Acquired ductopenia: an insight into imaging findings.

Hepatic ductopenia is a pathologic diagnosis characterized by a decrease in the number of intrahepatic bile ducts as a consequence of various underlying etiologies. Some etiologies, such as primary sclerosing cholangitis, primary biliary cholangitis, and ischemic cholangitis, often have distinctive imaging findings. In contrast, other causes such as chronic rejection following liver transplantation, drug-induced biliary injury, infection, malignancy such as lymphoma, and graft-versus-host disease may only have ancillary or non-specific imaging findings. Thus, diagnosing ductopenia in conditions with nonspecific imaging findings requires a multidimensional approach, including clinical evaluation, serological testing, imaging, and liver histology to identify the underlying cause. These etiologies lead to impaired bile flow, resulting in cholestasis, liver dysfunction, and, ultimately, cirrhosis and liver failure if the underlying cause remains untreated or undetected. In the majority of instances, individuals diagnosed with ductopenia exhibit a positive response to treatment addressing the root cause or cessation of the causative agent. This article focuses on acquired causes of ductopenia, its clinical manifestation, histopathology, imaging diagnosis, and management.

Early features of pancreatic cancer on magnetic resonance imaging (MRI): a case-control study.

PURPOSE: Magnetic resonance imaging has been recommended as a primary imaging modality among high-risk individuals undergoing screening for pancreatic cancer. We aimed to delineate potential precursor lesions for pancreatic cancer on MR imaging. METHODS: We conducted a case-control study at Kaiser Permanente Southern California (2008-2018) among patients that developed pancreatic cancer who had pre-diagnostic MRI examinations obtained 2-36 months prior to cancer diagnosis (cases) matched 1:2 by age, gender, race/ethnicity, contrast status and year of scan (controls). Patients with history of acute/chronic pancreatitis or prior pancreatic surgery were excluded. Images underwent blind review with assessment of a priori defined series of parenchymal and ductal features. We performed logistic regression to assess the associations between individual factors and pancreatic cancer. We further assessed the interaction among features as well as performed a sensitivity analysis stratifying based on specific time-windows (2-3 months, 4-12 months, 13-36 months prior to cancer diagnosis). RESULTS: We identified 141 cases (37.9% stage I-II, 2.1% III, 31.4% IV, 28.6% unknown) and 292 matched controls. A solid mass was noted in 24 (17%) of the pre-diagnostic MRI scans. Compared to controls, pre-diagnostic images from cancer cases more frequently exhibited the following ductal findings: main duct dilatation (51.4% vs 14.3%, OR [95% CI]: 7.75 [4.19-15.44], focal pancreatic duct stricture with distal (upstream) dilatation (43.6% vs 5.6%, OR 12.71 [6.02-30.89], irregularity (42.1% vs 6.0%, OR 9.73 [4.91-21.43]), focal pancreatic side branch dilation (13.6% vs1.6%, OR 11.57 [3.38-61.32]) as well as parenchymal features: atrophy (57.9% vs 27.4%, OR 46.4 [2.71-8.28], focal area of signal abnormality (39.3% vs 4.8%, OR 15.69 [6.72-44,78]), all p < 0.001). CONCLUSION: In addition to potential missed lesions, we have identified a series of ductal and parenchymal features on MRI that are associated with increased odds of developing pancreatic cancer.

Quantifying Radiation Doses in Common Endoscopic Retrograde Cholangiopancreatography Scenarios: An Evaluation of Radiation Safety Measures in a Real-World Environment.

