FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy.

The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG's glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.

Rapid whole cell imaging reveals a calcium-APPL1-dynein nexus that regulates cohort trafficking of stimulated EGF receptors.

The endosomal system provides rich signal processing capabilities for responses elicited by growth factor receptors and their ligands. At the single cell level, endosomal trafficking becomes a critical component of signal processing, as exemplified by the epidermal growth factor (EGF) receptors. Activated EGFRs are trafficked to the phosphatase-enriched peri-nuclear region (PNR), where they are dephosphorylated and degraded. The details of the mechanisms that govern the movements of stimulated EGFRs towards the PNR, are not completely known. Here, exploiting the advantages of lattice light-sheet microscopy, we show that EGFR activation by EGF triggers a transient calcium increase causing a whole-cell level redistribution of Adaptor Protein, Phosphotyrosine Interacting with PH Domain And Leucine Zipper 1 (APPL1) from pre-existing endosomes within one minute, the rebinding of liberated APPL1 directly to EGFR, and the dynein-dependent translocation of APPL1-EGF-bearing endosomes to the PNR within ten minutes. The cell spanning, fast acting network that we reveal integrates a cascade of events dedicated to the cohort movement of activated EGF receptors. Our findings support the intriguing proposal that certain endosomal pathways have shed some of the stochastic strategies of traditional trafficking and have evolved processes that provide the temporal predictability that typify canonical signaling.

Evaluating dose-limiting toxicities of MDM2 inhibitors in patients with solid organ and hematologic malignancies: A systematic review of the literature.

INTRODUCTION: Mouse double minute 2 protein (MDM2), a negative regulator of the p53 tumour suppressor gene, is frequently amplified in malignancies. MDM2 antagonists have shown efficacy in treating malignancies with MDM2 overexpression and can overcome chemoresistance in acute myeloid leukemia. We systematically evaluated the safety profile of MDM2 inhibitors in the treatment of solid organ and hematologic malignancies. MATERIALS AND METHODS: We searched Medline and EMBASE from January 1947 to November 2018 for prospective clinical studies, in English or French, investigating any MDM2 inhibitor in pediatric or adult cancers, and reporting dose and toxicity outcomes. Primary outcome was dose-limiting toxicity (DLT) and secondary outcome was death. RESULTS: The search yielded 493 non-duplicate citations. Eighteen studies of 10 inhibitors met inclusion criteria (total N = 1005 patients). Two-thirds of included studies did not define DLTs and the reporting of toxicities was highly variable. The most commonly reported DLTs were cytopenias, gastrointestinal toxicity, metabolic disturbances, fatigue and cardiovascular toxicity; there was one death attributed to treatment toxicity. CONCLUSION: MDM2 antagonists have been studied in a variety of malignancies with toxicities similar to other commonly used chemotherapy agents and may represent a safe adjuvant treatment for further study in in acute leukemia.

Prostate cancer and its mimics at multiparametric prostate MRI.

One in six males will develop prostate cancer during their lifetime. Prostate cancer is the second leading cause of cancer death in American males, behind only lung cancer. Unfortunately, even though this disease is so common, clinical screening methods such as prostate-specific antigen test and transrectal ultrasound-guided prostate biopsy lack sensitivity and specificity in diagnosing prostate cancer. In recent years, multiparametric prostate MRI has emerged as a very important tool in the diagnosis of prostate carcinoma with a high accuracy. However, diagnostic difficulty is often encountered even with an experienced abdominal radiologist. That is mainly because many normal and abnormal entities can mimic prostate carcinoma at multiparametric MRI. Therefore, the purpose of this pictorial review is to discuss the usefulness of multiparametric prostate MRI in the diagnosis of prostate carcinoma, emphasizing the key MRI features that help to make a distinction of prostate carcinoma from its mimics.

A prospective, randomized-controlled pilot study of ursodeoxycholic acid combined with mycophenolate mofetil in the treatment of primary sclerosing cholangitis.

