Multi-Center Follow-up Study to Develop a Classification System Which Differentiates Mucinous Cystic Neoplasm of the Liver and Benign Hepatic Cyst Using Machine Learning.

RATIONALE AND OBJECTIVES: To date, no clinically useful classification system has been developed for reliably differentiating mucinous cystic neoplasm (MCN) from a benign hepatic cyst (BHC) in the liver. The objective was to use machine learning and a multi-center study design to develop and assess the performance of a novel classification system for predicting whether a hepatic cystic lesion represents MCN or BHC. MATERIALS AND METHODS: A multi-center cohort study identified 154 surgically resected hepatic cystic lesions in 154 subjects which were pathologic confirmed as MCN (43) or BHC (111). Readers at each institution recorded seven pre-determined imaging features previously identified as potential differentiating features from prior publications. The contribution of each of these features to differentiating MCN from BHC was assessed by machine learning to develop an optimal classification system. RESULTS: Although several of the assessed imaging features demonstrated statistical significance, only 3 imaging features were found by machine learning to significantly contribute to a potential classification system: (1) solid enhancing nodule (2) all septations arising from an external macro-lobulation (3) whether the lesion was solitary or one of multiple cystic liver lesions. The optimal classification system had only four categories and correctly identified 144/154 lesion (93.5%). CONCLUSION: This multi-center follow-up study was able to use machine learning to develop a highly accurate classification system for differentiation of hepatic MCN from BHC, which could be readily applied to clinical practice.

Author Correction: Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas.

A Correction to this paper has been published: https://doi.org/10.1038/s41587-019-0392-8.

Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas.

Single-cell RNA sequencing (scRNA-seq) enables the systematic identification of cell populations in a tissue, but characterizing their spatial organization remains challenging. We combine a microarray-based spatial transcriptomics method that reveals spatial patterns of gene expression using an array of spots, each capturing the transcriptomes of multiple adjacent cells, with scRNA-Seq generated from the same sample. To annotate the precise cellular composition of distinct tissue regions, we introduce a method for multimodal intersection analysis. Applying multimodal intersection analysis to primary pancreatic tumors, we find that subpopulations of ductal cells, macrophages, dendritic cells and cancer cells have spatially restricted enrichments, as well as distinct coenrichments with other cell types. Furthermore, we identify colocalization of inflammatory fibroblasts and cancer cells expressing a stress-response gene module. Our approach for mapping the architecture of scRNA-seq-defined subpopulations can be applied to reveal the interactions inherent to complex tissues.

Targeting Poxvirus Decapping Enzymes and mRNA Decay to Generate an Effective Oncolytic Virus.

Through the action of two virus-encoded decapping enzymes (D9 and D10) that remove protective caps from mRNA 5'-termini, Vaccinia virus (VACV) accelerates mRNA decay and limits activation of host defenses. D9- or D10-deficient VACV are markedly attenuated in mice and fail to counter cellular double-stranded RNA-responsive innate immune effectors, including PKR. Here, we capitalize upon this phenotype and demonstrate that VACV deficient in either decapping enzyme are effective oncolytic viruses. Significantly, D9- or D10-deficient VACV displayed anti-tumor activity against syngeneic mouse tumors of different genetic backgrounds and human hepatocellular carcinoma xenografts. Furthermore, D9- and D10-deficient VACV hyperactivated the host anti-viral enzyme PKR in non-tumorigenic cells compared to wild-type virus. This establishes a new genetic platform for oncolytic VACV development that is deficient for a major pathogenesis determinant while retaining viral genes that support robust productive replication like those required for nucleotide metabolism. It further demonstrates how VACV mutants unable to execute a fundamental step in virus-induced mRNA decay can be unexpectedly translated into a powerful anti-tumor therapy.

Crosstalk between Regulatory T Cells and Tumor-Associated Dendritic Cells Negates Anti-tumor Immunity in Pancreatic Cancer.

Regulatory T (Treg) cell infiltration constitutes a prominent feature of pancreatic ductal adenocarcinoma (PDA). However, the immunomodulatory function of Treg cells in PDA is poorly understood. Here, we demonstrate that Treg cell ablation is sufficient to evoke effective anti-tumor immune response in early and advanced pancreatic tumorigenesis in mice. This response is dependent on interferon-γ (IFN-γ)-producing cytotoxic CD8+ T cells. We show that Treg cells engage in extended interactions with tumor-associated CD11c+ dendritic cells (DCs) and restrain their immunogenic function by suppressing the expression of costimulatory ligands necessary for CD8+ T cell activation. Consequently, tumor-associated CD8+ T cells fail to display effector activities when Treg cell ablation is combined with DC depletion. We propose that tumor-infiltrating Treg cells can promote immune tolerance by suppressing tumor-associated DC immunogenicity. The therapeutic manipulation of this axis might provide an effective approach for the targeting of PDA.

