of cases), xanthelasma (34%), and diabetes insipidus (36%). Median survival among patients with CNS involvement was significantly lower than that of patients with ECD without CNS involvement (124 months vs 146 months, = 0.03). Seventy-four CNS MRIs were centrally reviewed, which showed 3 patterns: tumoral in 66%, pseudo-degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF or MEK inhibitors) was associated with improved symptoms in 43% of patients and MRI improvement in 45%.

Conclusions: CNS manifestations are typically associated with poor prognosis in patients with ECD. Three distinct patterns can be recognized: tumoral, pseudodegenerative, and vascular.

Classification Of Evidence: This study provides Class III evidence that targeted therapy leads to clinical or imaging improvement in almost 50% of patients.
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http://dx.doi.org/10.1212/WNL.0000000000010748DOI Listing
November 2020

[Intracranial tumors].

Rev Prat 2020 02;70(2):e39-e46

Service de neurologie 2, division Mazarin, groupe hospitalier Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris, France.

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February 2020

One-year survival of patients with high-grade glioma discharged alive from the intensive care unit.

J Neurol 2021 Feb 29;268(2):516-525. Epub 2020 Aug 29.

Médecine Intensive Et Réanimation (Département R3S), Service de Pneumologie, AP-HP, Site Pitié-Salpêtrière, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Service de Neurologie 2-Mazarin, 75013, Paris, France.

Introduction: Only limited data are available regarding the long-term prognosis of patients with high-grade glioma discharged alive from the intensive care unit. We sought to quantify 1-year mortality and evaluate the association between mortality and (1) functional status, and (2) management of anticancer therapy in patients with high-grade glioma discharged alive from the intensive care unit.

Patients And Methods: Retrospective observational cohort study of patients with high-grade glioma admitted to two intensive care units between January 2009 and June 2018. Functional status was assessed by the Karnofsky Performance Status. Anticancer therapy after discharge was classified as (1) continued (unchanged), (2) modified (changed or stopped), or (3) initiated (for newly diagnosed disease).

Results: Ninety-one high-grade glioma patients (73% of whom had glioblastoma) were included and 78 (86%) of these patients were discharged alive from the intensive care unit. Anticancer therapy was continued, modified, and initiated in 41%, 42%, and 17% of patients, respectively. Corticosteroid therapy at the time of ICU admission [odds ratio (OR) 0.07] and cancer progression (OR 0.09) was independently associated with continuation of anticancer therapy. The mortality rate 1 year after ICU admission was 73%. On multivariate analysis, continuation of anticancer therapy (OR 0.18) and Karnofsky performance status on admission (OR 0.90) were independently associated with lower 1-year mortality.

Conclusion: The presence of high-grade glioma is not sufficient to justify refusal of intensive care unit admission. Performance status and continuation of anticancer therapy are associated with higher survival after intensive care unit discharge.

Previous Presentation: Preliminary results were presented at the most recent congress of the French Intensive Care Society, Paris, 2019.
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http://dx.doi.org/10.1007/s00415-020-10191-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456207PMC
February 2021

Initial surgical resection and long time to occurrence from initial diagnosis are independent prognostic factors in resected recurrent IDH wild-type glioblastoma.

Clin Neurol Neurosurg 2020 09 8;196:106006. Epub 2020 Jun 8.

Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, F-75013, Paris, France. Electronic address:

Objective: IDH wild-type glioblastoma is the most common and aggressive primary brain cancer in adults. At tumor recurrence, treatment decision-making is not standardized; several options include second surgery, reirradiation, and a second line of chemotherapy. In this retrospective monocentric study conducted at the era of WHO 2016 classification, we investigated IDH wild-type glioblastoma patients below the age of 70 to see (i) the clinical benefit of second surgery at recurrence and (ii) the prognostic factors in resected recurrent glioblastoma patients.

Methods: 229 newly diagnosed IDH wild-type glioblastoma patients below the age of 70 treated with the standard of care (SOC) were enrolled in the current study and stratified into two subgroups according to treatment at recurrence: re-resection and no re-resection.

