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Epigenomic changes are an important feature of malignant tumors. How tumor aggressiveness is affected by DNA methylation of specific loci is largely unexplored. In genome-wide DNA methylation analyses, we identified the KCa3.1 channel gene (KCNN4) promoter to be hypomethylated in an aggressive non-small-cell lung carcinoma (NSCLC) cell line and in patient samples. Accordingly, KCa3.1 expression was increased in more aggressive NSCLC cells. Both findings were strong predictors for poor prognosis in lung adenocarcinoma. Increased KCa3.1 expression was associated with aggressive features of NSCLC cells. Proliferation and migration of pro-metastatic NSCLC cells depended on KCa3.1 activity. Mechanistically, elevated KCa3.1 expression hyperpolarized the membrane potential, thereby augmenting the driving force for Ca2+ influx. KCa3.1 blockade strongly reduced the growth of xenografted NSCLC cells in mice as measured by positron emission tomography-computed tomography. Thus, loss of DNA methylation of the KCNN4 promoter and increased KCa3.1 channel expression and function are mechanistically linked to poor survival of NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: To evaluate medication-related risks in older patients with cancer and their association with severe toxicity during antineoplastic therapy.Methods: This is a secondary analysis of two prospective, single-center observational studies which included patients ≥ 70 years with cancer. The patients' medication lists were investigated regarding possible risks: polymedication (defined as the use of ≥ 5 drugs), potentially inappropriate medication (PIM), and relevant potential drug-drug interactions (rPDDI). The risks were analyzed before and after start of cancer therapy. Severe toxicity during antineoplastic therapy was captured from medical records according to the Common Terminology Criteria for Adverse Events (CTCAE). The association between grade ≥ 3 toxicity and medication risks was evaluated by univariate as well as multivariate regression adjusted by ECOG and age.Results: The study cohort comprised 136 patients (50% female, mean age 77 years, 42% hematological malignancies). Before the start of cancer therapy, patients took on average 5 drugs as long-term medication and 52% of patients were exposed to polymedication. More than half of patients used at least one PIM. Approximately one third of patients exhibited rPDDI. The prevalence of medication risks increased after start of cancer therapy. rPDDI were significantly associated with severe overall toxicity (OR, 5.07; p = 0.036; 95% Confidence Interval (CI) 1.11-23.14; toxicity in patients with rPDDI 94.1% (32/34) vs 75.9% (60/79) in patients without rPDDI) and hematological toxicity (OR, 3.95; p = 0.010; 95% CI 1.38-11.29; hematological toxicity in patients with rPDDI 85.3% (29/34) vs 59.5% (47/79) in patients without rPDDI). In the multivariate analysis adjusted by ECOG and age, only the association for rPDDI with hematological toxicity remained statistically significant (OR, 4.51; p = 0.007; 95% CI 1.52-13.38). These findings should be further investigated in larger studies.Conclusion: Medication risks are common in older patients with cancer and might be associated with toxicity. This raises the need for tailored interventions to ensure medication safety in this patient cohort. [ABSTRACT FROM AUTHOR]

Objectives: Intra-individual spatial overlap analysis of tumor volumes assessed by MRI, the amino acid PET tracer [18F]-FET and the nucleoside PET tracer [18F]-FLT in high-grade gliomas (HGG). Methods: MRI, [18F]-FET and [18F]-FLT PET data sets were retrospectively analyzed in 23 HGG patients. Morphologic tumor volumes on MRI (post-contrast T1 (cT1) and T2 images) were calculated using a semi-automatic image segmentation method. Metabolic tumor volumes for [18F]-FET and [18F]-FLT PETs were determined by image segmentation using a threshold-based volume of interest analysis. After co-registration with MRI the morphologic and metabolic tumor volumes were compared on an intra-individual basis in order to estimate spatial overlaps using the Spearman's rank correlation coefficient and the Mann-Whitney U test. Results: [18F]-FLT uptake was negative in tumors with no or only moderate contrast enhancement on MRI, detecting only 21 of 23 (91%) HGG. In addition, [18F]-FLT uptake was mainly restricted to cT1 tumor areas on MRI and [18F]-FLT volumes strongly correlated with cT1 volumes (r = 0.841, p<0.001). In contrast, [18F]-FET PET detected 22 of 23 (96%) HGG. [18F]-FET uptake beyond areas of cT1 was found in 61% of cases and [18F]-FET volumes showed only a moderate correlation with cT1 volumes (r = 0.573, p<0.001). Metabolic tumor volumes beyond cT1 tumor areas were significantly larger for [18F]-FET compared to [18F]-FLT tracer uptake (8.3 vs. 2.7 cm3, p<0.001). Conclusion: In HGG [18F]-FET but not [18F]-FLT PET was able to detect metabolic active tumor tissue beyond contrast enhancing tumor on MRI. In contrast to [18F]-FET, blood-brain barrier breakdown seems to be a prerequisite for [18F]-FLT tracer uptake. [ABSTRACT FROM AUTHOR]

