Boron neutron capture therapy (BNCT) is a unique anticancer technology that has demonstrated its efficacy in numerous phase I/II clinical trials with boronophenylalanine (BPA) and sodium borocaptate (BSH) used as ¹⁰B delivery agents. However, continuous drug administration at high concentrations is needed to maintain sufficient ¹⁰B concentration within tumors. To address the issue of ¹⁰B accumulation and retention in tumor tissue, we developed MMT1242, a novel boron-containing α-d-mannopyranoside. We evaluated the uptake, intracellular distribution, and retention of MMT1242 in cultured cells and analyzed biodistribution, tumor-to-normal tissue ratio and toxicity in vivo. Fluorescence imaging using nitrobenzoxadiazole (NBD)-labeled MMT1242 and inductively coupled mass spectrometry (ICP-MS) were performed. The effectiveness of BNCT using MMT1242 was assessed in animal irradiation studies at the Kyoto University Research Reactor. MMT1242 showed a high uptake and broad intracellular distribution in vitro, longer tumor retention compared to BSH and BPA, and adequate tumor-to-normal tissue accumulation ratio and low toxicity in vivo. A neutron irradiation study with MMT1242 in a subcutaneous murine tumor model revealed a significant tumor inhibiting effect if injected 24 h before irradiation. We therefore report that ¹⁰B-MMT1242 is a candidate for further clinical BNCT studies.

Glioblastoma (GBM) is the most common type of malignant brain tumor and has a very poor prognosis. Most patients relapse within 12 months despite aggressive treatment and patient outcome after recurrent is extremely worse. This study was designed to clarify the change of the molecular expression, including programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1), on the initial and secondary resected tumor specimens and to address the influence of these expressions for patient outcome after second surgery of glioblastoma. We investigated 16 patients, ranging in age from 14 to 65 years, with histologically verified WHO grade IV GBM, whose original tumor was resected between 2008 and 2014, and treated with fractionated radiotherapy and temozolomide. Four patients who were treated with immunotherapy using autologous formalin-fixed tumor vaccine were enrolled. All of the patients underwent secondary resection after tumor recurrence within 24 months. We carried out an immunohistochemical examination of the initial and secondary resected tumors from patients using a panel of immune system molecular markers, and assessed whether marker expression correlated with clinical outcomes. CD3, CD8 and PD-1 on tumor-infiltrating lymphocytes was significantly increased in secondary resected specimens compared with initially resected specimens (p ≤ 0.05). All patients expressed PD-L1 on tumor cells in initial and secondary resection specimens. Patients were divided into high or low expression group by median IHC score of PD-1 on initial or secondary resected specimens. No significant differences in patient outcomes were observed between high and low PD-1 or PD-L1 groups of initially resected specimens. In high expression group of secondary resected specimens, most patients score had increased which compared with initial resected tumor specimens. The PD-1 high expression score group of secondary resected specimens was associated with long progression-free survival and short survival after recurrence. PD-L1 expression was detected in almost all initial and secondary specimens. Patients with high PD-1 expression of secondary specimen had bad prognosis after secondary resection. PD-1/PD-L1 pathway may be associated with patient outcome after second surgery of glioblastoma.

Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells—including M2-type macrophages and myeloid-derived suppressor cells—that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment.

In clinical practice, acute post-stroke paresis of the extremities fundamentally complicates timely rehabilitation of motor functions; however, recently, residual and distorted musculoskeletal signals have been used to initiate feedback-driven solutions for establishing motor rehabilitation. Here, we investigate the possibilities of basic hand gesture recognition in acute stroke patients with hand paresis using a novel, acute stroke, four-component multidomain feature set (ASF-4) with feature vector weight additions (ASF-14NP, ASF-24P) and supervised learning algorithms trained only by surface electromyography (sEMG). A total of 19 (65.9 ± 12.4 years old; 12 men, seven women) acute stroke survivors (12.4 ± 6.3 days since onset) with hand paresis (Brunnstrom stage 4 ± 1/4 ± 1, SIAS 3 ± 1/3 ± 2, FMA-UE 40 ± 20) performed 10 repetitive hand movements reflecting basic activities of daily living (ADLs): rest, fist, pinch, wrist flexion, wrist extension, finger spread, and thumb up. Signals were recorded using an eight-channel, portable sEMG device with electrode placement on the forearms and thenar areas of both limbs (four sensors on each extremity). Using data preprocessing, semi-automatic segmentation, and a set of extracted feature vectors, support vector machine (SVM), linear discriminant analysis (LDA), and k-nearest neighbors (k-NN) classifiers for statistical comparison and validity (paired t-tests, p-value < 0.05), we were able to discriminate myoelectrical patterns for each gesture on both paretic and non-paretic sides. Despite any post-stroke conditions, the evaluated total accuracy rate by the 10-fold cross-validation using SVM among four-, five-, six-, and seven-gesture models were 96.62%, 94.20%, 94.45%, and 95.57% for non-paretic and 90.37%, 88.48%, 88.60%, and 89.75% for paretic limbs, respectively. LDA had competitive results using PCA whereas k-NN was a less efficient classifier in gesture prediction. Thus, we demonstrate partial efficacy of the combination of sEMG and supervised learning for upper-limb rehabilitation procedures for early acute stroke motor recovery and various treatment applications.