Analysis of Longitudinal Assessment: Role of Radiology Online Longitudinal Assessment-Type Questions.

OBJECTIVE: The purpose of this investigation was to assess gaps in radiologists' medical knowledge using abdominal subspecialty online longitudinal assessment (OLA)-type questions. Secondarily, we evaluated what question-centric factors influenced radiologists to pursue self-directed additional reading on topics presented. METHODS: A prospective OLA-type test was distributed nationally to radiologists over a 4-month period. Questions were divided into multiple groupings, including arising from three different time periods of literature (≤5 years, 6-15 years, and >20 years), relating to common versus uncommon modalities, and guideline-based versus knowledge-based characterization. After each question, participants rated their confidence in diagnosis and perceived question relevance. Answers were provided, and links to answer explanations and references were provided and tracked. A series of regression models were used to test potential predictors of correct response, participant confidence, and perceived question relevance. RESULTS: In all, 119 participants initiated the survey, with 100 answering at least one of the questions. Participants had significantly lower perceived relevance (mean: 51.3, 59.2, and 62.1 for topics ≤5 years old, 6-15 years old, and >20 years old, respectively; P < .001) and confidence (mean: 48.4, 57.8, and 63.4, respectively; P < .001) with questions on newer literature compared with older literature. Participants were significantly more likely to read question explanations for questions on common modalities compared with uncommon (46% versus 40%; P = .005) and on guideline-based questions compared with knowledge-based questions (49% versus 43%; P = .01). DISCUSSION: OLA-type questions function by identifying areas in which radiologists lack knowledge or confidence and highlight areas in which participants have interest in further education.

Pretargeting with Cucurbituril-Adamantane Host-Guest Pair in Xenograft Models.

The goal of reducing the total-body radiation dose of macromolecule-based nuclear medicine with a 2-step pretargeting strategy has been achieved with several pretargeting methodologies in preclinical and clinical settings. However, the lack of modularity, biocompatibility, and in vivo stability in existing pretargeting agents obstructs their respective platforms' wide clinical use. We hypothesized that host-guest chemistry would provide an optimal pretargeting methodology. A cucurbit[7]uril host and an adamantane guest molecule form a high-affinity host-guest complex (association constant, ∼1014 M-1), and in this work, we explored the use of this noncovalent interaction as the basis for antibody-based pretargeted PET. Along with the straightforward modularity of these agents, cucurbit[7]uril and adamantane are recognized to have high in vivo stability and suitability for human use, which is why we proposed this methodology as the ideal approach for pretargeted nuclear medicine. Methods: Three 64Cu-labeled adamantane guest radioligands were developed, and their in vitro stability, lipophilicity, and in vivo blood half-lives were compared. The adamantane radioligands were analyzed for pretargeting using a cucurbit[7]uril-modified carcinoembryonic antigen-targeting full-length antibody, hT84.66-M5A, as the macromolecule pretargeting agent with 2 different dosing schedules. These molecules were evaluated for pretargeting in human pancreatic cancer BxPC3 and MIAPaCa-2 mouse xenografts using PET and in vivo biodistribution studies. The dosimetry of the cucurbit[7]uril-adamantane (CB7-Adma) pretargeting approach in men was calculated and compared with that of the directly 89Zr-labeled hT84.66-M5A. Results: The adamantane radioligands possessed high in vitro stability up to 24 h (>90%). Pretargeted PET with CB7-Adma methodology resulted in specific tumor uptake (P < 0.05) with low background signal. The in vivo formed CB7-Adma complex was demonstrated to be stable, with high tumor uptake up to 24 h after radioligand injection (12.0 ± 0.9 percentage injected dose/g). The total-body radiation dose of the pretargeting strategy was only 3.3% that of the directly 89Zr-labeled hT84.66-M5A. Conclusion: The CB7-Adma strategy is highly suitable for pretargeted PET. The exceptional stability of the pretargeting agents and the specific and high tumor uptake of the pretargeted adamantane radioligands provide great potential for the platform.

Investigation of Copper-64-Based Host-Guest Chemistry Pretargeted Positron Emission Tomography.

