Non-tumorous Parenchyma Research Articles

Abstract 1953: MiRNA and piRNA expression profiles in renal cell carcinoma tissue detected by next generation sequencing

Abstract MicroRNAs (miRNAs) are the class of small non-coding RNAs, about 21-25 nucleotides in length, that play an important role in regulation of transcription. They affect gene expression at post-transcriptional levels through binding to complementary mRNAs and mediate their degradation in RISC complex. Piwi-interacting RNAs (piRNAs) is newly discovered class of non-coding RNA. PiRNAs are short single-stranded RNAs with 26-31 nucleotides in length. They are involved in silencing of transposable elements and it is assumed that also participate in sequence-specific chromatin modifications. It was repeatedly shown that piRNAs are present also in somatic cells and are dysregulated in kidney, bladder, gastric, breast, pancreatic and liver cancers. According to small non-coding RNA databases there are about 2600 mature miRNAs and more than 24 000 piRNAs in humans. There were extensive studies aiming to discover miRNAs and to analyze their functions. However, there are only few published studies of miRNA and piRNA profiles in renal cell carcinoma (RCC) using next generation sequencing (NGS) technology. In our study we used the tumor tissue and the paired adjacent non-tumor renal parenchyma of 12 patients (8 males and 4 females) with RCC treated in Masaryk Memorial Cancer Institute (Brno, Czech Republic). RNA was isolated with mirVana™ miRNA Isolation Kit. For preparing RNA library was used TruSeq Small RNA Sample Preparation Kit from Illumina and then the miSeq sequencing technology was employed to detect small RNAs. In our 12 paired samples of tumor tissue and the paired adjacent non-tumor renal parenchyma we detected 283 miRNAs with over 1 read in at least 7 samples. Expression levels of 55 miRNAs were significantly different expressed (p < 0.05) in tumor tissue and adjacent non-tumor parenchyma. Among miRNAs with the most significantly altered expression (p < 0.01) were for example, miR-129, miR-138, miR-142, miR-149, miR-154, miR-155, miR-200b, miR-210, miR-218, miR-340, miR-584, miR-885, miR-891a, miR-1270, miR-3690 and miR-7641. After analyzing piRNA sequences we found 440 piRNAs with over 1 read in at least 7 samples. From these piRNAs were 38 piRNAs significantly deregulated (p<0.01) in RCC tissue, whereas the most significantly different expression levels were determined in piR-1207, piR-2107, piR-2155, piR-12487, piR-12488, piR-21508, piR-23230, piR-26525, piR-26527and piR-28131. In our pilot study we found altered expression patterns of miRNAs and piRNAs in tumor tissue of RCC and paired adjacent non-tumor renal parenchyma. For the first time, we have described piRNAs expression profile in RCC tissue by NGS approach. This work was supported by Ministry of Health of the Czech Republic, grant nr. 15-33158A, 15-34553A, 15-31627A and 15-34678A. All rights reserved. Citation Format: Robert Iliev, Petra Faltejskova-Vychytilova, Zuzana Ozanova, Silvia Rybecka, Jaroslav Juracek, Jitka Mlcochova, Lenka Radova, Michal Stanik, Jan Dolezel, Michal Fedorko, Dalibor Pacik, Ondrej Slaby. MiRNA and piRNA expression profiles in renal cell carcinoma tissue detected by next generation sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1953.

Diffusion-weighted MR imaging of pancreatic cancer: A comparison of mono-exponential, bi-exponential and non-Gaussian kurtosis models