Parkinson's disease is characterized by a selective loss of dopaminergic neurons in the substantia nigra ( SN). However, whether regenerative endogenous neurogenesis is taking place in the mammalian SN of parkinsonian and non-parkinsonian brains remains of debate. Here, we tested whether proliferating cells in the SN and their neurogenic potential would be affected by anti-inflammatory treatment under physiological conditions and in the 6-hydroxy-dopamine (6- OHDA) Parkinson's disease mouse model. We report that the majority of newly generated nigral cells are positive for Doublecortin ( Dcx), which is an often used marker for neural progenitor cells. Yet, Dcx expression levels in these cells were much lower than in neural progenitor cells of the subventricular zone and the dentate gyrus neural progenitor cells. Furthermore, these newly generated nigral cells are negative for neuronal lineage markers such as Tu J1 and Neu N. Therefore, their neuronal commitment is questionable. Instead, we found evidence for oligodendrogenesis and astrogliosis in the SN. Finally, neither short-term nor long-term inhibition of neuroinflammation by Minocycline- or 6- OHDA-induced lesion affected the numbers of newly generated cells in our disease paradigm. Our findings of adult generated Dcx+ cells in the SN add important data for understanding the cellular composition and consequently the regenerative capacity of the SN. [ABSTRACT FROM AUTHOR]

: Addition of temozolomide (TMZ) to radiation therapy is the standard treatment for patients with glioblastoma (GBM). However, there is uncertainty regarding the effectiveness of TMZ. Considering the rapid evolution of the disease, methods to assess TMZ efficacy early during treatment would be of great benefit. Our aim was to monitor early effects of TMZ in a mouse model of GBM using positron emission tomography (PET) with 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT). Methods: Human glioma cells sensitive to TMZ (Gli36dEGFR-1) were treated with sub-lethal doses of TMZ to obtain cells with lower sensitivity to TMZ (Gli36dEGFR-2), as measured by growth and clonogenic assays. Gli36dEGFR-1 and Gli36dEGFR-2 cells were subcutaneously (s.c.) or intracranially (i.c.) xenografted into nude mice. Mice were treated for 7 days with daily injection of 25 or 50 mg/kg TMZ. Treatment efficacy was measured using [18F]FLT-PET before treatment and after 2 days. Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) were used to determine tumor volumes before treatment and after 7 days. Results: A significant difference was observed between TMZ and DMSO treated tumors in terms of variations of [18F]FLT T/B ratio as soon as day 2 in the i.c. as well as in the s.c. mouse model. Variations of [18F]FLT T/B uptake ratio between days 0 and 2 correlated with variations of tumor size between days 0 and 7 (s.c. model: ntumor = 17 in nmice = 11, P<0.01; i.c. model: ntumor/mice = 9, P<0.01). Conclusions: Our results indicate that [18F]FLT-PET may be useful for an early evaluation of the response of GBM to TMZ chemotherapy in patients with glioma. [ABSTRACT FROM AUTHOR]

The purpose of this positron emission tomography (PET) study was to compare the prognostic value of pretreatment volume of [11C]-methionine (MET) uptake and semiquantitative MET uptake ratio in patients with malignant glioma. The study population comprised 40 patients with malignant glioma. Pretreatment magnetic resonance imaging (MRI) and MET-PET imaging were performed before the initiation of glioma treatment in all patients. The pretreatment MET uptake ratios and volumes were assessed. To create prognostically homogeneous subgroups, patients' pretreatment prognostic factors were stratified according to the six classes of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA). Univariate and multivariate analyses were performed to determine significant prognostic factors. Survival analyses identified the pretreatment volume of MET uptake and a higher RTOG RPA class as significant predictors. In contrast, pretreatment maximum areas of contrast enhancement on MRI and semiquantitative MET uptake ratios could not be identified as significant prognostic factors. The patients' outcomes and Karnofsky Performance Scale scores were significantly correlated with pretreatment volume of MET uptake but not with semiquantitative MET uptake ratio. The data suggest that pretreatment volumetry of MET uptake but not the semiquantitative MET uptake ratio is a useful biologic prognostic marker in patients with malignant glioma. [ABSTRACT FROM AUTHOR]

Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis. Originally viewed as an immune-privileged organ, the central nervous system (CNS) is now recognized to have a constant interplay with the innate and the adaptive immune systems, where resident microglia and infiltrating immune cells from the periphery have important roles. Common diseases of the CNS, such as stroke, multiple sclerosis (MS), and neurodegeneration, elicit a neuroinflammatory response with the goal to limit the extent of the disease and to support repair and regeneration. However, various disease mechanisms lead to neuroinflammation (NI) contributing to the disease process itself. Molecular imaging is the method of choice to try to decipher key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the orchestrated inflammatory response in vivo in animal models and patients. Here, we review the basic principles of NI with emphasis on microglia and common neurologic disease mechanisms, the molecular targets which are being used and explored for imaging, and molecular imaging of NI in frequent neurologic diseases, such as stroke, MS, neurodegeneration, epilepsy, encephalitis, and gliomas. [ABSTRACT FROM AUTHOR]

In patients with World Health Organization (WHO) grade III glioma with a lack of or minimal (< 1 cm³) magnetic resonance imaging (MRI) contrast enhancement, the volume of the metabolically active part of the tumor was assessed by [11C]-methionine positron emission tomography (MET-PET). Eleven patients with WHO grade III gliomas underwent MET-PET and MRI (contrast-enhanced T1- and T2-weighted images). To calculate the volumes in cubic centimeters, threshold-based volume of interest analyses of the metabolically active tumor (MET uptake index ≥ 1.3), contrast enhancement, and the T2 lesion were performed after coregistration of all images. In all patients, the metabolically active tumor volume was larger than the volume of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) enhancement (20.8 ± 18.8 vs 0.29 ± 0.25 cm³; p < .001). With the exception of one patient, the volumes of contrast enhancement were located within the metabolically active tumor volume. In contrast, in the majority of patients, MET uptake overlapped with the T2 lesion and reached beyond it (in 10 of 12 MRIs/MET-PET scans). The present data suggest that in patients with WHO grade III glioma with minimal or a lack of contrast enhancement, MET-PET delineates metabolically active tumor tissue. These findings support the use of combined PET-MRI with radiolabeled amino acids (eg, MET) for the delineating of the true extent of active tumor in the diagnosis and treatment planning of patients with gliomas. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the potential of 3'-deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) to detect early treatment responses in gliomas. Human glioma cells were stably transduced with genes yielding therapeutic activity, sorted for different levels of exogenous gene expression, and implanted subcutaneously into nude mice. Multimodality imaging during prodrug therapy included (a) magnetic resonance imaging, (b) PET with 9-(4-[¹⁸F]fluoro-3-hydroxymethylbutyl)guanine assessing exogenous gene expression, and (c) repeat [¹⁸F]FLT PET assessing antiproliferative therapeutic response. All stably transduced gliomas responded to therapy with significant reduction in tumor volume and [¹⁸F]FLT accumulation within 3 days after initiation of therapy. The change in [¹⁸F]FLT uptake before and after treatment correlated to volumetrically calculated growth rates. Therapeutic efficacy as monitored by [¹⁸F]FLT PET correlated to levels of therapeutic gene expression measured in vivo. Thus, [¹⁸F]FLT PET assesses early antiproliferative effects, making it a promising radiotracer for the development of novel treatments for glioma. [ABSTRACT FROM AUTHOR]

