Improved diagnostic accuracy of readout-segmented echo-planar imaging for peripheral zone clinically significant prostate cancer: a retrospective 3T MRI study.

This study compares the readout-segmented echo-planar imaging (rsEPI) from the conventional single-shot EPI (ssEPI) diffusion-weighted imaging (DWI) for the discrimination of patients with clinically significant prostate cancer (csPCa) within the peripheral zone (PZ) using apparent diffusion coefficient (ADC) maps and pathology report from magnetic resonance imaging (MRI)-targeted biopsy. We queried a retrospective monocentric database of patients with targeted biopsy. csPCa patients were defined as an International Society of Urological Pathology grade group ≥ 2. Group-level analyses and diagnostic accuracy of mean ADC values (ADCmean) within the tumor volume were assessed from Kruskal-Wallis tests and receiving operating characteristic curves, respectively. Areas under the curve (AUC) and optimal cut-off values were calculated. 159 patients (105 rsEPI, 54 ssEPI; mean age ± standard deviation: 65 ± 8 years) with 3T DWI, PZ lesions and targeted biopsy were selected. Both DWI sequences showed significantly lower ADCmean values for patients with csPCa. The rsEPI sequence better discriminates patients with csPCa (AUCrsEPI = 0.84, AUCssEPI = 0.68, p < 0.05) with an optimal cut-off value of 1232 µm2/s associated with a sensitivity-specificity of 97%-63%. Our study showed that the rsEPI DWI sequence enhances the discrimination of patients with csPCa.

Grey areas and evidence gaps in the management of rectal cancer as revealed by comparing recommendations from clinical guidelines.

BACKGROUND: While the management of nonmetastatic and oligometastatic rectal cancer has rapidly evolved over the last few decades, many grey areas and highly debated topics remain that foster significant variation in clinical practice. We aimed to identify controversial points and evidence gaps in this disease setting by systematically comparing recommendations from national and international clinical guidelines. METHODS: Twenty-six clinical questions reflecting practical challenges in the routine management of nonmetastatic and oligometastatic rectal cancer patients were selected. Recommendations from the ESMO, NCCN, JSCCR, Australian and Ontario guidelines were extrapolated and compared using a 4-tier classification system (i.e., identical/very similar, similar, slightly different, different). Overall agreement between guidelines (i.e., substantial/complete disagreement, partial disagreement, partial agreement, substantial/complete agreement) was assessed for each clinical question and compared against the highest level of available evidence by using the χ2 statistic test. RESULTS: Guidelines were in substantial/complete agreement, partial agreement, partial disagreement, and substantial/complete disagreement for 8 (30.8%), 2 (7.7%), 7 (26.9%), and 9 (34.6%) clinical questions, respectively. High level of evidence supported clinical recommendations in 3/10 cases (30%) where guidelines were in agreement and in 10/16 cases (62.5%) where guidelines were in disagreement (χ2 = 2.6, p = 0.106). Agreement was frequently reached for questions regarding diagnosis, staging, and radiology/pathology pro-forma reporting, while disagreement characterised most of the treatment-related topics. CONCLUSIONS: Substantial variation exists across clinical guidelines in the recommendations for the management of nonmetastatic and oligometastatic rectal cancer. This variation is only partly explained by the lack of supporting, high-level evidence.

Benign biliary diseases.

Benign biliary diseases include a large spectrum of congenital and acquired disorders, which have different prognosis and require different treatment management. The diagnosis may be challenging since some benign disorders may mimic malignancy. Imaging has an important role in the diagnostic process, for treatment decision and planning and in patient follow up. Magnetic resonance (MR) with magnetic resonance cholangiopancreatography (MRCP) sequences is the imaging modality of choice for biliary diseases and has demonstrated high diagnostic accuracy. Moreover, the use of a hepato-specific MR contrast agent allows morphological and functional assessment of the liver and the biliary tree improving the diagnostic performance.

ESGAR consensus statement on liver MR imaging and clinical use of liver-specific contrast agents.

