Regenerative medicine based on the use of induced pluripotent stem cells is fast becoming a reality. However, there remain several issues in bridging the gap between basic research and clinical application. The keys to bridging this gap are scientific rationale, pre-clinical study with clinical cell lines, and cooperation. We developed a method for the efficient induction of dopaminergic neurons from human induced pluripotent stem cells and for sorting dopaminergic progenitor cells using CORIN, a floor plate marker. The grafted CORIN+ cells survived functioned well as midbrain dopaminergic neurons in rat and monkey models of Parkinson’s disease, even showing minimal risk of tumor formation. After discussion with a Japanese regulatory agency, we performed several pre-clinical studies using a clinical induced pluripotent stem cell line. We also collaborated with a pharmaceutical company from the early stage of development. These results and efforts led us to start a clinical trial in August 2018 to assess the effectiveness of our method for treating patients with Parkinson’s disease.
The poor outcomes of subarachnoid hemorrhage following the rupture of pre-existing intracranial aneurysms necessitates that novel diagnostic or therapeutic strategies be developed. Recent experimental findings, including those obtained from human specimens, have highlighted the key role of macrophage-mediated chronic inflammation to the machinery that regulates the formation and progression of intracranial aneurysms. In this way, such aneurysms can be recognized as a macrophage-mediated chronic inflammatory disease affecting intracranial arteries. Such a conceptualization and understanding is important for two reasons : 1) it can help develop novel therapeutic drugs to prevent rupture ; 2) it can help develop a diagnostic modality to estimate the qualitative nature of a lesion for proper stratification of rupture-prone intracranial aneurysms.
In animal models, several drugs with anti-inflammatory effects can successfully prevent the disease formation and progression. Furthermore, in cross-sectional studies of human cases, the usage of potent anti-inflammatory HMG-CoA reductase inhibitors and the usage of non-steroidal anti-inflammatory drugs are significantly lower in cases of unruptured intracranial aneurysm. These results clearly suggest that a medical therapy capable of targeting the factors that mediate chronic inflammatory responses in the microenvironment of lesions could prevent intracranial aneurysms from progressing. In addition, macrophage imaging has been reported as a potential aid in diagnosing the inflammatory status of each intracranial aneurysm, acting as a surrogate marker of disease activity. In this imaging technique, a macrophage is labeled by engulfed iron-containing nanoparticles and visualized by T2*images on magnetic resonance imaging. Because the positive rate in macrophage imaging is positively related to the aneurysm’s size, this technique can stratify intracranial aneurysms into rupture-prone and stable lesions. A new era of diagnosis and treatment is therefore expected.
In this, unruptured intracranial aneurysms will be identified through brain imaging, rupture-prone lesions will be selected by macrophage imaging, and pre-emptive medical therapy or surgery will be used to prevent subarachnoid hemorrhage in appropriately selected cases.
There are approximately 40 trillion cells in a human body. Were the DNA contained in each of these cells to be connected end-to-end, it would measure 74 billion kilometers, amounting to the distance from Earth to Sirius. Analysis of this length of DNA is now possible within a period as short as a few hours. Since the mid-2000s, next-generation sequencing (NGS) has become widely available, and we have now reached the era of the $1000 genome with which NGS platforms have been completed. Intron-reading whole genome sequencing (WGS) technology is now mainstream, replacing the use of targeted gene sequencing panels. By 2020, we should expect that WGS analysis will become standard over DNA analysis using panel-based NGS or exon sequencing. WGS is now also capable of rapidly screening millions of genetic abnormalities with the advent of artificial intelligence (AI), such as the representative AI, “Watson for Genomics”. In an era with such an abundance of electronic data and overwhelming amounts of published scientific literature, particularly research related to glioma, Watson for Genomics can help scientists more efficiently learn, analyze, and draw conclusions from information contained in 20 million papers on a daily basis, covering topics such as cancerous mutations and the mechanisms of the human body. Information related to genetic mutations can then offer insight into determining the most appropriate therapeutics. Further, the “Human Cell Atlas”, a project aiming to cultivate better understanding of the actions of individual cells in a variety of contexts such as cancer biology, neuroscience, and developmental biology, has now commenced. Within the biological central dogma comprised of the genome, the cell, and the body, medicine will likely evolve rapidly in the coming 2-3 years.
