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Purpose: There is limited knowledge about the associations between sodium and proton MRI measurements in brain tumors. The purpose of this study was to quantify intra- and intertumoral correlations between sodium, diffusion, and perfusion MRI in human gliomas. Methods: Twenty glioma patients were prospectively studied on a 3T MRI system with multinuclear capabilities. Three mutually exclusive tumor volumes of interest (VOIs) were segmented: contrast-enhancing tumor (CET), T2/FLAIR hyperintense non-enhancing tumor (NET), and necrosis. Median and voxel-wise associations between apparent diffusion coefficient (ADC), normalized relative cerebral blood volume (nrCBV), and normalized sodium measurements were quantified for each VOI. Results: Both relative sodium concentration and ADC were significantly higher in areas of necrosis compared to NET (P = 0.003 and P = 0.008, respectively) and CET (P = 0.02 and P = 0.02). Sodium concentration was higher in CET compared to NET (P = 0.04). Sodium and ADC were higher in treated compared to treatment-naïve gliomas within NET (P = 0.006 and P = 0.01, respectively), and ADC was elevated in CET (P = 0.03). Median ADC and sodium concentration were positively correlated across patients in NET (r = 0.77, P < 0.0001) and CET (r = 0.84, P < 0.0001), but not in areas of necrosis (r = 0.45, P = 0.12). Median nrCBV and sodium concentration were negatively correlated across patients in areas of NET (r=-0.63, P = 0.003). Similar associations were observed when examining voxel-wise correlations within VOIs. Conclusion: Sodium MRI is positively correlated with proton diffusion MRI measurements in gliomas, likely reflecting extracellular water. Unique areas of multinuclear MRI contrast may be useful in future studies to understand the chemistry of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Context: Diclofenac is commonly used as pain relief. Hypoglycemia has rarely been reported due to aspirin and indomethacin use but not of any other nonsteroidal anti-inflammatory drugs. Case report: A 69-years old endocrinologist participated as a control in a glucagon-like peptide-1 (GLP-1) study. He decreased his plasma glucose to 1.8 mmol/L and developed full-blown hypoglycemic symptoms during an oral glucose tolerance test (OGTT). He had taken a 50 mg diclofenac tablet at 10 pm the evening before for a harmless muscle stretch in the lower back. Apart from well-controlled hypothyroidism he was healthy. During medical school he often had reactive hypoglycemia which came after intake of a carbohydrate rich but otherwise poor breakfast followed by bicycling. However, he had never experienced problems later in life after more decent meals containing slower absorbable carbohydrates. A 3-day continuous glucose monitoring (CGM) was performed three weeks after the OGTT test. A glucose value of 3.1 mmol/L was registered on the third CGM day in the afternoon after intake of 500 mg aspirin in the early morning the same day. Otherwise, all values were normal. A second OGGT where no medications apart from levothyroxine had been taken during at least a 2-week period adjacent was normal. Detailed analyses of the OGTTs showed that the GLP-1 levels before the test were higher after diclofenac exposure while the insulin levels increased after the glucose challenge which suggesting uncoupling. Conclusion: With this case report we would like to draw attention to that diclofenac may cause hypoglycemia. [ABSTRACT FROM AUTHOR]

Glioblastomas remain the most lethal primary brain tumors. Natural killer (NK) cell-based therapy is a promising immunotherapeutic strategy in the treatment of glioblastomas, since these cells can select and lyse therapy-resistant glioblastoma stem-like cells (GSLCs). Immunotherapy with super-charged NK cells has a potential as antitumor approach since we found their efficiency to kill patient-derived GSLCs in 2D and 3D models, potentially reversing the immunosuppression also seen in the patients. In addition to their potent cytotoxicity, NK cells secrete IFN-γ, upregulate GSLC surface expression of CD54 and MHC class I and increase sensitivity of GSLCs to chemotherapeutic drugs. Moreover, NK cell localization in peri-vascular regions in glioblastoma tissues and their close contact with GSLCs in tumorospheres suggests their ability to infiltrate glioblastoma tumors and target GSLCs. Due to GSLC heterogeneity and plasticity in regards to their stage of differentiation personalized immunotherapeutic strategies should be designed to effectively target glioblastomas. "Super-charged" NK cells kill patient-derived glioblastoma stem-like cells (GSLCs) in 2D and 3D tumor models, secrete IFN-γ and upregulate the surface expression of CD54 and MHC class I in GSLCs. [ABSTRACT FROM AUTHOR]