OBJECTIVES: To develop a consensus and provide updated recommendations on liver MR imaging and the clinical use of liver-specific contrast agents. METHODS: The European Society of Gastrointestinal and Abdominal Radiology (ESGAR) formed a multinational European panel of experts, selected on the basis of a literature review and their leadership in the field of liver MR imaging. A modified Delphi process was adopted to draft a list of statements. Descriptive and Cronbach's statistics were used to rate levels of agreement and internal reliability of the consensus. RESULTS: Three Delphi rounds were conducted and 76 statements composed on MR technique (n = 17), clinical application of liver-specific contrast agents in benign, focal liver lesions (n = 7), malignant liver lesions in non-cirrhotic (n = 9) and in cirrhotic patients (n = 18), diffuse and vascular liver diseases (n = 12), and bile ducts (n = 13). The overall mean score of agreement was 4.84 (SD ±0.17). Full consensus was reached in 22 % of all statements in all working groups, with no full consensus reached on diffuse and vascular diseases. CONCLUSIONS: The consensus provided updated recommendations on the methodology, and clinical indications, of MRI with liver specific contrast agents in the study of liver diseases. KEY POINTS: • Liver-specific contrast agents are recommended in MRI of the liver. • The hepatobiliary phase improves the detection and characterization of hepatocellular lesions. • Liver-specific contrast agents can improve the detection of HCC.

[Multidisciplinary management of hepatocellular carcinoma in cirrhotic patients]. / Traitement du carcinome hépato-cellulaire chez le patient cirrhotique: la nécessité d'une approche pluridisciplinaire.

The treatment of hepatocellular carcinoma (HCC) in cirrhotic patients is challenging: the incidence is increasing, the cirrhosis dramatically limits the tolerance to treatment possibilities, there are many therapeutic modalities but resources are limited, namely in the context of organ shortage for transplantation. Liver transplantation (LT) is the optimal treatment as it combines the largest tumor resection possible and the correction of the underlying liver disease. Due to organ shortage however, LT is reserved for early-stages HCC. Surgical resection and radiofrequency destruction represent potentially curative options in highly selected patients. Arterial embolizations, chemo- or radio-embolizations, allow local tumor control but are not curative. These techniques could be performed before surgical resection or LT, to downstage the tumor and/or to control tumor progression while waiting for a graft. Finally, sorafenib is the only systemic treatment which has shown a survival benefit in advanced HCC. The benefit of combination of sorafenib and surgical treatments remains undetermined. The challenge in the management of HCC in cirrhotic patients is to integrate both individual (age, comorbidities, cirrhosis stage, tumor stage, specific contraindications to LT, etc.) and collective variables (expected waiting time before LT) to determine the best therapeutic option for each patient. In this process, multidisciplinarity is a key for success.

Late-onset fracture-associated osteosarcoma in a cat.

An 18-year-old male, castrated Domestic Shorthaired cat was presented with the complaint of acute severe lameness of the left pelvic limb. There was no history of trauma, apart from a distal physeal left femoral fracture that had been repaired 17 years previously. Radiology revealed a displaced distal metaphyseal femoral fracture with marked areas of bone lysis and periosteal proliferations. A pathological fracture due to a bone neoplasia was suspected. An amputation with coxofemoral disarticulation was performed. Histopathology confirmed the tentative diagnosis of appendicular osteo-sarcoma. No postoperative complications were encountered and the cat made a full recovery. This case shows an unusual presentation of a late-onset fracture-associated feline osteosarcoma.

New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel.

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.

Liver transplantation in cases of portal vein thrombosis in the recipient: a case report and review of the various options.

Several surgical techniques have been developed to allow liver transplantation in cases of complete portal vein thrombosis in the recipient. Despite this, these transplantations remain associated with a significant complication rate. We report herein a case of liver transplantation in a patient with complete portal vein thrombosis, underlying the potential pitfalls and the risk of intestinal sutures in case of hepaticojejunostomy. We discuss the technical options and their relative indications in such cases.

Endoscopic therapy for chronic pancreatitis.

When endoscopic therapy is used for the treatment of patients with painful chronic pancreatitis, extracorporeal shock wave lithotripsy (ESWL) can be proposed as a first-line approach when obstructive ductal stone(s) induce upstream dilation of the main pancreatic duct. Stone fragmentation by ESWL is followed by endoscopic ductal drainage using pancreatic sphincterotomy, fragmented stone(s) extraction, and pancreatic stenting in case of ductal stricture. After completion of endoscopic pancreatic ductal drainage, long-term clinical benefit can be expected for two thirds of the patients. Best clinical results are associated with absence or cessation of smoking and with early treatment in the course of chronic pancreatitis, while alcohol abuse increases the risks of diabetes, steatorrhea and mortality. The complications of chronic pancreatitis are mainly the development of pseudocyst secondary to the downstream ductal obstruction, and biliary obstruction caused by fibrotic changes in the head of the pancreas. Successful endoscopic pseudocyst drainage is currently obtained in most patients, and carries a low complication rate. Biliary stenting is a safe and effective technique for the short-term treatment of symptomatic bile duct stricture due to chronic pancreatitis, but permanent resolution is obtained in only 25% of cases. In conclusion, endoscopic management is now considered to be the preferred interventional treatment of chronic pancreatitis, for patients selected on the basis of the anatomical changes caused by the disease. This treatment is generally safe, minimally invasive, often effective for years, does not prevent further surgery, and can be repeated.