Results: All experienced tumor recurrence with a median progression-free survival of 11 months. 25 % of patients were reoperated. Patients reoperated at recurrence had longer post-progression median overall survival compared to their non-reoperated counterparts (14 versus 9 months, p < .05). Initial surgical resection and a long time from the initial diagnosis to the first recurrence were independent prognostic factors for good outcomes in resected recurrent IDH-wild-type glioblastoma patients; however, tumor size before and after surgery did not impact post-surgical survival.

Conclusion: Our study supports surgical resection at recurrence as therapeutic in IDH wild-type glioblastoma patients aged below 70 and in good clinical condition regardless of preoperative tumor size, particularly in patients who experienced a longer time before first recurrence and surgery at initial diagnosis. Further prospective and larger studies are warranted to validate our findings.
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http://dx.doi.org/10.1016/j.clineuro.2020.106006DOI Listing
September 2020

Sensitivity of the Montreal Cognitive Assessment in screening for cognitive impairment in patients with newly diagnosed high-grade glioma.

J Neurooncol 2020 Jun 15;148(2):335-342. Epub 2020 May 15.

Centre Borelli, Service de Santé Des Armées, Paris-Saclay University, Paris Universities, CNRS, Inserm, 94230, Cachan, France.

Introduction: Cognitive impairment is frequent in patients with high-grade glioma and requires cognitive follow-up. Cognitive screening tools such as the Montreal Cognitive Assessment (MoCA) have been used to assess cognition in these patients. Here we assessed the sensitivity of the MoCA in screening for cognitive impairment in a cohort of 156 patients with newly-diagnosed high-grade glioma, after surgery and before radiochemotherapy.

Methods: We assessed cognitive performance with the MoCA and a neuropsychological battery. Cognitive scores were analyzed in terms of a previously validated framework designed to control false positives and data for 1003 control participants from the GRECOGVASC study. After comparison of performance on the tests, we used stepwise logistic regression to produce a cognitive summary score from the neuropsychological battery. Then we analyzed sensitivity and specificity of the MoCA with receiver operator characteristic (ROC) curve analysis.

Results: Both raw and adjusted MoCA scores showed only moderate sensitivity. The area under the ROC curve was 0.759 (95% CI 0.703-0.815) for the raw score and 0.788 (95% CI 0.734-0.842) for the adjusted score. Optimal discrimination was obtained with a raw score ≤ 25 (sensitivity: 0.526; specificity: 0.832; positive predictive value: 0.2; negative predictive value: 0.96) and an adjusted score - 0.603 (sensitivity: 0.716; specificity: 0.768; positive predictive value: 0.24; negative predictive value: 0.96).

Conclusion: The moderate sensitivity of MoCA indicates that it is not a suitable screening tool for detecting cognitive impairment in patients with newly-diagnosed high-grade glioma.
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http://dx.doi.org/10.1007/s11060-020-03524-6DOI Listing
June 2020

Use of FDG-PET/CT for systemic assessment of suspected primary central nervous system lymphoma: a LOC study.

J Neurooncol 2020 Jun 13;148(2):343-352. Epub 2020 May 13.

Médecine Nucléaire, Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.

Introduction: Primary Central Nervous System Lymphoma (PCNSL) is a rare disease with different therapeutic implications than systemic lymphoma. In this study, we evaluated whole-body FDG-PET/CT for pre-chemotherapy imaging of suspected PCNSL.

Methods: One hundred and thirty consecutive immunocompetent patients were retrospectively included. The results of initial FDG-PET/CT, contrast-enhanced CT (CeCT) and bone marrow biopsy (BMB) when available were compared to a gold standard based on pathological diagnosis or follow-up.