Primary brain tumors, such as glioblastoma (GBM), are remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, here we take advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 blockade increases T cell infiltration and the proportion of a progenitor exhausted population of T cells found within the tumor. We identify an early activated and clonally expanded CD8+ T cell cluster whose TCR overlaps with a CD8+ PBMC population. Distinct changes are also observed in conventional type 1 dendritic cells that may facilitate T cell recruitment. Macrophages and monocytes still constitute the majority of infiltrating immune cells, even after anti-PD-1 therapy. Interferon-mediated changes in the myeloid population are consistently observed following PD-1 blockade; these also mediate an increase in chemotactic factors that recruit T cells. However, sustained high expression of T-cell-suppressive checkpoints in these myeloid cells continue to prevent the optimal activation of the tumor infiltrating T cells. Therefore, future immunotherapeutic strategies may need to incorporate the targeting of these cells for clinical benefit. Immune-checkpoint blockade has shown limited benefits in patients with glioblastoma. To understand how the composition of the tumor immune microenvironment might limit clinical responses, here the authors present a high dimensional profiling of the immune landscape in patients with glioblastoma following neoadjuvant PD-1 checkpoint blockade. [ABSTRACT FROM AUTHOR]

Objective: To develop a robust amine chemical exchange saturation transfer (CEST) physical phantom, validate the temporal stability, and create a supporting software for automatic image processing and quality assurance. Materials and methods: The phantom was designed as an assembled laser-cut acrylic rack and 18 vials of phantom solutions, prepared with different pHs, glycine concentrations, and gadolinium concentrations. We evaluated glycine concentrations using ultraviolet absorbance for 70 days and measured the pH, relaxation rates, and CEST contrast for 94 days after preparation. We used Spearman's correlation to determine if glycine degraded over time. Linear regression and Bland–Altman analysis were performed between baseline and follow-up measurements of pH and MRI properties. Results: No degradation of glycine was observed (p > 0.05). The pH and MRI measurements stayed stable for 3 months and showed high consistency across time points (R2 = 1.00 for pH, R1, R2, and CEST contrast), which was further validated by the Bland–Altman plots. Examples of automatically generated reports are provided. Discussion: We designed a physical phantom for amine CEST-MRI, which is easy to assemble and transfer, holds 18 different solutions, and has excellent short-term chemical and MRI stability. We believe this robust phantom will facilitate the development of novel sequences and cross-scanners validations. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this work was to evaluate changes in glycaemic control (HbA1c) and rates of severe hypoglycaemia over a 2 year period after initiation of flash glucose monitoring (FM) in type 1 diabetes. Methods: Using data from the Swedish National Diabetes Registry, 14,372 adults with type 1 diabetes with a new registration of FM during 2016–2017 and with continued FM for two consecutive years thereafter, and 7691 control individuals using conventional self-monitoring of blood glucose (SMBG) during the same observation period, were included in a cohort study. Propensity sores and inverse probability of treatment weighting (IPTW) were used to balance FM users with SMBG users. Changes in HbA1c and events of severe hypoglycaemia were compared. Results: After the start of FM, the difference in IPTW change in HbA1c was slightly greater in FM users compared with the control group during the follow-up period, with an estimated mean absolute difference of −1.2 mmol/mol (−0.11%) (95% CI −1.64 [−0.15], −0.75 [−0.07]; p < 0.0001) after 15–24 months. The change in HbA1c was greatest in those with baseline HbA1c ≥70 mmol/mol (8.5%), with the estimated mean absolute difference being −2.5 mmol/mol (−0.23%) (95% CI −3.84 [−0.35], −1.18 [−0.11]; p = 0.0002) 15–24 months post index. The change was also significant in the subgroups with initial HbA1c ≤52 mmol/mol (6.9%) and 53–69 mmol/mol (7.0–8.5%). Risk of severe hypoglycaemic episodes was reduced by 21% for FM users compared with control individuals using SMBG (OR 0.79 [95% CI 0.69, 0.91]; p = 0.0014)]. Conclusions/interpretation: In this large cohort, the use of FM was associated with a small and sustained improvement in HbA1c, most evident in those with higher baseline HbA1c levels. In addition, FM users experienced lower rates of severe hypoglycaemic events compared with control individuals using SMBG for self-management of glucose control. [ABSTRACT FROM AUTHOR]

