The Rationale for Radiation Therapy in Alzheimer's Disease.

Alzheimer's Disease (AD) represents a major health problem without effective treatments. As the incidence of the disease will continue to rise, it is imperative to find new treatment options to halt or slow disease progression. In recent years, several groups have begun to study the utility of low total dose radiation therapy (LTDRT) to inhibit some of the pathological features of AD and improve cognition in a variety of animal models. These preclinical studies have led to Phase 1 and 2 trials in different centers around the world. In this review, we present and interpret the pre-clinical evidence report some preliminary clinical data from a Phase 2 trial in early-stage AD patients.

Low-Dose Whole Brain Radiation Therapy for Alzheimer's Dementia: Results From a Pilot Trial in Humans.

PURPOSE: We report neurocognitive, imaging, ophthalmologic, and safety outcomes following low-dose whole brain radiation therapy (LD-WBRT) for patients with early Alzheimer dementia (eAD) treated in a pilot trial. METHODS AND MATERIALS: Trial-enrolled patients were at least 55 years of age, had eAD meeting NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) Alzheimer's Criteria with confirmatory fluorodeoxyglucose and florbetapir positron emission tomography findings; had the capacity to complete neurocognitive function, psychological function, and quality-of-life assessments; had a Rosen modified Hachinski score ≤4; and had estimated survival >12 months. RESULTS: Five patients were treated with LD-WBRT (2 Gy × 5 over 1 week; 3 female; mean age, 73.2 years [range, 69-77]). Four of 5 patients had improved (n = 3) or stable (n = 1) Mini-Mental State Examination (second edition) T-scores at 1 year. The posttreatment scores of all 3 patients who improved increased to the average range. There were additional findings of stability of naming and other cognitive skills as well as stability to possible improvement in imaging findings. No safety issues were encountered. The only side effect was temporary epilation with satisfactory hair regrowth. CONCLUSIONS: Our results from 5 patients with eAD treated with LD-WBRT (10 Gy in 5 fractions) demonstrate a positive safety profile and provide preliminary, hypothesis-generating data to suggest that this treatment stabilizes or improves cognition. These findings will require further evaluation in larger, definitive, randomized trials.

Roadmap for precision preclinical x-ray radiation studies.

This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined. Finally, clinical translation and reverse translation are discussed.

Investigation of the physiological response of radiation-induced cystitis patients using hyperbaric oxygen.

Introduction: In this pilot study we have taken a novel functional approach to assess whether differences exist in the activity of key genes involved in the response to radiation and oxidative stress between patients with radiation cystitis. Materials and methods: Arm 1 consisted of patients who had previously been treated for prostate cancer and who had received definitive radiation treatment and had subsequently developed cystitis and/or proctitis and were being treated by hyperbaric oxygen (HBO). Arm 2 consisted of patients who had never been treated by radiation but who were scheduled for HBO treatment for another pathology. The genes chosen for the study were HMOX1, NOS2, SOD2, TNFα, IL-6 and TGFß. Blood and urine was collected pre and post HBO treatment. Results: Gene expression showed a significant difference in NOS2 (p = 0.0178) and TNFα (p = 0.037) between the control and cystitis patients. The plasma levels of VEGF-A were significantly elevated in cystitis patients and there was a strong trend for significant overexpression in urine. Comparing pre and post-dive samples showed little difference in both groups of patients except for VEGF-A which was reduced after the dive in plasma from cystitis patients. Conclusions: This study uncovered some physiological differences in patients with radiation-induced cystitis using HBO treatment as a stimulus to induce mild oxidative stress. Further research is ongoing to assess whether the acute exposure to HBO might be a physiological screening tool to identify patients susceptible to chronic radiation toxicity.

Intratumoural haematopoietic stem and progenitor cell differentiation into M2 macrophages facilitates the regrowth of solid tumours after radiation therapy.