Results: CNS lesion pathology showed large B-cell lymphoma in 95% of patients, including 11 patients with primary vitro-retinal lymphoma. Ten patients (8%) where ultimately diagnosed with systemic lymphoma involvement, including five pathologically confirmed cases, all of which were detected by FDG-PET/CT. FDG-PET/CT showed incidental systemic findings unrelated to lymphoma in 14% of patients. An SUVmax threshold of nine enabled good discrimination between systemic lymphoma and other lesions (sensitivity 92% and specificity 89%). CeCT and BMB performed in 108 and 77 patients respectively revealed systemic lesions in only three patients.

Conclusion: FDG-PET/CT detected concomitant occult systemic involvement in a non-negligible proportion of suspected PCNSL cases (8%). In this setting its sensitivity is higher than that of CeCT. All of our patients ultimately diagnosed with concomitant systemic involvement had positive FDG-PET/CT. We believe it constitutes a safe one-stop shop evaluation for the systemic pre-treatment imaging of suspected PCNSL.
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http://dx.doi.org/10.1007/s11060-020-03525-5DOI Listing
June 2020

Mechanisms and therapeutic implications of hypermutation in gliomas.

Nature 2020 04 15;580(7804):517-523. Epub 2020 Apr 15.

Drug Development Department (DITEP), INSERM U1015, Université Paris Saclay, Gustave Roussy, Villejuif, France.

A high tumour mutational burden (hypermutation) is observed in some gliomas; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
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http://dx.doi.org/10.1038/s41586-020-2209-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235024PMC
April 2020

Primary vitreoretinal lymphomas display a remarkably restricted immunoglobulin gene repertoire.

Blood Adv 2020 04;4(7):1357-1366

Department of Biological Hematology, Assistance Publique-Hopitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Sorbonne Université, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.

Primary vitreoretinal lymphoma (PVRL) is a high-grade lymphoma affecting the vitreous and/or the retina. The vast majority of cases are histopathologically classified as diffuse large B-cell lymphoma (DLBCL) and considered a subtype of primary central nervous system lymphoma (PCNSL). To obtain more insight into the ontogenetic relationship between PVRL and PCNSL, we adopted an immunogenetic perspective and explored the respective immunoglobulin gene repertoire profiles from 55 PVRL cases and 48 PCNSL cases. In addition, considering that both entities are predominantly related to activated B-cell (ABC) DLBCL, we compared their repertoire with that of publicly available 262 immunoglobulin heavy variable domain gene rearrangement sequences from systemic ABC-type DLBCLs. PVRL displayed a strikingly biased repertoire, with the IGHV4-34 gene being used in 63.6% of cases, which was significantly higher than in PCNSL (34.7%) or in DLBCL (30.2%). Further repertoire bias was evident by (1) restricted associations of IGHV4-34 expressing heavy chains, with κ light chains utilizing the IGKV3-20/IGKJ1 gene pair, including 5 cases with quasi-identical sequences, and (2) the presence of a subset of stereotyped IGHV3-7 rearrangements. All PVRL IGHV sequences were highly mutated, with evidence of antigen selection and ongoing mutations. Finally, half of PVRL and PCNSL cases carried the MYD88 L265P mutation, which was present in all 4 PVRL cases with stereotyped IGHV3-7 rearrangements. In conclusion, the massive bias in the immunoglobulin gene repertoire of PVRL delineates it from PCNSL and points to antigen selection as a major driving force in their development.
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http://dx.doi.org/10.1182/bloodadvances.2019000980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160258PMC
April 2020

5-Azacitidine in patients with IDH1/2-mutant recurrent glioma.

Neuro Oncol 2020 08;22(8):1226-1228

Sorbonne University, Institute of the Brain and Spinal Cord, Department of Neurosurgery, University Hospitals of Pitié Salpêtrière‒Charles Foix, Neurology Service 2-Mazarin, Paris, France.

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http://dx.doi.org/10.1093/neuonc/noaa074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594550PMC
August 2020

Management and outcome of primary CNS lymphoma in the modern era: An LOC network study.

Neurology 2020 03 6;94(10):e1027-e1039. Epub 2020 Jan 6.

