Abstract BACKGROUND MR-guided Laser Interstitial Thermal Therapy (MRgLITT) is a minimally invasive neurosurgical treatment that was recently introduced in Europe for managing newly diagnosed and recurrent gliomas, as well as drug-resistant epilepsy (DRE). Emerging research suggests that MRgLITT facilitates localized disruption of the blood-brain barrier (BBB) surrounding the lesion. In this study, we investigated the effects of MRgLITT on BBB permeability using perfusion MRI and biochemical markers. MATERIAL AND METHODS Twenty-five patients referred for MRgLITT were prospectively included: 12 with brain tumors and 13 with DRE. To assess the integrity of the BBB, we employed Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) one day preoperatively, and on days 1, 15, 30, and 45 postoperatively. Concurrently, we collected blood samples at these time points to evaluate biomarkers indicative of BBB integrity and circulating tumor DNA. RESULTS Quantitative analysis using DCE-MRI revealed a significant postoperative increase in regional BBB permeability on days 15, 30, and 45 (p < 0.005), as measured by the permeability constant (Ki) in both patient groups. However, no significant change in permeability was observed on the first postoperative day. Permeability reached its maximum between days 15 and 30 following MRgLITT and remained high on day 45, at 70% of the maximum. CONCLUSIONS Our findings confirm the existence of a therapeutic window lasting several weeks, during which the blood-brain barrier (BBB) opens in response to laser ablation. This temporal pattern lays a foundation for designing future clinical trials that aim to integrate MRgLITT with adjuvant antitumor therapies. Such trials could exploit the period of elevated BBB permeability to enhance the delivery and efficacy of therapeutic agents, thereby advancing treatment strategies for brain tumor patients.

Abstract BACKGROUND Quantitative blood volume (BV) imaging using dynamic T1-weighted contrast enhanced (DCE) perfusion MRI may be of diagnostic value in patients with suspected recurrent high-grade glioma, but the association of DCE BV measurements with survival is not known. The aim of the study was to compare the prognostic information of DCE BV measurements with that of O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET imaging in treated IDH wildtype high-grade astrocytoma and glioblastoma (2016 WHO classification). MATERIAL AND METHODS A total of 94 hybrid [18F]FET PET/MRI scans with DCE from unique adult patients were retrospectively analysed. Scans were obtained after surgery/biopsy (n=94) and radiotherapy (n=93) due to variable suspicion of residual or progressive disease. In each scan the visually BV positive (VOLBV), the [18F]FET PET avid (VOLFET) and the contrast-enhancing (VOLCE) volumes were delineated, and fractional tumour volumes (fVOL) within VOLCE, as well as maximal BV (BVmax) and maximal [18F]FET tumour-to-background ratio (TBRmax) were determined. Accuracy for prediction of 6-month progression free survival and 1 year overall survival were assessed by logistics regression. Associations with overall survival were assessed for each parameter by Cox proportional hazard analysis. RESULTS In a univariate analysis, adjusted for age and MGMT, both VOLCE, and all [18F]FET and DCE BV derived metrics were predictive of both 6 month progression free survival, 1 year survival and overall survival. ROC AUC for prediction of 6 month progression free survival and 1 year overall survival tended to be higher for [18F]FET derived metrics, but ROC AUC values were not significantly different between any [18F]FET and DCE BV derived metrics. In Cox models for overall survival (adjusting for age, MGMT and VOLCE) only TBRmax and VOLBV had independent prognostic value among [18F]FET PET and DCE BV derived metrics, respectively. In a final model including both TBRmax and VOLBV, only TBRmax remained significant.. CONCLUSION DCE BV and [18F]FET PET derived metrics provides prognostic information independent of age, MGMT status and contrast enhancing tumour volume in treated glioblastoma, with volume of increased BV and [18F]FET TBRmax providing strongest associations with overall survival. Accounting for functional imaging biomarkers may be important in balancing future randomized clinical trials.