Purpose: Epidermal growth factor receptor (EGFR) amplification promotes gliomagenesis and is linked to lack of oxygen within the tumor microenvironment. Using hypoxia-sensitive spin-and-gradient echo echo-planar imaging and perfusion MRI, we investigated the influence of EGFR amplification on tissue oxygen availability and utilization in human gliomas. Methods: This study included 72 histologically confirmed EGFR-amplified and non-amplified glioma patients. Reversible transverse relaxation rate (R2′), relative cerebral blood volume (rCBV), and relative oxygen extraction fraction (rOEF) were calculated for the contrast-enhancing and non-enhancing tumor regions. Using Student t test or Wilcoxon rank-sum test, median R2′, rCBV, and rOEF were compared between EGFR-amplified and non-amplified gliomas. ROC analysis was performed to assess the ability of imaging characteristics to discriminate EGFR amplification status. Overall survival (OS) was determined using univariate and multivariate cox models. Kaplan-Meier survival curves were plotted and compared using the log-rank test. Results: EGFR amplified gliomas exhibited significantly higher median R2′ and rOEF than non-amplified gliomas. ROC analysis suggested that R2′ (AUC = 0.7190; P = 0.0048) and rOEF (AUC = 0.6959; P = 0.0156) could separate EGFR status. Patients with EGFR-amplified gliomas had a significantly shorter OS than non-amplified patients. Univariate cox regression analysis determined both R2′ and rOEF significantly influence OS. No significant difference was observed in rCBV between patient cohorts nor was rCBV found to be an effective differentiator of EGFR status. Conclusion: Imaging of tumor oxygen characteristics revealed EGFR-amplified gliomas to be more hypoxic and contribute to shorter patient survival than EGFR non-amplified gliomas. [ABSTRACT FROM AUTHOR]

Purpose: Several studies have reported an association between hyponatremia and lethality. However, it remains elusive whether hyponatremia independently contributes to lethality. The aim of the study was to investigate associations between hyponatremia and lethality and differences in lethality between men and women hospitalized due to hyponatremia. Methods: Four registries were utilized in this population-based retrospective study: The National Patient Registry, the Cause of Death Register, the Swedish Prescribed Drug Register and the Total Population Register (NPR) from which the controls were sampled. All hospitalized patients with a first-ever principal ICD10 diagnosis of hyponatremia or syndrome of inappropriate ADH secretion in the NPR between 1 October 2005 and 31 December 2014 were defined as cases. Cox regression with adjustment for potential confounders was used. Results: 14,359 individuals with a principal diagnosis of hyponatremia, and 57,382 matched controls were identified. Median age was 76 years and the majority were women (72%). Median age for women and men was 79 and 68 years, respectively. Adjusted hazard ratios (and 95% CI) for lethality in those with hyponatremia compared with controls were for the entire population 5.5 (4.4–7.0) and in the subgroup free from previously known underlying disease 6.7 (3.3–13.3). Lethality in women with hyponatremia was lower compared with men: HR: 0.56 (0.49–0.64). In the healthier group the lethality remained lower for women: HR: 0.49 (0.34–0.71). Conclusions: Patients hospitalized due to hyponatremia faced an increased subsequent lethality that was independent of concomitant disease. This increase was nearly twice as large among men compared with women. [ABSTRACT FROM AUTHOR]