Compartmental modelling of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET-derived kinetics provides a method for noninvasive assessment of the proliferation rate of gliomas. Such analyses, however, require an input function generally derived by serial blood sampling and counting. In the current study, 18F-FLT kinetic parameters obtained from image-derived input functions were compared with those from input functions derived from arterialized blood samples. Based on the analysis of 11 patients with glioma (WHO grade II–IV) a procedure for the automated extraction of an input function from 18F-FLT brain PET data was derived. The time–activity curve of the volume of interest with the maximum difference in 18F-FLT uptake during the first 5 min after injection and the period from 60 to 90 min was corrected for partial-volume effects and in vivo metabolism of 18F-FLT. For each patient a two-compartment kinetic model was applied to the tumour tissue using the image-derived input function. The resulting kinetic rate constants K1 (transport across the blood–brain barrier) and Ki (metabolic rate constant or net influx constant) were compared with those obtained from the same data using the input function derived from blood samples. Additionally, the metabolic rate constant was correlated with the frequency of tumour cells stained with Ki-67, a widely used immunohistochemical marker of cell proliferation. The rate constants from kinetic modelling were comparable when the blood sample-derived input functions were replaced by the image-derived functions (K1,img and K1,sample, r = 0.95, p < 10−5; Ki,img and Ki,sample, r = 0.86, p < 0.001). A paired t-test showed no significant differences in the parameters derived with the two methods (K1,img and K1,sample, p = 0.20; Ki,img and Ki,sample, p = 0.92). Furthermore, a significant correlation between Ki,img and the percentage of Ki-67-positive cells was observed ( r = 0.73, p = 0.01). Kinetic modelling of 18F-FLT brain PET data using image-derived input functions extracted from human brain PET data with the practical procedure described here provides information about the proliferative activity of brain tumours which might have clinical relevance especially for monitoring of therapy response in future clinical trials. [ABSTRACT FROM AUTHOR]

Radioligand theranostics (RT) in oncology use cancer-type specific biomarkers and molecular imaging (MI), including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and planar scintigraphy, for patient diagnosis, therapy, and personalized management. While the definition of theranostics was initially restricted to a single compound allowing visualization and therapy simultaneously, the concept has been widened with the development of theranostic pairs and the combination of nuclear medicine with different types of cancer therapies. Here, we review the clinical applications of different theranostic radiopharmaceuticals in managing different tumor types (differentiated thyroid, neuroendocrine prostate, and breast cancer) that support the combination of innovative oncological therapies such as gene and cell-based therapies with RT. [ABSTRACT FROM AUTHOR]

Background: Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. Methodology/Principal Findings: We performed a systematic comparison of 39-Deoxy-39-[18F]-fluoro-L-thymidine ([18F]FLT) and 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [18F]FLT uptake after only two days of treatment, [18F]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [18F]FLT PET but not [18F]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [18F]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [18F]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [18F]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [18F]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to monitor the metabolic effects of temozolomide (TMZ) chemotherapy in malignant gliomas by means of repeated positron emission tomography (PET) with [11C]methionine (MET). Methods: Fifteen patients with histologically proven malignant glioma were treated by TMZ chemotherapy. MET-PET studies were performed before and after the third cycle of TMZ chemotherapy in all patients, and in 12 patients also after the sixth cycle. Gadolinium-enhanced MRI studies were performed in 12 patients before the first and after the sixth cycle. Clinical status was assessed by the modified Rankin scale. Long-term outcome was assessed by calculating the time to progression (TTP) in months. Results: Decline in MET uptake during therapy corresponded to a stable clinical status. The median TTP was significantly longer in patients with decline in MET uptake than in those with increasing MET uptake (23 vs 3.5 months; p=0.01, log rank test). There was no significant correlation between change in MET uptake and change in contrast enhancement during treatment for all patients. Conclusion: The present data demonstrate that clinical stability, which is often achieved under TMZ chemotherapy of malignant glioma, corresponds to a decline in or stability of tumour amino acid metabolism. Tumour responses can already be demonstrated with MET-PET after three cycles of chemotherapy, and absence of progression at that time indicates a high probability of further stability during the next three cycles. A reduction in MET uptake during TMZ treatment predicts a favourable clinical outcome. Molecular imaging of amino acid uptake by MET-PET offers a new method of measurement of the biological activity of recurrent glioma. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with brain metastasis are at a severe stage of cancer, and brain surgery can prevent neurological morbidity. However, the success of brain surgery might require a patient's physical integrity prior to the operation. In the present study, we asked whether a preoperative physical decline affects survival in patients with brain metastasis from lung cancer. In order to measure the physical condition, we used a commonly-known index—the so-called frailty index—and additionally measured the thickness of a particular masticatory muscle as muscle loss correlates to physical decline. We found that a decreased muscle thickness was accompanied by worsened survival for patients < 65 years and an increased frailty index correlated to worsened survival for patients ≥ 65 years. These results encourage to use of the frailty index and muscle thickness as easily available parameters in order to more sufficiently estimate individual treatment success in patients with metastatic lung cancer. Neurosurgical resection represents an important therapeutic pillar in patients with brain metastasis (BM). Such extended treatment modalities require preoperative assessment of patients' physical status to estimate individual treatment success. The aim of the present study was to analyze the predictive value of frailty and sarcopenia as assessment tools for physiological integrity in patients with non-small cell lung cancer (NSCLC) who had undergone surgery for BM. Between 2013 and 2018, 141 patients were surgically treated for BM from NSCLC at the authors' institution. The preoperative physical condition was assessed by the temporal muscle thickness (TMT) as a surrogate parameter for sarcopenia and the modified frailty index (mFI). For the ≥65 aged group, median overall survival (mOS) significantly differed between patients classified as 'frail' (mFI ≥ 0.27) and 'least and moderately frail' (mFI < 0.27) (15 months versus 11 months (p = 0.02)). Sarcopenia revealed significant differences in mOS for the <65 aged group (10 versus 18 months for patients with and without sarcopenia (p = 0.036)). The present study confirms a predictive value of preoperative frailty and sarcopenia with respect to OS in patients with NSCLC and surgically treated BM. A combined assessment of mFI and TMT allows the prediction of OS across all age groups. [ABSTRACT FROM AUTHOR]

