Prediction of Normal Tissue Complication Probability (NTCP) After Radiation Therapy Using Imaging and Molecular Biomarkers and Multivariate Modelling.

The aim of this study was to design a predictive radiobiological model of normal brain tissue in low-grade glioma following radiotherapy based on imaging and molecular biomarkers. Fifteen patients with primary brain tumors prospectively participated in this study and underwent radiation therapy. Magnetic resonance imaging (MRI) was obtained from the patients, including T1- and T2-weighted imaging and diffusion tensor imaging (DTI), and a generalized equivalent dose (gEUD) was calculated. The radiobiological model of the normal tissue complication probability (NTCP) was performed using the variables gEUD; axial diffusivity (AD) and radial diffusivity (RD) of the corpus callosum; and serum protein S100B by univariate and multivariate logistic regression XLIIIrd Sir Peter Freyer Memorial Lecture and Surgical Symposium (2018). Changes in AD, RD, and S100B from baseline up to the 6 months after treatment had an increasing trend and were significant in some time points (P-value < 0.05). The model resulting from RD changes in the 6 months after treatment was significantly more predictable of necrosis than other univariate models. The bivariate model combining RD changes in Gy40 dose-volume and gEUD, as well as the trivariate model obtained using gEUD, RD, and S100B, had a higher predictive value among multivariate models at the sixth month of the treatment. Changes in RD diffusion indices and in serum protein S100B value were used in the early-delayed stage as reliable biomarkers for predicting late-delayed damage (necrosis) caused by radiation in the corpus callosum. Current findings could pave the way for intervention therapies to delay the severity of damage to white matter structures, minimize cognitive impairment, and improve the quality of life of patients with low-grade glioma.

PrACTiC: A Predictive Algorithm for Chemoradiotherapy-Induced Cytopenia in Glioblastoma Patients.

BACKGROUND: Chemotherapy-induced cytopenia is the most frequent side effect of chemoradiotherapy in glioblastoma patients which may lead to reduced delivery of treatment. This study aims to develop a predictive model that is able to forecast the cytopenia induced by temozolomide (TMZ) during concomitant chemoradiotherapy. METHODS: Medical records of 128 patients with newly diagnosed glioblastoma were evaluated to extract the baseline complete blood test before and during the six weeks of chemoradiotherapy to create a dataset for the development of ML models. Using the constructed dataset, different ML algorithms were trained and tested. RESULTS: Our proposed algorithm achieved accuracies of 85.6%, 88.7%, and 89.3% in predicting thrombocytopenia, lymphopenia, and neutropenia, respectively. CONCLUSIONS: The algorithm designed and developed in this study, called PrACTiC, showed promising results in the accurate prediction of thrombocytopenia, neutropenia, and lymphopenia induced by TMZ in glioblastoma patients. PrACTiC can provide valuable insight for physicians and help them to make the necessary treatment modifications and prevent the toxicities.

Early Detection of Radiation-Induced Injury and Prediction of Cognitive Deficit by MRS Metabolites in Radiotherapy of Low-Grade Glioma.

PURPOSE: To compare the sensitivity of MRS metabolites and MoCA and ACE-R cognitive tests in the detection of radiation-induced injury in low grade glioma (LGG) patients in early and early delayed postradiation stages. METHODS: MRS metabolite ratios of NAA/Cr and Cho/Cr, ACE-R and MoCA cognitive tests, and dosimetric parameters in corpus callosum were analyzed during RT and up to 6-month post-RT for ten LGG patients. RESULTS: Compared to pre RT baseline, a significant decline in both NAA/Cr and Cho/Cr in the corpus callosum was seen at the 4th week of RT, 1, 3, and 6-month post-RT. These declines were detected at least 3 months before the detection of declines in cognitive functions by ACE-R and MoCA tools. Moreover, NAA/Cr alterations at 4th week of RT and 1-month post-RT were significantly negatively correlated with the mean dose received by the corpus callosum, as well as the corpus callosum 40 Gy dose volume, i.e., the volume of the corpus callosum receiving a dose greater than 40 Gy. CONCLUSION: MRS-based biomarkers may be more sensitive than the state-of-the-art cognitive tests in the prediction of postradiation cognitive impairments. They would be utilized in treatment planning and dose sparing protocols, with a specific focus on the corpus callosum in the radiation therapy of LGG patients.

Temporal and extratemporal atrophic manifestation of temporal lobe epilepsy using voxel-based morphometry and corticometry: clinical application in lateralization of epileptogenic zone.