Pretargeting is a technique that uses macromolecules as targeting agents for nuclear imaging and therapy with the goal of reducing the radiation toxicity to healthy tissues often associated with directly radiolabeled macromolecules. In pretargeting, a macromolecule is radiolabeled in vivo at the target site using a radiolabeled small molecule (radioligand) that interacts with the macromolecule with high specificity. We report an investigation of host-guest chemistry-driven pretargeting using copper-64 radiolabeled ferrocene (Fc; guest) compounds and a cucurbit[7]uril (CB7; host) molecule functionalized carcinoembryonic antigen targeting hT84.66-M5A monoclonal antibody (CB7-M5A). Two novel ferrocene-based radioligands ([64Cu]Cu-NOTA-PEG3-Fc and [64Cu]Cu-NOTA-PEG7-Fc) were prepared, and their in vitro stability, pharmacokinetic in vivo profile in healthy mice, and pretargeting performance in a subcutaneous BxPC3 human pancreatic cancer cell xenograft mouse model were compared. The antibody dosing was optimized using a zirconium-89 radiolabeled M5A antibody ([89Zr]Zr-DFO-M5A) in a BxPC3 xenograft model, and the dosimetry of [89Zr]Zr-DFO-M5A and the pretargeting approach were compared. Finally, the effects of varying lag times up to 9 days between CB7-M5A and radioligand injection were investigated. In vivo pretargeting studies with both ferrocene radioligands resulted in specific tumor uptake (p = 0.0006 and p = 0.003) and also showed that the host-guest-based pretargeting approach excels with extended lag times up to 9 days with good tumor localization, suggesting that host-guest pretargeting may be suitable for use without clearing agents which have complicated clinical application of this technique. To our knowledge, the reported lag time of 9 days is the longest investigated lag time in any reported pretargeting studies.

Cucurbituril-Ferrocene: Host-Guest Based Pretargeted Positron Emission Tomography in a Xenograft Model.

Pretargeted positron emission tomography is a macromolecule-driven nuclear medicine technique that involves targeting a preadministered antigen target-bound macromolecule with a radioligand in vivo, aiming to minimize the overall radiation dose. This study investigates the use of antibody based host-guest chemistry methodology for pretargeted positron emission tomography. We hypothesize that the novel pretargeting approach reported here overcomes the challenges the current pretargeting platforms have with the in vivo stability and modularity of the pretargeting components. A cucurbit[7]uril host molecule modified, anti-carcinoembryonic antigen antibody (M5A; CB7-M5A) and a 68Ga-radiolabeled ferrocene guest radioligand ([68Ga]Ga-NOTA-PEG3-NMe2-Fc) were studied as potential host-guest chemistry pretargeting agents for positron emission tomography in BxPC3 xenografted nude mice. The viability of the platform was studied via in vivo biodistribution and positron emission tomography. Tumor uptake of [68Ga]Ga-NOTA-PEG3-NMe2-Fc was significantly higher in mice which received CB7-M5A prior to the radioligand injection (pretargeted) (3.3 ± 0.7%ID/g) compared to mice which only received the radioligand (nonpretargeted) (0.2 ± 0.1%ID/g).

Electromagnetic Navigational Bronchoscopy versus CT-guided Percutaneous Sampling of Peripheral Indeterminate Pulmonary Nodules: A Cohort Study.