ObjectivesTo compare two Gaussian diffusion-weighted MRI (DWI) models including mono-exponential and bi-exponential, with the non-Gaussian kurtosis model in patients with pancreatic ductal adenocarcinoma. Materials and methodsAfter written informed consent, 15 consecutive patients with pancreatic ductal adenocarcinoma underwent free-breathing DWI (1.5T, b-values: 0, 50, 150, 200, 300, 600 and 1000s/mm2). Mean values of DWI-derived metrics ADC, D, D*, f, K and DK were calculated from multiple regions of interest in all tumours and non-tumorous parenchyma and compared. Area under the curve was determined for all metrics. ResultsMean ADC and DK showed significant differences between tumours and non-tumorous parenchyma (both P<0.001). Area under the curve for ADC, D, D*, f, K, and DK were 0.77, 0.52, 0.53, 0.62, 0.42, and 0.84, respectively. ConclusionADC and DK could differentiate tumours from non-tumorous parenchyma with the latter showing a higher diagnostic accuracy. Correction for kurtosis effects has the potential to increase the diagnostic accuracy of DWI in patients with pancreatic ductal adenocarcinoma.

Breast parenchymal signal enhancement ratio at preoperative magnetic resonance imaging: association with early recurrence in triple-negative breast cancer patients

The signal enhancement ratio (SER) of surrounding non-tumor parenchyma at breast magnetic resonance imaging (MRI) can be helpful in breast cancer patients, but has not been investigated in patients with triple negative breast cancer (TNBC). To investigate the association between background parenchymal SER around the tumor on preoperative dynamic contrast-enhanced MRI with recurrence-free survival in patients with TNBC. Between April 2012 and May 2013, 71 TNBC patients who underwent preoperative MRI were included. SER values were calculated from regions of interest placed in the breast parenchyma around the tumor. Cox proportional hazards models were used to determine associations between MRI variables, clinical-pathologic variables, and recurrence-free survival. Recurrence occurred in 8.5% (6/71) of patients. At univariate analysis, a higher SER around the tumor, larger tumor size, lymphovascular invasion, lymph node metastasis, receipt of neoadjuvant chemotherapy, receipt of total mastectomy, and not receiving adjuvant chemotherapy were associated with worse recurrence-free survival. At multivariate analysis of preoperative variables, a higher SER around the tumor was independently associated with worse recurrence-free survival (hazard ratio [HR] = 7.072, P = 0.003 for SER1; HR = 6.268, P = 0.006 for SER2; HR = 3.004, P = 0.039 for SER3). Higher SER around the tumor at preoperative dynamic contrast-enhanced MRI is an independent predictor for recurrence in TNBC patients.

Gastric cancer-associated enhancement of von Willebrand factor is regulated by vascular endothelial growth factor and related to disease severity.

Backgroundvon Willebrand factor (vWF) is a potent regulator of angiogenesis, tumor growth, and metastasis. Yet, the expression pattern of vWF in human gastric cancer (GC) tissues and its relation to clinicopathological features of these cases remains unknown.MethodsTumor and 5-cm adjacent non-tumoral parenchyma specimens were collected from 99 patients with GC (early stages I/II and late stages III/IV), and normal specimens were collected from 32 healthy controls (reference group). Plasma vWF antigen (vWF:Ag) and vWF activity were assessed by ELISA. The role of vascular endothelial growth factor (VEGF) in differential vWF expression was investigated using cultured human umbilical vein endothelial cells (HUVECs). vWF and VEGF protein and mRNA expression levels were investigated by qRT-PCR, western blotting and immunohistochemistry (IHC) respectively. The correlation of IHC-detected vWF expression with patient clinicopathological characteristics was analyzed.ResultsCompared to the reference group, the patients with late GC showed significantly higher levels of vWF:Ag (72% (21-115) vs. 101% (40-136)) and vWF activity (62% (20-112) vs. 117% (33-169)) (both P < 0.001). The GC tumor tissues also showed higher vWF mRNA and protein levels than the adjacent non-tumoral parenchyma. Patients at late GC stage had significantly higher median number of vWF-positive cells than patients at early GC stage (P < 0.05). VEGF induced vWF mRNA and protein expression in HUVECs in dose- and time-dependent manners. Patients with late GC stage also had significantly higher serum VEGF than patients at early GC stage (23 ± 26 vs. 10 ± 12 pg/mL, P < 0.01). Most of the undifferentiated GC tumor tissues at late disease stage exhibited strong VEGF and VEGFR2 protein staining, which co-localized with the vWF protein staining pattern.ConclusionsGC-related plasma vWF:Ag and vWF activity levels become substantially elevated in the late stage of disease. The higher mRNA and protein expression of vWF in GC tumor stroma may be regulated by the VEGF-VEGFR2 signaling pathway in vitro and may contribute to GC progression in vivo.