Introduction Radiation safety training remains variable among gastroenterologists performing endoscopic retrograde cholangiopancreatography (ERCP). This study sought to ascribe dosimeter readings to various real-world ERCP scenarios to provide data supporting the 3 pillars of radiation safety: distance, time, and shielding. Methods An ERCP fluoroscopy unit was used to generate radiation scatter from 2 differently sized anthropomorphic phantoms. Radiation scatter was measured at various distances from the emitter, with and without a lead apron, and at various frame rates (measured in frames per second, fps) and degrees of fluoroscopy pedal actuation. An image quality phantom was used to assess resolution at various frame rates and air gaps. Results Increasing the distance resulted in a decrease in measured scatter (from 0.75 mR/h at 1.5 ft to 0.15 mR/h at 9 ft with the average phantom and from 50 mR/h at 1.5 ft to 3.06 mR/h at 9 ft with the large phantom). Depressing the fluoroscopy pedal less frequently, or decreasing the frame rate (ie, increasing the time per frame), resulted in a linear decrease in scatter (from 55 mR/h at 8 fps to 24.5 mR/h at 4 fps and 13.60 mR/h at 2 fps). Providing shielding through the presence of a 0.5-mm lead apron reduced scatter (from 4.10 to 0.11 mR/h with the average phantom; from 15.30 mR/h to 0.43 mR/h with the large phantom). However, decreasing the frame rate from 8 fps to 2 fps did not change the number of line pairs identified on the image phantom. A greater air gap increased the number of line pairs resolved. Conclusions Implementing the 3 pillars of radiation safety led to a quantifiable, clinically significant decrease in radiation scatter. The authors hope that these findings spark greater implementation of radiation safety measures among practitioners utilizing fluoroscopy.

Quantitative Radiomic Features From Computed Tomography Can Predict Pancreatic Cancer up to 36 Months Before Diagnosis.

INTRODUCTION: Pancreatic cancer is the third leading cause of cancer deaths among men and women in the United States. We aimed to detect early changes on computed tomography (CT) images associated with pancreatic ductal adenocarcinoma (PDAC) based on quantitative imaging features (QIFs) for patients with and without chronic pancreatitis (CP). METHODS: Adults 18 years and older diagnosed with PDAC in 2008-2018 were identified. Their CT scans 3 months-3 years before the diagnosis date were matched to up to 2 scans of controls. The pancreas was automatically segmented using a previously developed algorithm. One hundred eleven QIFs were extracted. The data set was randomly split for training/validation. Neighborhood and principal component analyses were applied to select the most important features. A conditional support vector machine was used to develop prediction algorithms separately for patients with and without CP. The computer labels were compared with manually reviewed CT images 2-3 years before the index date in 19 cases and 19 controls. RESULTS: Two hundred twenty-seven of 554 scans of non-CP cancer cases/controls and 70 of 140 scans of CP cancer cases/controls were included (average age 71 and 68 years, 51% and 44% females for non-CP patients and patients with CP, respectively). The QIF-based algorithms varied based on CP status. For non-CP patients, accuracy measures were 94%-95% and area under the curve (AUC) measures were 0.98-0.99. Sensitivity, specificity, positive predictive value, and negative predictive value were in the ranges of 88%-91%, 96%-98%, 91%-95%, and 94%-96%, respectively. QIFs on CT examinations within 2-3 years before the index date also had very high predictive accuracy (accuracy 95%-98%; AUC 0.99-1.00). The QIF-based algorithm outperformed manual rereview of images for determination of PDAC risk. For patients with CP, the algorithms predicted PDAC perfectly (accuracy 100% and AUC 1.00). DISCUSSION: QIFs can accurately predict PDAC for both non-CP patients and patients with CP on CT imaging and represent promising biomarkers for early detection of pancreatic cancer.

Risk Prediction of Pancreatic Cancer in Patients With Abnormal Morphologic Findings Related to Chronic Pancreatitis: A Machine Learning Approach.