BACKGROUND: Advances in MRI acquisition and data processing have become important for revealing brain structural changes. Previous studies have reported widespread structural brain abnormalities and cortical thinning in patients with temporal lobe epilepsy (TLE), as the most common form of focal epilepsy. METHODS: In this research, healthy control cases (n = 20) and patients with left TLE (n = 19) and right TLE (n = 14) were recruited, all underwent 3.0 T MRI with magnetization-prepared rapid gradient echo sequence to acquire T1-weighted images. Morphometric alterations in gray matter were identified using voxel-based morphometry (VBM). Volumetric alterations in subcortical structures and cortical thinning were also determined. RESULTS: Patients with left TLE demonstrated more prevailing and widespread changes in subcortical volumes and cortical thickness than right TLE, mainly in the left hemisphere, compared to the healthy group. Both VBM analysis and subcortical volumetry detected significant hippocampal atrophy in ipsilateral compared to contralateral side in TLE group. In addition to hippocampus, subcortical volumetry found the thalamus and pallidum bilaterally vulnerable to the TLE. Furthermore, the TLE patients underwent cortical thinning beyond the temporal lobe, affecting gray matter cortices in frontal, parietal, and occipital lobes in the majority of patients, more prevalently for left TLE cases. Exploiting volume changes in individual patients in the hippocampus alone led to 63.6% sensitivity and 100% specificity for lateralization of TLE. CONCLUSION: Alteration of gray matter volumes in subcortical regions and neocortical temporal structures and also cortical gray matter thickness were evidenced as common effects of epileptogenicity, as manifested by the majority of cases in this study.

Health management and pattern analysis of daily living activities of people with dementia using in-home sensors and machine learning techniques.

The number of people diagnosed with dementia is expected to rise in the coming years. Given that there is currently no definite cure for dementia and the cost of care for this condition soars dramatically, slowing the decline and maintaining independent living are important goals for supporting people with dementia. This paper discusses a study that is called Technology Integrated Health Management (TIHM). TIHM is a technology assisted monitoring system that uses Internet of Things (IoT) enabled solutions for continuous monitoring of people with dementia in their own homes. We have developed machine learning algorithms to analyse the correlation between environmental data collected by IoT technologies in TIHM in order to monitor and facilitate the physical well-being of people with dementia. The algorithms are developed with different temporal granularity to process the data for long-term and short-term analysis. We extract higher-level activity patterns which are then used to detect any change in patients' routines. We have also developed a hierarchical information fusion approach for detecting agitation, irritability and aggression. We have conducted evaluations using sensory data collected from homes of people with dementia. The proposed techniques are able to recognise agitation and unusual patterns with an accuracy of up to 80%.

Immune cell trafficking from the brain maintains CNS immune tolerance.

In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.

Functional analyses of lymphocytes and granulocytes isolated from the thymus, spiral valve intestine, spleen, and kidney of juvenile Australian lungfish, Neoceratodus forsteri.

Our current understanding of the lungfish immune system is limited. This study is characterizing the immune cells separated from primary and secondary immune organs of the Australian lungfish, Neoceratodus forsteri. Our functional studies utilized flow cytometry to study the immune cells extracted from the thymus, spiral valve intestine, spleen, and kidney. The different characteristics of lymphocytes and granulocytes were analyzed by utilization of viability, phagocytosis, oxidative burst, and apoptosis assays. Most of the nonviable intestinal cells were lymphocytes. Depending on the organ, 6-25% of the total population, predominantly granulocytes, underwent phagocytosis where the splenic cells were the most and intestinal cells the least phagocytic cells. Cells responded positively but differently to stimulation with phorbol myristate acetate (PMA) to produce radical oxygen species, an indication of their oxidative burst activity, which was mainly associated with granulocytes. Although cells were induced by dexamethasone to undergo apoptosis, such an induction did not follow a consistent pattern of dose of dexamethasone or incubation time between the different organs. In the absence of monoclonal antibodies against lungfish immune cells, these functional flow cytometric analyses aid our understanding on the functionality of immune cells.

Dendritic cells and multiple sclerosis: disease, tolerance and therapy.

Multiple sclerosis (MS) is a devastating neurological disease that predominantly affects young adults resulting in severe personal and economic impact. The majority of therapies for this disease were developed in, or are beneficial in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. While known to target adaptive anti-CNS immune responses, they also target, the innate immune arm. This mini-review focuses on the role of dendritic cells (DCs), the professional antigen presenting cells of the innate immune system. The evidence for a role for DCs in the appropriate regulation of anti-CNS autoimmune responses and their role in MS disease susceptibility and possible therapeutic utility are discussed. Additionally, the current controversy regarding the evidence for the presence of functional DCs in the normal CNS is reviewed. Furthermore, the role of CNS DCs and potential routes of their intercourse between the CNS and cervical lymph nodes are considered. Finally, the future role that this nexus between the CNS and the cervical lymph nodes might play in site directed molecular and cellular therapy for MS is outlined.