Objective The autoinflammatory disease familial Mediterranean fever (FMF), characterized by recurrent attacks of sterile fever, serosal, and/or synovial inflammation, is caused by variants in the Mediterranean fever gene, MEFV, coding for the pyrin inflammasome sensor. The diagnosis of FMF is mainly based on clinical symptoms and confirmed by detection of disease-associated MEFV variants. However, the diagnosis is challenging among patients carrying variants of uncertain clinical significance (VUS). In this study, we aimed to identify potential FMF discriminatory diagnostic markers in a cohort of clinically characterized FMF patients. Method We established a cohort of clinically and MEFV genotype-characterized FMF patients by enrolling patients from major Danish hospitals (n = 91). The secretory profile of pyrin inflammasome-activated monocytes from healthy donors (HDs) and MEFV-characterized FMF patients (n = 28) was assessed by analysing cell supernatants for a custom-designed panel of 23 cytokines, chemokines, and soluble tumour necrosis factor receptors associated with monocyte and macrophage function. Results MEFV genotypes in Danish FMF patients were associated with age at symptom onset (p < 0.05), FMF among relatives (p < 0.01), proportion of patients in colchicine treatment (p < 0.01), and treatment response (p < 0.05). Secretion of chemokines CCL1 and CXCL1 from pyrin-activated FMF monocytes was significantly decreased compared to HDs (p < 0.05), and could discriminate FMF patients with 'non-confirmatory' MEFV genotypes from HDs with 80.0% and 70.0% sensitivity for CCL1 and CXCL1, respectively (p < 0.05). Conclusion Our data suggest that a functional diagnostic assay based on CCL1 or CXCL1 levels in pyrin-activated patient monocytes may contribute to FMF diagnosis in patients with VUS.

BACKGROUND AND PURPOSE: The Normal Pressure Hydrocephalus Radscale is a combined scoring of 7 different structural imaging markers on preoperative brain CT or MR imaging in patients with idiopathic normal pressure hydrocephalus: callosal angle, Evans Index, Sylvian fissure dilation, apical sulcal narrowing, mean temporal horn diameter, periventricular WM lesions, and focal sulcal dilation. The purpose of this retrospective study was to assess the performance of the Normal Pressure Hydrocephalus Radscale in distinguishing idiopathic normal pressure hydrocephalus shunt responders from nonresponders. MATERIALS AND METHODS: The preoperative MR imaging and CT scans of 119 patients with idiopathic normal pressure hydrocephalus were scored using the Normal Pressure Hydrocephalus Radscale. A summary shunt-response score assessed within 6 months from ventriculoperitoneal shunt surgery, combining the effect on cognition, gait, and urinary incontinence, was used as a reference. The difference between the mean Normal Pressure Hydrocephalus Radscale for responders and nonresponders was tested using the Student t test. The area under the curve was calculated for the Normal Pressure Hydrocephalus Radscale to assess shunt response. To ascertain reproducibility, we assessed the interobserver agreement between the 2 independent observers as intraclass correlation coefficients for the Normal Pressure Hydrocephalus Radscale for 74 MR imaging scans and 19 CT scans. RESULTS: Ninety-four (79%) of 119 patients were shunt responders. The mean Normal Pressure Hydrocephalus Radscale score for shunt responders was 8.35 (SD, 1.53), and for nonresponders, 7.48 (SD, 1.53) (P?=?.02). The area under the curve for the Normal Pressure Hydrocephalus Radscale was 0.66 (range, 0.54?0.78). The intraclass correlation coefficient for the Normal Pressure Hydrocephalus Radscale was 0.86 for MR imaging and 0.82 for CT. CONCLUSIONS: The Normal Pressure Hydrocephalus Radscale showed moderate discrimination for shunt response but cannot, on its own, be used for selecting patients with idiopathic normal pressure hydrocephalus for shunt surgery.

Dense water (DW) formation commonly occurs in the shallow Northern Adriatic Sea during winter outbreaks, when there is a combination of the cooling of surface waters by the winds and high salinity as a result of reduced river inputs. These DWs subsequently propagate southwards over a period of weeks/months, eventually arriving in the Southern Adriatic Sea. The investigation is based on a new nonhydrostatic (NH) formulation of the 3D finite element model SHYFEM that is validated for a number of theoretical test cases. Subsequently this model is used to simulate, through high-resolution numerical simulations, an extreme DW event that occurred in the Adriatic Sea in 2012. We perform both hydrostatic (HY) and NH simulations in order to explicitly see the impact of NH processes on the DW dynamics. The modeled results are compared to observations collected in the field campaign of March–April 2012 in the Southern Adriatic Sea. The NH run correctly reproduces the across isobath bottom-trapped gravity current characterizing the canyon DW pathways. It also more accurately captures the frequency and intensity of dense water cascading pulsing events, as the inclusion of NH processes produces stronger currents with different DW mixing characteristics. Finally, the NH run simulates internal gravity waves (IGW), generated during the cascading at the edge of the canyon, which propagate downslope. This IGW activity is not captured in the HY case.

