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The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6–12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. ClinicalTrials.gov number: NCT00874614.

Arginine methylation has been recognized as a post-translational modification with pleiotropic effects that span from regulation of transcription to metabolic processes that contribute to aberrant cell proliferation and tumorigenesis. This has brought significant attention to the development of therapeutic strategies aimed at blocking the activity of protein arginine methyltransferases (PRMTs), which catalyze the formation of various methylated arginine products on a wide variety of cellular substrates. GSK3368715 is a small molecule inhibitor of type I PRMTs currently in clinical development. Here, we evaluate the effect of type I PRMT inhibition on arginine methylation in normal human peripheral blood mononuclear cells and utilize a broad proteomic approach to identify type I PRMT substrates. This work identified heterogenous nuclear ribonucleoprotein A1 (hnRNP-A1) as a pharmacodynamic biomarker of type I PRMT inhibition. Utilizing targeted mass spectrometry (MS), methods were developed to detect and quantitate changes in methylation of specific arginine residues on hnRNP-A1. This resulted in the development and validation of novel MS and immune assays useful for the assessment of GSK3368715 induced pharmacodynamic effects in blood and tumors that can be applied to GSK3368715 clinical trials.

TO THE EDITOR: I am writing with regard to the article “The Standard of Care: From Nuclear Radiology to Nuclear Medicine,” by Johannes Czernin, in the May 2020 edition of The Journal of Nuclear Medicine ( JNM ) ([1][1]). In this article, Dr. Czernin speaks to the rapidly evolving future of our

Background: Pheochromocytoma/Paraganglioma (PPGL) are rare neuroendocrine tumors with a 5-yr survival rate as low as 12%. There is a high unmet medical need for effective treatment options for patients with advanced disease. AZEDRA®, a high-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131-MIBG), is the first and only FDA-approved therapeutic radiopharmaceutical agent indicated for the treatment of adult and pediatric patients with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. Methods: Patients with advanced PPGL who were heavily pre-treated and were ineligible for curative surgery or chemotherapy received a dosimetric dose followed by up to two therapeutic doses (each at 296 MBq/kg to a max of 18.5 GBq). The primary endpoint, defined as the proportion of patients with at least 50% reduction of all antihypertensive medication(s) lasting ≥6 months, was met and previously reported. Updated secondary endpoints including overall survival (OS) and safety are reported. Results: A dosimetric dose of HSA I-131-MIBG was administered to 74 patients. Of those, 68 patients received one therapeutic dose and 50 received two doses of HSA I-131-MIBG. Clinical benefit rates (objective tumor responses defined by RECIST 1.0 and stable disease) were observed in 71.4% and 98.0% of patients receiving one and two therapeutic doses, respectively. As of October 10, 2019, median survival time for all patients was 43.2 months (95% CI 31.4, >60). Median survival time was 19.3 months (95% CI 4.5, 32.4) and 49.1 months (95% CI 36.9, >60) in patients receiving one and two doses, respectively. The overall survival was 73.8% at 2 yrs, 47.5% at 4 yrs and 41.5% at 5 yrs. The most common (≥50%) adverse events were nausea, fatigue, and myelosuppression. Myelosuppressive events resolved within 4-8 wks without requiring stem cell transplantation. Late radiation toxicity included 7 patients with secondary malignancies (myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), colon cancer, and lung carcinoma) of which MDS, ALL and AML were considered related to I-131 radiotherapy. Conclusions: Results from this pivotal phase 2 study suggest that HSA I-131-MIBG is an efficacious and safe treatment for advanced PPGL.

