A clinical evaluation of an ex vivo organ culture system to predict patient response to cancer therapy.

Introduction: Ex vivo organ cultures (EVOC) were recently optimized to sustain cancer tissue for 5 days with its complete microenvironment. We examined the ability of an EVOC platform to predict patient response to cancer therapy. Methods: A multicenter, prospective, single-arm observational trial. Samples were obtained from patients with newly diagnosed bladder cancer who underwent transurethral resection of bladder tumor and from core needle biopsies of patients with metastatic cancer. The tumors were cut into 250 µM slices and cultured within 24 h, then incubated for 96 h with vehicle or intended to treat drug. The cultures were then fixed and stained to analyze their morphology and cell viability. Each EVOC was given a score based on cell viability, level of damage, and Ki67 proliferation, and the scores were correlated with the patients' clinical response assessed by pathology or Response Evaluation Criteria in Solid Tumors (RECIST). Results: The cancer tissue and microenvironment, including endothelial and immune cells, were preserved at high viability with continued cell division for 5 days, demonstrating active cell signaling dynamics. A total of 34 cancer samples were tested by the platform and were correlated with clinical results. A higher EVOC score was correlated with better clinical response. The EVOC system showed a predictive specificity of 77.7% (7/9, 95% CI 0.4-0.97) and a sensitivity of 96% (24/25, 95% CI 0.80-0.99). Conclusion: EVOC cultured for 5 days showed high sensitivity and specificity for predicting clinical response to therapy among patients with muscle-invasive bladder cancer and other solid tumors.

Alleviation of ADHD symptoms by non-invasive right prefrontal stimulation is correlated with EEG activity.

Attention deficit hyperactivity disorder (ADHD) is a prevalent disorder with effective pharmacological treatment that benefits most patients. However, about one-third fail to benefit while others search non-pharmacological alternatives, and for those options are scarce. One alternative treatment option is to alter abnormal right prefrontal cortex (rPFC) activity, given that rPFC abnormality has been repeatedly implicated in ADHD neurophathology. Here, we evaluated whether targeting the rPFC with multiple sessions of repetitive transcranial magnetic stimulation (rTMS), which can modulate neuronal excitability, activity, and plasticity in a non-invasive manner, will affect clinical symptoms in adults suffering from ADHD. Concomitantly, we used EEG to characterize electrophysiological alterations induced by treatment and to search for correlation between baseline neuronal activity and clinical response. Forty-three drug free adults with ADHD were randomized to receive either Real, Active Control, or Sham treatment (13 females, age ranging 21-46; n = 15, 14, 14, respectively), and underwent three weeks of daily high-frequency (18 Hz) stimulation sessions. We found that Real treatment was safe and resulted in significant improvement of symptoms (η2p = 0.34; Cohen's d(against Sham) = 0.96; Cohen's d(against AC) = 0.68; p = 0.00085). Furthermore, based on EEG recorded within the first treatment session we established a novel biomarker, composed of the Alpha and Low-gamma power, which highly correlated the magnitude of the clinical outcome (r = 0.92, p = 0.0001). Taken together, the results of this pilot study indicate safety and effectiveness of rTMS directed to the rPFC for treatment of adult ADHD patients. The biomarker is suggested to reflect the responsiveness of the cortex to this rTMS intervention. Following validation of the results in larger samples, this study may represent a step towards a non-pharmacological treatment for adults with ADHD using EEG-based selection of optimal candidates for treatment.

Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery.

UNLABELLED: The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. SIGNIFICANCE STATEMENT: In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.