Cristina H. Hajdu

Assessment of Tumor Necrosis of Hepatocellular Carcinoma After Chemoembolization: Diffusion-Weighted and Contrast-Enhanced MRI With Histopathologic Correlation of the Explanted Liver

OBJECTIVE The purpose of this study was to compare, with histopathologic examination of the liver explant as the reference standard, diffusion-weighted MRI with contrast-enhanced subtraction MRI in the assessment of necrosis of hepatocellular carcinoma (HCC) after trans arterial chemoembolization (TACE). MATERIALS AND METHODS The cases of 21 patients with HCC who underwent MRI after TACE were evaluated. Two independent observers calculated the apparent diffusion coefficient (ADC) of HCC and measured percentage tumor necrosis on subtraction images. The ADCs of necrotic and viable tumor tissues were compared. ADC and percentage necrosis on subtraction images were correlated with percentage necrosis found at pathologic examination. Receiver operating characteristics analysis was performed on the diagnosis of complete tumor necrosis. RESULTS Twenty-eight HCCs (mean diameter, 2.3 cm) were evaluated. There were significant differences between the ADC of viable tissue and that of necrotic tumor tissue (1.33 +/- 0.41 vs 2.04 +/- 0.38 x 10(-3) mm(2)/s, p < 0.0001). There was significant moderate correlation between ADC and the pathologic finding of percentage necrosis (r = 0.64, p < 0.001) and significant strong correlation between subtraction image and pathologic percentage necrosis (r = 0.89-0.91, depending on the phase; p < 0.001). In the diagnosis of complete tumor necrosis, ADC had an area under the curve, sensitivity, and specificity of 0.85, 75%, and 87.5% compared with 0.82-0.89, 100%, and 58.3-79.1% for subtraction imaging (p > 0.5 between ADC and subtraction imaging). CONCLUSION Compared with diffusion-weighted imaging, contrast-enhanced MRI with subtraction technique had more significant correlation with the histopathologic findings in the evaluation of necrosis of HCC after TACE. There was no difference, however, between the two methods in diagnosis of complete tumor necrosis.

MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells

MyD88 blockade exaggerates the ability of dendritic cells to promote the transition from chronic pancreatitis to pancreatic cancer.

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c-Myc, SHPTP1, TGF-β, PPARγ, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-κB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer.

Diagnosis of Liver Fibrosis and Cirrhosis With Diffusion-Weighted Imaging: Value of Normalized Apparent Diffusion Coefficient Using the Spleen as Reference Organ

OBJECTIVE The purpose of this study is to compare the diagnostic accuracy of liver apparent diffusion coefficient (ADC) versus normalized liver ADC using the spleen as a reference organ for the diagnosis of liver fibrosis and cirrhosis. MATERIALS AND METHODS Fifty-six patients, 34 with liver disease and 22 control subjects, were assessed with breath-hold single-shot echo-planar diffusion-weighted imaging using b values of 0, 50, and 500 s/mm(2). Liver ADC and normalized liver ADC (defined as the ratio of liver ADC to spleen ADC) were compared between patients stratified by fibrosis stage. Receiver operating characteristic (ROC) analysis was used to determine the performance of ADC and normalized liver ADC for prediction of liver fibrosis and cirrhosis. Reproducibility was assessed by measuring coefficient of variation (n = 7). RESULTS Liver ADC failed to distinguish individual stages of fibrosis, except between stages 0 and 4. There were significant differences in normalized liver ADC between control livers and intermediate stages of fibrosis (stages 2-3) and cirrhosis (stage 4) and between stages 1 and 4, and there was a trend toward significance between stages 0 and 1 (p = 0.051) and stages 1 and 3 (p = 0.06). ROC analysis showed that normalized liver ADC was superior to liver ADC for detection of stage > or = 2 (area under the ROC curve, 0.864 vs 0.655; p = 0.013) and stage > or =3 (0.805 vs 0.689; p = 0.015), without a difference for diagnosing cirrhosis (0.935 vs 0.720; p = 0.185). Normalized liver ADC had higher reproducibility than ADC (mean coefficient of variation, 3.5% vs 12.6%). CONCLUSION Our results suggest that normalizing liver ADC with spleen ADC improves diagnostic accuracy for detection of liver fibrosis and cirrhosis when using breath-hold diffusion-weighted imaging, with better reproducibility.

