Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B

術中フローサイトメトリーを用いた頭蓋内悪性リンパ腫と膠芽腫の鑑別

博士(医学) 甲第697号(主論文の要旨、要約、審査結果の要旨、本文)，著者名:Shunichi KORIYAMA・Masayuki NITTA・Takahiro SHIOYAMA・Takashi KOMORI・Takashi MARUYAMA・Takakazu KAWAMATA・Yoshihiro MURAGAKI，タイトル:Intraoperative Flow Cytometry Enables the Differentiation of Primary Central Nervous System Lymphoma from Glioblastoma，掲載誌:World neurosurgery(1878-8750)，巻・頁・年:112巻 p.e261-e268(2018)，著作権関連情報:ª 2018 Elsevier Inc. All rights reserved.，DOI:10.1016/j.wneu.2018.01.033博士(医学)東京女子医科大

Primary CNS Lymphoma

Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system is an aggressive malignancy that exhibits unique biological features and characteristic clinical behaviour, with overall long-term survival rates of around 20–40 %. Clinical outcome has improved following the advent of chemoradiation protocols incorporating high-dose methotrexate in the mid-1980s, but disease relapse and adverse neurocognitive sequelae remain major clinical challenges. To address this, investigators have focused on improving drug therapy with novel cytotoxic combinations, monoclonal antibody therapy, and intensive chemotherapy consolidation approaches, in an attempt to improve disease control whilst reducing the requirement for whole-brain radiotherapy. Outcomes for patients that are older, immunocompromised, or have relapsed/refractory disease remain unsatisfactory and there is a paucity of clinical trial data to guide treatment of these groups. This review highlights recent advances in pathobiology, imaging, and clinical management of PCNSL and looks ahead to research priorities for this rare and challenging lymphoid malignancy

First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)—a systematic review and individual patient data meta-analysis

Evidence for prognosis and treatment of elderly patient with primary central nervous system is limited. High-dose methotrexate should be applied whenever possible, especially combination with oral alkylating agents is a promising approach. Further combinations with other intravenous drugs do not seem to improve outcome. More prospective trials designed for elderly PCNSL patients are warrante

Recent Advances in Treatment of Primary Central Nervous System Lymphoma

Opinion statement Therapeutic options are limited in primary central nervous system lymphoma (PCNSL) with no uniform consensus on optimal management and few published, randomized trials. High-dose methotrexate in combination with other chemotherapeutic agents forms the mainstay of treatment. There hasn’t been much progress beyond high-dose methotrexate in this disease, and although results from trials using high-dose chemotherapy and autologous stem-cell transplant seem promising, these need to be further validated. Moreover, the role of whole brain radiation in the upfront setting remains to be determined. However, international efforts in this direction are underway, with ongoing randomized trials in newly diagnosed PCNSL, more research on the molecular pathogenesis and biomarkers, and the use of novel agents in salvage therapy. There also is emphasis on quality of life parameters and neurocognitive status. Future treatment options should optimize high-efficacy rates while minimizing the risk of neurotoxicity

Real-time monitoring of human blood-brain barrier disruption

Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography ( DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 mu V followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for bloodbrain barrier disruption augmented drug delivery.Peer reviewe

B-cell lymphoma of the brainstem with central neurogenic hyperventilation

Non-Hodgkin\u27s lymphoma of the brainstem is a rare entity. Central Neurogenic Hyperventilation (CNH), an associated manifestation of this disease, is an even rarer event. We report a case of an immunocompetent individual who presented to us with tachypnea and facial nerve palsy. Neuroimaging showed a Cerebellopontine angle tumour which on histopathology showed feature consistent with a Non-Hodgkin\u27s B-Cell Lymphoma. The patient went on to develop severe respiratory alkalosis with findings consistent with CNH. Chemotherapy with Methotrexate was started and high dose Dexamethasone was added to the regimen a month later. Radiologically, the tumour size decreased by 50% but the patient\u27s clinical condition deteriorated. He eventually expired due to cardiopulmonary arrest. Some common clinical presentations of this disease and various diagnostic modalities and treatment options available to such patients are discussed

Linfoma primário do sistema nervoso central: estratégias relevantes na conduta inicial

Universidade Federal de São Paulo (UNIFESP) Department of Neurology and NeurosurgeryHospiltal Israelita Albert Einstein Neuro-oncology ProgramUNIFESP, Department of Neurology and NeurosurgerySciEL