From Service de Neurologie 2-Mazarin, Sorbonne Université, IHU, ICM (C. Houillier, A.A., D.D., H.D., D.G., B.A., K.H.-X.), Service d'Hématologie (S. Choquet), Service de Neuro-Radiologie (N.M.-D.), Service d'Ophtalmologie (V.T.), Service de Médecine Nucléaire (A.K.), Service de Neuro-Pathologie (K.M.), Service d'Anatomie et Cytologies Pathologiques (F.C.), Service de Radiothérapie (L.F.), Service d'Hémato-Biologie (M.L.G.-T., M.C.), and Service de Neurochirurgie (B.M., M.P.), APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris; Service d'Hématologie (C. Soussain), Institut Curie, Site Saint-Cloud; Service d'Hématologie (H.G.), CHU Lyon Sud; Service d'Hématologie (P.S., A.S.), Institut Bergonié, Bordeaux; Service de Neuro-Oncologie (O. Chinot), Aix-Marseille Université, CNRS, INP, AP-HM, CHU de la Timone, Marseille; Service de Neurologie (L.T., M.B.), CHU de Nancy; Service d'Hématologie (R.H.), Inserm U1236 Université de Rennes 1 (T.L.), CHU de Rennes; Service de Neurologie (G.A.), Hôpitaux Civils, Colmar; Service d'Hématologie (G.D.), CHU de Caen; Service d'Oncologie Médical (P.A.), Institut de Cancérologie de l'Ouest, Saint Herblain; Service d'Hématologie (C.M.-C.), CHU de Clermont-Ferrand; Service de Neurologie (A.A.), CHU de Toulouse; Service d'Oncologie Hématologique et de Thérapie Cellulaire (V.D.), CHU de Poitiers, INSERM, CIC 1402, Centre d'Investigation Clinique, Université de Poitiers; Service d'Oncologie Médicale (M.F.), Institut du Cancer de Montpellier Val d'Aurelle; Service d'Hématologie (F.J.), Centre Henri Becquerel, Rouen; Service d'Hématologie (A.C.), CHU de Besançon; Service d'Hématologie (M.P.M.-M.), CHU d'Angers; Service d'Hématologie (F.M., E.B.), CHRU de Lille; Service d'Hématologie (O. Casasnovas), CHU de Dijon; Service d'Onco-Hématologie (R.G.), CHU de Grenoble; Service d'Hématologie (L.M.F.), CHU de Strasbourg; Service d'Hématologie (J.A.), CHU de Limoges; Service d'Hématologie (J.-P.M.), CHU d'Amiens; Service d'Hématologie (A.T.), CHU de Brest; Service de Neurologie (C.C.) and Service d'Hématologie (A.W.), CHU de Nîmes; Clinique Courlancy (P.C.), Reims; Service d'Hématologie (J.T.), Hôpital Cochin, APHP, Paris; Service d'Hématologie Clinique (K.L.), Centre Hospitalier, Le Mans; Service d'Hématologie (C. Serrier), Centre Hospitalier de Perpignan; Service d'Hématologie (C. Haioun), Hôpital Henri Mondor, Créteil, APHP; Service d'Hématologie Clinique (S. Chebrek), Centre Hospitalier d'Avignon; Service d'Hématologie (J.O.B.), CHU de Clermont-Ferrand; Service d'Hématologie (L.O.), Institut Universitaire du Cancer de Toulouse; Service de Neuro-Oncologie (E.T.), Aix-Marseille Univ, CNRS, INP, AP-HM, CHU de la Timone; Service d'Ophtalmologie (N.C.), Institut Curie, Université Paris V Descartes et PSL (Paris Science et Lettre), Paris; and Service d'Hématologie et Thérapie Cellulaire (E.G.), Centre d'Investigations Cliniques INSERM U1517, Centre Hospitalier Universitaire, Université de Tours, France.

Objective: Real-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.

Methods: The French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.

Results: We identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients <60 years of age received consolidation treatment in 77% of cases, consisting of whole-brain radiotherapy (WBRT) (54%) or high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) (23%). Among patients >60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (<60 years: not reached [NR], 70%, and 61%; >60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.