Simple Summary: Meningiomas are most commonly benign intracranial tumors, and surgical resection represents the treatment modality of choice. However, especially for patients of higher age and with increasing comorbidities, brain surgery might be accompanied by the need for postoperative prolonged intensive care, which might impair intended operative benefit. In the present study, we therefore analyzed prolonged mechanical ventilation (PMV) as an indicator variable for such intensive care treatment with regard to potential effects on mortality after meningioma resection in patients aged 70 years and older. We found that patients with postoperative PMV exhibited a profoundly increased probability to die within 1 year after surgery. Based on these findings, we identified risk factors for postoperative PMV occurrence and developed an easy-to-use score which allows us to estimate the risk of PMV occurrence preliminary to the surgical resection. We believe that this score might help to more sufficiently guide patients in the course of risk–benefit assessment and preoperative counseling. Indication for surgical treatment in patients with intracranial meningioma must include both clinical aspects and an individual risk–benefit stratification, especially in geriatric patients. Prolonged mechanical ventilation (PMV) has not been investigated for its potential effects in patients with meningioma. We therefore analyzed the impact of PMV on mortality in geriatric patients who had undergone meningioma resection. Between 2009 and 2019, 261 patients aged ≥ 70 years were surgically treated for intracranial meningioma at our institution. PMV was defined as postoperative invasive ventilation of >7 days. Postoperative PMV was present in 17 of 261 geriatric meningioma patients (7%). Twenty-five geriatric patients (10%) died within 1 year after surgery. A scoring system ("ACKT") based on the variables of age, preoperative C-reactive protein (CRP) value, Karnofsky performance scale and tumor size supports prediction of postoperative PMV (sensitivity 73%, specificity 84%). PMV is significantly associated with increased mortality after surgical treatment of meningiomas in geriatric patients. Furthermore, we suggest a novel score ("ACKT") to preoperatively estimate the risk of PMV occurrence, which might help to guide future risk–benefit assessment and patient counseling in the geriatric meningioma population. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that systemic TNFα is associated with increased disease progression in AD and that this may be modulated by the anti‐TNFα agent Etanercept. The effect of Etanercept on microglial activation in patients with MCI due to AD is unknown. Method: A total of 13 patients (from a planned 46 patients) with a clinical diagnosis of MCI due to AD were randomised to receive either placebo or 50 mg of Etanercept (weekly s.c injection) over one year. Aß deposition was established by AmyvidTM ([18F]Florbetapir‐PET) scan. Clinical assessments, [11C]‐(R)‐PK‐11195 PET (a marker of microglial activation) and [18F]Florbetapir‐PET were performed at baseline and after 1 year. Result: 10 out 13 enrolled participants completed the whole study. 6 on Etanercept and 4 on placebo. The region of interest analysis of the [11C]‐(R)‐PK‐11195 binding potential (BP) at baseline showed a widespread increase in MCI patients as compared to age‐matched controls with the cingulate gyrus being targeted. When comparing the change of regional and global PK11195 BP for these 10 patients between baseline and follow‐up after one year, there were no significant differences in the placebo or in the active drug group. Likewise, we found no major changes in measurement of memory function or other cognitive tasks in those subjects taking Etanercept compared with placebo. However, study power was severely compromised. Conclusion: MCI patients show increased microglial activation as compared to healthy controls. In our relatively small treatment group Etanercept does not seem to modify microglial activation as measured with [11C]‐(R)‐PK‐11195 PET. [ABSTRACT FROM AUTHOR]