BACKGROUND AND AIMS: A significant factor contributing to poor survival in pancreatic cancer is the often late stage at diagnosis. We sought to develop and validate a risk prediction model to facilitate the distinction between chronic pancreatitis-related vs potential early pancreatic ductal adenocarcinoma (PDAC)-associated changes on pancreatic imaging. METHODS: In this retrospective cohort study, patients aged 18-84 years whose abdominal computed tomography/magnetic resonance imaging reports indicated duct dilatation, atrophy, calcification, cyst, or pseudocyst between January 2008 and November 2019 were identified. The outcome of interest is PDAC in 3 years. More than 100 potential predictors were extracted. Random survival forests approach was used to develop and validate risk models. Multivariable Cox proportional hazard model was applied to estimate the effect of the covariates on the risk of PDAC. RESULTS: The cohort consisted of 46,041 (mean age 66.4 years). The 3-year incidence rate was 4.0 (95% confidence interval CI 3.6-4.4)/1000 person-years of follow-up. The final models containing age, weight change, duct dilatation, and either alkaline phosphatase or total bilirubin had good discrimination and calibration (c-indices 0.81). Patients with pancreas duct dilatation and at least another morphological feature in the absence of calcification had the highest risk (adjusted hazard ratio [aHR] = 14.15, 95% CI 8.7-22.6), followed by patients with calcification and duct dilatation (aHR = 7.28, 95% CI 4.09-12.96), and patients with duct dilation only (aHR = 6.22, 95% CI 3.86-10.03), compared with patients with calcifications alone as the reference group. CONCLUSION: The study characterized the risk of pancreatic cancer among patients with 5 abnormal morphologic findings based on radiology reports and demonstrated the ability of prediction algorithms to provide improved risk stratification of pancreatic cancer in these patients.

Imaging of the Pancreas in New-Onset Diabetes: A Prospective Pilot Study.

INTRODUCTION: The aim of this study was to assess the feasibility of cross-sectional imaging for detection of pancreatic cancer (PDAC) in patients with new-onset hyperglycemia and diabetes (NOD). METHODS: We conducted a prospective pilot study from November 2018 to March 2020 within an integrated health system. Patients aged 50-85 years with newly elevated glycemic parameters without a history of diabetes were invited to complete a 3-phase contrast-enhanced computed tomography pancreas protocol scan while participating in the Prospective Study to Establish a NOD Cohort. Abnormal pancreatic findings, incidental extrapancreatic findings, and subsequent clinical evaluation were identified. Variability in clinical reporting between medical centers based on descriptors of pancreatic duct and parenchyma was assessed. RESULTS: A total of 130 of 147 participants (88.4%) consented to imaging; 93 scans were completed (before COVID-19 stay-at-home order). The median age was 62.4 years (interquartile range 56.3-68.8), 37.6% women; Hispanic (39.8%), White (29.0%), Black (14.0%), and Asian (13.3%). One (1.1%) case of PDAC (stage IV) was diagnosed, 12 of 93 participants (12.9%) had additional pancreatic findings: 5 fatty infiltration, 3 cysts, 2 atrophy, 1 divisum, and 1 calcification. There were 57 extrapancreatic findings among 52 of 93 (56%) unique patients; 12 of 57 (21.1%) prompted clinical evaluation with 2 additional malignancies diagnosed (nonsmall cell lung and renal oncocytoma). Reports from 1 participating medical center more frequently provided description of pancreatic parenchyma and ducts (92.9% vs 18.4%), P < 0.0001. DISCUSSION: High proportion of incidental findings and variability in clinical reports are challenges to be addressed for a successful NOD-based early detection strategy for PDAC.

Medical biotechnology as a paradigm for forest restoration and introduction of the transgenic American chestnut.

For over 40 years, biotechnology and genetic engineering (GE) have been used in the development of medicines and biologic agents important in protecting and augmenting human health and have been met with broad public acceptance in the health care arena. GE has also been used to improve and develop plants important to agriculture and forestry, but in these areas, it has often encountered intense opposition that has prevented or delayed the introduction of potentially useful plants. Much of the opposition to GE's application in agriculture and forestry may be driven by concerns that GE plants will serve primarily to encourage the domination of the food and wood products industries by monopolistic corporations or will be disruptive to the environment. But to conflate genetic modifications intended to promote healthy ecosystems or preserve threatened species with GE projects aimed at benefiting corporate agriculture and forestry is misleading and illogical. Further, the pervasive human disruption and damage to forest ecosystems makes it prudent to bring the best that science can offer to the protection and restoration of critical woodland denizens and broader ecosystem health. The notion that minimal human intervention in the forest environment may be the best approach ignores humanity's responsibility to help manage and protect some of the very places that have been most damaged by human intrusion. GE intended to improve forest health should be afforded the same consideration, acceptance, and support as GE intended to improve human health. These efforts should include the use of GE technology such as carefully developed transgenic trees to cure ongoing forest pathogenesis, such as the chestnut blight (Cryphonectria parasitica), which threatens to drive the American chestnut (Castanea dentata) to extinction.

