The Imageable Genome.

Understanding human disease on a molecular level, and translating this understanding into targeted diagnostics and therapies are central tenets of molecular medicine1. Realizing this doctrine requires an efficient adaptation of molecular discoveries into the clinic. We present an approach to facilitate this process by describing the Imageable Genome, the part of the human genome whose expression can be assessed via molecular imaging. Using a deep learning-based hybrid human-AI pipeline, we bridge individual genes and their relevance in human diseases with specific molecular imaging methods. Cross-referencing the Imageable Genome with RNA-seq data from over 60,000 individuals reveals diagnostic, prognostic and predictive imageable genes for a wide variety of major human diseases. Having both the critical size and focus to be altered in its expression during the development and progression of any human disease, the Imageable Genome will generate new imaging tools that improve the understanding, diagnosis and management of human diseases.

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 (58.1%) had evidence of intracranial extension on MRI, while four (22.0%) demonstrated cyst formation at the brain-tumor interface. The extent of intracranial extension was by far the strongest predictor for intracranial cyst formation, regardless of Hyams tumor grade, using a binary logistics regression model (p = 0.002) and ROC curve analysis (AUC 94.6%). Cyst formation at the brain-tumor interface was an uncommon imaging finding, and tends to occur with a larger component of intracranial tumor extension.

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. SEARCH METHODS: We identified studies through systematic searches of the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947 to December 2020. In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. SELECTION CRITERIA: We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses. A frequentist approach was used to compare the efficacy of therapies. MAIN RESULTS: We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299 participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes (e.g. overall survival and quality of life). AUTHORS' CONCLUSIONS: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

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). This review discusses the currently available radioisotope imaging techniques for evaluation of thyroid nodules, including the mechanism of radiotracer uptake and the indications for their use.

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. Key search terms included neuroendocrine tumors, gastrointestinal neoplasms, therapy, and randomized controlled trial. STUDY SELECTION: Randomized clinical trials comparing 2 or more therapies in patients with NETs (primarily gastrointestinal and pancreatic) were evaluated. Thirty RCTs met the selection criteria. DATA EXTRACTION AND SYNTHESIS: Pairs of independent reviewers screened studies, extracted data, and assessed the risk of bias. A network meta-analysis with a frequentist approach was used to compare the efficacy of therapies; the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. MAIN OUTCOMES AND MEASURES: Disease control, progression-free survival, overall survival, adverse events, and quality of life. RESULTS: The systematic review identified 30 relevant RCTs comprising 3895 patients (48.4% women) assigned to 22 different therapies for NETs. These therapies showed a broad range of risk for serious and nonserious adverse events. The network meta-analyses included 16 RCTs with predominantly a low risk of bias; nevertheless, precision-of-treatment estimates and estimated heterogeneity were limited. The network meta-analysis found 7 therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.35 [95% CI, 0.28-0.45]), everolimus plus somatostatin analogue (HR, 0.35 [95% CI, 0.25-0.51]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.44 [95% CI, 0.26-0.75]), interferon (HR, 0.37 [95% CI, 0.16-0.83]), interferon plus somatostatin analogue (HR, 0.31 [95% CI, 0.13-0.71]), somatostatin analogue (HR, 0.46 [95% CI, 0.33-0.66]), and sunitinib (HR, 0.42 [95% CI, 0.26-0.67]), and 5 therapies for gastrointestinal NETs: bevacizumab plus somatostatin analogue (HR, 0.22 [95% CI, 0.05-0.99]), everolimus plus somatostatin analogue (HR, 0.31 [95% CI, 0.11-0.90]), interferon plus somatostatin analogue (HR, 0.27 [95% CI, 0.07-0.96]), Lu 177-dotatate plus somatostatin analogue (HR, 0.08 [95% CI, 0.03-0.26], and somatostatin analogues (HR, 0.40 [95% CI, 0.21-0.78]) with higher efficacy than placebo and suggests an overall superiority of combination therapies. CONCLUSIONS AND RELEVANCE: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for patients with NETs.