Background: Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. Methodology/Principal Findings: We performed a systematic comparison of 3′-Deoxy-3′-[\(^{18}F\)]-fluoro-L-thymidine ([\(^{18}F\)]FLT) and 2-[\(^{18}F\)]-fluoro-2-deoxy-D-glucose ([\(^{18}F\)]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [\(^{18}F\)]FLT uptake after only two days of treatment, [\(^{18}F\)]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [\(^{18}F\)]FLT PET but not [\(^{18}F\)]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [\(^{18}F\)]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [\(^{18}F\)]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [\(^{18}F\)]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [\(^{18}F\)]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC.

Background: The development of heart failure is accompanied by complex changes in cardiac electrophysiology and functional properties of cardiomyocytes and fibroblasts. Histone deacetylase (HDAC) inhibitors hold great promise for the pharmaceutical therapy of several malignant diseases. Here, we describe novel effects of the class I HDAC inhibitor Entinostat on electrical and structural remodeling in an in vivo model of pacing induced heart failure. Methods: Rabbits were implanted a pacemaker system, subjected to rapid ventricular pacing and treated with Entinostat or placebo, respectively. Following stimulation, rabbit hearts were explanted and subsequently subjected to electrophysiological studies and further immunohistological analyses of left ventricles. Results: In vivo, rapid ventricular stimulation caused a significant prolongation of monophasic action potential duration compared to sham hearts (from 173 ± 26 ms to 250 ± 41 ms; cycle length 900 ms; p < 0.05) and an increased incidence of Early afterdepolarisations (+ 150%), while treatment with Entinostat in failing hearts could partially prevent this effect (from 250 ± 41 ms to 170 ± 53 ms, p < 0.05; reduction in EAD by 50%). Entinostat treatment partially restored KCNH2 and Cav1.3 gene expressions in failing hearts, and inhibited the development of cardiac fibrosis in vivo. Conclusion: In a rabbit model of heart failure, Entinostat diminishes heart failure related prolongation of repolarization and partially restores KCNH2 and Cav1.3 expression. In addition, Entinostat exerts antifibrotic properties both in vitro and in vivo. Thus, Entinostat might be an interesting candidate for the pharmaceutical therapy of heart failure directed against structural and electrical remodeling. [ABSTRACT FROM AUTHOR]

Activated andin vitroexpanded natural killer (NK) cells have substantial cytotoxicity against many tumor cells, but theirin vivoefficacy to eliminate solid cancers is limited. Here, we used chimeric antigen receptors (CARs) to enhance the activity of NK cells against Ewing sarcomas (EwS) in a tumor antigen-specific manner. Expression of CARs directed against the ganglioside antigen GD2in activated NK cells increased their responses to GD2+ allogeneic EwS cellsin vitroand overcame resistance of individual cell lines to NK cell lysis. Second-generation CARs with 4-1BB and 2B4 co-stimulatory signaling and third-generation CARs combining both co-stimulatory domains were all equally effective. By contrast, adoptive transfer of GD2-specific CAR gene-modified NK cells both by intratumoral and intraperitoneal delivery failed to eliminate GD2-expressing EwS xenografts. Histopathology review revealed upregulation of the immunosuppressive ligand HLA-G in tumor autopsies from mice treated with NK cells compared to untreated control mice. Supporting the relevance of this finding,in vitroco-incubation of NK cells with allogeneic EwS cells induced upregulation of the HLA-G receptor CD85j, and HLA-G1 expressed by EwS cells suppressed the activity of NK cells from three of five allogeneic donors against the tumor cellsin vitro. We conclude that HLA-G is a candidate immune checkpoint in EwS where it can contribute to resistance to NK cell therapy. HLA-G deserves evaluation as a potential target for more effective immunotherapeutic combination regimens in this and other cancers. [ABSTRACT FROM AUTHOR]