La Biotecnología Médica como Paradigma para la Restauración de Bosques y la Introducción del Castaño Americano Transgénico Resumen Durante más de 40 años, la biotecnología y la ingeniería genética (IG) se han usado en el desarrollo de medicamentos y agentes biológicos importantes para la protección y el aumento de la salud humana, recibiendo una aceptación generalizada del público en el ámbito de la atención médica. La ingeniería genética también ha sido utilizada para mejorar y desarrollar plantas importantes para la agricultura y la silvicultura, pero ha sido en estas áreas en las que con frecuencia se ha enfrentado con una oposición intensa que ha prevenido o retrasado la introducción de plantas potencialmente útiles. La mayor parte de la oposición a la aplicación de la IG en la agricultura y en la silvicultura puede estar dirigida por la inquietud de que las plantas con ingeniería genética servirán principalmente para promover el dominio de las industrias de productos alimenticios y de madera por parte de las compañías monopólicas o que serán perjudiciales para el ambiente. La idea de mezclar las modificaciones genéticas cuya intención es promover los ecosistemas sanos o preservar las especies amenazadas con proyectos de IG enfocados en el beneficio de la agricultura y la silvicultura corporativas es errónea e ilógica. Además, la perturbación humana dominante y el daño a los ecosistemas boscosos hacen que sea prudente traer a la mesa lo mejor que la ciencia puede ofrecer para la protección y restauración de importantes de las zonas boscosas y para una salud ambiental más amplia. El concepto de que la menor intervención humana en el ecosistema boscoso sea la mejor estrategia ignora la responsabilidad que tiene la humanidad para manejar y proteger algunos de los lugares que más han sufrido por la intrusión humana. La ingeniería genética que se plantea mejorar la salud de los bosques debería recibir la misma consideración, aceptación y apoyo que la IG cuya intención es mejorar la salud humana. Estos esfuerzos deberían incluir el uso de la tecnología de la IG, como los árboles transgénicos desarrollados cuidadosamente, para curar las patogénesis persistentes en algunos bosques, como la plaga del castaño (Cryphonectria parasitica), que amenaza con llevar a la extinción al castaño americano (Castanea dentata).

Watch-and-Wait Compared to Operation for Patients with Complete Response to Neoadjuvant Therapy for Rectal Cancer.

BACKGROUND: Trimodality therapy with neoadjuvant chemoradiation (nCRT), surgery, and adjuvant chemotherapy is the standard treatment for locally advanced rectal cancer. There is evidence that surgery can be deferred in patients with complete response (CR) to nCRT, a strategy termed "watch-and-wait" (WW). We compare WW to surgery in patients with CR to nCRT. STUDY DESIGN: We reviewed records of patients treated with nCRT for nonmetastatic rectal cancer at our institution. Complete endoscopic response (CER) was defined as negative digital rectal exam and negative endoscopy at the end of neoadjuvant therapy (NAT). Clinical complete response (cCR) was defined as CER with negative rectal MRI. Patients with CER refusing surgery were offered WW, which included strict surveillance with digital rectal exam and endoscopy. RESULTS: From January 2015 through February 2019, 465 patients completed nCRT; 406 patients had response assessment, of which 95 (23%) had CER. Of these patients, 53 patients underwent WW and 42 patients had surgery. Median follow-up was 35 months. In the WW group, 3-year freedom from local regrowth was 85%. In the surgical and WW groups, 3-year overall survival, rectal cancer-specific survival, and freedom from nonregrowth recurrence were 100% vs 88% (p = 0.03), 100% vs 95% (p = 0.16), and 92% vs 85% (p = 0.36), respectively. Of the 6 WW patients with local regrowth, 5 (83%) eventually developed distant recurrence. CONCLUSIONS: WW in lieu of surgery appears to be a safe and feasible treatment approach for patients achieving CR to nCRT. Careful evaluation to confirm cCR after nCRT is valuable in selecting patients for WW.

