Use of percutaneous imaging-guided biopsy for Liver Imaging and Reporting Data System (LI-RADS) observations: A retrospective study from two liver transplant centers.

Since the adoption of guidelines for the non-invasive imaging diagnosis of hepatocellular carcinoma (HCC), the need for sampling of a lesion in cirrhosis has decreased. We aimed to retrospectively investigate the use of percutaneous imaging-guided biopsy for LI-RADS observations in cirrhosis in two large liver transplant centers. A review of the pathology database in the two Institutions (Institution A, Institution B) was conducted to identify patients that underwent percutaneous imaging-guided biopsy for a liver lesion in the interval time 01/01/2015-12/312020. Liver observations on pre-procedure contrast-enhanced CT or MRI were classified according to LI-RADS v2018. Among the 728 patients who underwent imaging guided biopsy of a liver lesion in Institution A, and among the 749 patients who underwent imaging guided biopsy of a liver lesion in Institution B, respectively 50 (6.8 %) and 16 (2.1 %) were cirrhotic with available pre-procedural contrast-enhanced CT or MRI. A total of 67 lesions were biopsied. 30/67 (45 %) biopsied observations were classified as LR-M. 55/67 (82 %) biopsies were positive for malignancy at histopathology and among them 33 (60 %) were HCC. In conclusion, a small percentage of percutaneous, imaging-guided biopsies for liver lesions are performed in cirrhosis, and more frequently for LR-M observations.

Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents during the first year of life. The main features of the disease are normochromic and macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. The patients also present with growth retardation and craniofacial, upper limb, heart and urinary system congenital malformations in ~30-50 % of cases. The disease has been associated with point mutations and large deletions in ten ribosomal protein (RP) genes RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, RPS26, and RPL26 and GATA1 in about 60-65 % of patients. Here, we report a novel large deletion in RPL15, a gene not previously implicated to be causative in DBA. Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1. In addition, we detected five deletions in RP genes in which mutations have been previously shown to cause DBA: one each in RPS19, RPS24, and RPS26, and two in RPS17. Pre-ribosomal RNA processing was affected in cells established from the patients bearing these deletions, suggesting a possible molecular basis for their pathological effect. These data identify RPL15 as a new gene involved in DBA and further support the presence of large deletions in RP genes in DBA patients.

Immediate and Late Complications After Liver Transplantation.

Other than rejection, hepatic artery and portal vein thrombosis are the most common complications in the immediate postoperative period with hepatic arterial thrombosis more common and more devastating. Hepatic artery stenosis is more common 1 month after transplantation, whereas portal and hepatic vein stenosis is more often seen as a late complication. Ultrasound is the first-line imaging examination to diagnose vascular complications with contrast-enhanced CT useful if ultrasound findings are equivocal. MR cholangiography is often most helpful in diagnosing bile leaks, biliary strictures, and biliary stones.

Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia.

Diamond-Blackfan anemia (DBA) is an inherited form of pure red cell aplasia that usually presents in infancy or early childhood and is associated with congenital malformations in ∼30-50% of patients. DBA has been associated with mutations in nine ribosomal protein (RP) genes in about 53% of patients. We completed a large-scale screen of 79 RP genes by sequencing 16 RP genes (RPL3, RPL7, RPL8, RPL10, RPL14, RPL17, RPL19, RPL23A, RPL26, RPL27, RPL35, RPL36A, RPL39, RPS4X, RPS4Y1, and RPS21) in 96 DBA probands. We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities. This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits. We also found a deletion in RPL19 and missense mutations in RPL3 and RPL23A, which may be variants of unknown significance. Together with RPL5, RPL11, and RPS7, RPL26 is the fourth RP regulating p53 activity that is linked to DBA.

Thioredoxin reductase is inhibited by the carbamoylating activity of the anticancer sulfonylhydrazine drug laromustine.

The thioredoxin system facilitates proliferative processes in cells and is upregulated in many cancers. The activities of both thioredoxin (Trx) and its reductase (TrxR) are mediated by oxidation/reduction reactions among cysteine residues. A common target in preclinical anticancer research, TrxR is reported here to be significantly inhibited by the anticancer agent laromustine. This agent, which has been in clinical trials for acute myelogenous leukemia and glioblastoma multiforme, is understood to be cytotoxic principally via interstrand DNA crosslinking that originates from a 2-chloroethylating species generated upon activation in situ. The spontaneous decomposition of laromustine also yields methyl isocyanate, which readily carbamoylates thiols and primary amines. Purified rat liver TrxR was inhibited by laromustine with a clinically relevant IC(50) value of 4.65 µM. A derivative of laromustine that lacks carbamoylating activity did not appreciably inhibit TrxR while another derivative, lacking only the 2-chloroethylating activity, retained its inhibitory potency. Furthermore, in assays measuring TrxR activity in murine cell lysates, a similar pattern of inhibition among these compounds was observed. These data contrast with previous studies demonstrating that glutathione reductase, another enzyme that relies on cysteine-mediated redox chemistry, was not inhibited by methylcarbamoylating agents when measured in cell lysates. Mass spectrometry of laromustine-treated enzyme revealed significant carbamoylation of TrxR, albeit not on known catalytically active residues. However, there was no evidence of 2-chloroethylation anywhere on the protein. The inhibition of TrxR is likely to contribute to the cytotoxic, anticancer mechanism of action for laromustine.

Update on MR Contrast Agents for Liver Imaging: What to Use and When.

Contrast-enhanced liver MR imaging is an important diagnostic tool for many different liver diseases with the sensitivity and specificity in diagnosing liver diseases typically far exceeding other imaging modalities. The safety profile of GBCA is excellent with minimal adverse events. Both extracellular and hepatobiliary contrast agents offer unique advantages and potential limitations. ECA is excellent for obtaining high-quality arterial phase imaging and can be particularly useful for the evaluation of hepatocellular carcinoma (HCC) in cirrhotic patients. In contrast, hepatobiliary agent (HBA) can help distinguish FNH from adenomas, detect liver metastases, and provide biliary imaging due to their uptake within normal hepatocytes and biliary excretion.

The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update.

Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database.