BACKGROUND: Ursodeoxycholic acid has been ineffective in the treatment of primary sclerosing cholangitis. Because the pathogenesis of primary sclerosing cholangitis is related to immune destruction of bile duct epithelium, several immune suppressive agents have been evaluated. Mycophenolate mofetil is a potent immunosuppressant that is now widely used in organ transplantation. AIM: In this pilot study to determine if mycophenolate mofetil when combined with ursodeoxycholic acid could prevent evidence of clinical progression and improve the biochemical, histological and/or cholangiographic features of primary sclerosing cholangitis compared with patients treated with ursodeoxycholic acid alone. METHODS: Twenty-five patients with well-defined primary sclerosing cholangitis were randomized to ursodeoxycholic acid (13-15 mg/kg/day) with or without mycophenolate mofetil (1000 mg b.d.). Cholangiography and liver biopsy were performed at study entry and after 2 years of treatment. Symptoms, clinical features of liver disease and biochemical tests were monitored at 3-month intervals. RESULTS: The mean age 44 years, 58% male, 84% Caucasian and 64% had ulcerative colitis. After 2 years, there were no differences in laboratory values, histological stage or cholangiograms between patients treated with ursodeoxycholic acid alone and those treated with mycophenolate mofetil + ursodeoxycholic acid. CONCLUSIONS: Mycophenolate mofetil combined with ursodeoxycholic acid does not appear to provide additional benefit compared with standard doses of ursodeoxycholic acid alone in the treatment of primary sclerosing cholangitis.

Non-resective ablation and liver transplantation in patients with cirrhosis and hepatocellular carcinoma (HCC): safety and efficacy.

We investigated the efficacy of nonresective ablation techniques and the tumor-free survival of cirrhotic patients undergoing liver transplantation for hepatocellular carcinoma (HCC). In group 1, 11 HCC patients were treated with these techniques and transplanted. On the waiting list, patients were treated to complete ablation, judged by gadolinium-enhanced MRI and alpha-fetoprotein (AFP) levels. Group 1 was compared with a concurrent group of 10 liver transplant patients (group 2) with incidental HCC (stages T1 three patients, T2 seven patients). The group 1 patients received 36 procedures (4 alcohol ablations, 14 trans -hepatic artery chemo-embolizations, 15 trans -hepatic chemo-infusions, and 3 radio frequency ablations) for treatment of 13 liver masses. Tumor-node-metastasis (TNM) stage was reduced in eight patients (72.7%), unchanged in two patients and increased in one patient before transplantation. The mean waiting time for transplantation was 12.9 7.6 months. Both groups had a tumor-free survival of 100%, at 30 12 months post transplant. On pathology, 54.5% of explanted livers had residual viable HCC after tumor treatment, and 36.4% (4/11) explants had synchronous lesions. Non-resective ablation therapy is safe and effective in reducing the HCC progression in cirrhotic patients awaiting liver transplantation. The cancer-free survival rate in this treatment group is equal to that for incidental T1-T2 HCCs.

Right lobe living donor liver transplantation: preoperative evaluation of the donor with MR imaging.

OBJECTIVE: The purpose of this study was to report our experience in preoperative evaluation of right hepatic lobe donors with a comprehensive MR examination and to compare abdominal MR images, MR cholangiograms, and MR angiograms with findings at surgery, intraoperative cholangiography, and digital subtraction angiography. MATERIALS AND METHODS: Twenty-eight right hepatic lobe donors underwent preoperative evaluation with MR imaging, MR cholangiography, and MR angiography. Two abdominal radiologists independently and randomly reviewed these studies. Points of assessment included focal and diffuse liver disease, calculation of right lobe volumes, depiction of the biliary tract and ductal anomalies, and depiction of the liver vasculature and vascular anomalies. Comparison was made with intraoperative cholangiograms (n = 20) and digital subtraction angiograms (n = 28). RESULTS: MR imaging revealed and characterized focal liver lesions in eight of 28 patients. Calculated right lobe volumes agreed with surgically determined volumes within 7% for reviewer 1 and within 15% for reviewer 2. Intrahepatic bile ducts were depicted completely with MR cholangiography in 25 of 28 patients and with intraoperative cholangiography in nine of 20 patients. MR cholangiography revealed ductal anomalies in six patients. MR imaging and MR angiography depicted the portal veins more completely than digital subtraction angiography. MR imaging and MR angiography correctly excluded portal venous anomalies in all patients and revealed surgically confirmed accessory hepatic veins in six of 28 patients. Angiographically confirmed arterial anomalies were correctly detected in three of 28 patients by at least one reviewer on MR imaging and MR angiography. CONCLUSION: MR imaging, MR cholangiography, and MR angiography provide a comprehensive, accurate means of evaluating donors for factors that may preclude or complicate right hepatic lobe donation.

The cystic duct: normal anatomy and disease processes.