Paget's disease of the anus masking a mixed adenoneuroendocrine tumour of the rectum.

A man aged 83 years with vague perirectal symptoms had a delayed diagnosis of Paget's disease of the anus. A lack of thorough digital rectal examination failed to diagnose a mixed adenonueroendocrine tumour of the rectum in a timely matter.

Direct acting antiviral therapy is curative for chronic hepatitis C/autoimmune hepatitis overlap syndrome.

Autoimmune phenomena are common in patients with chronic hepatitis C. Management of chronic hepatitis C/autoimmune hepatitis syndrome has until recently been problematic due to the adverse effects of interferon on autoimmune processes and immunosuppression on viral replication. In this report we describe 3 patients with chronic hepatitis C/autoimmune hepatitis overlap syndrome who responded rapidly to direct acting anti-viral therapy. The resolution of the autoimmune process supports a direct viral role in its pathophysiology.

Comparison of MRI features of pathologically proven hepatocellular carcinoma between patients with hepatitis B and hepatitis C infection.

PURPOSE: To compare MRI features of pathologically-proven hepatocellular carcinoma (HCC) between patients with hepatitis B (HBV) and hepatitis C (HCV) infection. METHODS: Two radiologists assessed 51 confirmed HCCs on MRI in HBV (n=18) or HCV (n=33) patients; a third, more experienced, radiologist resolved discrepancies. RESULTS: Arterial hyperenhancement occurred more frequently in HCV (90.9% vs. 66.7%; P=.032), DWI/T2WI hyperintensity more frequently in HBV [(DWI: 78.6% vs. 45.8%, T2WI: 77.8% vs. 48.5%; P=.073-0.088)]. Tumors were larger in HBV (P≤.016). Washout, pseudocapsule, homogeneity, circumscribed margins, lipid, iron, and visually low ADC were not different. CONCLUSION: Larger studies are required to confirm these preliminary findings.

Utility of diffusion-weighted MRI for differentiating acute from chronic cholecystitis.

PURPOSE: To assess the use of diffusion-weighted imaging (DWI) for differentiating acute from chronic cholecystitis, in comparison with conventional magnetic resonance imaging (MRI) features. MATERIALS AND METHODS: Liver MRI including DWI (b-values 0/500/1000s/mm(2) ) was performed at 1.5T ≤30 days before cholecystectomy in 83 patients with abdominal pain. Two radiologists assessed cases for conventional (gallstones, wall thickening, pericholecystic fluid, pericholecystic fat changes, gallbladder distension, pericholecystic liver enhancement, mural T2 -hyperintensity, mural hyperenhancement, mural striations, abscess, intraluminal membranes, and mural defect) and DWI (increased mural signal on high b-value images, visually low apparent diffusion coefficient [ADC], and ADC values) features. RESULTS: Acute cholecystitis was present in 43%; chronic cholecystitis was present in 57%. Nine of 12 conventional features were more frequent in acute cholecystitis for both readers (P ≤ 0.003). Increased mural signal on high b-value images was more frequent (P < 0.001) in acute than chronic cholecystitis for R1 (92% vs. 32%) and R2 (83% vs. 30%). Sensitivity and specificity of increased signal on high b-value images were: R1, 92%/68%; R2, 83%/70%. Visually low ADC was more frequent in acute cholecystitis for R2 (P < 0.001) but not R1 (P = 0.406); ADC values were not different between groups for either reader (P = 0.104-0.139). Among conventional and DWI features, only increased signal on high b-value DWI was independently associated with acute cholecystitis for both readers (P = 0.006-0.012). CONCLUSION: Visually increased mural signal on high b-value DWI was highly sensitive and moderately specific for acute cholecystitis, being an independent predictor relative to conventional features for both readers. Although requiring larger studies, DWI (particularly the high b-value images) may have additive value relative to conventional MRI-suspected acute cholecystitis. J. Magn. Reson. Imaging 2016;44:89-97.

IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia.