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. METHODS: Patients who underwent MRI with DWI for suspicion of spinal infections and microbiological sampling from 2002 to 2010 were identified and reviewed retrospectively in this institutional review board approved study. In addition to DWI, scans included sagittal and axial T1, fast-spin echo (FSE) T2, and post-gadolinium T1 with fat saturation. Regions of interest were drawn on apparent diffusion coefficient (ADC) maps in the area of suspected infections, and ADC values were correlated with microbiological sampling. RESULTS: Of 38 patients with suspected spinal infections, 29 (76%) had positive microbiological sampling, and 9 (24%) had negative results. The median ADC value was 740â€¯× 10-6 mm2/s for patients with positive microbiological sampling and 1980â€¯× 10-6 mm2/s for patients with negative microbiological sampling (p < 0.001). Using an ADC value of 1250â€¯× 10-6 mm2/s or less as the cut-off value for a positive result for spinal infection, sensitivity was 66%, specificity was 88%, positive predictive value was 95%, negative predictive value was 41% and accuracy was 70%. CONCLUSION: In patients with suspected spine infection, ADC values on DWI are significantly reduced in those patients with positive microbiological sampling compared to patients with negative microbiological sampling. The DWI of the spine correlates well with the presence or absence of spinal infection and may complement conventional magnetic resonance imaging (MRI).

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. Methods: 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. Thyrocyte-specific double-mutant BRAFV600E PIK3CAH1047R mice were treated with a MEK inhibitor followed by radioiodine treatment, and tumor burden was monitored by ultrasound imaging. Results: ATC cell lines showed an increase in sodium-iodine symporter transcription when treated with a MEK or BRAFV600E inhibitor alone and in combination with PI3'K inhibitor. This translated into a dose-dependent elevation of iodine uptake after treatment with a MEK inhibitor alone and in combination with a PI3'K inhibitor. In vivo, MEK inhibition but not BRAF or PI3'K inhibition upregulated sodium-iodine symporter transcription. This translated into a stable reduction of tumor burden when mice were treated with a MEK inhibitor before radioiodine administration. Conclusion: This study confirms the ability of MEK inhibition to induce iodine uptake in in vitro and in vivo models of ATC. The approach of using a MEK inhibitor before radioiodine treatment could readily be translated into clinical practice and provide a much-needed therapeutic option for patients with ATC.

The prognostic and predictive value of sstr2-immunohistochemistry and sstr2-targeted imaging in neuroendocrine tumors.

PURPOSE: Our aim was to assess the prognostic and predictive value of somatostatin receptor 2 (sstr2) in neuroendocrine tumors (NETs). METHODS: We established a tissue microarray and imaging database from NET patients that received sstr2-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 sstr2-imaging and sstr2-immunohistochemistry. RESULTS: We included a total of 279 patients. In these patients, sstr2-immunohistochemistry was an independent prognostic marker for overall survival (HR: 0.82, 95 % CI: 0.67 - 0.99, n = 279, p = 0.037). In DOTATOC patients, sstr2-expression on immunohistochemistry correlated with tumor uptake on sstr2-imaging (n = 170, p < 0.001); however, sstr2-imaging showed a higher prognostic accuracy (positive predictive value: +27 %, 95 % CI: 3 - 56 %, p = 0.025). Sstr2-expression did not predict a benefit of DOTATOC over alternative treatment (p = 0.93). CONCLUSIONS: Our results suggest sstr2 as an independent prognostic marker in NETs. Sstr2-immunohistochemistry correlates with sstr2-imaging; however, sstr2-imaging is more accurate for determining the individual prognosis.

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. Multivariable Cox regression analyses were used to study predictors of survival. RESULTS: Overall, 74 treatment cycles were performed on 34 patients. Stable disease was achieved in 23 patients. Severe hematotoxicity occurred in 3 patients, and severe renal toxicity in 1 patient. Mean survival was 8.6 y from the time of recruitment. Stable disease after treatment (hazard ratio, 0.017 vs. progressive disease; 95% confidence interval, 0.001-0.35; n = 34; P = 0.01) and high tumor uptake (hazard ratio, 0.046 vs. intermediate or low tumor uptake; 95% confidence interval, 0.004-0.63; n = 34; P = 0.019) were associated with longer survival. CONCLUSION: (90)Y-DOTATOC and (177)Lu-DOTATOC are promising tools for treating progressive unresectable meningioma, especially in cases of high tracer uptake in the tumor.

