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Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin's lymphoma confined to the central nervous system with a diffuse large B-cell lymphoma (DLBCL) histology and is highly prevelant in elderly patients. Whole brain radiotherapy (WBRT) does not provide considerable remission; rather it is highly involved in the development of leukoencephalopathy with delayed neurotoxicity, notably in elderly patients. Standard care for newly diagnosed patients with PCNSL comprised induction with high-dose methotrexate (HD-MTX)-based multi-agent immunochemotherapy, such as R-MPV (rituximab, MTX, procarbazine, vincristine) yielding 70-75% complete response rate, followed by HD-cytarabine consolidation. Consolidation high-dose chemotherapy with the key drug thiotepa supported by autologous stem cell transplant has recently been investigated to replace WBRT in multiple randomized trials, demonstrating non-inferiority to WBRT with less neurotoxicity. Comprehensive genetic analyses have revealed high rates of oncogenic mutations in CD79B and MYD88 genes, the hallmarks for MCD/C5 subtype of DLBCL, leading to constitutive activation of NF-κB signaling pathways in PCNSL. Bruton's tyrosine kinase (BTK), an intermediate kinase downstream to CD79B/MYD88, has emerged as a promising therapeutic target. Furthermore, tirabrutinib, a second-generation BTK inhibitor, has shown substantial activity against relapsed/refractory PCNSL, resulting in its approval in 2020 in Japan. Additionally, other new agents against PI3-kinase and immunotherapies including immunomodulatory agents, immune checkpoint blockade, and CAR-T have been actively tested in clinical trials.

Primary central nervous system lymphoma(PCNSL)is an aggressive, extranodal non-Hodgkin lymphoma that arises from the central nervous system, eyes, leptomeninges, and the spinal cord. Most PCNSLs are a type of diffuse large B-cell lymphoma(DLBCL), and the majority are categorized as a non-germinal center B-cell(GCB)subtype. Recent genetic studies have revealed several common genetic abnormalities in PCNSL, such as MYD88 and CD79B mutations, suggesting dependence on the B-cell receptor/Toll-like receptor signaling pathway. These genetic findings have rationalized targeted therapy targeting Bruton's tyrosine kinase(BTK), a key molecule of the B-cell receptor pathway in PCNSL and systemic non-GCB DLBCL. The first-generation BTK inhibitor ibrutinib has been widely studied in clinical trials for PCNSL and systemic non-GCB DLBCL. In Japan, a second-generation BTK inhibitor tirabrutinib was studied in a phase I/II trial and approved by the Japanese Ministry of Health and Welfare in March 2020 for relapsed and refractory PCNSL. While the current standard-of-care therapy for PCNSL is methotrexate(MTX)-based multi-agent induction immunochemotherapy like R-MPV(rituximab, MTX, procarbazine, and vincristine)followed by consolidation chemotherapy and/or radiation therapy, further investigation into the optimal use of BTK inhibitors in the standard-of-care therapy of PCNSL is warranted.

Management of primary central nervous system lymphoma (PCNSL) includes induction and consolidation therapies in newly diagnosed patients, as well as second-line therapy in relapsed or refractory patients. The current standard-of-care induction therapy involves methotrexate (MTX)-based multi-agent immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine. Deferral or dose reduction of radiation therapy is considered in consolidation therapy, especially in elderly patients who carry a high risk of radiation-induced delayed neurotoxicity. Since elderly patients comprise the main population of PCNSL, minimally toxic treatments that are effective and feasible for them are strongly needed. For second-line therapy, rechallenge using MTX-based chemotherapy (in patients with a prior durable response to MTX-based chemotherapy) or radiation therapy is considered. Bruton's tyrosine kinase inhibitor tirabrutinib (for relapsed and refractory PCNSL) and high-dose chemotherapy with autologous stem cell transplantation support using thiotepa and busulfan (BuTT) were approved by the Japanese Ministry of Health and Welfare in March 2020 and has recently become available for clinical practice. While these novel treatments seem promising, the optimal use of these treatments along with the standard-of-care therapy of PCNSL should be defined and investigated in clinical trials.