UNLABELLED: A salient feature of pancreatic ductal adenocarcinoma (PDAC) is an abundant fibroinflammatory response characterized by the recruitment of immune and mesenchymal cells and the consequent establishment of a protumorigenic microenvironment. Here, we report the prominent presence of B cells in human pancreatic intraepithelial neoplasia and PDAC lesions as well as in oncogenic Kras-driven pancreatic neoplasms in the mouse. The growth of orthotopic pancreatic neoplasms harboring oncogenic Kras was significantly compromised in B-cell-deficient mice (µMT), and this growth deficiency could be rescued by the reconstitution of a CD1d(hi)CD5(+) B-cell subset. The protumorigenic effect of B cells was mediated by their expression of IL35 through a mechanism involving IL35-mediated stimulation of tumor cell proliferation. Our results identify a previously unrecognized role for IL35-producing CD1d(hi)CD5(+) B cells in the pathogenesis of pancreatic cancer and underscore the potential significance of a B-cell/IL35 axis as a therapeutic target. SIGNIFICANCE: This study identifies a B-cell subpopulation that accumulates in the pancreatic parenchyma during early neoplasia and is required to support tumor cell growth. Our findings provide a rationale for exploring B-cell-based targeting approaches for the treatment of pancreatic cancer.

Solitary fibrous tumor of the pancreas.

Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms of fibroblastic origin. Most commonly they affect the pleura but they been described in other viscera. SFT of the pancreas is extremely rare, and only eight cases have been reported to date. We perform a literature review and report a ninth case. The patient is a 54-year-old African-American female who presented with several months of abdominal pain. Abdominal radiography demonstrated a lesion in the head of the pancreas, and she underwent a Whipple operation. Pathology demonstrated SFT of the pancreas. She is alive and well 1 year post-operatively. SFT of the pancreas predominately affects middle-aged women. These tumors are difficult to distinguish radiologically from neuroendocrine tumors. While SFT of the pancreas tend to have an indolent course, there is the potential for malignancy. We recommend complete surgical excision.

Differentiation of Malignant Omental Caking from Benign Omental Thickening using MRI.

PURPOSE: To determine multi-parametric MRI features that can help differentiate malignant omental caking from benign omental thickening in the setting of portal hypertension. METHODS: We identified 19 patients with an abnormal omentum on MRI and an available reference standard: 11 patients with portal hypertension and benign omental thickening (9 male, 2 female, mean age 58 ± 6 years) and 8 patients with metastatic omental caking (4 male, 4 female, mean age 61 ± 13 years). Criteria for benign omental thickening were no evidence of malignancy for at least 24 months of follow-up (n = 7), negative ascites cytology (n = 2), or absence of malignancy on pathologic analysis of liver explant (n = 2). Criteria for omental malignancy were positive omental biopsy (n = 6) or ascites cytology (n = 2). Two radiologists (R1 and R2) evaluated characteristics of the thickened omentum on MRI. RESULTS: Findings occurring with significantly higher frequency in malignant omental caking were hyperintensity on high b-value diffusion-weighted imaging (DWI) (R1 88% vs. 0%, R2 88% vs. 0%), hyperenhancement (R1 75% vs. 0%, R2 75% vs. 0%), and convex outer omental contour (R1 88% vs. 0%, R2 75% vs. 9%) (all p ≤ 0.001); discrete omental nodules were significantly more frequent in malignant omental thickening for R1 (63% vs. 0%, p = 0.005). Features not significantly different between groups included decreased ADC, T2 hyperintensity, vessels coursing through the omentum, moderate/large volume ascites, splenomegaly, and mesenteric edema (all p ≥ 0.058). CONCLUSION: Abnormal signal on DWI, hyperenhancement, and convex outer contour are helpful MRI features to differentiate malignant from benign omental thickening.

Comparison of MRI pulse sequences for prediction of size of hepatocellular carcinoma at explant evaluation.