Recent advances in the methods of brain activity measurement and machine learning have facilitated research into how our brains work under naturalistic perceptual and cognitive conditions. Such studies may provide quantitative bases for future techniques, such as whole-brain functional mapping for pre- and intra-operational guidance or high-efficiency brain-machine interfaces for invasive brain measurement and stimulation techniques. This review introduces the recent advancements in functional brain reading technology and discusses their potential.
The standard treatment for primary central nervous system lymphoma (PCNSL) is high-dose methotrexate (HD-MTX) and whole brain radiotherapy (WBRT). However, relapse rates are high despite remission after initial treatment, and there is no effective standard treatment for recurrent PCNSL. We aimed to determine the effectiveness of gamma knife stereotactic radiosurgery (GK surgery) for recurrent PCNSL and to clarify its acceptability as salvage treatment at the time of relapse.
We performed a retrospective analysis of patients who underwent salvage GK surgery for recurrent PCNSL from October 2010 to May 2017. The radiographic response of target lesions, the median progression-free survival, the median overall survival, the median overall survival from initial treatment, and any adverse events after GK surgery were assessed as endpoints. In total, 13 patients with 109 target lesions were treated with GK surgery : seven were initially treated with both HD-MTX and WBRT (mean age, 59.7 years), and six were initially treated with only HD-MTX (mean age, 79.5 years). The mean period from initial treatment to the first GK surgery was 9.8 months, the mean target tumor volume was 3.0 cm3, and the mean marginal dose was 12.6 Gy (this was prescribed to the 50% isodose line that encompassed the target volume).
Of the 109 lesions, 87 achieved complete response (84%) over a mean period of 1.8 months. The response rate was 91%. Although radiation necrosis occurred in 10 lesions (9%), all cases were asymptomatic according to the Common Terminology Criteria for Adverse Events (i.e., Grade 1). From the first GK surgery, median progression-free survival was 7 months (5 months in the HD-MTX+WBRT group and 7 months in the HD-MTX group) and median overall survival was 19 months (19 months in the HD-MTX+WBRT group and 51 months in the HD-MTX group). The median overall survival from initial treatment was 47 months (47 months in the HD-MTX+WBRT group and 52 months in the HD-MTX group).
In conclusion, GK surgery has fewer adverse events while retaining comparable median progression-free survival and median overall survival to other treatments. Alternative treatments for recurrent PCNSL are chemotherapy with rituximab or temozolomide and high-dose chemotherapy combined with autologous stem cell transplantation. GK surgery benefits from showing a high remission rate and immediate effect for recurrent PCNSL, while being relatively safe and less invasive. Overall, GK surgery appears to be a safe and effective option for salvage treatment in patients with recurrent PCNSL, even after WBRT and when treating the elderly.
Several randomized controlled clinical trials conducted in 2015 validated the effectiveness of mechanical thrombectomy for acute ischemic stroke. In Japan, this form of treatment is generally recommended for patients within 8 hours of ischemia onset. Sometimes, however, clinicians are hesitant about deciding the best treatment for patients with so-called “wake-up stroke” or “unknown-onset stroke”. Here we report a case of internal carotid artery occlusion in which neurological recovery was achieved by mechanical thrombectomy performed 18 hours after onset. Notably, in this case there was a mismatch between the findings of diffusion-weighted imaging (DWI)-fluid attenuated IR (FLAIR) and those of MRI. One possible reason could have been a cascade of emboli from a giant clot at the orifice of the internal carotid artery.
This case suggests that mechanical thrombectomy might also be effective for patients with MRI/DWI-FLAIR mismatch, even if diagnosis is delayed for more than 8 hours after onset.