Purpose To compare the diagnostic yield and complication rates of electromagnetic navigational bronchoscopic (ENB)-guided and computed tomography (CT)-guided percutaneous tissue sampling of lung nodules. Materials and Methods Retrospectively identified were 149 patients sampled percutaneously with CT guidance and 146 patients who underwent ENB with transbronchial biopsy of a lung lesion between 2013 and 2015. Clinical data, incidence of complications, and nodule pathologic analyses were assessed through electronic medical record review. Lung nodule characteristics were reviewed through direct image analysis. Molecular marker studies and pathologic analyses from surgical excision were reviewed when available. Multiple-variable logistic regression models were built to compare the diagnostic yield and complication rates for each method and for different patient and disease characteristics. Results CT-guided sampling was more likely to be diagnostic than ENB-guided biopsy (86.0% [129 of 150] vs 66.0% [99 of 150], respectively), and this difference remained significant even after adjustments were made for patient and nodule characteristics (P < .001). Age, American Society of Anesthesiologists class, emphysema grade, nodule size, and distance from pleura were not significant predictors of increased diagnostic yield. Intraprocedural time for physicians was significantly lower with CT-guided sampling (P < .001). Similar yield for molecular analyses was noted with the two approaches (ENB-guided sampling, 88.9% [32 of 36]; CT-guided sampling, 82.0% [41 of 50]). The two groups had similar rates of major complications (symptomatic hemorrhage, P > .999; pneumothorax requiring chest tube and/or admission, P = .417). Conclusion CT-guided transthoracic biopsy provided higher diagnostic yield in the assessment of peripheral pulmonary nodules than navigational bronchoscopy with a similar rate of clinically relevant complications. © RSNA, 2017 Online supplemental material is available for this article.

Low Compliance in a Health-Conscience Spending Era Likely Helps Obviates the Need for 6 month BI-RADS 3 Breast MRI Follow-up After 1 year.

The goal of our IRB-approved study was to assess if a follow-up MRI every 6 months for 2 years is the most appropriate short-interval follow-up schedule. 203 breast MRI exams were performed from October 2009 to January 2014 as part of a BI-RADS 3 follow-up representing 2.6% of all breast MRIs (7,822) performed. We performed a retrospective longitudinal medical records review of compliance; malignancy rate of BI-RADS 3 exams; and average time and number of breast MRIs necessary prior to definitive disposition. While 77.8% eventually returned, only 45.5% of patients were compliant with follow-up at or near 6 months (4.5-7.5 months). Of those who eventually returned, it took an average of 1.31 follow-up MRIs (95% CI: 1.20-1.43 exams) and 10.3 months (95% CI: 9.0-11.7 months) before definitive disposition. 93.5% of initial findings were dispositioned as benign after two follow-up MRI exams (malignancy rate: 0.98%). Our results lend support to the possibility that the follow-up interval for BI-RADS 3 breast MRIs could be lengthened to 12 months if additional follow-up MRIs are necessary after the first year of 6-month follow-up breast MRIs. Foremost, this appears to be a safe follow-up alternative since benign definitive disposition can usually be made in less than 1 year. Supplemental reasons include persistent low-patient compliance (as redemonstrated in our study) and the higher cost of breast MRI compared to mammogram/ultrasound follow-up. Finally, this paper's findings further support the suggested MRI follow-up interval in the newest BI-RADS atlas.

Prognostic value of RV function before and after lung transplantation.

OBJECTIVES: We investigated the effects of lung transplantation on right ventricular (RV) function as well as the prognostic value of pre- and post-transplantation RV function. BACKGROUND: Although lung transplantation success has improved over recent decades, outcomes remain a challenge. Identifying predictors of mortality in lung transplant recipients may lead to improved long-term outcomes after lung transplantation. METHODS: Eighty-nine (age 60 ± 6 years, 58 men) consecutive patients who underwent single or double lung transplantation and had pre- and post-transplantation echocardiograms between July 2001 and August 2012 were evaluated. Echocardiographic measurements were performed before and after lung transplantation. Left ventricular (LV) and RV longitudinal strains were analyzed using velocity vector imaging. Cox proportional prognostic hazard models predicting all-cause death were built. RESULTS: There were 46 all-cause (52%) and 17 cardiac (19%) deaths during 43 ± 33 months of follow-up. After lung transplantation, echocardiography showed improved systolic pulmonary artery pressure (SPAP) (50 ± 19 mm Hg to 40 ± 13 mm Hg) and RV strain (-17 ± 5% to -18 ± 4%). No pre-transplantation RV parameter predicted all-cause mortality. After adjustment for age, sex, surgery type, and etiology of lung disease in a Cox proportional hazards model, both post-transplantation RV strain (hazard ratio: 1.13, 95% confidence interval: 1.04 to 1.23, p = 0.005), and post-transplantation SPAP (hazard ratio: 1.03, 95% confidence interval: 1.01 to 1.05, p = 0.011) were independent predictors of all-cause mortality. When post-transplantation RV strain and post-transplantation SPAP were added the clinical predictive model based on age, sex, surgery type, and etiology, the C-statistic improves from 0.60 to 0.80 (p = 0.002). CONCLUSIONS: Alterations of RV function and pulmonary artery pressure normalize, and post-transplantation RV function may provide prognostic data in patients after lung transplantation. Our study is based on a highly and retrospectively selected group. We believe that larger prospective studies are warranted to confirm this result.