The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression

Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle—its cognate receptor—was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

Hepatocellular carcinoma: Detection with diffusion-weighted versus contrast-enhanced magnetic resonance imaging in pretransplant patients†

This study evaluates the performance of diffusion‐weighted magnetic resonance imaging (DWI) for the detection of hepatocellular carcinoma (HCC) in pre–liver transplantation patients, compared and combined with contrast‐enhanced T1‐weighted imaging (CET1WI), using liver explant as the standard of reference. We included 52 patients with cirrhosis (40 men, 12 women; mean age, 56 years) who underwent DWI and CET1WI within 90 days of liver transplantation. Magnetic resonance images were analyzed for HCC detection in three separate sessions by two independent observers: DWI images (DW‐set), CET1WI (CE‐set), and all images together (All‐set). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), per‐patient accuracy, and per‐lesion PPV were calculated for each image set. A total of 72 HCCs were present in 33 patients at explant (mean size, 1.5 cm [range, 0.3‐6.2 cm]). Per‐patient sensitivity and NPV of CE‐set were significantly higher than those of DW‐set when using pooled data between observers (P = 0.02 and 0.03, respectively), whereas specificity, PPV, and accuracy were equivalent. Per‐lesion sensitivity was significantly higher for CE‐set versus DW‐set (59.0% versus 43.8%; P = 0.008, pooled data from two observers). When stratified by lesion size, the difference was significant only for lesions with a size between 1 and 2 cm (42.0% for DW‐set versus 74.0% for CE‐set; P = 0.001). The addition of DWI to CET1WI improved sensitivity for the more experienced observer. Conclusion: DWI is outperformed by CET1WI for detection of HCC, but represents a reasonable alternative to CET1WI for detection of HCC with a size above 2 cm. The addition of DWI to CET1WI slightly increases the detection rate. (HEPATOLOGY 2012;56:140–148)

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.

Microvascular Invasion in Hepatocellular Carcinoma: Is It Predictable With Pretransplant MRI?

OBJECTIVE The purpose of this article is to correlate clinicopathologic and MRI parameters with the presence of microvascular invasion at histopathologic examination in patients with hepatocellular carcinoma (HCC) who are undergoing liver transplantation. MATERIALS AND METHODS In this retrospective single-center study, we assessed 60 patients (47 men and 13 women; mean age, 58 years) with HCC who underwent liver transplantation and pretransplant MRI (performed within 90 days before liver transplantation). Two observers analyzed the following tumor parameters in consensus: number, size, T1 and T2 signal intensity, margins, presence of capsule or pseudocapsule, distance to closest vessel, distance to liver capsule, and quantitative tumor enhancement. The size and number of HCCs, tumor differentiation, and the presence or absence of microvascular invasion were determined at histopathologic examination. Odds ratios (ORs) were calculated and logistic regression analysis was performed to assess the utility of these clinicopathologic and imaging parameters for predicting microvascular invasion. RESULTS None of the clinical parameters or morphologic and enhancement MRI features of HCC was predictive of microvascular invasion. Tumor multifocality, on both MRI and pathologic examination, was the only variable that predicted microvascular invasion (OR = 2.43 and p = 0.013 for MRI; OR = 1.94 and p = 0.013 for pathologic examination). The presence of three or more tumors on MRI and four or more tumors at pathologic examination had high specificity (88.2% and 91.2%, respectively) for the prediction of microvascular invasion. CONCLUSION Tumor multifocality on MRI was the only parameter that correlated significantly with microvascular invasion. All other MRI tumor characteristics failed to predict microvascular invasion.

Hepatocellular carcinoma: assessment of response to transarterial chemoembolization with image subtraction.

To assess the diagnostic accuracy of image subtraction compared with nonsubtracted images obtained with contrast‐enhanced T1‐weighted imaging (CE T1WI) for the diagnosis of hepatocellular carcinoma (HCC) necrosis after transarterial chemoembolization (TACE), using liver explant as the reference standard.

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.