Background Abnormal beta-amyloid (Aβ) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer’s disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1–4, 2017). Previously, we established the scopolamine challenge test (SCT) as a “cognitive stress test” screening measure to identify individuals at risk for AD (Alzheimer’s & Dementia 10(2):262–7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval. Methods Older adults (N = 63, aged 55–75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam. Results Significant differences in both cognitive performance and in Aβ neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period. Conclusions Cognitive response to the SCT (Alzheimer’s & Dementia 10(2):262–7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

The range of pathology in adults that can produce abdominal pain is broad and necessitates an imaging approach to evaluate many different organ systems. Although localizing pain prompts directed imaging/management, clinical presentations may vary and result in nonlocalized symptoms. This review focuses on imaging the adult population with nonlocalized abdominal pain, including patients with fever, recent abdominal surgery, or neutropenia. Imaging of the entire abdomen and pelvis to evaluate for infectious or inflammatory processes of the abdominal viscera and solid organs, abdominal and pelvic neoplasms, and screen for ischemic or vascular etiologies is essential for prompt diagnosis and treatment. Often the first-line modality, CT quickly evaluates the abdomen/pelvis, providing for accurate diagnoses and management of patients with abdominal pain. Ultrasound and tailored MRI protocols may be useful as first-line imaging studies, especially in pregnant patients. In the postoperative abdomen, fluoroscopy may help detect anastomotic leaks/abscesses. While often performed, abdominal radiographs may not alter management. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity 131I-meta-iodobenzylguanidine (HSA 131I-MIBG) in patients with advanced PPGL. Methods: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA 131I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA 131I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 mo. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0, biochemical tumor marker response, overall survival, and safety. Results: Of the 68 patients who received at least 1 therapeutic dose of HSA 131I-MIBG, 17 (25%; 95% confidence interval, 16%–37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 mo. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed, with confirmed complete and partial responses 12 mo after treatment in 19 of 28 patients (68%). The median overall survival was 36.7 mo (95% confidence interval, 29.9–49.1 mo). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA 131I-MIBG. Conclusion: HSA 131I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.

Background: High-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131 MIBG; AZEDRA®) has been approved for the treatment of adult and pediatric patients (pts) 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. We have previously presented data showing improved biomarker responses in pts treated with HSA I-131 MIBG. Here we report the impact of biomarker status on the study primary endpoint and objective tumor response. Methods: Pts with iobenguane-avid PPGL who were ineligible for surgery, failed prior therapy or not candidates for chemotherapy, and on a stable antihypertensive medication regimen were treated. Pts received up to two therapeutic doses, each at ~18.5 GBq (or 296 MBq/kg for pts ≤62.5 kg), administered ~90 days apart. Biomarkers were analyzed at baseline and over a 12-month efficacy period. Confirmed biochemical responses (at least ≥ 50% decrease in abnormal tumor marker value for all hypersecreted biomarkers) required subsequent responses to be identical to or better compared with the previous assessment. The primary endpoint was clinical benefit, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) for ≥6 months beginning during the efficacy period. The secondary endpoint, confirmed objective tumor response by RECIST, was also evaluated. Results: 68 pts received at least one therapeutic dose of HSA I-131 MIBG. For all pts with hypersecretory tumors (with a baseline biochemical marker level of ≥1.5× ULN) (n=60), a comparison of biomarker response with antihypertensive therapy yielded a correlation coefficient of 0.35 (P = 0.006; Fisher exact P = 0.012). For pts with norepinephrine only-hypersecreting tumors (n=31), a correlation coefficient of 0.47 (P = 0.008; Fisher exact P = 0.015) was observed. The overall biomarker response also correlated with objective tumor response (n=55) yielding a correlation coefficient of 0.36 (P = 0.007; Fisher exact P = 0.012) for all pts with hypersecreted biomarkers. Pts who were not biochemical hypersecretors for any biomarker (n=6) had only one responder for the primary endpoint and no objective tumor responses. Conclusions: The biomarker data from this study establish a moderate but statistically significant correlation between biomarker response following treatment with HSA I-131 MIBG and objective tumor response and durable reduction of antihypertensive therapy. This correlation was improved with norepinephrine only-hypersecreting tumors in pts with unresectable, locally advanced or metastatic PPGL.

Context No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States. Objective To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL. Design Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg. Setting Three centers. Patients Twenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Intervention Open-label use of high-specific-activity I-131 MIBG therapy. Main Outcome Measures Dose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival. Results The MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received >18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity. Conclusions These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg.