HIV-1 infection is facilitated in T cells by decreasing p56lck protein tyrosine kinase activity.

Several studies have suggested an important role for the protein tyrosine kinase p56lck (Lck) in HIV infection; however, the exact nature of this role remains unclear. Using a series of well characterized Jurkat-derived cell lines having a wide range of Lck kinase activity, our results showed that, while the entry of HIV-1 into these cell lines was similar, the kinetics of virus production by these cells were very different. Cells expressing a kinase-inactive Lck showed accelerated viral replication, whereas, cells expressing Lck with normal or elevated enzymatic activity showed a delay in virus replication that was proportional to the initial level of endogenous Lck activity. The cell line having the highest initial Lck kinase activity showed the slowest rate of productive HIV-1 infection. Analysis of 2-LTR circles revealed that this inhibitory effect of Lck was not due to inhibition of reverse transcription of HIV-1 genome or migration of the proviral DNA into the nuclei. This affect of Lck was confirmed in additional studies that used either the S1T cell line lacking completely Lck or where the Lck activity was altered in Jurkat cells prior to infection. S1T cells showed a 3- to 12-fold increase in the level of infection compared to Jurkat cells despite similar CD4 and chemokine coreceptor expression and cell doubling times. Pretreatment of Jurkat with an antisense lck oligodeoxynucleotide inhibited the synthesis of functional Lck and facilitated the viral replication by the cells as did expressing a dominant-negative mutant Lck which increased the productive infection>3-fold. Conversely, whereas IL-16 had no affect on productive infection in S1T cells that lack Lck, IL-16 pretreatment of Jurkat cells resulted in an immediate (within 5 min) and sustained and gradual (over 5 h) increase in Lck activity that resulted in a reduction of HIV-1 replication that paralleled the increasing Lck kinase activity. These results show that the enzymatic activity of Lck kinase can affect viral replication, that a lack of, or decreased Lck activity facilitates viral replication. Conversely, Lck can mediate a delay in HIV-1 infection that is proportional to the initial endogenous Lck enzyme activity.

Localized Castleman's disease and nephrotic syndrome not responsive to resection plus colchicine therapy.

We describe one patient with localized Castleman's disease (CD) of the mixed hyaline vascular and plasma cell type located at the mesentery of the small bowel, associated with systemic amyloidosis and nephrotic syndrome. A true nephrotic syndrome has rarely been reported in patients with CD. In the literature, it has been suggested that clinical and laboratory manifestations generally improved after surgical resection of the tumor. However, in our case, clinical and laboratory findings did not regress after operation followed by colchicine therapy.

Primary high grade malignant lymphoma of bladder.

Primary malignant lymphoma of bladder is one of the rarest extranodal site for lymphomas. Less than 100 cases have been reported so far. A history of chronic cystitis has been shown to be a preceding feature in many cases (40%) of primary bladder lymphoma. Most of the cases reported in the literature have a low-grade lymphoma including the subtypes of mucosa-associated lymphoid tissue. The diffuse large cell lymphoma is the most frequent type among the subtypes of high-grade bladder lymphomas. In this report, a case with high-grade primary malignant lymphoma of bladder is reported and the clinical, pathological aspects of diseases are reviewed.

A modelling study of feedforward activation in human erythrocyte glycolysis.