Characterization of patients with advanced chronic pancreatitis using natural language processing of radiology reports.

STUDY AIM: To develop and apply a natural language processing algorithm for characterization of patients diagnosed with chronic pancreatitis in a diverse integrated U.S. healthcare system. METHODS: Retrospective cohort study including patients initially diagnosed with chronic pancreatitis (CP) within a regional integrated healthcare system between January 1, 2006 and December 31, 2015. Imaging reports from these patients were extracted from the electronic medical record system and split into training, validation and implementation datasets. A natural language processing (NLP) algorithm was first developed through the training dataset to identify specific features (atrophy, calcification, pseudocyst, cyst and main duct dilatation) from free-text radiology reports. The validation dataset was applied to validate the performance by comparing against the manual chart review. The developed algorithm was then applied to the implementation dataset. We classified patients with calcification(s) or ≥2 radiographic features as advanced CP. We compared etiology, comorbid conditions, treatment parameters as well as survival between advanced CP and others diagnosed during the study period. RESULTS: 6,346 patients were diagnosed with CP during the study period with 58,085 radiology studies performed. For individual features, NLP yielded sensitivity from 88.7% to 95.3%, specificity from 98.2% to 100.0%. A total of 3,672 patients met cohort inclusion criteria: 1,330 (36.2%) had evidence of advanced CP. Patients with advanced CP had increased frequency of smoking (57.8% vs. 43.0%), diabetes (47.6% vs. 35.9%) and underweight body mass index (6.6% vs. 3.6%), all p<0.001. Mortality from pancreatic cancer was higher in advanced CP (15.3/1,000 person-year vs. 2.8/1,000, p<0.001). Underweight BMI (HR 1.6, 95% CL 1.2, 2.1), smoking (HR 1.4, 95% CL 1.1, 1.7) and diabetes (HR 1.4, 95% CL 1.2, 1.6) were independent risk factors for mortality. CONCLUSION: Patients with advanced CP experienced increased disease-related complications and pancreatic cancer-related mortality. Excess all-cause mortality was driven primarily by potentially modifiable risk factors including malnutrition, smoking and diabetes.

Prediction of Pancreatic Cancer Based on Imaging Features in Patients With Duct Abnormalities.

OBJECTIVES: Abnormalities of the main pancreatic duct may be an early indicator of pancreatic ductal adenocarcinoma (PDAC). We develop and validate algorithms that predict the risk of PDAC using features identified on cross-sectional imaging and other clinical characteristics collected through electronic medical records. METHODS: Adult patients with abdominal computed tomography or magnetic resonance imaging in January 2006 to June 2016 demonstrating dilatation of main pancreatic duct were identified. Pancreas-related morphologic features were extracted from radiology reports using natural language processing. The cumulative incidence of PDAC with death as a competing risk was estimated using multistate models. Model discrimination was assessed using c-index. The models were internally validated using bootstrapping. RESULTS: The cohort consisted of 7819 patients (mean age, 71 years; 65% female). A total of 781 patients (10%) developed PDAC within 3 years after the first eligible imaging study. The final models achieved reasonable discrimination (c-index, 0.825-0.833). The 3-year average risk of PDAC in the top 5% of the total eligible patients was 56.0%, more than 20 times of the average risk among the bottom 50% of patients. CONCLUSIONS: Prediction models combining imaging features and clinical measures can be used to further stratify the risk of pancreatic cancer among patients with pancreas ductal dilatation.