Pancreatic adenocarcinoma is associated with poor overall prognosis. Complete surgical resection is the only possible option for cure. As such, increasingly complex surgical techniques including sophisticated vascular reconstruction are being used. Continued advances in surgical techniques, in conjunction with use of combination systemic therapies, and radiation therapy have been suggested to improve outcomes. A key aspect to surgical success is reporting of pivotal findings beyond absence of distant metastases, such as tumor size, location, and degree of tumor involvement of specific vessels associated with potential perineural tumor spread. Multiphase contrast-enhanced multidetector CT and MRI are the imaging modalities of choice for pretreatment staging and presurgical determination of resectability. Imaging modalities such as endoscopic ultrasound and fluorine-18-2-fluoro-2-deoxy-D-glucose imaging with PET/CT are indicated for specific scenarios such as biopsy guidance and confirmation of distant metastases, respectively. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Because liver fibrosis can be treated, it is important to diagnose liver fibrosis noninvasively and monitor response to treatment. Although ultrasound (grayscale and Doppler) can diagnose cirrhosis, it does so unreliably using morphologic and sonographic features and cannot diagnose the earlier, treatable stages of hepatic fibrosis. Transient elastography, ultrasound elastography with acoustic radiation force impulse, and MR elastography are modalities that can assess for hepatic fibrosis. Although all international organizations recommend ultrasound for screening for hepatocellular carcinoma, ultrasound is particularly limited for identifying hepatocellular carcinoma in patients with obesity, nonalcoholic fatty liver disease, and nodular cirrhotic livers. In these patient groups as well as patients who are on the liver transplant wait list, ultrasound is so limited that consideration can be made for screening for hepatocellular carcinoma with either MRI or multiphase CT. Additionally, patients who have been previously diagnosed with and treated for hepatocellular carcinoma require continued surveillance for recurrent hepatocellular carcinoma. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Liver metastases are the most common malignant liver tumors. The accurate and early detection and characterization of liver lesions is the key to successful treatment strategies. Increasingly, surgical resection in combination with chemotherapy is effective in significantly improving survival if all metastases are successfully resected. MRI and multiphase CT are the primary imaging modalities in the assessment of liver metastasis, with the relative preference toward multiphase CT or MRI depending upon the clinical setting (ie, surveillance or presurgical planning). The optimization of imaging parameters is a vital factor in the success of either modality. PET/CT, intraoperative ultrasound are used to supplement CT and MRI. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

OBJECTIVE. The purpose of this study was to compare the sensitivity, specificity, and helpfulness to referring clinicians of labeled leukocyte scintigraphy versus FDG PET/CT in inpatients with suspected infection. MATERIALS AND METHODS. In this retrospective study, labeled leukocyte scintigraphy and FDG PET/CT examinations performed from 2009 to 2017 for suspected infection in inpatients were identified. Sensitivity, specificity, and helpfulness of PET/CT versus labeled leukocyte scintigraphy were calculated by means of a mixed generalized linear model. Number of yearly tests and radiopharmaceutical costs were also assessed. RESULTS. Fifty-seven patients (30 men, 27 women; median age, 65 years; range, 21-91 years) underwent whole-body labeled leukocyte scintigraphy. Forty-two patients (30 male patients, 12 female patients; median age, 62.5 years; range, 12-91 years) underwent PET/CT for suspected infection. Labeled leukocyte scintigraphy was 66.7% sensitive, whereas the sensitivity of PET/CT was 89.7% (p = 0.0485). The higher sensitivity of PET/CT did not come at a cost to specificity, which was 73.3% as opposed to 76.9% for labeled leukocyte scintigraphy (p = 0.8050). The odds of a positive study being helpful increased 4.6-fold for PET/CT versus labeled leukocyte scintigraphy (p = 0.0412). From 2009 to 2011, 33 labeled leukocyte scintigraphic examinations were performed versus two PET/CT examinations; and from 2012 to 2014, 16 labeled leukocyte scintigraphic versus 22 PET/CT examinations; from 2015 to 2017, eight labeled leukocyte scintigraphic versus 18 PET/CT examinations. The cost of labeled leukocytes increased between 2009 and 2017, but that of FDG decreased. By 2017, a labeled leukocyte radiopharmaceutical dose was approximately 10 times the cost of an FDG dose. CONCLUSION. PET/CT was more sensitive than and as specific as labeled leukocyte scintigraphy for identifying a source of infection in inpatients, and it was more helpful to referring clinicians. Use of PET/CT increased over time and was associated with substantial savings in radiopharmaceutical cost.