BACKGROUND: Bone-marrow-derived haematopoietic stem and progenitor cells (HSPCs) are a prominent part of the highly complex tumour microenvironment (TME) where they localise within tumours and maintain haematopoietic potency. Understanding the role HSPCs play in tumour growth and response to radiation therapy (RT) may lead to improved patient treatments and outcomes. METHODS: We used a mouse model of non-small cell lung carcinoma where tumours were exposed to RT regimens alone or in combination with GW2580, a pharmacological inhibitor of colony stimulating factor (CSF)-1 receptor. RT-PCR, western blotting and immunohistochemistry were used to quantify expression levels of factors that affect HSPC differentiation. DsRed+ HSPC intratumoural activity was tracked using flow cytometry and confocal microscopy. RESULTS: We demonstrated that CSF-1 is enhanced in the TME following exposure to RT. CSF-1 signaling induced intratumoural HSPC differentiation into M2 polarised tumour-associated macrophages (TAMs), aiding in post-RT tumour survival and regrowth. In contrast, hyperfractionated/pulsed radiation therapy (PRT) and GW2580 ablated this process resulting in improved tumour killing and mouse survival. CONCLUSIONS: Tumours coopt intratumoural HSPC fate determination via CSF-1 signaling to overcome the effects of RT. Thus, limiting intratumoural HSPC activity represents an attractive strategy for improving the clinical treatment of solid tumours.

Correlation between tumor voxel dose response matrix and tumor biomarker profile in patients with head and neck squamous cell carcinoma.

BACKGROUND: We have developed a novel imaging analysis procedure that is highly predictive of local failure after chemoradiation in head and neck cancer. In this study we investigated whether any pretreatment biomarkers correlated with key imaging parameters. METHODS: Pretreatment biopsy material was available for 28 patients entered into an institutional trial of adaptive radiotherapy in which FDG-PET images were collected weekly during treatment. The biopsies were immunohistochemically stained for CD44, EGFR, GLUT1, ALDH1, Ki-67 and p53 and quantified using image analysis. Expression levels were correlated with previously derived imaging parameters, the pretreatment SUVmax and the dose response matrix (DRM). RESULTS: The different parameters of the SUVmax and DRM did not correlate with each other. We observed a positive and highly significant (p = 0.0088) correlation between CD44 expression and volume of tumor with a DRM greater than 0.8. We found no correlation between any DRM parameter and GLUT1, p53, Ki-67 and EGFR or ALDH1. GLUT1 expression did correlate with the maximum SUV0 and the volume of tumor with an SUV0 greater than 20. CONCLUSIONS: The pretreatment SUVmax and DRM are independent imaging parameters that combine to predict local recurrence. The significant correlation between CD44 expression, a known cancer stem cell (CSC) marker, and volume of tumor with a DRM greater than 0.8 is consistent with concept that specific foci of cells are responsible for tumor recurrence and that CSCs may be randomly distributed in tumors in specific niches. Dose painting these small areas may lead to improved tumor control.

A new genus and species of groundwater isopod of the family Protojaniridae (Isopoda: Asellota: Gnathostenetroidoidea) from southern Chile.

A new asellotan isopod of the family Protojaniridae Fresi, Idato Scipione, 1980 is described from freshwater springs in the Osorno province, Los Lagos region, southern Chile. Wiyufiloides osornoensis gen. sp. n. is the third South American protojanirid species and the first known groundwater isopod in Chile. The new genus and species is principally characterized by the presence of a vestigial antennal scale, a strongly subchelate pereiopod I and the absence of an apical lobe on the protopod of pleopod II. The new taxon is described in detail and figures are given.

Redescriptions and new species in the 'emAustrosignum/em-Munnogonium' complex sensu Just amp; Wilson (2007), mainly from the Southern Hemisphere (Crustacea: Isopoda: Paramunnidae).

Type material is used to illustrate and redescribe the following species in the paramunnid Austrosignum-Munnogonium complex (classification sensu Just and Wilson 2007): Cryosignum incisum (Richardson, 1908), Cryosignum latifrons (Menzies, 1962) comb. nov., Meridiosignum kerguelensis (Vanhöffen, 1914), Munnogonium falklandicum (Nordenstam, 1933), Munnogonium globifrons (Menzies, 1962), and Munnogonium tillerae (Menzies Barnard, 1959,-topotypes). In addition, seven new species in the complex are described, Austrosignum pilosum, Austrosignum latum, Cryosignum nordenstami, Meridiosignum convexum, Meridiosignum macquariensis, Munnogonium longicaudatum, and Tethygonium monocuspis. Boreosignum Just and Wilson, 2007 is reported from Australia for the first time as Boreosignum specimens.                Keys to species in Austrosignum, Cryosignum, Meridiosignum, Munnogonium and Tethygonium are given. A summary of distribution with a list of all species in the complex including occurrence is presented.