Though feedforward activation (FA) is a little known principle of control in metabolic networks, there is one well-known example; namely, the activation of pyruvate kinase (PK) by fructose-1,6-biphosphate (FBP) in glycolysis. The effects of this activation on the enzyme's kinetics are well characterised, but its possible role in glycolytic control has not been determined, and, experimentally, there is as yet no direct way of modifying the enzyme to remove just the FBP activation without affecting other aspects of the enzyme's kinetics. Given this limitation, we used a detailed numerical simulation of human erythrocyte glycolysis to simulate the effects of selective removal of the activation of PK by FBP on steady-state metabolite concentrations and on the dynamic response of glycolytic flux to a sudden increase of the cell's demand for ATP. Our modelling results predict that in the absence of FA steady-state levels of metabolites within the activation loop, i.e. from FBP to phosphoenolpyruvate, would be four- to thirteen-fold higher than normal, whereas levels of ATP and metabolites outside the loop, i.e. glucose-6-phosphate, fructose-6-phosphate and pyruvate, would be lower than normal. Existing clinical evidence in a patient with haemolytic anaemia, correlated with a lack of activation of PK by FBP (Paglia D.E., Valentine W.N., Holbrook C.T., Brockway R., Blood (1983) 62 972-979), is consistent with this prediction. In response to changing demand for ATP, the model predicts that the corresponding change of glycolytic flux would entail changes of metabolite concentrations in the absence of FA, but that in its presence the levels of metabolites within the activation loop remain essentially unperturbed. Thus, our results suggest that by stabilising metabolite pools in the face of variable glycolytic flux, FA may serve to avoid perturbations of the oxygen affinity of haemoglobin (sensitive to the levels of 2,3-phosphoglycerate) and of cell osmolality that would otherwise occur during variations in the cell's demand for ATP. In addition, by significantly raising the steady-state setpoint of intermediate metabolite pools, the productivity index (ratio of glycolytic flux to total metabolites in the pathway) of glycolysis would fall almost four-fold in the absence of forward activation.

Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function.

The number of complex cystic fibrosis transmembrane conductance regulator (CFTR) genotypes identified as having double-mutant alleles with two mutations inherited in cis has been growing. We investigated the structure-function relationships of a severe cystic fibrosis (CF)-associated double mutant (R347H-D979A) to evaluate the contribution of each mild mutation to the phenotype. CFTR mutants expressed in HeLa cells were analyzed for protein biosynthesis and Cl(-) channel activity. Our data show that R347H is associated with mild defective Cl(-) channel activity and that the D979A defect leads to misprocessing. The mutant R347H-D979A combines both defects for a dramatic decrease in Cl(-) current. To decipher the molecular mechanism of this phenotype, single and double mutants with different charge combinations at residues 347 and 979 were constructed as charged residues were involved in this complex genotype. These studies revealed that residue 979, located in the third cytoplasmic loop, is critical for CFTR processing and Cl(-) channel activity highlighting the role of charged residues. These results have also important implications for CF, as they show that two mutations in cis can act in concert to alter dramatically CFTR function contributing to the wide phenotypic variability of CF disease.

Adenomatoid tumor of the uterus in a patient with chronic renal failure.

A case of adenomatoid tumor of the uterus in a 34-year-old patient, who had received a renal transplant and was undergoing immunosuppresive therapy is presented. At surgery, there were a total of eight nodular intramural and subserous masses thought to be leiomyoma nodules, and tumor excision was unusually, hardly performed because the nodules were strictly adherent to the myometrium. All the specimens yielded the same pathological diagnosis - adenomatoid tumor. This case is unusual because of the multiple nodular pattern and its association with the immunocompromised status of the patient. Although adenomatoid tumors have not been shown to recur, we are in doubt in our case, because the uterus is still intact and the immunocompromised status of the patient might have a role in the extensive growth and also in the possibility of recurrence.

Aspirin and some other nonsteroidal anti-inflammatory drugs inhibit cystic fibrosis transmembrane conductance regulator protein gene expression in T-84 cells.

Cystic fibrosis (CF) is caused by mutations in the CF gene, which encodes CF transmembrane conductance regulator protein (CFTR), a transmembrane protein that acts as a cAMP-regulated chloride channel The disease is characterized by inflammation but the relationship between inflammation, abnormal transepithelial ion transport, and the clinical manifestations of CF are uncertain. The present study was undertaken to determine whether three nonsteroidal anti-inflammatory drugs (NSAIDs) (aspirin, ibuprofen, and indomethacin) modulate CFTR gene expression in T-84 cells. Treatment with NSAIDs reduced CFTR transcripts, and decreased cAMP-stimulated anion fluxes, an index of CFTR function. However, the two phenomena occurred at different concentrations of both drugs. The results indicate that NSAIDs can regulate both CFTR gene expression and the function of CFTR-related chloride transport, and suggest that NSAIDs act via multiple transduction pathways.