Jaundice is the end result of myriad causes, which makes the role of imaging in this setting particularly challenging. In the United States, the most common causes of all types of jaundice fall into four categories including hepatitis, alcoholic liver disease, blockage of the common bile duct by a gallstone or tumor, and toxic reaction to a drug or medicinal herb. Clinically, differentiating between the various potential etiologies of jaundice requires a detailed history, targeted physical examination, and pertinent laboratory studies, the results of which allow the physician to categorize the type of jaundice into mechanical or nonmechanical causes. Imaging modalities used to evaluate the jaundiced patient (all etiologies) include abdominal ultrasound (US), CT, MR cholangiopancreatography, endoscopic retrograde cholangiopancreatography and endoscopic US. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

The objective of the study was to determine if time to positive (TTP), defined as the time from the start of (99m)Tc-labeled RBC scanning to the appearance of a radionuclide blush (considered to be a positive finding for acute lower gastrointestinal bleeding [LGIB]), and lag time (LT), defined as the time from the appearance of a radionuclide blush to the start of catheter angiography (CA), affected the yield of CA for the detection of acute LGIB.TTP and LT were retrospectively evaluated in 120 patients who had positive findings for acute LGIB on (99m)Tc-labeled RBC scanning and subsequently underwent CA for the diagnosis and localization of gastrointestinal bleeding. Two nuclear medicine fellowship-trained radiologists independently reviewed the (99m)Tc-labeled RBC scans. Two fellowship-trained interventional radiologists independently reviewed the angiograms. All data were analyzed using SAS software.When a TTP threshold of ≤ 9 minutes was used, the sensitivity, specificity, positive predictive value, and negative predictive value for a positive CA study were 92%, 35%, 27%, and 94%, respectively. In addition, the odds of detecting bleeding on CA increased 6.1-fold with a TTP of ≤ 9 minutes relative to a TTP of9 minutes (p = 0.020). A significant inverse relationship was found between LT and a positive CA study (p = 0.041).TTP and LT impact the rate of positive CA studies. A TTP threshold of ≤ 9 minutes allows the detection of almost all patients who would benefit from CA for treatment and allows a reduction in unnecessary negative CA studies. The likelihood of positive findings on CA decreases with a delay in the performance of CA.

Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.

INTRODUCTION AND OBJECTIVE:Pheochromocytoma/Paraganglioma (PPGL) are rare neuroendocrine tumors with a 5-yr survival rate as low as 12%. Effective treatment options for patients with advanced disea...

The range of pathology in adults that can produce abdominal pain is broad and necessitates an imaging approach to evaluate many different organ systems. Although localizing pain prompts directed imaging/management, clinical presentations may vary and result in nonlocalized symptoms. This review focuses on imaging the adult population with nonlocalized abdominal pain, including patients with fever, recent abdominal surgery, or neutropenia. Imaging of the entire abdomen and pelvis to evaluate for infectious or inflammatory processes of the abdominal viscera and solid organs, abdominal and pelvic neoplasms, and screen for ischemic or vascular etiologies is essential for prompt diagnosis and treatment. Often the first-line modality, CT quickly evaluates the abdomen/pelvis, providing for accurate diagnoses and management of patients with abdominal pain. Ultrasound and tailored MRI protocols may be useful as first-line imaging studies, especially in pregnant patients. In the postoperative abdomen, fluoroscopy may help detect anastomotic leaks/abscesses. While often performed, abdominal radiographs may not alter management. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Founded in 1951, the Joint Commission, formerly known as the Joint Commission on Accreditation of Healthcare Organizations and, previous to that, the Joint Commission on Accreditation of Hospitals, is a United States–based nonprofit organization that accredits more than 20,000 health care