Immunosuppressive cells in the tumor microenvironment allow cancer cells to escape immune recognition and support cancer progression and dissemination. To improve therapeutic efficacy, we designed a liposomal oxaliplatin formulation (PCL8-U75) that elicits cytotoxic effects toward both cancer and immunosuppressive cells via protease-mediated, intratumoral liposome activation. The PCL8-U75 liposomes displayed superior therapeutic efficacy across all syngeneic cancer models in comparison to free-drug and liposomal controls. The PCL8-U75 depleted myeloid-derived suppressor cells and tumor-associated macrophages in the tumor microenvironment. The combination of improved cancer cell cytotoxicity and depletion of immunosuppressive populations of immune cells is attractive for combination with immune-activating therapy. Combining the PCL8-U75 liposomes with a TLR7 agonist induced immunological rejection of established tumors. This combination therapy increased intratumoral numbers of cancer antigen-specific cytotoxic T cells and Foxp3- T helper cells. These results are encouraging toward advancing liposomal drug delivery systems with anticancer and immune-modulating properties into clinical cancer therapy.

Objectives: To investigate epidemiology, demography, and genetic and clinical characteristics of patients with familial Mediterranean fever (FMF) in Denmark. Method: In this population-based, cross-sectional cohort study, we identified FMF patients from discharge diagnoses using ICD-10 codes in the Danish National Patient Register, and linked data from the Danish Civil Registration System and laboratory databases for results of MEFV gene variant screening. Results: We identified 495 FMF patients (prevalence 1:11 680) with a median age of 29 years and a female ratio of 51%. The median age at diagnosis of FMF was 13 (IQR 7–22) years, with an estimated median diagnostic delay of 3 (IQR 0.7–6.9) years. The predominant ethnicities were Turkish (41.8%), Lebanese (15.8%), Syrian (6.5%), South-West Asian (7.9%), and South-East Asian (3.0%). The MEFV genotype distribution was 18.7% homozygous, 21.2% compound heterozygous, 32.0% heterozygous, 11.0% with complex alleles or unresolved zygosity, and 17.1% with no detected variants. M694V was the most prevalent variant in the overall cohort (32.5%). Homozygous or compound heterozygous MEFV exon 10 variants were associated with younger age at diagnosis (p < 0.001) and reduced number of hospital contacts before diagnosis (p = 0.008). The Charlson Comorbidity Index was ≥ 2 in 8.1% of patients. The prevalence of amyloidosis was 1.0%. Conclusions: FMF in Denmark is rare and patients are mainly of Eastern Mediterranean ethnicity. Diagnostic delay was long but patients with exon 10 MEFV variants were diagnosed at a younger age. Prolonged diagnostic delay is probably caused by lack of FMF awareness in the Danish healthcare system.

This work aims at collecting relevant information on QC procedures and PET quantification across a European PET/MRI network, including the assessment of variations of PET(/MR) quantification using NEMA image quality phantom scans.

Purpose or ObjectiveBackground: oral mucositis (OM)is one of the most important adverse event (AE)in head and neck cancer treatment.The objective of the trial was to evaluate the safety and efficacy of melatonin (MLT) oral gel in the prevention and treatment of oral mucositis (OM) in H&N cancer patients.We present the results in patients treated for oral cavity and oropharyngeal cancer (OCOC). Material and MethodsMethods: Multicenter, prospective, randomized, doubleblind, placebo-controlled study.Eligible patients were randomly assigned (1:1 ratio) to receive 3% MLT or matching placebo (PLC) oral gel.Patients received once daily (5 days/week) IMRT radiation therapy (total dose ≥ 66 Gy).Concurrent systemic treatments were cisplatin Q3W or cetuximab Q1W.All patients received concomitant standard symptomatic treatment for OM.Efficacy analyses were performed on a mITT population (patients receiving at least one medication dose) or ITT.Efficacy endpoints were either RTOG or NCI CTCv4, G3-4 oral mucositis (SOM) and G2-4 ulcerative oral mucositis (UOM).Comparison of incidence rates of SOM/UOM: Fisher exact test; comparison of duration of SOM/UOM: U Mann-Whitney test.No stratification by location was done. ResultsResults: 79 patients were included in the mITT population (40 MLT/39 PLC).Oropharynx and oral cavity (OCO) were the most frequent locations (n=58; 73%), larynx and hypopharynx (n=11; 14%), and nasopharynx (n=10; 13%).In patients with OCO tumours, concurrent systemic treatments were cisplatin Q3W (n=36, 19 in MLT group and 17 in PCB group) and cetuximab Q1W (n=22, 12 in MLT group and 10 in PCB group).The efficacy results in patients diagnosed with oral cavity and oropharynx tumors were as follows:

Radiotherapy is a frequently used strategy to fight cancer - however, this therapy is seldom curative, and increasing evidence points to the great advantage of combining radiation therapy with immunotherapy to increase the curative potential. Immunotherapy has a great potential as cancer therapy, with the prospect of training our own immune cells to actively kill cancer cells, not only targeting primary tumors, but also metastases. Within this platform, one induces not only a treatment for current cancers, but could potentially prevent recurrence in the future by the induction of an immune memory response. In the current project (XVac, supported by the Danish innovation fund) we are elucidating various strategies for combining radiation therapy and immune stimulatory compounds. The primary goal of the XVac project is the development of new drug delivery technology platforms, which can induce a potent anti-tumor immune response. We will investigate how the combination of radiation and immunotherapy engages the immune system. We will evaluate 1) the infiltration of immune cells to the tumor lesions, 2) systemic alterations in immune reactivity and immune regulation, and 3) the ability to induce T-cell recognition of cancer specific antigens. These parameters will be evaluated as markers of tumor rejection capacity in pre-clinical tumor models. Mutation-derived antigens (neoantigens) are of prime interest as these provide a set of tumor specific targets and are truly foreign to the immune system. For the identification of the T-cell specific neoantigen landscaping pre- and post-immunization, a novel technology, based on multimerized peptide-MHC-I coupled with a specific barcode, will be performed. This technique gives the possibility of detecting >1000 antigen-specific T cells in one sample. This will allow us to gain insight to T cells that recognize targeted tumor cells and provide basis for rational design of personalized cancer vaccines. Radiotherapy is effective, but does not effectively stimulate a specific immunogenic eradication of all cancer cells. With the combination of immunotherapy this could be overcome. The end goal of this project is to find effective and safe delivery mechanisms of immune stimulatory compounds that can provide sustained clinical efficacy in cancer patients.

Cytotoxic drugs encapsulated into liposomes were originally designed to increase the anticancer response, while minimizing off-target adverse effects. The first liposomal chemotherapeutic drug was approved for use in humans more than 20 years ago, and the first publication regarding its use in a canine cancer patient was published shortly thereafter. Regardless, no general application for liposomal cytotoxic drugs has been established in veterinary oncology till now. Due to the popularity of canines as experimental models for pharmacokinetic analyses and toxicity studies, multiple publications exist describing various liposomal drugs in healthy dogs. Also, some evidence for its use in veterinary cancer patients exists, especially in canine lymphoma, canine splenic hemangiosarcoma and feline soft tissue sarcoma, however, the results have not been overwhelming. Reasons for this may be related to inherent issues with the enhanced permeability and retention effect, the tumour phenomenon which liposomal drugs exploit. This effect seems very heterogeneously distributed in the tumour. Also, it is potentially not as ubiquitously occurring as once thought, and it may prove important to select patients for liposomal therapy on an individual, non-histology-oriented, basis. Concurrently, new developments with active-release modified liposomes in experimental models and humans will likely be relevant for veterinary patients as well, and holds the potential to improve the therapeutic response. It, however, does not resolve the other challenges that liposomal chemotherapy faces, and more work still needs to be done to determine which veterinary patients may benefit the most from liposomal chemotherapy.

Glycolysis, hypoxia, and proliferation are important factors in the tumor microenvironment contributing to treatment-resistant aggressiveness. Imaging these factors using combined functional positron emission tomography and computed tomography can potentially guide diagnosis and management of cancer patients. A dog with fibrosarcoma was imaged using 18F-FDG, 64Cu-ATSM, and 18F-FLT before, during, and after 10 fractions of 4.5 Gy radiotherapy. Uptake of all tracers decreased during treatment. Fluctuations in 18F-FDG and 18F-FLT PET uptakes and a heterogeneous spatial distribution of the three tracers were seen. Tracer distributions partially overlapped. It appears that each tracer provides distinct information about tumor heterogeneity and treatment response. OPEN ACCESS Diagnostics 2015, 5 373