Metastatic meningioma: Case report of a WHO grade I meningioma with liver metastases and review of the literature.

Meningioma represents the most frequently diagnosed primary brain tumor, accounting for over one-third of central nervous system neoplasms. The majority of tumors are categorized as benign. However, albeit rarely, meningiomas may metastasize to distant sites. We describe a 78-year-old man with a history of recurrent World Health Organization grade I meningioma managed who presented for evaluation of weakness and urinary retention. A computed tomography scan obtained in the emergency department revealed multiple scattered low-density liver lesions. Subsequent magnetic resonance imaging showed a 5.5-centimeter heterogeneous enhancing mass with 2 smaller enhancing lesions suspicious for a primary or secondary malignant neoplasm. Microscopic examination of a tissue sample obtained via liver biopsy demonstrated a metastatic spindle cell neoplasm with histologic features compatible with a diagnosis of World Health Organization grade I transitional meningioma. The patient was referred to hematology/oncology for systemic therapy.

Transthoracic Echocardiography: Pitfalls and Limitations as Delineated at Cardiac CT and MR Imaging.

Transthoracic echocardiography ( TTE transthoracic echocardiography ) is a critical tool in the field of clinical cardiology. It often serves as one of the first-line imaging modalities in the evaluation of cardiac disease owing to its low cost, portability, widespread availability, lack of ionizing radiation, and ability to evaluate both anatomy and function of the heart. Consequently, a large majority of patients undergoing a cardiac computed tomography (CT) or magnetic resonance (MR) imaging examination will have a TTE transthoracic echocardiography available for review. Therefore, it is imperative that cardiac imagers be familiar with the fundamentals of a routine TTE transthoracic echocardiography examination and common TTE transthoracic echocardiography pitfalls and limitations that may lead to a referral for cardiac CT or MR imaging. The four standard TTE transthoracic echocardiography windows and their corresponding views will be discussed and the relevant anatomy highlighted. Common pitfalls and limitations of TTE transthoracic echocardiography will be highlighted using cardiac CT and MR imaging as the problem-solving modality. In this article, we have categorized the relevant pitfalls and limitations of TTE transthoracic echocardiography into four broad categories: (a) masses and mass mimics (crista terminalis, eustachian valve, right ventricle moderator band, atrioventricular groove fat, left ventricular band [or left ventricular false tendon], hiatal hernia, caseous calcification of the mitral annulus, lipomatous hypertrophy of the interatrial septum, cardiac tumors), (b) poorly visualized apical lesions (aneurysm, thrombus, infarct, and hypertrophic and other nonischemic cardiomyopathies), (c) evaluation for ascending thoracic aortic dissections (false positive, false negative, dissecting aneurysms), and (d) pericardial disease (acute and chronic/constrictive pericarditis, pericardial tamponade, pericardial cysts and diverticula, congenital absence of the pericardium). Online supplemental material is available for this article. ©RSNA, 2017.

MR Imaging of the Penis and Scrotum.

Traditionally, due to its low cost, ready availability, and proved diagnostic accuracy, ultrasonography (US) has been the primary imaging modality for the evaluation of scrotal and, to a lesser extent, penile disease. However, US is limited by its relatively small useful field of view, operator dependence, and inability to provide much information on tissue characterization. Magnetic resonance (MR) imaging, with its excellent soft-tissue contrast and good spatial resolution, is increasingly being used as both a problem-solving tool in patients who have already undergone US and as a primary modality for the evaluation of suspected disease. Specifically, MR imaging can aid in differentiating between benign and malignant lesions seen at US, help define the extent of inflammatory processes or traumatic injuries, and play a vital role in locoregional staging of tumors. Consequently, it is becoming more important for radiologists to be familiar with the wide range of penile and scrotal disease entities and their MR imaging appearances. The authors review the basic anatomy of the penis and scrotum as seen at MR imaging and provide a basic protocol for penile and scrotal imaging, with emphasis on the advantages of MR imaging. Pathologic processes are organized into traumatic (including penile fracture and contusion), infectious or inflammatory (including Fournier gangrene and scrotal abscess), and neoplastic (including both benign and malignant scrotal and penile tumors) processes.

Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering.

Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological target for decreasing low-density lipoprotein (LDL) in cardiovascular disease, although seemingly inaccessible to small molecule approaches. Compared with therapeutic IgG antibodies currently in development, targeting circulating PCSK9 with smaller molecular scaffolds could offer different profiles and reduced dose burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family derived from human fibronectin-10th-type III-domain and engineered for high-affinity target binding. BMS-962476, an ∼11-kDa polypeptide conjugated to polyethylene glycol to enhance pharmacokinetics, binds with subnanomolar affinity to human. The X-ray cocrystal structure of PCSK9 with a progenitor Adnectin shows ∼910 Å(2) of PCSK9 surface covered next to the LDL receptor binding site, largely by residues of a single loop of the Adnectin. In hypercholesterolemic, overexpressing human PCSK9 transgenic mice, BMS-962476 rapidly lowered cholesterol and free PCSK9 levels. In genomic transgenic mice, BMS-962476 potently reduced free human PCSK9 (ED50 ∼0.01 mg/kg) followed by ∼2-fold increases in total PCSK9 before return to baseline. Treatment of cynomolgus monkeys with BMS-962476 rapidly suppressed free PCSK9 >99% and LDL-cholesterol ∼55% with subsequent 6-fold increase in total PCSK9, suggesting reduced clearance of circulating complex. Liver sterol response genes were consequently downregulated, following which LDL and total PCSK9 returned to baseline. These studies highlight the rapid dynamics of PCSK9 control over LDL and liver cholesterol metabolism and characterize BMS-962476 as a potent and efficacious PCSK9 inhibitor.

Combined hepatocellular and cholangiocarcinoma (biphenotypic) tumors: imaging features and diagnostic accuracy of contrast-enhanced CT and MRI.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracy of preoperative imaging for diagnosis of combined hepatocellular cholangiocarcinoma tumors and to evaluate the clinical and imaging features and demographics of patients presenting to our institution with such tumors. MATERIALS AND METHODS: From January 2001 to January 2011, 29 patients presented with pathologically proven combined hepatocellular cholangiocarcinoma tumors to our institution. A retrospective review of the imaging studies, clinical data, and demographic information in these patients was conducted. Two radiologists with 6 and 18 years of experience reviewed the imaging studies of patients with combined hepatocellular cholangiocarcinoma tumors and matched control cases of hepatocellular carcinoma (HCC) (n = 15) and cholangiocarcinoma (n = 18). The reviewers were blinded to the pathologic diagnosis. Imaging features on contrast-enhanced MRI and CT with the suggested final diagnosis were recorded. RESULTS: The demographics of our patient population were similar to other reported U.S. populations, with cirrhosis and hepatitis present in a minority of patients. The imaging features of combined hepatocellular cholangiocarcinoma tumors overlapped with those of HCC and cholangiocarcinoma. The correct diagnosis of combined hepatocellular cholangiocarcinoma tumors was made in a minority of cases by either radiologist, with misdiagnosis more often leading to suggestion of cholangiocarcinoma than HCC. Sensitivities and specificities for diagnosis of combined hepatocellular cholangiocarcinoma tumors ranged from 33% to 34% and 81% to 100%, respectively. CONCLUSION: Preoperative diagnosis of combined hepatocellular cholangiocarcinoma tumors on the basis of imaging features is accurate in the minority of cases. Tumor markers and risk factors may help improve accuracy; however, in the absence of classic imaging features and supportive information for HCC or cholangiocarcinoma, biopsy should be considered for confirmation of diagnosis.

Bile acid and sterol metabolism with combined HMG-CoA reductase and PCSK9 suppression.