Pancreatic adenocarcinoma is associated with poor overall prognosis. Complete surgical resection is the only possible option for cure. As such, increasingly complex surgical techniques including sophisticated vascular reconstruction are being used. Continued advances in surgical techniques, in conjunction with use of combination systemic therapies, and radiation therapy have been suggested to improve outcomes. A key aspect to surgical success is reporting of pivotal findings beyond absence of distant metastases, such as tumor size, location, and degree of tumor involvement of specific vessels associated with potential perineural tumor spread. Multiphase contrast-enhanced multidetector CT and MRI are the imaging modalities of choice for pretreatment staging and presurgical determination of resectability. Imaging modalities such as endoscopic ultrasound and fluorine-18-2-fluoro-2-deoxy-D-glucose imaging with PET/CT are indicated for specific scenarios such as biopsy guidance and confirmation of distant metastases, respectively. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Introduction Postmortem studies suggest that fibrillar brain amyloid places people at higher risk for hazardous driving in the preclinical stage of Alzheimer's disease (AD). Methods We administered driving questionnaires to 104 older drivers (19 AD, 24 mild cognitive impairment, and 61 cognitive normal) who had a recent 18 F-florbetapir positron emission tomography scan. We examined associations of amyloid standardized uptake value ratios with driving behaviors: traffic violations or accidents in the past 3 years. Results The frequency of violations or accidents was curvilinear with respect to standardized uptake value ratios, peaking around a value of 1.1 (model r 2 = 0.10, P = .002); moreover, this relationship was evident for the cognitively normal participants. Discussion We found that driving risk is strongly related to accumulating amyloid on positron emission tomography, and that this trend is evident in the preclinical stage of AD. Brain amyloid burden may in part explain the increased crash risk reported in older adults.

Breast lymphoscintigraphy using 99mTc-sulfur colloid (99mTc-SC) is well established in clinical practice for staging patients with breast carcinoma. Nearly all patients report having pain during the procedure. However, techniques used to minimize pain during breast lymphoscintigraphy are highly variable across institutions. Our study was to determine whether anesthetizing the skin with sodium bicarbonatehether–buffered lidocaine before performing breast lymphoscintigraphy reduced the pain experienced by the patients. The second objective of this study was to evaluate whether anesthetizing the skin with buffered lidocaine changed visualization of lymph nodes. Methods: This prospective, patient-masked and randomized study involved performing breast lymphoscintigraphy in a control group and experimental group of female breast cancer patients. The control group did not receive skin anesthetic before 99mTc-SC injections, whereas the experimental group first underwent skin anesthesia with an injection of 2% sodium bicarbonate–buffered lidocaine. All patients were asked to rate their pain levels, using the National Institutes of Health pain scale, before the procedure and immediately after the injections. The change in pain from baseline was compared between the 2 groups. After the injections, scintigraphic imaging of the axilla was performed, and the number of axillary lymph nodes visualized was recorded. Results: No significant difference was found in preprocedural baseline pain from the control group, compared with the experimental group. There was a statistically significant difference in the increase in pain experienced during the procedure between the control group and the experimental group (P = 0.009). There was no significant difference in the detection of lymph nodes between the control and experimental groups (P = 0.56). Conclusion: The results from our study indicate that injecting subcutaneous buffered lidocaine before intradermal injection of 99mTc-SC for breast lymphoscintigraphy significantly decreases patient pain without interfering with lymph node visualization.

Recent studies have proposed that overdiagnosis is probably the principal cause of the increased incidence of thyroid cancer. The controversy around radioiodine ablation is complicated by the ever increasing numbers of small, low-risk thyroid cancers being diagnosed. This article examines the history and evolving epidemiology of the disease and treatment.