The cystic duct can be depicted with a variety of imaging modalities but is optimally visualized with direct cholangiography or magnetic resonance cholangiopancreatography. Nevertheless, unrecognized anatomic variants of the cystic duct may cause confusion on imaging studies and complicate subsequent surgical, endoscopic, and percutaneous procedures. Primary entities involving the cystic duct include calculous disease, Mirizzi syndrome, cystic duct-duodenal fistula, biliary obstruction, neoplasia, and primary sclerosing cholangitis. The cystic duct may also be secondarily involved by adjacent malignant or inflammatory processes. Postoperative alterations are seen after liver transplantation or cholecystectomy when a portion of the cystic duct is left behind as a remnant. Recognized postoperative complications include retained cystic duct stones, cystic duct leakage, and malposition of T tubes in the remnant. Pitfalls encountered in cystic duct imaging include pseudocalculous defects from overlap of the cystic duct and common bile duct, underfilling of the cystic duct during direct cholangiography, and admixture defects at the cystic duct orifice. Pseudomass or pseudotumor defects may result from an impacted cystic duct stone or from a tortuous, redundant cystic duct. Familiarity with the imaging appearance of the normal cystic duct, its anatomic variants, and related disease processes facilitates accurate diagnosis and helps avoid misinterpretation.

Use of imaging for living donor liver transplantation.

Living donor liver transplantation is emerging as an alternative to cadaveric liver transplantation. The authors present multimodality images obtained in 44 cases of living donor liver transplantation. The images in this article were derived from the pre-, intra-, and postoperative imaging protocol for their institutional transplantation program. Preoperative magnetic resonance (MR) imaging in the donor allows detection of focal liver lesions and accurate determination of liver volume. The latter is crucial to ensure adequate postoperative liver function for donors and recipients. MR cholangiography depicts donor biliary anatomy. MR angiography and digital subtraction arteriography are performed to assess vascular anatomy. Intraoperative ultrasonography (US) helps determine the resection plane during donor hepatectomy. Postoperative MR imaging documents liver regrowth. MR imaging, US, and computed tomography help assess complications in donors and recipients.

Gynecologic brachytherapy: digital fluoroscopy for placement verification and treatment planning.

The authors evaluated the feasibility of using digital fluoroscopic images for device placement verification and dosimetric planning for gynecologic brachytherapy. Adequate images were obtained rapidly, and the limited pincushion distortion on digital fluoroscopic images produced negligible variations in brachytherapy dose calculations compared with those calculated with standard radiographs. Intraoperative digital fluoroscopy can facilitate both placement verification and dosimetric planning for gynecologic brachytherapy.

Magnetic resonance cholangiopancreatography (MRCP) in the assessment of pancreatic duct trauma and its sequelae: preliminary findings.

BACKGROUND: The purpose of this study was to determine the utility of magnetic resonance cholangiopancreatography (MRCP) in the evaluation of pancreatic duct trauma and pancreas-specific complications. METHODS: Ten hemodynamically stable patients with clinically suspected pancreatic injury related to blunt abdominal trauma (n = 8), penetrating trauma (n = 1), or iatrogenic trauma (n = 1) underwent MRCP. Two abdominal radiologists conducted a review of the MRCPs to assess for the presence or absence of pancreatic duct trauma and pancreas-specific complications such as pseudocysts. The MRCP findings were correlated with endoscopic retrograde cholangiopancreatograms (n = 2), surgical findings (n = 1), computed tomographic scans (n = 10), and with clinical, biochemical or imaging follow-up (n = 10). RESULTS: Diagnostic quality MRCPs were obtained in each of the 10 patients. A mean imaging time of 5 minutes was required to perform the MRCPs. Pancreatic duct injuries were detected in four patients; pseudocysts were detected in three of these four patients. The pancreatic duct injuries in three patients were acute or subacute. In one of the three patients, disruption of a side branch of the pancreatic duct diagnosed with MRCP was not detected with endoscopic retrograde cholangiopancreatography but was confirmed surgically. In the fourth patient, the pancreatic duct injury was chronic; MRCP revealed a posttraumatic stricture in this patient who had sustained blunt abdominal trauma 17 years previously. In the remaining six patients, pancreatic duct trauma was excluded with MRCP. The information derived from the MRCPs was used to guide clinical decision-making in all 10 patients. CONCLUSIONS: MRCP enables noninvasive detection and exclusion of pancreatic duct trauma and pancreas-specific complications and provides information that may be used to guide management decisions.

Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver transplantation.