Proprotein convertase subtilisin-kexin-9 (PCSK9) inhibition markedly augments the LDL lowering action of statins. The combination is being evaluated for long-term effects on atherosclerotic disease outcomes. However, effects of combined treatment on hepatic cholesterol and bile acid metabolism have not yet been reported. To study this, PCSK9-Y119X mutant (knockout) and wild-type mice were treated with or without atorvastatin for 12 weeks. Atorvastatin progressively lowered plasma LDL in each group, but no differences in liver cholesterol, cholesterol ester, or total bile acid concentrations, or in plasma total bile acid levels were seen. In contrast, atorvastatin increased fecal total bile acids (≈ 2-fold, P < 0.01) and cholesterol concentrations (≈ 3-fold, P < 0.01) versus controls for both PCSK9-Y119X and wild-type mice. All 14 individual bile acids resolved by LC-MS, including primary, secondary, and conjugated species, reflected similar increases. Expression of key liver bile acid synthesis genes CYP7A1 and CYP8B1 were ≈ 2.5-fold higher with atorvastatin in both strains, but mRNA for liver bile acid export and reuptake transporters and conjugating enzymes were not unaffected. The data suggest that hepatocyte cholesterol and bile acid homeostasis is maintained with combined PCSK9 and HMG-CoA reductase inhibition through efficient liver enzymatic conversion of LDL-derived cholesterol into bile acids and excretion of both, with undisturbed enterohepatic recycling.

Substituted piperidinyl glycinyl 2-cyano-4,5-methano pyrrolidines as potent and stable dipeptidyl peptidase IV inhibitors.

Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.

MR imaging findings of ectopic pregnancy: a pictorial review.

Because of its lack of ionizing radiation and excellent soft-tissue contrast, magnetic resonance (MR) imaging is being increasingly used in the evaluation of acute abdominal pain in the pregnant patient. Roughly 2% of all pregnancies are ectopic. Although ectopic pregnancy is usually diagnosed on the basis of a combination of clinical, laboratory, and ultrasonographic findings, it occasionally is initially identified at MR imaging. Thus, it is imperative that the radiologist should be familiar with the variable appearance of ectopic pregnancy at MR imaging and should evaluate for ectopic pregnancy at any time when (a) a patient has positive results of a pregnancy test and (b) an intrauterine pregnancy is not definitively seen. Because of potential issues of fetal safety, a conservative approach should be used for MR imaging in pregnancy. An MR imaging protocol for the evaluation of possible appendicitis in pregnant women is detailed. Specific findings that can aid in the diagnosis of ectopic pregnancy are the lack of an intrauterine pregnancy, isolated hemoperitoneum, tubal masses, hematosalpinx, and interstitial masses. In the differential diagnosis of acute abdominal pain in pregnancy, consideration should be given to the more unusual forms of ectopic pregnancy, such as angular pregnancy, cornual pregnancy, and abdominal pregnancy. Potential mimics of ectopic pregnancy include placental abnormalities, ovarian neoplasms, and corpus luteum cysts.

The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications.

Metabolic complications associated with HIV infection and treatment frequently present as a relative lack of peripheral adipose tissue associated with dyslipidemia and insulin resistance. In this review we explain the connection between abnormalities of intermediary metabolism, observed either in vitro or in vivo, and this group of metabolic effects. We review molecular mechanisms by which the HIV protease inhibitor (PI) class of drugs may affect the normal stimulatory effect of insulin on glucose and fat storage. We then propose that both chronic inflammation from HIV infection and treatment with some drugs in this class trigger cellular homeostatic stress responses with adverse effects on intermediary metabolism. The physiologic outcome is such that total adipocyte storage capacity is decreased, and the remaining adipocytes resist further fat storage. The excess circulating and dietary lipid metabolites, normally "absorbed" by adipose tissue, are deposited ectopically in lean (muscle and liver) tissue, where they impair insulin action. This process leads to a pathologic cycle of lipotoxicity and lipoatrophy and a clinical phenotype of body fat distribution with elevated waist-to-hip ratio similar to the metabolic syndrome.