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. A total of 36 patients were enrolled; 30 patients received (90)Y-DOTATOC (median activity per patient 11.8GBq; range: 6.1-62.2GBq) and 6 patients received (90)Y-DOTATOC plus (177)Lu-DOTATOC (median activity per patient: 14.8GBq; range: 7.4-14.8GBq). Response was found in 26 patients (72.2%), including morphological (n=12, 33.3%), biochemical (n=14, 38.9%) and/or clinical response (n=6, 16.2%). A total of 21 patients (58.3%) experienced hematotoxicity grade 1/2, while 1 patient (2.8%) experienced hematotoxicity grade 3; no grade 4 hematotoxicity occurred. Furthermore, 2 patients (5.6%) developed grade 4 renal toxicity; no grade 5 renal toxicity occurred. Responders had a significantly longer median survival from time of enrollment than non-responders (45.1 months, range: 37.1-53.1 months vs. 12.6 months, range: 11.0-14.2, hazard ratio: 0.12 (0.027-0.52), p=0.005). Additionally, there was a trend towards longer median survival with (90)Y-DOTATOC plus (177)Lu-DOTATOC as compared to (90)Y-DOTATOC alone (60.2 months, range: 19.8-100.6 months vs. 27.0 months, range: 4.0-50.0, hazard ratio: 0.21 (0.01-3.98), p=0.16). Response to (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC therapy is associated with a longer survival in patients with metastasized gastrinoma. Both treatment regimens are promising tools for management of progressive gastrinoma.

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. PC-3 cell proliferation and (177)Lu-RM2 uptake after treatment with rapamycin were assessed in vitro. To determine the influence of rapamycin on (177)Lu-RM2 tumor uptake, in vivo small-animal PET studies with (68)Ga-RM2 were performed after treatment with rapamycin. To study the efficacy of (177)Lu-RM2 in vivo, mice with subcutaneous PC-3 tumors were treated with (177)Lu-RM2 alone or after pretreatment with rapamycin. RESULTS: Stable expression of GRPr was maintained after rapamycin treatment with doses up to 4 mg/kg in vivo. Monotherapy with (177)Lu-RM2 at higher doses (72 and 144 MBq) was effective in inducing complete tumor remission in 60% of treated mice. Treatment with 37 MBq of (177)Lu-RM2 and rapamycin in combination led to significantly longer survival than with either agent alone. No treatment-related toxicity was observed. CONCLUSION: Radiotherapy using a (177)Lu-labeled GRPr antagonist alone or in combination with rapamycin was efficacious in inhibiting in vivo tumor growth and may be a promising strategy for treatment of prostate cancer.

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. We observed strong neovascularization in the murine inflamed intestinal tract (IT) during GvHD. Positron emission tomography imaging demonstrated abundant αvß3 integrin expression within intestinal neovascularization areas. To interfere with neovascularization, we targeted αv integrin-expressing endothelial cells, which blocked their accumulation in the IT and reduced GvHD severity independent of immune reconstitution and graft-versus-tumor effects. Additionally, enhanced neovascularization and αv integrin expression correlated with GvHD severity in humans. Expression analysis of miRs in the inflamed IT of mice developing GvHD identified miR-100 as significantly downregulated. Inactivation of miR-100 enhanced GvHD indicating a protective role for miR-100 via blocking inflammatory neovascularization. Our data from the mouse model and patients indicate that inflammatory neovascularization is a central event during intestinal GvHD that can be inhibited by targeting αv integrin. We identify negative regulation of GvHD-related neovascularization by miR-100, which indicates common pathomechanistic features of GvHD and ischemia.