Artificial intelligence and leukocyte epigenomics: Evaluation and prediction of late-onset Alzheimer's disease.

We evaluated the utility of leucocyte epigenomic-biomarkers for Alzheimer's Disease (AD) detection and elucidates its molecular pathogeneses. Genome-wide DNA methylation analysis was performed using the Infinium MethylationEPIC BeadChip array in 24 late-onset AD (LOAD) and 24 cognitively healthy subjects. Data were analyzed using six Artificial Intelligence (AI) methodologies including Deep Learning (DL) followed by Ingenuity Pathway Analysis (IPA) was used for AD prediction. We identified 152 significantly (FDR p<0.05) differentially methylated intragenic CpGs in 171 distinct genes in AD patients compared to controls. All AI platforms accurately predicted AD with AUCs ≥0.93 using 283,143 intragenic and 244,246 intergenic/extragenic CpGs. DL had an AUC = 0.99 using intragenic CpGs, with both sensitivity and specificity being 97%. High AD prediction was also achieved using intergenic/extragenic CpG sites (DL significance value being AUC = 0.99 with 97% sensitivity and specificity). Epigenetically altered genes included CR1L & CTSV (abnormal morphology of cerebral cortex), S1PR1 (CNS inflammation), and LTB4R (inflammatory response). These genes have been previously linked with AD and dementia. The differentially methylated genes CTSV & PRMT5 (ventricular hypertrophy and dilation) are linked to cardiovascular disease and of interest given the known association between impaired cerebral blood flow, cardiovascular disease, and AD. We report a novel, minimally invasive approach using peripheral blood leucocyte epigenomics, and AI analysis to detect AD and elucidate its pathogenesis.

Association of human papillomavirus integration with better patient outcomes in oropharyngeal squamous cell carcinoma.

BACKGROUND: The molecular drivers of human papillomavirus-related head and neck squamous cell carcinoma (HPV + HNSCC) are not entirely understood. This study evaluated the relationship between HPV integration, expression of E6/E7, and patient outcomes in p16+ HNSCCs. METHODS: HPV type was determined by HPV PCR-MassArray, and integration was called using detection of integrated papillomavirus sequences polymerase chain reaction (PCR). We investigated whether fusion transcripts were produced by reverse transcriptase polymerase chain reaction (RT-PCR). E6/E7 expression was assessed by quantitative RT-PCR. We assessed if there was a relationship between integration and E6/E7 expression, clinical variables, or patient outcomes. RESULTS: Most samples demonstrated HPV integration, which sometimes resulted in a fusion transcript. HPV integration was positively correlated with age at diagnosis and E6/E7 expression. There was a significant difference in survival between patients with vs without integration. CONCLUSIONS: Contrary to previous reports, HPV integration was associated with improved patient survival. Therefore, HPV integration may act as a molecular marker of good prognosis.

Dacomitinib and gedatolisib in combination with fractionated radiation in head and neck cancer.

BACKGROUND AND PURPOSE: There has been little success targeting individual genes in combination with radiation in head and neck cancer. In this study we investigated whether targeting two key pathways simultaneously might be more effective. MATERIALS AND METHODS: We studied the effect of combining dacomitinib (pan-HER, irreversible inhibitor) and gedatolisib (dual PI3K/MTOR inhibitor) with radiation in well characterized, low passage xenograft models of HNSCC in vitro and in vivo. RESULTS: Dacomitinib showed differential growth inhibition in vitro that correlated to EGFR expression whilst gedatolisib was effective in both cell lines. Neither agent radiosensitized the cell lines in vitro. In vivo studies demonstrated that dacomitinib was an effective agent alone and in combination with radiation whilst the addition of gedatolisib did not enhance the effect of these two modalities despite inhibiting phosphorylation of key genes in the PI3K/MTOR pathway. CONCLUSIONS: Our results showed that combining two drugs with radiation provided no added benefit compared to the single most active drug. Dacomitinib deserves more investigation as a radiation sensitizing agent in HNSCC.

Pulsed radiation therapy for the treatment of newly diagnosed glioblastoma.

