The Theranostic Genome.

Theranostic drugs represent an emerging path to deliver on the promise of precision medicine. However, bottlenecks remain in characterizing theranostic targets, identifying theranostic lead compounds, and tailoring theranostic drugs. To overcome these bottlenecks, we present the Theranostic Genome, the part of the human genome whose expression can be utilized to combine therapeutic and diagnostic applications.

Olfactory Neuroblastoma: Re-Evaluating the Paradigm of Intracranial Extension and Cyst Formation.

The purpose of the current study was to assess the prevalence of cyst formation at the brain-tumor interface in olfactory neuroblastoma. We used the UCLA patient-based Pathology and Radiology Head and Neck Database (UPP&R HAND) to identify the largest patient cohort reported to date with imaging and pathology data. Eighteen of thirty-one patients (58.

Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis.

Background: Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete.

Objectives: To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis.

Radioisotope imaging for discriminating benign from malignant cytologically indeterminate thyroid nodules.

The risk of malignancy in thyroid nodules with indeterminate cytological classification (Bethesda III-IV) ranges from 10% to 40%, and early delineation is essential as delays in diagnosis can be associated with increased mortality. Several radioisotope imaging techniques are available for discriminating benign from malignant cytologically indeterminate thyroid nodules, and for supporting clinical decision-making. These techniques include iodine-123, technetium-99m-pertechnetate, technetium-99m-methoxy-isobutyl-isonitrile (technetium-99m-MIBI), and fluorine-18-fluorodeoxyglucose (fluorine-18-FDG).

Therapeutic Options for Neuroendocrine Tumors: A Systematic Review and Network Meta-analysis.

Importance: Multiple therapies are currently available for patients with neuroendocrine tumors (NETs), yet many therapies have not been compared head-to-head within randomized clinical trials (RCTs).

Objective: To assess the relative safety and efficacy of therapies for NETs.

Data Sources: PubMed, Embase, the Cochrane Central Register of Controlled Trials, trial registries, meeting abstracts, and reference lists from January 1, 1947, to March 2, 2018, were searched.

MEK Inhibition Induces Therapeutic Iodine Uptake in a Murine Model of Anaplastic Thyroid Cancer.

Anaplastic thyroid carcinoma (ATC) is refractory to radioiodine therapy in part because of impaired iodine metabolism. We targeted the mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3'K) pathways with the intent to induce radioiodine uptake for radioiodine treatment of ATC. Human ATC cells were used to evaluate the ability of pharmacologic inhibition of the mitogen-activated protein kinase and PI3'K pathways to induce radioiodine uptake.

Clinical Utility of Diffusion-Weighted Imaging in Spinal Infections.

Purpose: Both laboratory markers and radiographic findings in the setting of spinal infections can be nonspecific in determining the presence or absence of active infection, and can lag behind both clinical symptoms and antibiotic response. Magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) has been shown to be helpful in evaluating brain abscesses but has not been commonly used in evaluating spinal infections. We aimed to correlate findings on DWI of the spine to results of microbiological sampling in patients with suspected spinal infections.

The prognostic and predictive value of sstr-immunohistochemistry and sstr-targeted imaging in neuroendocrine tumors.

Purpose: Our aim was to assess the prognostic and predictive value of somatostatin receptor 2 (sstr) in neuroendocrine tumors (NETs).

Methods: We established a tissue microarray and imaging database from NET patients that received sstr-targeted radiopeptide therapy with yttrium-90-DOTATOC, lutetium-177-DOTATOC or alternative treatment. We used univariate and multivariate analyses to identify prognostic and predictive markers for overall survival, including sstr-imaging and sstr-immunohistochemistry.

Survival after somatostatin based radiopeptide therapy with (90)Y-DOTATOC vs. (90)Y-DOTATOC plus (177)Lu-DOTATOC in metastasized gastrinoma.