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. METHODS: We retrospectively analyzed 101 consecutive patients who underwent (18)F-DOPA PET or (18)F-DOPA PET/CT for known or suspected pheochromocytomas or paragangliomas. Maximum (18)F-DOPA tumor uptake was quantified relative to uptake in the liver. RESULTS: Histopathology, cross-sectional imaging, and follow-up indicated the presence of paragangliomas and pheochromocytomas in 68 patients and the absence of a tumor in 33 patients. The average (18)F-DOPA uptake by paragangliomas and pheochromocytomas, expressed as a tumor-to-liver ratio, was 5.9 ± 5.2. There was no significant difference in uptake among patients with von Hippel Lindau syndrome (VHL; n = 19), succinate dehydrogenase B-D mutation (n = 21), neurofibromatosis type 1 (n = 1), RET (n = 1), no germline mutation (n = 20), or unknown mutation status (n = 6) (P = 0.84). All 8 patients with an SDHD mutation were true-positive on (18)F-DOPA PET. There were 2 cases of false-negative results each in the group with SDHB (2/12) and VHL mutations (2/19) and 1 false-negative result in the subgroup of patients with unknown mutation status (1/6). Overall, (18)F-DOPA PET yielded a sensitivity of 93% and a specificity of 88% for the detection of paragangliomas and pheochromocytomas on a patient basis (positive and negative predictive value, 94% and 85%, respectively). CONCLUSION: (18)F-DOPA PET is a sensitive and specific imaging modality for the detection and staging of pheochromocytomas and paragangliomas in different genotypes, including VHL-, SDHB-, and SDHD-mutation carriers, and in patients with no germline mutation.

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-ß (TGF-ß) signaling by protecting phospho-Smad 2 and 3 from dephosphorylation. CLIC4 expression is diminished in multiple human epithelial cancers, and the protein is excluded from the nucleus. We now show that CLIC4 expression is reduced in chemically induced mouse skin papillomas, mouse and human squamous carcinomas and squamous cancer cell lines, and the protein is excluded from the nucleus. The extent of reduction in CLIC4 coincides with progression of squamous tumors from benign to malignant. Inhibiting antioxidant defense in tumor cells increases S-nitrosylation and nuclear translocation of CLIC4. Adenoviral-mediated reconstitution of nuclear CLIC4 in squamous cancer cells enhances TGF-ß-dependent transcriptional activity and inhibits growth. Adenoviral targeting of CLIC4 to the nucleus of tumor cells in orthografts inhibits tumor growth, whereas elevation of CLIC4 in transgenic epidermis reduces de novo chemically induced skin tumor formation. In parallel, overexpression of exogenous CLIC4 in squamous tumor orthografts suppresses tumor growth and enhances TGF-ß signaling. These results indicate that CLIC4 suppresses the growth of squamous cancers, that reduced CLIC4 expression and nuclear residence detected in cancer cells is associated with the altered redox state of tumor cells and the absence of detectable nuclear CLIC4 in cancers contributes to TGF-ß resistance and enhances tumor development.

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

UNLABELLED: PET with (18)F-labeled arginine-glycine-aspartic acid (RGD) peptides can visualize and quantify α(ν)ß(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[6.6.2]hexadecane (CB-TE2A) to radiolabel the cyclic pentapeptide c(RGDfK) with (68)Ga or (64)Cu. NODAGA-c(RGDfK) was labeled at room temperature with both radionuclides within 10 min. Incubation at 95°C for up to 30 min was used for the other conjugates. The affinity profile of the metallopeptides was evaluated by a cell-based receptor-binding assay. Small-animal PET studies and biodistribution studies were performed in nude mice bearing subcutaneous U87MG glioblastoma xenografts. RESULTS: The conjugates were labeled with a radiochemical purity greater than 97% and specific activities of 15-20 GBq/µmol. The affinity profile was similar for all metallopeptides and comparable to the reference standard c(RGDfV). In the biodistribution studies, all compounds demonstrated a relatively similar tumor and normal organ uptake at 1 h after injection that was comparable to published data on (18)F-labeled RGD peptides. At 18 h after injection, however, (64)Cu-NODAGA-c(RGDfK) and (64)Cu-CB-TE2A-c(RGDfK) showed up to a 20-fold increase in tumor-to-organ ratios. PET studies demonstrated high-contrast images of the U87MG tumors at 18 h, confirming the biodistribution data. CONCLUSION: The ease of radiolabeling makes (68)Ga-NODAGA-c(RGDfK) an attractive alternative to (18)F-labeled RGD peptides. The high tumor-to-background ratios of (64)Cu-NODAGA-c(RGDfK) and (64)Cu-CB-TE2A-c(RGDfK) at 18 h warrant testing of (64)Cu-labeled RGD peptides in patients.