Glioblastoma(GBM)is the most malignant and frequent primary brain tumor. The current standard of care consists of maximum safe resection and radiotherapy with concomitant and subsequent temozolomide(TMZ)treatment. With this treatment plan, the prognosis of patients with GBM remains dismal, with a 5-year survival rate of<10%; thus development of effective, novel therapies is needed. Bevacizumab(Bev, Avastin®)is a humanized monoclonal antibody against vascular endothelial growth factor(VEGF), one of the major potent angiogenic factors for the growth of human cancers, including GBM. Bev has been shown to effectively shrink enhancing lesions of recurrent GBM and decrease symptom burden and brain edema. These positive results led to its approval for malignant glioma treatment in June 2013 in Japan. Two double-blind, placebo-controlled, randomized phase III studies of Bev in newly diagnosed GBM were conducted to verify its efficacy as a first-line therapy used in combination with TMZ. The results, which were reported at the American Society for Clinical Oncology(ASCO)meeting in June 2013, failed to show an increase in overall survival, despite prolongation in progression-free survival. These results led to many unsolved issues regarding the use of Bev for the treatment of GBM. We discuss these problems in this paper and highlight our institutional experience with Bev monotherapy for recurrent high-grade gliomas.

Over the last decade, significant progress has been made in understanding glioma on a molecular level. However, optimal incorporation of molecular markers into clinical care is still controversial. Here, the potential utility of genetic alterations found in gliomas in refining histological diagnosis, prognosis, and predictive values for treatment selection is reviewed. Among all, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, 1p/19q codeletion, and isocitrate dehydrogenase 1 (IDH1) mutations have been identified as favorable prognostic markers. MGMT promoter methylation is the only potential predictive marker for response to temozolomide and alkylating agents in glioblastoma (GBM), but it is not of assistance in diagnostics. IDH1 mutations and 1p/19q codeletion are also useful for classifying and grading gliomas, since 1p/19q codeletion is tightly linked to oligodendroglial lineage, and IDH1 mutations are restricted to grade II/III gliomas, while not to primary GBM. BRAF fusion is a good marker for pilocytic astrocytoma. High-throughput profiling techniques for gene expression and epigenetic modification have provided new subtype classifications for GBM as well as lower grade gliomas, which may be of prognostic and predictive values. Efforts to identify molecular markers that predict the benefits of novel molecularly targeted treatments will enable better patient stratification and individualization of treatment.

A 38-year-old man gradually developed gait instability, dysarthria, and dysphagia over two months associated with an elevated blood pressure after starting hemodialysis therapy for diabetic nephropathy. Brain MRI studies indicated vasogenic edema in the brainstem, extending from the lower midbrain to the upper medulla oblongata. The patient's high blood pressure was refractory to treatment, and his neurological disabilities and MRI abnormalities progressed. FDG-PET, MR spectroscopy, and cerebrospinal fluid studies did not suggest neoplastic pathologies. The patient was diagnosed with a brainstem variant of reversible posterior leukoencephalopathy syndrome, and received three courses of steroid pulse therapy. After the pulse therapy, the clinical manifestations and MR findings improved. By maintaining strict management of blood pressure and body water balance during hemodialysis, he did not experience any further clinical exacerbation, and the lesion on MR images continued to regress. Ten months after the pulse therapy, T1-weighted images showed slightly hyperintense signal. This case suggests that reversible posterior leukoencephalopathy syndrome (RPLS) may take a chronic clinical course without acute onset.