BACKGROUND: Regeneration of the liver to a predetermined size after resection or transplantation is a well described phenomenon, but the time course over which these events occur has not been well defined. It is not clear how initial liver mass, reperfusion, immunosuppression, or steatosis influence this process. METHODS: Liver regeneration was assessed prospectively by volumetric magnetic resonance imaging (MRI) in living right lobe liver donors and the recipients of these grafts. Imaging was performed at regular intervals through 60 days after resection/transplantation, and liver mass was determined. Liver function tests and synthetic function were monitored throughout the study period in donors and recipients of these grafts as well as recipients of cadaveric grafts. RESULTS: MRI consistently overestimated liver mass by a mean of 45 g (+/-65) (range 10-123). Donor liver mass increased by 101%, 110%, 115%, and 144% at 7, 14, 30, and 60 days after resection, respectively. Recipient liver mass increased by 87,101, 119, and 99% at 7, 14, 30, and 60 days after transplantation, respectively. Steatosis did not influence the degree of regeneration or graft function, nor was there a functional difference between grafts of >1% graft to recipient body weight ratio or <1%. CONCLUSIONS: MRI accurately determines right lobe mass. Most liver regeneration occurs in the 1st week after resection or transplantation, and the time course does not differ significantly in donors or recipients. The mass of the graft or remnant segment affects the duration of the regeneration process, with a smaller initial liver mass prolonging the course. Steatosis of <30% had no bearing on liver function or regeneration and, therefore, should not be an absolute criterion for exclusion of donors. A calculated graft to recipient body weight ratio of 0.8% is adequate for right lobe living donor liver transplantation.

Primary sclerosing cholangitis: evaluation with MR cholangiography-a case-control study.

PURPOSE: To determine the accuracy of magnetic resonance (MR) cholangiography for detection of primary sclerosing cholangitis (PSC) and localization of PSC in the biliary tract. MATERIALS AND METHODS: In a prospective case-control study involving 102 patients, the MR cholangiograms obtained in 34 patients with PSC established with endoscopic retrograde cholangiopancreatography (ERCP) were compared with the MR cholangiograms obtained in 68 age-matched control patients with hepatobiliary diseases other than PSC. Two abdominal radiologists conducted an independent, blinded random review of the MR cholangiograms to assess for the presence or absence of PSC and determine the location of PSC in the biliary tract, and then compared the findings with those at ERCP. RESULTS: MR cholangiography was found to be accurate in detecting PSC and in defining the extent of disease. In the detection of PSC, the sensitivities were 88% and 85%; specificities, 97% and 92%; positive predictive values, 94% and 85%; and negative predictive values, 94% and 93% for readers 1 and 2, respectively. Interobserver agreement was excellent (kappa = 0.79). In the localization of extrahepatic PSC, the sensitivities were 83% and 89%; and specificities, 83% and 83% for readers 1 and 2, respectively. Interobserver agreement was good (kappa = 0.62). In the localization of intrahepatic PSC, the sensitivity was 87% for both readers; interobserver agreement was good (kappa = 0.71). CONCLUSION: MR cholangiography enables accurate detection and localization of PSC.

Magnetic resonance pancreatography (MRP).

Magnetic resonance pancreatography (MRP) is a technique that permits accurate evaluation of the pancreatic duct without instrumentation, contrast material administration, or ionizing radiation. Because MRP is entirely noninvasive, MRP avoids complications associated with endoscopic retrograde pancreatography (ERP) such as pancreatitis and perforation. MRP allows for the noninvasive evaluation of patients with acute and chronic pancreatitis, variant anatomy of the pancreatic duct, pancreatic duct trauma, and pancreatic neoplasia. MRP yields diagnostic information in the setting of a failed or incomplete ERP. When MRP is performed in conjunction with conventional abdominal MR, the result is a comprehensive examination of the pancreatic duct as well as the pancreas and other solid organs of the abdomen.

Benign diseases of the biliary tract: evaluation with MR cholangiography.

MR cholangiography (MRC) is a noninvasive, rapid means of evaluating the biliary tract that, in many instances, may replace invasive procedures such as diagnostic endoscopic retrograde cholangiography and percutaneous transhepatic cholangiography. This article describes and illustrates the MRC features of benign diseases of the biliary tract such as choledocholithiasis; intrahepatic bile duct calculi; congenital anomalies, including aberrant bile ducts and choledochal cysts; postsurgical strictures; and strictures related to chronic pancreatitis.

Recurrent cervical carcinoma: typical and atypical manifestations.