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. Pooled or aggregate information from 11 key articles, including information on type and duration of IHE, study and comparison group characteristics, and measured outcomes such as self-reported changes in cultural competency, clinical skills, and specialty choice, were extracted and summarized. RESULTS: Findings suggest that having IHE experiences contributed to a more well-rounded training for medical students; students reported being more culturally competent and were more likely to choose a primary care specialty and/or a public service career. CONCLUSIONS: Although IHE experiences appear to have educational benefits, the quality and availability of these electives vary by institution. Barriers to ensuring that students attain a safe and rich experience include the lack of consistent categorical funding, safety concerns when traveling, and limited faculty experience and resources to support and guide students during their rotations abroad.

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. Eleven patients underwent standardized (18)F-FDOPA PET and 14 patients underwent (18)F-FDOPA PET/CT studies, with a median of 511 MBq of (18)F-FDOPA (range, 206-625 MBq). Two readers, unaware of the reports of other imaging studies and clinical data, analyzed all scans visually and quantitatively (maximum standardized uptake value [SUVmax] and maximum transverse diameter). Histology and long-term clinical follow-up served as the gold standard. Correlation between SUVmax of tumors and biochemical markers was evaluated. SUVmax of the benign and malignant tumors was compared. RESULTS: Seventeen patients underwent surgery. Histology confirmed pheochromocytoma or paraganglioma in 11 cases (8 adrenal, including 2 malignant tumors, and 3 extraadrenal, including 1 malignant tumor). The diagnosis of pheochromocytoma was established by follow-up in 2 additional patients (1 adrenal and 1 unknown location) and ruled out in 6 patients. Visual analysis detected and localized pheochromocytoma in 11 of 13 patients without false-positive results (sensitivity, 84.6%; specificity, 100%; accuracy, 92%). These lesions had an SUVmax of 2.3-34.9 (median, 8.3). Evaluation of the false-negative cases revealed a 13 x 5 mm lesion with an SUVmax of 1.96 in 1 case; no lesion was localized in the second case using multiple additional modalities. Spearman nonparametric analysis did not show statistically significant correlation between SUVmax of the tumors and biochemical markers. The Mann-Whitney nonparametric test did not demonstrate a statistically significant difference between the SUVmax of (18)F-FDOPA in malignant and benign tumors. CONCLUSION: (18)F-FDOPA PET and PET/CT are highly sensitive and specific tools that can provide additional independent information for diagnosis and localization of benign and malignant pheochromocytomas.

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. The aim of this study was to evaluate whether imaging of alpha(V)beta(3) integrin activity with positron emission tomography (PET) and [(64)Cu]DOTA-cyclo-(Arg-Gly-Asp-dPhe-Lys) {[(64)Cu]DOTA-c(RGDfK)} can be used for monitoring response to the SFK inhibitor dasatinib. Severe combined immunodeficient mice bearing U87MG xenografts were gavaged daily over 72 hours with 72 or 95 mg/kg of dasatinib or vehicle. Tumor uptake of [(64)Cu]DOTA-c(RGDfK) was measured by small-animal PET. In parallel, fluorodeoxyglucose (FDG) scans were performed to assess tumor metabolism in response to dasatinib treatment. Dasatinib significantly (P<0.0001) reduced [(64)Cu]DOTA-c(RGDfK) uptake by up to 59% in U87MG xenografts [2.10+/-0.14% injected dose/gram (ID/g) in the 95 mg/kg group and 3.12+/-0.18% ID/g in the 72 mg/kg group, versus 5.08+/-0.80% ID/g in controls]. In contrast, tumor FDG uptake showed no significant reduction with dasatinib therapy (8.13+/-0.45% ID/g in treated versus 10.39+/-1.04% ID/g in controls; P=0.170). Histologically, tumors were viable at the time of the follow-up PET scan but showed inhibition of focal adhesion kinase. Continued dasatinib treatment resulted in a significant inhibition of tumor growth (tumor size on day 10 of therapy: 21.13+/-2.60 mm(2) in treated animals versus 122.50+/-17.68 mm(2) in controls; P=0.001). [(64)Cu]DOTA-c(RGDfK) may provide a sensitive means of monitoring tumor response to SFK inhibition in alpha(V)beta(3)-expressing cancers early in the course of therapy.