A 22-year-old woman harboring recurrent malignant astrocytoma presented with intracranial hypertension by tumor hemorrhage during repeated administration of lymphokine-activated killer (LAK) cells via Ommaya's reservoir. She first suffered from the tumor located at the right occipital lobe at the age of 13. The tumor regressed completely by subtotal removal of the tumor, followed by external irradiation. Nine years later, however, the occipital tumor recurred and was subtotally resected. Pathological diagnosis was astrocytoma grade 3. Postoperatively, LAK cells induced from her peripheral blood lymphocytes incubated with interleukin-2 and anti-CD3 antibody were injected into the tumor cavity via Ommaya's reservoir for eight times. At the end of the LAK therapy, the tumor regrew with massive hemorrhage in the tumor cavity causing intracranial hypertension. At the reoperation, thick granulation tissue covered the surface of the recurrent tumor and dense deposits of clot were noted around the tip of the Ommaya's tube. Histologically the superficial layer of the tumor was infiltrated with macrophages and lymphocytes, mostly CD3-positive T cells, accompanied with capillary hyperplasia. Viable astrocytoma cells were abundant beneath the granulation layer. It should be considered that in local LAK therapy granulation tissue formation with hypervascularization at the surface of the tumor cavity may lead to tumor bleeding as well as resistance to the treatment.

Application of flow cytometric DNA analysis was tried to determine the sensitivity of ACNU, one of nitrosourea derivatives which had been used very commonly for malignant brain tumors, to tumor cells. To evaluate the degree of chemo-sensitivity of ACNU, factor B was introduced, indicating the accumulated cells in SG2M phases after ACNU treatment as the percentage of cells that was previously in the SG2M phases and it revealed that ACNU sensitive cell clones gave much larger values of Factor B than ACNU resistant ones at the concentration of 10 micrograms/ml ACNU treatments. Twenty clinical materials obtained by operation were examined by measuring the degree of values of this Factor B, and the findings indicated that this method would be applicable as a clinical test for chemo-sensitivity of malignant brain tumors, after some improvement of the method.

A 6-month-old boy having intraspinal lipoma with lumbosacral subcutaneous lipoma and occult spinal dysraphism is described. CT scan and magnetic resonance imaging (MRI) are demonstrated. On admission, the patient showed no neurological deficits. Lumbosacral hemangioma and subcutaneous lipoma were noticed on physical examination. A plain spinal roentogenogram revealed occult spinal dysraphism extending from L 4 level down to the sacral region. A plain CT scan disclosed a round-shaped low density area surrounded by a relatively high density area corresponding to the neural tissue in the spinal canal. MRI (1.5-T superconducting system) with sagittal views clearly showed an oval-shaped high signal intensity (SI) area-an intraspinal lipoma-with the neural tissue running longitudinally within and on its surface. The lipoma appeared to be attached to the spinal cord at L 1/2 level. On operation, we found an extramedullary lipoma which had a certain connection to the sacral epidural adipose tissue with an opening of the dural sac, as far as the subcutaneous lipoma. Tethered cord and thickened filum terminale were not identified. Generally, lipoma is demonstrated as a low density area of approximately -90 H.U. on a CT scan. In MRI, we can obtain a high contrast between the lipoma, the spinal cord, and the cerebrospinal fluid, since they are shown as a high, an intermediate, and a low SI area respectively, on T1-weighted spin echo images. Furthermore, sagittal section of MRI is regarded as a potent diagnostic modality to get the precise anatomy of the spinal cord lesion. These short spin echo images can be taken in a relatively brief time. It is a great advantage for patients with spinal lipoma, who are usually infants. MRI is considered to be a quite useful modality to diagnose spinal lipoma, and is able to lead to an early diagnosis non-invasively and accurately, facilitating appropriate surgical treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was designed to investigate the effects of psychological stress upon attention as subjects performed on the MFF test. Thirty-four undergraduate students served as subjects. They participated in two experimental conditions: "stress condition" and "non-stress condition". Main sources of stress were competitive instruction and anxiety caused by unfamiliar experimental setting. Heart rate and state anxiety were measured as the indices of those stressors. Their performance on the MFF test was measured in terms of reaction time and the number of correct responses in each condition. The main results were as follows. Reaction time in stress condition was found significantly shorter than that in non-stress condition. However, there was no significant difference in the number of correct responses between these two conditions. Besides, there was no linear relationship found between either heart rate or state anxiety scores and MFF test performance. These results suggest that attention measured by MFF test differs in its reaction time, depending upon whether stressful instruction exists or not, but it holds constancy in its correct responses throughout the experiment.