Purpose: Radiotherapy (RT) constitutes an important part of breast cancer treatment. However, triple negative breast cancers (TNBC) exhibit remarkable resistance to most therapies, including RT. Developing new ways to radiosensitize TNBC cells could result in improved patient outcomes. The M2 isoform of pyruvate kinase (PK-M2) is believed to be responsible for the re-wiring of cancer cell metabolism after oxidative stress. The aim of the study was to determine the effect of ionizing radiation (IR) on PK-M2-mediated metabolic changes in TNBC cells, and their survival. In addition, we determine the effect of PK-M2 activators on breast cancer stem cells, a radioresistant subpopulation of breast cancer stem cells. Methods: Glucose uptake, lactate production, and glutamine consumption were assessed. The cellular localization of PK-M2 was evaluated by western blot and confocal microscopy. The small molecule activator of PK-M2, TEPP46, was used to promote its pyruvate kinase function. Finally, effects on cancer stem cell were evaluated via sphere forming capacity. Results: Exposure of TNBC cells to IR increased their glucose uptake and lactate production. As expected, PK-M2 expression levels also increased, especially in the nucleus, although overall pyruvate kinase activity was decreased. PK-M2 nuclear localization was shown to be associated with breast cancer stem cells, and activation of PK-M2 by TEPP46 depleted this population. Conclusions: Radiotherapy can induce metabolic changes in TNBC cells, and these changes seem to be mediated, at least in part by PK-M2. Importantly, our results show that activators of PK-M2 can deplete breast cancer stem cells in vitro. This study supports the idea of combining PK-M2 activators with radiation to enhance the effect of radiotherapy in resistant cancers, such as TNBC. [ABSTRACT FROM AUTHOR]

Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The global diabetes epidemic affects countries differently. We aimed to describe trends in the incidence and prevalence of type 2 diabetes mellitus requiring glucose-lowering treatment, together with associated life expectancy and risks of significant clinical complications. Methods: Data on patients with type 2 diabetes who filled a prescription for any glucose-lowering drug (GLD) during the period 2006-2013 were extracted from the Swedish Prescribed Drug Register, Cause of Death Register and Swedish National Patient Register. Results: In 2013, the prevalence of GLD-treated type 2 diabetes was 4.4% ( n = 352,436) and the incidence was 399 per 100,000 population ( n = 30,620). During 2006-2013, the prevalence increased by 61% while the incidence remained relatively stable; the prevalence of cardiovascular disease (CVD, 34% in 2013) and microvascular disease (16% in 2013) was also stable. Insulin use increased by 29% while sulfonylurea use declined by 55%. Compared with the general population, patients with type 2 diabetes had increased risk of myocardial infarction, stroke and all-cause mortality, with age-standardised risks of ∼1.7-, 1.5- and 1.3-fold, respectively. These risks declined over time. Life-years lost due to diabetes was most pronounced at younger ages and improved in women over time from 2006 to 2013. Conclusions/interpretation: The prevalence of type 2 diabetes requiring GLD treatment in Sweden increased substantially in recent years, while the incidence remained stable. Use of sulfonylurea declined while insulin use increased. The high prevalence of diabetes-related comorbidities, increased risk of complications and life-years lost highlights the need for optimised and new preventive strategies in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Cryoablation is a well-established technique to treat fibroadenomas. Pilot studies suggest this could be an effective non-surgical treatment for breast cancer. American College of Surgeons Oncology Group Z1072 is a phase II trial exploring the effectiveness of cryoablation in the treatment of breast cancers. Methods: The primary endpoint of Z1072 was the rate of complete tumor ablation, defined as no remaining invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) on pathologic examination of the targeted lesion. A secondary objective was to evaluate the negative predictive value of magnetic resonance imaging (MRI) to determine residual IBC or DCIS. Eligible patients included those with unifocal invasive ductal breast cancer ≤2 cm, with <25 % intraductal component and tumor enhancement on MRI. A total of 19 centers contributed 99 patients, of which 86 patients (87 breast cancers) were evaluable for data analysis. Results: Final pathology results, regardless of whether residual IBC/DCIS was in the targeted ablation zone or elsewhere in the breast, showed successful ablation in 66/87 (75.9 %) cancers. The 90 % confidence interval for the estimate of successful cryoablation was 67.1-83.2, with the one-sided lower-sided 90 % CI of 69.0. The negative predictive value of MRI was 81.2 % (90 % CI 71.4-88.8). When multifocal disease outside of the targeted cryoablation zone was not defined as an ablation failure, 80/87 (92 %) of the treated cancers had a successful cryoablation. Conclusion: Further studies with modifications on the Z1072 protocol could be considered to evaluate the role for cryoablation as a non-surgical treatment of early-stage breast cancer. [ABSTRACT FROM AUTHOR]