Developing a protocol for gastrostomy tube insertion in patients diagnosed with head and neck cancer.

Selecting patients with head and neck cancer requiring a pretreatment gastrostomy feeding tube is not straightforward. The nutritional status and functional deficits associated with the cancer, its treatment, and the long-term side effects predicate the need for gastrostomy tube placement. However, gastrostomy tubes are not without morbidity and are an added burden to the patient. The aim of this retrospective case series review was to evaluate the clinical characteristics of newly diagnosed patients with head and neck cancer treated with curative intent having gastrostomy placement, with the intent of developing a protocol to help with the timely selection of patients for pretreatment gastrostomy insertion. A gastrostomy tube was placed in 32%. A regression model identified 5 independent predictors (P < .001) to predict gastrostomy tube placement: overall clinical stage, tumor site, clinical T stage, patient age, and clinical N stage. A protocol to help the multidisciplinary team to decide whether a pretreatment gastrostomy tube should be placed is suggested.

Uptake and translocation of metals in fenugreek grown on soil amended with tannery sludge: involvement of antioxidants.

Agricultural and industrial activities cause heavy metal pollution in the soil, which adversely affect the plant growing therein. The plants of fenugreek (Trigonella foenum-graecum L.) were grown in soil amended with different percent of tannery sludge (TS) (10%, 25%, 35%, 50%, and 100% TS) in order to study the effect on antioxidant levels due to translocation of metals (Fe, Zn, Mn, Cu, Cr, Pb). The accumulation of the metals was found more in shoots than roots, except Fe and Cr. The level of metals in seeds of the plant increased with increase in sludge amendments ratio except Mn, which decreased in roots, shoots, and seeds of the plant. Chromium was found below detection limits in the seeds at 10% and 25% TS. Correlation coefficient (r) between total metal accumulation and extractable metals showed that Zn (P<0.01), Cr (P<0.01), and Cu (P<0.05) are significantly correlated, whereas, correlation with pH showed significant positive relation with all the studied metals except Mn. Significant positive correlation was recorded between metal accumulation (Fe, Zn, Cu) and electrical conductivity, cation exchange capacity, and organic matter, however, Zn, Cr, and Cu showed significant positive correlation with bulk density, nitrate, ammonia, and available phosphorus. The analysis of the results showed that total chlorophyll content showed significant (P< 0.5) increase in lower amendment of sludge (up to 35% TS at 30 d and 25% TS at 60 d) as over their controls. In roots, malondialdehyde, cysteine, non-protein thiol, proline, protein, ascorbic acid contents increased up to 35% TS at 30 d. Principal component analysis also showed that strong association exists among malondialdehyde, nonprotein thiol, protein, and cysteine contents in the plants grown on different amendments of TS. The level of antioxidants increased which enabled the plant to cope up the stress induced in the plants grown on lower amendments of TS, however, toxicity was observed at higher amendments.

Adhesion control of cyclin D1 and p27Kip1 levels is deregulated in melanoma cells through BRAF-MEK-ERK signaling.