We aimed to explore the effects of (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC on survival of patients with metastasized gastrinoma. Patients with progressive metastasized gastrinoma were treated with repeated cycles of (90)Y-DOTATOC or with cycles alternating between (90)Y-DOTATOC and (177)Lu-DOTATOC until tumor progression or permanent toxicity. Multivariable Cox regression analyses were used to study predictors of survival.

Somatostatin receptor-targeted radiopeptide therapy with 90Y-DOTATOC and 177Lu-DOTATOC in progressive meningioma: long-term results of a phase II clinical trial.

Unlabelled: Meningiomas express members of the somatostatin receptor family. The present study assessed the long-term benefits and harm of somatostatin-based radiopeptide therapy in meningioma patients.

Methods: Patients with progressive unresectable meningioma were treated with (90)Y-DOTATOC and (177)Lu-DOTATOC until tumor progression or permanent toxicity occurred.

Targeted radiotherapy of prostate cancer with a gastrin-releasing peptide receptor antagonist is effective as monotherapy and in combination with rapamycin.

Unlabelled: The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer and is an attractive target for radionuclide therapy. In addition, inhibition of the protein kinase mammalian target of rapamycin (mTOR) has been shown to sensitize various cancer cells to the effects of radiotherapy.

Methods: To determine the effect of treatment with rapamycin and radiotherapy with a novel (177)Lu-labeled GRPr antagonist ((177)Lu-RM2, BAY 1017858) alone and in combination, in vitro and in vivo studies were performed using the human PC-3 prostate cancer cell line.

Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100.

Acute graft-versus-host disease (GvHD) is a complex process involving endothelial damage and neovascularization. Better understanding of the pathophysiology of neovascularization during GvHD could help to target this process while leaving T-cell function intact. Under ischemic conditions, neovascularization is regulated by different micro RNAs (miRs), which potentially play a role in inflamed hypoxic GvHD target organs.

Correlation of the genotype of paragangliomas and pheochromocytomas with their metabolic phenotype on 3,4-dihydroxy-6-18F-fluoro-L-phenylalanin PET.

Unlabelled: Paragangliomas and pheochromocytomas are genetically heterogeneous diseases. The purpose of this study was to determine the sensitivity and specificity of PET with 3,4-dihydroxy-6-(18)F-fluoro-L-phenylalanin ((18)F-DOPA) for the detection and staging of pheochromocytomas/paragangliomas. Furthermore, we assessed whether the genotypes of pheochromocytomas and paragangliomas correlate with the uptake of (18)F-DOPA.

CLIC4 is a tumor suppressor for cutaneous squamous cell cancer.

Chloride intracellular channel (CLIC) 4 is a member of a redox-regulated, metamorphic multifunctional protein family, first characterized as intracellular chloride channels. Current knowledge indicates that CLICs participate in signaling, cytoskeleton integrity and differentiation functions of multiple tissues. In metabolically stressed skin keratinocytes, cytoplasmic CLIC4 is S-nitrosylated and translocates to the nucleus where it enhances transforming growth factor-β (TGF-β) signaling by protecting phospho-Smad 2 and 3 from dephosphorylation.

Novel (64)Cu- and (68)Ga-labeled RGD conjugates show improved PET imaging of α(ν)β(3) integrin expression and facile radiosynthesis.

Unlabelled: PET with (18)F-labeled arginine-glycine-aspartic acid (RGD) peptides can visualize and quantify α(ν)β(3) integrin expression in patients, but radiolabeling is complex and image contrast is limited in some tumor types. The development of (68)Ga-RGD peptides would be of great utility given the convenience of (68)Ga production and radiolabeling, and (64)Cu-RGD peptides allow for delayed imaging with potentially improved tumor-to-background ratios.

Methods: We used the chelators DOTA,1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), and 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.

Effects of international health electives on medical student learning and career choice: results of a systematic literature review.

Background And Objectives: The present study reviewed the published literature to examine the effects of international health electives (IHEs) on medical student learning and career choice.