Malignant gliomas are intractable and among the most lethal human malignancies. Like other cancers, metabolic reprogramming is a key feature of glioma and is thought to accommodate the heightened nutrient requirements for tumor cell proliferation, growth, and survival. This metabolic rewiring, driven by oncogenic signaling and molded by the unique environment of the brain, may impose vulnerabilities that could be exploited therapeutically for increased tumor control. In this review, we discuss the prominent metabolic features of malignant glioma, the key pathways regulating glioma metabolism, and the potential therapeutic opportunities for targeting metabolic processes. [ABSTRACT FROM AUTHOR]

Stroke is the leading cause of adult disability in Westernized societies with increased incidence along ageing and it represents a major health and economical threat. Inactive lifestyle, smoking, hypertension, atherosclerosis, obesity and diabetes all dramatically increase the risk of stroke. While preventive strategies based on lifestyle changes and risk factor management can delay or decrease the likelihood of having a stroke, post stroke pharmacological strategies aimed at minimizing stroke-induced brain damage are highly needed. Unfortunately, several candidate drugs that have shown significant preclinical neuroprotective efficacy, have failed in clinical trials and no treatment for stroke based on neuroprotection is available today. Glucagon-like peptide 1 (GLP-1) is a peptide originating in the enteroendocrine L-cells of the intestine and secreted upon nutrient ingestion. The activation of the GLP-1R by GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon secretion and exerts multifarious extrapancreatic effects. Stable GLP-1 analogues and inhibitors of the proteolytic enzyme dipeptidyl peptidase 4 (DPP-4) (which counteract endogenous GLP-1 degradation) have been developed clinically for the treatment of type 2 diabetes. Besides their antidiabetic properties, experimental evidence has shown neurotrophic and neuroprotective effects of GLP-1R agonists and DPP-4 inhibitors in animal models of neurological disorders. Herein, we review recent experimental data on the neuroprotective effects mediated by GLP-1R activation in stroke. Due to the good safety profile of the drugs targeting the GLP-1R, we also discuss the high potential of GLP-1R stimulation in view of developing a safe clinical treatment against stroke based on neuroprotection in both diabetic and non-diabetic patients. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADCL values, the average ADC in the lower distribution using a double Gaussian mixed model. ADCL values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADCL tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADCL levels and DCN protein expression between tumors (Pearson R2 = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R2 = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADCL on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM. [ABSTRACT FROM AUTHOR]

To evaluate the association between a vessel size index (VSIMRI) derived from dynamic susceptibility contrast (DSC) perfusion imaging using a custom spin-and-gradient echo echoplanar imaging (SAGE-EPI) sequence and quantitative estimates of vessel morphometry based on immunohistochemistry from image-guided biopsy samples. The current study evaluated both relative cerebral blood volume (rCBV) and VSIMRI in eleven patients with high-grade glioma (7 WHO grade III and 4 WHO grade IV). Following 26 MRI-guided glioma biopsies in these 11 patients, we evaluated tissue morphometry, including vessel density and average radius, using an automated procedure based on the endothelial cell marker CD31 to highlight tumor vasculature. Measures of rCBV and VSIMRI were then compared to histological measures. We demonstrate good agreement between VSI measured by MRI and histology; VSIMRI = 13.67 μm and VSIHistology = 12.60 μm, with slight overestimation of VSIMRI in grade III patients compared to histology. rCBV showed a moderate but significant correlation with vessel density (r = 0.42, p = 0.03), and a correlation was also observed between VSIMRI and VSIHistology (r = 0.49, p = 0.01). The current study supports the hypothesis that vessel size measures using MRI accurately reflect vessel caliber within high-grade gliomas, while traditional measures of rCBV are correlated with vessel density and not vessel caliber. [ABSTRACT FROM AUTHOR]