Conclusions: Our study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.
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http://dx.doi.org/10.1212/WNL.0000000000008900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238921PMC
March 2020

Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations.

Oncologist 2019 12 25;24(12):1584-1592. Epub 2019 Jul 25.

Sorbonne Université, Inserm, CNRS, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France

Background: Astroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined.

Materials And Methods: We performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM.

Results: Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival ( = .021). Mitogen-activated protein kinase pathway alterations (including fusion, and mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma.

Conclusion: We suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway.

Implications For Practice: Astroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.
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http://dx.doi.org/10.1634/theoncologist.2019-0223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975955PMC
December 2019

Optimization of CSF biological investigations for CNS lymphoma diagnosis.

Am J Hematol 2019 10 13;94(10):1123-1131. Epub 2019 Aug 13.

Hematology Laboratory, APHP Pitié-Salpêtrière Hospital and Sorbonne Université, Paris, France.

Diagnosis of lymphoma leptomeningeal dissemination is challenging and relies on a wide array of methods. So far, no consensus biological guidelines are available. This increases the chance of intra- and interpractice variations, despite the shared concern to perform the minimum amount of tests while preserving clinically relevant results.We evaluated a training cohort of 371 cerebrospinal fluid (CSF) samples from patients with putative lymphomatous central nervous system (CNS) localization using conventional cytology (CC), flow cytometry (FCM), molecular clonality assesment by PCR and cytokine quantification (CQ). This led us to propose a biological algorithm, which was then verified on a validation cohort of 197 samples. The samples were classified according to the clinical context and the results of each technique were compared. Using all four techniques was not useful for exclusion diagnosis of CNS lymphoma (CNSL), but they proved complementary for cases with suspected CNSL. This was particularly true for CQ in primary CNSL. Overall, diagnosis can be obtained with a two-step approach. The first step comprises CC and FCM, as results are available quickly and FCM is a sensitive method. Both PCR and CQ can be postponed and performed in a second step, depending on the results from the first step and the clinical context.The proposed algorithm missed none of the CNSL samples of the validation cohort. Moreover, applying this algorithm would have spared 30% of PCR tests and 20% of CQ over a one-year period, without compromising clinical management.
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http://dx.doi.org/10.1002/ajh.25578DOI Listing
October 2019

Treatment of Primary Central Nervous System Lymphoma in Immunocompetent Patients.

Curr Treat Options Neurol 2019 Jul 19;21(8):39. Epub 2019 Jul 19.

AP-HP, Department of Neurology-2, Groupe Hospitalier Pitié Salpêtrière, Paris, France.

Purpose Of Review: This review focuses on the findings of recent randomized prospective trials evaluating new therapeutic options for primary central nervous system lymphoma (PCNSL) in first-line treatment and on the most promising novel agents.

Recent Findings: The current standard treatment of newly diagnosed PCNSL has long been depending on high-dose methotrexate (HD-MTX)-based polychemotherapy followed by whole-brain radiotherapy (WBRT). Recent randomized trials have provided evidence that high-dose chemotherapy with autologous stem cell transplantation (ASCT) is a valuable alternative option to WBRT as consolidation after induction HD-MTX-based chemotherapy. For the elderly, cumulative studies confirm that chemotherapy alone as initial treatment is the best approach in this frail population in order to reduce chemoradiation neurotoxicity. If the role of rituximab needs to be further investigated, novel agents such as imids and ibrutinib have shown to be promising drugs to be incorporated in innovative combination treatment. The role of WBRT, at least at conventional dose, is declining in first-line treatment in favor of intensive consolidation chemotherapy with or without ASCT and possibly maintenance chemotherapy in the elderly. Despite their rarity, it has been shown that ambitious randomized trials in PCNSL are feasible thanks to collaborative networks.
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http://dx.doi.org/10.1007/s11940-019-0578-xDOI Listing
July 2019
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