OBJECTIVE: The purpose of this study was to retrospectively compare the size of hepatocellular carcinoma (HCC) on images obtained using different MRI pulse sequences with the tumor size determined at pathologic evaluation of liver explant specimens. MATERIALS AND METHODS: Ninety-two patients with HCC who underwent contrast-enhanced liver MRI within 90 days before liver transplant were included. A single pathologist measured the dominant HCC in each case. In different sessions, two abdominal radiologists (readers 1 and 2) aware only of the location of the dominant HCC independently measured lesion size on images obtained using the following sequences: T2-weighted imaging; b-500 diffusion-weighted imaging; and arterial, portal venous, and equilibrium phases of contrast enhancement. Size measurements on MR images were compared with explant measurements by use of Pearson correlation coefficients, paired t tests, and Bland-Altman plots. RESULTS: Correlation with pathologic findings was highest for reader 1 for portal venous (r = 0.890) and equilibrium (r = 0.828) phase images and for reader 2 for arterial, portal venous, and equilibrium phase images (r = 0.842-0.860). Absolute error relative to pathologic size was lowest for reader 1 using portal venous (4.3 mm) and for reader 2 using portal venous and arterial phase images (both 4.7 mm). Systematic error for both readers was lowest with portal venous and equilibrium phase images (reader 1, systematic under-measurement of 0.5 mm in both sequences; reader 2, systematic over-measurement of 0.1 mm with portal venous phase images and systematic under-measurement of 1.1 mm with equilibrium phase images). Sequences in which reader 1 made systematic over-measurements were diffusion-weighted images, arterial phase images, and T2-weighted images (by 3.5, 2.9, and 1.6 mm). Reader 2 made systematic over-measurements using arterial phase and T2-weighted images (by 1.5 and 0.4 mm). CONCLUSION: The data suggest the arterial phase may be suboptimal for measuring HCC at MRI. Portal venous phase acquisition warrants further investigation as a potential standard approach for such measurements.

Optimizing needle direction during transjugular liver biopsy provides superior biopsy specimens.

PURPOSE: Transjugular liver biopsy (TJLB) is commonly performed for staging of liver fibrosis and cirrhosis among patients with coagulopathy and/or ascites. We hypothesized that device orientation during needle firing influences hepatic tissue apposition with the specimen notch and specimen quality. METHODS: Needle biopsies were performed in ex vivo bovine livers with specimen notch of the biopsy device oriented at cranial, caudal, or lateral directions with respect to the guiding metal cannula. Biopsy specimen length was measured and evaluated for fragmentation using light microscopy. In addition, a consecutive cohort of patients (n = 50) who underwent TJLB with random (n = 22) or caudal (n = 28) needle orientation was retrospectively reviewed. The number of needle passes was documented, and pathology specimen adequacy was graded using an ordinal scale. RESULTS: A total of 400 biopsies were performed (100 in each orientation) in ex vivo bovine livers. Longer specimens were obtained with caudal orientation of the needle specimen notch (p < 0.0001, ANOVA and Kruskal-Wallis tests). There was no difference in the degree of fragmentation. In the retrospective clinical study, specimen adequacy was significantly higher among patients in the caudal orientation group (p = 0.0002, Mann-Whitney U test). CONCLUSION: Caudal orientation of the needle specimen notch of the biopsy device during TJLB produces superior core biopsy specimens. This simple technical modification may assist in obtaining higher-quality biopsy specimens during TJLB.

Hepatocellular carcinoma: perfusion quantification with dynamic contrast-enhanced MRI.

OBJECTIVE: The objective of our study was to report our initial experience with dynamic contrast-enhanced MRI (DCE-MRI) for perfusion quantification of hepatocellular carcinoma (HCC) and surrounding liver. SUBJECTS AND METHODS: DCE-MRI of the liver was prospectively performed on 31 patients with HCC (male-female ratio, 26:5; mean age, 61 years; age range, 41-83 years). A dynamic coronal 3D FLASH sequence was performed at 1.5 T before and after injection of gadolinium-based contrast agent with an average temporal resolution of 3.8 seconds. Regions of interest were drawn on the abdominal aorta, portal vein, liver parenchyma, and HCC lesions by two observers in consensus. Time-activity curves were analyzed using a dual-input single-compartment model. The following perfusion parameters were obtained: arterial flow, portal venous flow, arterial fraction, distribution volume, and mean transit time (MTT). RESULTS: Thirty-three HCCs (mean size, 3.9 cm; range, 1.1-12.6 cm) were evaluated in 26 patients. When compared with liver parenchyma, HCC showed significantly higher arterial hepatic blood flow and arterial fraction (p < 0.0001) and significantly lower distribution volume and portal venous hepatic blood flow (p < 0.0001-0.023), with no difference in MTT. Untreated HCCs (n = 16) had a higher arterial fraction and lower portal venous hepatic blood flow value than chemoembolized HCCs (n = 17, p < 0.04). CONCLUSION: DCE-MRI can be used to quantify perfusion metrics of HCC and liver parenchyma and to assess perfusion changes after HCC chemoembolization.