BACKGROUND: Pulsed radiation therapy (PRT) has shown effective tumor control and superior normal-tissue sparing ability compared with standard radiotherapy (SRT) in preclinical models and retrospective clinical series. This is the first prospective trial to investigate PRT in the treatment of patients with newly diagnosed glioblastoma (GBM). METHODS: This is a single-arm, prospective study. Patients with newly diagnosed GBM underwent surgery, followed by 60 Gy of PRT with concurrent temozolomide (TMZ). Each day, a 2-Gy fraction was divided into ten 0.2-Gy pulses, separated by 3-minute intervals. Patients received maintenance TMZ. Neurocognitive function (NCF) and quality of life (QoL) were monitored for 2 years using the Hopkins Verbal Learning Test‒Revised and the European Organisation for Research and Treatment of Cancer QLQ-C30 QoL questionnaire. Change in NCF was evaluated based on a minimal clinically important difference (MCID) threshold of 0.5 standard deviation. RESULTS: Twenty patients were enrolled with a median follow-up of 21 months. Median age was 60 years. Forty percent underwent subtotal resection, and 60% underwent gross total resection. One patient had an isocitrate dehydrogenase (IDH)-mutated tumor. Median progression-free survival (PFS) and overall survival (OS) were 10.7 and 20.9 months, respectively. In a post-hoc comparison, median OS for the prospective cohort was longer, compared with a matched cohort receiving SRT (20.9 vs 14 mo, P = 0.042). There was no decline in QoL, and changes in NCF scores did not meet the threshold of an MCID. CONCLUSIONS: Treatment of newly diagnosed GBM with PRT is feasible and produces promising effectiveness while maintaining neurocognitive function and QoL. Validation of our results in a larger prospective trial warrants consideration.

The Eophreatoicus Nicholls, 1926 species flock from Kakadu and Arnhem Land, with a description of a new genus of Amphisopidae (Crustacea : Isopoda : Phreatoicidea).

We present descriptions of 28 new species of Amphisopidae from Arnhem Land and Kakadu National Park of Australia's Northern Territory. We identified five additional species that are not yet fully characterized and are not provided with formal species recognition. This is the first taxonomic treatment highlighting the high species richness within the Phreatoicidea that occur in Australia and likely elsewhere. We document each species fully with scanning electron and light micrographic images, diagnoses, detailed descriptions, keys to identification and justification of each species using parsimony analysis of their morphological and genetic characters. The distributional data show that all species, except for one, have microendemic distributions, with some sibling species occurring within a few kilometers of each other. Because of the age of this group of species, they appear to have spread throughout the region of the Arnhem sandstone plateau and then back-colonized the same habitats so that as many as three morphologically and genetically distinct species may co-occur syntopically. Our research has uncovered a new genus-level taxon of the family Amphisopidae, Kakadubeh gen. nov. This new genus is unlike Eophreatoicus, not only in its general appearance, but also in having an inferred reproductive strategy different from most of the other members of the family. While Eophreatoicus species have males that are much larger than the females and practice precopula, a form of pre-insemination mate guarding, males of the new species, Kakadubeh rangemyahwurd sp. nov., are much smaller than females. In addition, males of this species have a fourth walking leg that is not specialized for holding females, suggesting that they have a reproductive strategy that does not involve precopula of the form seen in Eophreatoicus and Eremisopus Wilson Keable, 2002a. Most of our research has been undertaken in Kakadu National Park, although recent collections have been made in Arnhem Land, yielding additional distinctive species. Given the size of unexplored territory around the Arnhem Plateau and the geographic frequency of discovering new species, we predict that the diversity of this group in the Northern Territory may be many more than the ~35 species described here. At this time, these microendemic isopods appear to be unthreatened by human activities, largely owing to the environmental protection afforded by Kakadu National Park and Arnhem Land, and their cryptic habits during the dry season. Because they are dependent on small springs of permanent groundwater, future changes in hydrology owing to water use and climate change, as well as invasive introduced species, may present risks to populations and species.

Effect of uncertainties in quantitative 18 F-FDG PET/CT imaging feedback for intratumoral dose-response assessment and dose painting by number.

