Peripheral arterial occlusive disease: Diagnostic performance and effect on therapeutic management of 64-section CT angiography

Purpose: To evaluate the diagnostic performance and effect on therapeutic management of 64-section computed tomographic (CT) angiography in the assessment of steno-occlusive disease in patients with peripheral arterial disease (PAD), with conventional digital subtraction angiography (DSA) as the reference standard. Materials and Methods: The study protocol was approved by the institutional review board, and written informed consent was obtained from all patients. A total of 212 patients with symptomatic PAD underwent CT angiography and subsequent DSA. For stenosis analysis ( ≥70% stenosis), the arterial bed was divided into 35 segments and evaluated by three readers. Interobserver agreement was determined with generalized k statistics. Accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were calculated. In addition, according to the TransAtlantic Inter-Society Consensus (TASC) Document on Management of Peripheral Arterial Disease guidelines, treatment recommendations based on CT angiographic and DSA fi ndings were compared. McNemar test was used to prove signifi cant differences between CT angiographic and DSA fi ndings. Results: A total of 7420 arterial segments were evaluated, with excellent agreement between readers ( κ ≥ 0.928). On a segmental basis, both sensitivity and specifi city for stenosis of 70% or more were at least 96% (3072 of 3113 segments and 4141 of 4279 segments, respectively), with an accuracy of 98% (7213 of 7392 segments), a PPV of 96% (3072 of 3187 segments), an NPV of 99% (3141 of 3187 segments), a PLR of 36.7, and an NLR of 0.013. There was no significant difference between CT angiographic and DSA findings ( P = .62-.87 ). In accordance with TASC II guidelines, 49 patients were referred for conservative treatment, 87 underwent endovascular procedures, 38 underwent surgery, and 17 received hybrid treatment. Therapy recommendations based on CT angiographic fi ndings alone were identical to those based on DSA fi ndings in all but one patient. Conclusion: The diagnostic performance of 64-section CT angiography is excellent in patients with clinical symptoms of PAD. The results can be used to effectively guide therapeutic decision making in these patients. © RSNA, 2011

Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells

Introduction: Posttranslational modification of proteins by reversible acetylation regulates key biological processes. Histone deacetylases (HDACs) catalyze protein deacetylation and are frequently dysregulated in tumors. This has spurred the development of HDAC inhibitors (HDACi). Such epigenetic drugs modulate protein acetylation, eliminate tumor cells, and are approved for the treatment of blood cancers. Objectives: We aimed to identify novel, nanomolar HDACi with increased potency over existing agents and selectivity for the cancer-relevant class I HDACs (HDAC1,-2,-3,-8). Moreover, we wanted to define how such drugs control the apoptosis-autophagy interplay. As test systems, we used human leukemic cells and embryonic kidney-derived cells. Methods: We synthesized novel pyrimidine-hydroxamic acid HDACi (KH9/KH16/KH29) and performed in vitro activity assays and molecular modeling of their direct binding to HDACs. We analyzed how these HDACi affect leukemic cell fate, acetylation, and protein expression with flow cytometry and immunoblot. The publicly available DepMap database of CRISPR-Cas9 screenings was used to determine sensitivity factors across human leukemic cells. Results: Novel HDACi show nanomolar activity against class I HDACs. These agents are superior to the clinically used hydroxamic acid HDACi SAHA (vorinostat). Within the KH-series of compounds, KH16 (yanostat) is the most effective inhibitor of HDAC3 (IC50 = 6 nM) and the most potent inducer of apoptosis (IC50 = 110 nM; p < 0.0001) in leukemic cells. KH16 though spares embryonic kidney-derived cells. Global data analyses of knockout screenings verify that HDAC3 is a dependency factor in 115 human blood cancer cells of different lineages, independent of mutations in the tumor suppressor p53. KH16 alters pro- and anti-apoptotic protein expression, stalls cell cycle progression, and induces caspase-dependent processing of the autophagy proteins ULK1 and p62. Conclusion: These data reveal that HDACs are required to stabilize autophagy proteins through suppression of apoptosis in leukemic cells. HDAC3 appears as a valid anti-cancer target for pharmacological intervention

Chest CT for early detection and management of coronavirus disease (COVID-19): a report of 314 patients admitted to Emergency Department with suspected pneumonia

Purpose: The purpose of our study was to assess the potential role of chest CT in the early detection of COVID-19 pneumonia and to explore its role in patient management in an adult Italian population admitted to the Emergency Department. Methods: Three hundred and fourteen patients presented with clinically suspected COVID-19, from March 3 to 23, 2020, were evaluated with PaO2/FIO2 ratio from arterial blood gas, RT-PCR assay from nasopharyngeal swab sample and chest CT. Patients were classified as COVID-19 negative and COVID-19 positive according to RT-PCR results, considered as a reference. Images were independently evaluated by two radiologists blinded to the RT-PCR results and classified as “CT positive” or “CT negative” for COVID-19, according to CT findings. Results: According to RT-PCR results, 152 patients were COVID-19 negative (48%) and 162 were COVID-19 positive (52%). We found substantial agreement between RT-PCR results and CT findings (p &lt; 0.000001), as well as an almost perfect agreement between the two readers. Mixed GGO and consolidation pattern with peripheral and bilateral distribution, multifocal or diffuse abnormalities localized in both upper lung and lower lung, in association with interlobular septal thickening, bronchial wall thickening and air bronchogram, showed higher frequency in COVID-positive patients. We also found a significant correlation between CT findings and patient’s oxygenation status expressed by PaO2/FIO2 ratio. Conclusion: Chest CT has a useful role in the early detection and in patient management of COVID-19 pneumonia in a pandemic. It helps in identifying suspected patients, cutting off the route of transmission and avoiding further spread of infection