After treatment of cervical carcinoma, recurrent disease may be observed in multiple sites at imaging. Both typical and atypical manifestations of recurrent disease occur. Typical manifestations of recurrent cervical carcinoma involve the pelvis and lymph nodes. Pelvic recurrences may be observed as masses involving the cervix and uterus, vagina or vaginal cuff, parametria, bladder, ureters, rectum, or ovaries and may result in fistula formation or hydronephrosis. Nodal recurrence may be identified as enlarged pelvic and retroperitoneal nodes. Atypical manifestations of recurrent cervical carcinoma are being recognized with greater frequency due to the use of intensive pelvic radiation therapy, the evolution of improved imaging techniques, and the more frequent use of imaging as a means of surveillance. These atypical manifestations may involve the solid organs of the abdomen (focal masses) as well as the peritoneum, mesentery, and omentum (implants); gastrointestinal tract (obstruction, fistula formation, ischemia); chest (metastases to the lung parenchyma, pleura, and pericardium); bones (destructive lesions); and other sites. Familiarity with the imaging features of recurrent cervical carcinoma in these anatomic locations will facilitate prompt, accurate diagnosis and treatment.

Orthotopic liver transplantation: evaluation with MR cholangiography.

PURPOSE: To determine the accuracy of magnetic resonance (MR) cholangiography for demonstration of the biliary tract and detection of biliary complications in patients who have undergone orthotopic liver transplantation. MATERIALS AND METHODS: Breath-hold half-Fourier rapid acquisition with relaxation enhancement MR cholangiography was performed in 25 patients who had undergone orthotopic liver transplantation. MR cholangiograms were prospectively and independently interpreted by two radiologists for depiction of the biliary tract and ductal anastomosis and for complications (eg, biliary dilatation, stricture, stones). MR cholangiographic findings were correlated with findings from direct cholangiography (n = 24) and surgery (n = 1). RESULTS: MR cholangiography completely demonstrated first-order intrahepatic bile ducts in 23 (92%) patients, the donor extrahepatic bile duct in 25 (100%), the recipient extrahepatic bile duct in 17 of 18 (94%), and the anastomosis in 24 (96%). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of MR cholangiography for detection of biliary dilatation and stricture were each 100%. Complete interobserver agreement occurred in the detection of biliary dilatation and stricture. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of MR cholangiography for detection of stones were 100% for one radiologist and 86%, 100%, 96%, 100%, and 95%, respectively, for the other. Both radiologists agreed on the diagnosis of bile duct stones in six of seven cases (kappa = 0.90). CONCLUSION: MR cholangiography enables accurate depiction of the biliary tract and detection of biliary complications in patients with an orthotopic liver transplant.

Thoracopancreatic fistula: clinical and imaging findings.

PURPOSE: The goal of this work was to describe the clinical and imaging features of thoracopancreatic fistula, a rare complication of pancreatitis. METHOD: Nine cases of thoracopancreatic fistula proved by thoracentesis, endoscopic retrograde cholangiopancreatography (ERCP), or surgery were retrospectively and independently reviewed by two abdominal radiologists. All available imaging examinations [chest radiographs = 9, CT = 9, MR and MR cholangiopancreatography (MRCP) = 2, and ERCP = 6] were analyzed, and findings were recorded on a standardized datasheet. Available medical records (n = 7) were reviewed to determine the clinical presentation of the patients and thoracentesis results. RESULTS: Seven of the nine patients presented with pulmonary symptoms such as dyspnea or cough. Of the seven patients with pleural fluid analysis, all demonstrated elevated amylase levels (mean 13,007 U/L). Imaging examinations revealed pancreaticopleural fistulas in six patients, a mediastinal pseudocyst in one patient, and both a pancreaticopleural fistula and a mediastinal pseudocyst in two patients. Chest radiography showed pleural fluid collections in eight patients. CT demonstrated a fluid-containing fistula in all nine patients. MR and MRCP depicted a fistula extending from the abdomen to the pleural space in the two patients with MR correlation. ERCP showed pancreatic ductal changes characteristic of chronic pancreatitis in the six patients with ERCP correlation but failed to demonstrate the fistula in two of the six patients. CONCLUSION: The CT, MR, MRCP, or ERCP finding of a fluid-filled tract extending from the pancreas to the thorax is characteristic of a thoracopancreatic fistula, particularly when identified in a patient who presents with pulmonary symptoms and a history of chronic pancreatitis.