PURPOSE: Intratumoral dose response can be detected using serial fluoro-2-deoxyglucose-(FDG) positron emission tomography (PET)/computed tomography (CT) imaging feedback during treatment and used to guide adaptive dose painting by number (DPbN). However, to reliably implement this technique, the effect of uncertainties in quantitative PET/CT imaging feedback on tumor voxel dose-response assessment and DPbN needs to be determined and reduced. METHODS: Three major uncertainties, induced by (a) PET imaging partial volume effect (PVE) and (b) tumor deformable image registration (DIR), and (c) variation of the time interval between FDG injection and PET image acquisition (TI), were determined using serial FDG-PET/CT images acquired during chemoradiotherapy of 18 head and neck cancer patients. PET imaging PVE was simulated using the discrepancy between with and without iterative deconvolution-based PVE corrections. Effect of tumor DIR uncertainty was simulated using the discrepancy between two DIR algorithms, including one with and one without soft-tissue mechanical correction for the voxel displacement. The effect of TI variation was simulated using linear interpolation on the dual-point PET/CT images. Tumor voxel pretreatment metabolic activity (SUV0 ) and dose-response matrix (DRM) discrepancies induced by each of the three uncertainties were quantified, respectively. Adverse effects of tumor voxel SUV0 and DRM discrepancies on tumor control probability (TCP) in DPbN were assessed. RESULTS: Partial volume effect and TI variations of 10 mins induced a mean ± standard deviation (SD) of tumor voxel SUV0 discrepancies to be -0.7% ± 9.2% and 0% ± 4.8%, respectively. Tumor voxel DRM discrepancies induced by PVE, tumor DIR discrepancy, and TI variations were 0.6% ± 8.9%, 1.7% ± 9.1%, and 0% ± 7%, respectively. Partial volume effect induced SUV0 and DRM discrepancies correlated significantly with the tumor shape and FDG uptake heterogeneity. Tumor DIR uncertainty-induced DRM discrepancy correlated significantly with the tumor volume and shrinkage during treatment. Among the three uncertainties, PVE dominated the adverse effects on the TCP, with a mean ± SD of TCP reduction to be 12.7% ± 9.8% for all tumors if no compensation was applied for. CONCLUSIONS: Effect of uncertainties in quantitative FDG-PET/CT imaging feedback on intratumoral dose-response quantification was not negligible. These uncertainties primarily caused by PVE and tumor DIR were highly dependent on individual tumor shape, volume, shrinkage during treatment, and pretreatment SUV heterogeneity, which can be managed individually. The adverse effects of these uncertainties could be minimized by using proper PVE corrections and DIR methods and compensated for in the clinical implementation of DPbN.

Low Dose Brain Irradiation Reduces Amyloid-ß and Tau in 3xTg-AD Mice.

We have previously reported that low doses of external beam ionizing irradiation reduced amyloid-ß (Aß) plaques and improved cognition in APP/PS1 mice. In this study we investigated the effects of radiation in an age-matched series of 3xTg-AD mice. Mice were hemibrain-irradiated with 5 fractions of 2 Gy and sacrificed 8 weeks after the end of treatment. Aß and tau were assessed using immunohistochemistry and quantified using image analysis with Definiens Tissue Studio. We observed a significant reduction in Aß plaque burden and tau staining; these two parameters were significantly correlated. This preliminary data is further support that low doses of radiation may be beneficial in Alzheimer's disease.

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation.

BACKGROUND: The mechanistic target of rapamycin (MTOR) plays a key role in regulating cell growth and metabolism and is commonly overexpressed in head and neck cancer (HNSCC). This study investigated the association of MTOR with clinical outcome in human papilloma virus (HPV) positive and negative HNSCC patients treated by chemoradiation. METHODS: A tissue microarray (TMA) consisting of cores from 109 HNSCC patients treated by definitive chemoradiation was constructed and stained with antibodies against p16 and MTOR and expression correlated with clinicopathological features and clinical outcome. RESULTS: MTOR varied widely between tumor cores and was not associated with HPV status or clinicopathological features. There was a positive correlation with pre-treatment FDG uptake. (P = .01). In HPV negative patients, MTOR predicted for shorter locoregional control (P = .02), diseases free survival (P = .02), and overall survival (P = .04). MTOR expression was not associated with outcome in HPV positive patients. CONCLUSIONS: Prognostic significance of MTOR expression depends on HPV status.