LXRs have been of interest as targets for the treatment of atherosclerosis for over a decade. In recent years, LXR modulators have also garnered interest for potential use in the treatment of inflammation, Alzheimer's disease (AD), dermatological conditions, hepatic steatosis, and oncology. To date, no LXR modulator has successfully progressed beyond phase I clinical trials. In this Perspective, we summarize published medicinal chemistry efforts in the context of the available crystallographic data, druglikeness, and isoform selectivity. In addition, we discuss the challenges that need to be overcome before an LXR modulator can reach clinical use.

4108 Background: PPGL, rare neuroendocrine tumors with a 5-yr survival rate as low as 12%, have a high unmet need for effective treatment options. AZEDRA, a high-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131-MIBG), is the first and only FDA- approved therapeutic radiopharmaceutical agent indicated for the treatment of adult and pediatric pts with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. Methods: Pts with advanced disease who were heavily pre-treated and were ineligible for curative surgery or chemotherapy received a dosimetric dose followed by up to two therapeutic doses (each at 296 MBq/kg to a max of 18.5 GBq). The primary endpoint, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) lasting ≥6 months, was met and previously reported. Updated secondary endpoints including overall survival (OS) and safety are reported. Results: A dosimetric dose of HSA I-131-MIBG was administered to 74 pts. Of those, 68 pts received one therapeutic dose and 50 received two doses of HSA I-131-MIBG. Clinical benefit rates (objective tumor responses defined by RECIST 1.0 and stable disease) were observed in 71.4% and 98.0% of pts receiving one and two therapeutic doses, respectively. As of Jan 25, 2019, median OS for all pts was 41.1 months (95% CI 31.1, 91.2). Median OS was 17.5 months (95% CI 4.0, 31.5) and 48.7 months (95% CI 33.2, 91.2) in pts receiving one and two doses, respectively. A tail of survival was observed, with OS of 73.1% at 2 yrs and 44.2% at 4 yrs. The most common (≥50%) adverse events were nausea, fatigue, and myelosuppression. Myelosuppressive events resolved within 4-8 wks without requiring stem cell transplantation. Late radiation toxicity included 8 pts with secondary malignancies (myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), colon cancer, and lung carcinoma) of which MDS, ALL and AML were considered related to I-131 radiotherapy. Conclusions: Updated results from this pivotal phase 2 study suggest that HSA I-131-MIBG is an efficacious and safe treatment for advanced PPGL. Clinical trial information: NCT00874614.

Fever without source is a febrile illness without localizing signs or initial obvious cause. Early workup will often include chest radiography and computed tomography (CT) of the abdomen and pelvis, with or without CT of the chest. To evaluate localizing signs or symptoms or to further evaluate findings from initial studies, targeted imaging according to body part can be performed by using radiography, ultrasonography, CT, or magnetic resonance (MR) imaging. Nuclear medicine studies can provide imaging of the whole body and may be helpful when the clinical and conventional imaging workup findings are negative or equivocal in identifying a source of fever. Nuclear medicine studies can be used to detect pathologic changes early in a disease course, even in the absence of an anatomic abnormality. Gallium 67 scintigraphy, indium 111- and technetium 99m-labeled leukocyte scintigraphy, and fluorine 18 fluorodeoxyglucose positron emission tomography (PET)/CT studies are all useful in the evaluation of fever, but the radiopharmaceutical cost for PET/CT is much lower than that for radiolabeled leukocyte studies. The increased use of bundled payments for inpatient admissions requires updated cost evaluations for the preferred nuclear medicine study. For inpatients in whom the findings from the initial clinical workup and imaging studies are nondiagnostic, PET/CT examination may be preferable to radiolabeled leukocyte studies because of its high sensitivity and lower cost. Negative findings at PET/CT can be helpful in excluding a suspected site of infection, and positive findings at PET/CT can be helpful in confirming a suspected site of infection or in identifying an unexpected cause of fever. (©)RSNA, 2016.

Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aβ) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aβ levels was detected.

This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor β (LXRβ) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRβ and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRβ with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.