Comparison of CT and MRI findings in the differentiation of acute from chronic cholecystitis.

We compared individual computed tomography (CT) and MRI findings in differentiating acute from chronic cholecystitis. Thirty-seven patients undergoing both studies before cholecystectomy were included. Two radiologists (R1/R2) independently assessed all cases. For detecting acute cholecystitis, MRI showed better sensitivity (R1) using gallbladder wall thickening, accuracy (R1) and sensitivity (R1) using gallstones, sensitivity (R1 and R2) and accuracy (R2) using gallbladder wall hyperemia, accuracy (R1 and R2) using gallbladder wall defect, and accuracy (R2) using adjacent liver hyperemia (P=.004-.063). MRI also showed better specificity (R2) using pericholecystic fat stranding (P=.016). Overall, several findings showed better sensitivity and/or accuracy for acute cholecystitis on MRI than CT.

Primary rhabdomyosarcoma of the diaphragm: case report and review of the literature.

BACKGROUND: Diaphragmatic sarcomas are extremely rare and mostly described in children. We present the case of an adult with rhabdomyosarcoma of the diaphragm. METHODS: We performed a literature review, highlighted possible diagnostic pitfalls, and discussed multidisciplinary treatment options.

Serial diffusion-weighted MRI in patients with hepatocellular carcinoma: Prediction and assessment of response to transarterial chemoembolization. Preliminary experience.

OBJECTIVE: To assess the role of apparent diffusion coefficient (ADC) measured with diffusion-weighted imaging (DWI) in predicting and assessing response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE). METHODS: Thirty-six patients with cirrhosis and untreated HCC who underwent TACE and MRI within 3 months before and after TACE were assessed. MRI included DWI and contrast-enhanced T1-weighted imaging. Two observers measured ADC of HCCs and liver parenchyma on pre- and post-TACE MRIs and measured degree of tumor necrosis on subtracted post-contrast images on post-TACE MRI. Pre-, post-TACE tumor ADC, and changes in tumor ADC (ΔADC) were compared between lesions stratified by degree of tumor necrosis (measured on post-TACE MRI). RESULTS: Forty seven HCCs were evaluated (mean size 4.4cm, range 1.0-14.1cm). HCCs with poor and incomplete response to TACE (<50% necrosis on post-TACE MRI) had significantly lower pre-treatment ADC and lower post TACE ADC compared to HCCs with good/complete response (≥50% necrosis): ADC pre-TACE 1.35±0.42 vs. 1.64±0.39×10(-3)mm(2)/s (p=0.042); post-TACE ADC 1.34±0.36 vs. 1.92±0.47 (p=0.0008). There was no difference in ΔADC values. CONCLUSION: This preliminary data suggests that pre-TACE tumor ADC can be used to predict HCC response to TACE.

The effect of liver iron deposition on hepatic apparent diffusion coefficient values in cirrhosis.

OBJECTIVE: The purpose of this study was to assess the effect of hepatic iron deposition on apparent diffusion coefficient (ADC) values measured with single-shot echo-planar imaging (EPI) diffusion-weighted MRI (DWI) in patients with liver cirrhosis and in vitro. MATERIALS AND METHODS: Fifty-two patients with liver cirrhosis who underwent breath-hold single-shot EPI DWI at 1.5 T before liver transplantation were retrospectively assessed. Estimated signal-to-noise ratio (SNRest) and ADC were measured in the right hepatic lobe (for b values of 50 and 500 s/mm2). SNRest and ADC were compared between patients stratified by pathologic iron grade using the Mann-Whitney test. Hepatic ADC values were correlated to T2* values using the Spearman correlation test in a subset of patients. In addition, a phantom consisting of solutions of varying iron concentrations was imaged with single-shot EPI DWI and T2* imaging, and iron concentration was correlated with ADC and T2*. RESULTS: In phantoms, there was a decrease in ADC and T2* with increasing iron concentration (r=-0.95 and -0.92, respectively; p<0.05). Patients with hepatic siderosis had significantly lower SNRest and ADC compared with patients without siderosis (p<0.0001). SNRest at b=50 s/mm2 and b=500 s/mm2 and ADC had a significant negative correlation with pathologic iron grade (r=-0.67 to 0.77, p<0.0001). There was a significant correlation between liver T2* and ADC (r=0.83, p<0.0001). CONCLUSION: Hepatic siderosis lowers liver ADC and should be taken into account when using ADC for diagnosing liver cirrhosis.