Methods: A systematic literature review was conducted to identify key English-language articles on IHEs, using PubMed journal databases for the period 1990--2009. Article inclusion for this review was vetted by a rigorous evaluation of each article's study methods, content, and data quality.

Noninvasive imaging of alphaVbeta3 function as a predictor of the antimigratory and antiproliferative effects of dasatinib.

Src family kinases (SFKs) are commonly deregulated in cancer cells. Among other functions, SFKs are critical for cellular migration and invasion. SFK inhibitors are being studied as targeted cancer drugs, but there are no biomarkers for noninvasive assessment of SFK inhibition.

18F-FDOPA PET and PET/CT accurately localize pheochromocytomas.

Unlabelled: Successful treatment of pheochromocytoma requires accurate diagnosis and localization of tumors. Herein, we investigated the accuracy of PET using 3,4-dihydroxy-6-(18)F-fluoro-phenylalanine ((18)F-FDOPA), an amino acid transporter substrate, as an independent marker for detection of benign and malignant pheochromocytomas.

Methods: The study comprised 25 consecutive patients (9 men, 16 women) whose median age was 51 y (range, 25-68 y), with known or suspected pheochromocytoma.

Derivation of a compartmental model for quantifying 64Cu-DOTA-RGD kinetics in tumor-bearing mice.

Unlabelled: Radiolabeled arginine-glycine-aspartate (RGD) peptides are increasingly used in preclinical and clinical studies to assess the expression and function of the alphavbeta3 integrin, a cellular adhesion molecule involved in angiogenesis and tumor metastasis formation. To better understand the PET signal obtained with radiolabeled RGD peptides, we have constructed a compartmental model that can describe the time-activity curves in tumors after an intravenous injection.

Methods: We analyzed 60-min dynamic PET scans obtained with 64Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-RGD in 20 tumor-bearing severe combined immunodeficient (SCID) mice after a bolus dose (18,500 kBq [500 microCi]), using variations of the standard 2-compartment (4k) tissue model augmented with a compartment for irreversible tracer internalization.

CLIC4 mediates and is required for Ca2+-induced keratinocyte differentiation.

Keratinocyte differentiation requires integrating signaling among intracellular ionic changes, kinase cascades, sequential gene expression, cell cycle arrest, and programmed cell death. We now show that Cl(-) intracellular channel 4 (CLIC4) expression is increased in both mouse and human keratinocytes undergoing differentiation induced by Ca(2+), serum and the protein kinase C (PKC)-activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Elevation of CLIC4 is associated with signaling by PKCdelta, and knockdown of CLIC4 protein by antisense or shRNA prevents Ca(2+)-induced keratin 1, keratin 10 and filaggrin expression and cell cycle arrest in differentiating keratinocytes.

Monitoring tumor glucose utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors.

Purpose: The mechanisms underlying the sensitivity of non-small cell lung cancer to epidermal growth factor receptor (EGFR) kinase inhibitors are complex, and there are no established markers to accurately predict treatment outcome in individual patients.

Experimental Design: We investigated whether tumors responding to EGFR inhibitors can be identified by measuring treatment-induced changes in glucose utilization by positron emission tomography with the glucose analogue fluorodeoxyglucose (FDG-PET). We studied a panel of cell lines with a spectrum of sensitivity to EGFR kinase inhibitors.

Antisense suppression of the chloride intracellular channel family induces apoptosis, enhances tumor necrosis factor {alpha}-induced apoptosis, and inhibits tumor growth.

mtCLIC/CLIC4 is a p53 and tumor necrosis factor alpha (TNFalpha) regulated intracellular chloride channel protein that localizes to cytoplasm and organelles and induces apoptosis when overexpressed in several cell types of mouse and human origin. CLIC4 is elevated during TNFalpha-induced apoptosis in human osteosarcoma cell lines. In contrast, inhibition of NFkappaB results in an increase in TNFalpha-mediated apoptosis with a decrease in CLIC4 protein levels.