Objectifs : determiner le profil epidemioclinique de la population source en nephrologie afin d’orienter la mise en place des moyens de prevention nephrologique au Togo. Methodologie : etude monocentrique prospective et descriptive du 1er janvier au 31 decembre 2012 dans le service de nephrologie et d’hemodialyse du CHU Sylvanus Olympio. Les donnees recueillies sont : la specialite du correspondant medical, le motif de consultation (MDC), les caracteristiques sociodemographiques et le bilan renal initial des patients. Resultats : en 2012, 198 nouveaux patients ont ete recus en consultation externe de nephrologie ; l’âge moyen des patients etait de 51 ± 18 ans (16 a 82 ans) et un sex-ratio H/F de 1,5. Le patient a ete adresse par un medecin generaliste dans quatre-vingt-dix-sept cas (49 %), un assistant medical dans dix-neuf cas (9,6 %), un cardiologue dans vingt-trois cas (11,6 %), un infirmier dans douze cas (6,1 %) et il est venu de lui-meme dans sept cas (3,5 %). Le MDC etait l’insuffisance renale dans 145 cas (73,2 %), un syndrome nephrotique dans dix cas (5 %), une hypertension arterielle dans onze cas (5,6 %) et une polykystose renale dans six cas (3 %). La creatininemie moyenne de consultation etait de 90 mg/L (15 a 398 mg/L). Leur debit de filtration glomerulaire initial etait inferieur a 15 mL/min dans 130 cas (89,7 %), entre 15 et 30 mL/min dans neuf cas (6,2 %) et entre 30 et 60 mL/min dans six cas (4,1 %). Conclusion : l’insuffisance renale, surtout a un stade avance, reste malheureusement le principal motif de consultation au Togo.

Dramatic improvements in diagnostic imaging have developed with and enabled increasingly sophisticated treatments for metastatic colorectal cancer. Advances in therapeutic techniques, such as surgical resection and percutaneous therapies, demand that diagnostic imaging provide an accurate assessment of disease burden as well as precise localization. In this article, we present the current state-of-the-art of diagnostic imaging for evaluation of metastatic colorectal cancer. J. Surg. Oncol. 2010;102:909–913. © 2010 Wiley-Liss, Inc.

4005Background: AZEDRA, a high-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131 MIBG), has been developed for the treatment of iobenguane-avid malignant (metastatic) or recurrent or...

e21211Background: Radium-223 dichloride (Ra-223) is a targeted- alpha particle emitting therapy directed at bone metastases with high-linear energy transfer at a short-range. This study investigate...

Objectives Sentinel lymph node (SLN) dissections have a high sensitivity and negative predictive value for the detection of metastatic disease. The objective of this study was to examine the inguinal recurrence rate along with complication rates for patients undergoing inguinal SLN dissection alone for vulvar carcinoma. Methods An IRB approved prospective study enrolled patients with biopsy proven squamous cell carcinoma of the vulva. Peritumoral injection of Tc-99 sulfur colloid and methylene blue dye was used to identify SLNs intraoperatively. Patients with SLNs negative for metastatic disease were followed clinically. Patients with metastasis detected in a SLN subsequently underwent a full groin node dissection followed by standard treatment protocols. Results Thirty-six patients were enrolled onto study with 35 undergoing a SLN dissection. All SNL dissections were successful with a mean of 2 SLN obtained per groin. There were 24 patients with stage I disease, 8 stage II, 3 stage III and 1 stage IV. A total of 56 SLN dissections were performed with 4 patients found to have inguinal metastasis by SLN dissection. There were 31 patients with a total of 46 SLN dissections found to be negative for metastatic disease. The median follow-up has been 29 months (range 8 to 51) with 2 groin recurrences for a groin recurrence rate of 4.3% and a recurrence rate per patient of 6.4%. There have been no reports of groin breakdown, extremity cellulitis or lymphedema. Conclusions The recurrence rate for patients undergoing inguinal sentinel node dissection alone is low. These patients did not experience any complications as seen with complete groin node dissections. Sentinel lymph node dissection should be considered as an option for evaluation of inguinal nodes for metastatic disease.