Mutations in BRAF, a component of extracellular signal-regulated kinases 1 and 2 (ERK) cascade, are frequent in melanoma. It is important to understand how BRAF mutations contribute to malignant traits including anchorage- and growth factor-independence. We have previously shown that efficient activation of ERK in normal human epidermal melanocytes (NHEM) requires both adhesion to the extracellular matrix and growth factors. Mutant V599E BRAF is sufficient to promote ERK activation independent of adhesion and growth factors. Here, we analysed regulation of G1 cell cycle events in NHEM and human melanoma cells. We show that S phase entry in NHEM requires both adhesion and growth factor signaling through the MEK-ERK pathway. This control correlates with induction of cyclin D1 and downregulation of p27Kip1, two key G1 cell cycle events. In melanoma cells expressing V599E BRAF, cyclin D1 was constitutively expressed independent of adhesion but dependent upon MEK activation and nuclear accumulation of ERK. Reduction of cyclin D1 levels by RNA interference inhibited S phase entry in melanoma cells. Importantly, expression of V599E BRAF in NHEM was sufficient to promote cyclin D1 promoter activity in the absence of adhesion. Additionally, p27Kip1 levels were downregulated in V599E BRAF-expressing melanoma cells and active BRAF was sufficient to downregulate p27Kip1 in serum-starved NHEM. Thus, adhesion-growth factor cooperation, leading to efficient activation of ERK, regulates cyclin D1 and p27Kip1 levels in human melanocytes and mutant BRAF overrides adhesion-growth factor control of these two G1 cell cycle proteins in melanomas. These findings provide important insight into how BRAF mutations contribute to aberrant human melanocyte proliferation.

Response of antioxidants in sunflower (Helianthus annuus L.) grown on different amendments of tannery sludge: its metal accumulation potential.

The interaction of metals present in tannery waste and their tolerance in the plants of sunflower (Helianthus annuus L.) was studied in the present paper under field conditions. Effects of 100% tannery sludge and various amendments of tannery sludge (10%, 25%, 35%, 50%, 75%) along with one set of control were studied on the physiological and biochemical parameters of the plant along with their metal accumulation potential after 30, 60 and 90d after sowing. The plants of H. annuus were found effective in the accumulation of metals (Cr, Fe, Zn and Mn) in roots, shoots and leaves, however, the level of toxic metal, Cr was found below detection limit in the seeds of the plant. The oil was extracted from the seeds of the plant and the level of oil content was increased up to 35% tannery sludge as compared to control followed by decrease at higher tannery sludge ratio. An increase in the chlorophyll, protein, cysteine, non-protein thiol and sugar contents was observed at the lower amendment of tannery sludge at initial exposure periods followed by decrease than their respective controls. Malondialdehyde content in the roots and leaves was increased beyond 50% sludge amendments at all the exposure periods as compared to control. However, proline and ascorbic acid contents of the roots and leaves of the plant increased at all the exposure periods and sludge amendments, compared to their respective controls.

Translocation of metals and its effects in the tomato plants grown on various amendments of tannery waste: evidence for involvement of antioxidants.

A field experiment was conducted to study the effect of different amendments of tannery sludge on physiological and biochemical parameters of tomato plant (Lycopersicon esculentum L. Mill). The accumulation of metals (Cr, Fe) in different parts of tomato plants grown on tannery sludge amended soil increased in a concentration and duration-dependent manner. The accumulation of both the metals was found lowest in the fruits of the plant. The statistical analysis of the results showed an increase in chlorophyll and protein contents in lower sludge amendment ratio at all exposures followed by a decrease at highest (100%) sludge amendment ratio. Lipid peroxidation enhanced in both root and leaves of sludge grown plants of tomato at all the sludge amendments and exposure periods, which is evidenced by increased malondialdehyde content, however the maximum increase was found in the roots (43.63%) and leaves (56.66%) of the plant grown on 100% tannery sludge at 60 d, over respective controls. The level of antioxidants, cysteine, non-protein thiol and ascorbic acid increased in the sludge grown plants of tomato to cope up with stress induced by the excess amount of the heavy metals present in the tannery sludge. The maximum increase was found in cysteine content (75.53% in the leaves), non-protein thiol content (92.68% in the roots) and ascorbic acid content (29.66% in the roots) of the plant at 75% tannery sludge after 30 d. The tomato plants were found well adopted for minimizing damage induced by reactive oxygen species, when grown on tannery sludge amendments in the present study.