Elevated CA19-9 Is Associated With Increased Mortality In A Prospective Cohort Of Hepatocellular Carcinoma Patients.

Objectives:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. CA19-9 is a glycoprotein that predicts poor prognosis in pancreatic and biliary malignancies. We evaluated it as a prognostic biomarker for patients with HCC.Methods:We prospectively enrolled 145 patients with HCC, diagnosed using American Association for Study of Liver Diseases criteria, between October 2008 and November 2012. We examined whether baseline serum CA19-9 levels predicted overall survival. We also examined immunostains of hepatic resections and explants of patients with elevated and normal serum CA19-9.Results:In a cohort of predominantly hepatitis C and B patients, CA19-9 ≥100 U/ml was associated with a 2.7-fold increased mortality (hazard ratio (HR): 2.72; 95% confidence interval (CI): 1.52–4.88, P<0.001). It remained a significant predictor (HR: 2.58; 95% CI: 1.41–4.72, P=0.002) in a multivariable model adjusted for Child–Pugh score, alpha-fetoprotein, Barcelona Clinic Liver Cancer stage, and Model for End-Stage Liver Disease. CA19-9 immunohistochemistry performed on a subset of liver resection and explant specimens showed increased CA19-9 immunostaining of non-tumor liver parenchyma in patients with elevated serum CA19-9. It also showed staining of native and reactive bile ducts, and of progenitor-like cells at the periphery of cirrhotic nodules.Conclusions:Elevated serum CA19-9 ≥100 U/ml is an independent predictor of poor overall survival in this hypothesis-generating study. The unfavorable prognosis seen with elevated serum levels may be related to progenitor-like cells in the non-tumor liver.

Microsphere Localization and Dose Quantification Using Positron Emission Tomography/CT following Hepatic Intraarterial Radioembolization with Yttrium-90 in Patients with Advanced Hepatocellular Carcinoma

PurposeTo characterize the distribution of absorbed radiation dose after glass microsphere radioembolization for hepatocellular carcinoma (HCC) using yttrium-90 (90Y) positron emission tomography/computed tomography (PET/CT). Materials and MethodsIn this retrospective study, 64 90Y PET/CT scans performed after treatment were evaluated following 90Y glass-bead radioembolization in patients with advanced HCC. The intended dose to the target volume ranged from 83–129 Gy. Three-dimensional “dose maps” were created from reconstructed PET images using a voxel-based S-value transformation. Liver parenchyma and liver tumors were contoured on cross-sectional imaging and aligned with the created dose maps. ResultsThere were 113 tumors examined as part of 64 lobar treatments. The average tumor size was 4.8 cm ± 4.0 with an average tumor dose of 173 Gy ± 109. The average dose to the nontumor parenchyma within the target volume was 93.4 Gy ± 32.6, with on average 50% of the parenchymal voxels receiving > 79 Gy ± 23 and 10% receiving > 173 Gy ± 55. The average and median tumor-to-parenchymal weighted dose ratios were 2.2 and 1.9, respectively. ConclusionsUsing recommended dosimetry and administration techniques for lobar glass microsphere radioembolization, high doses to target tumors as well as background parenchyma were achieved on average with modest preferential uptake within tumors. There was wide variation in measured tumor and parenchymal doses after hepatic radioembolization for HCC, suggesting the need for continued development of patient-specific dosimetry.

Clinical significance of autophagic protein LC3 levels and its correlation with XIAP expression in hepatocellular carcinoma.

Autophagy is a cellular recycling process to enable cell survival in less favorable conditions through degradation of their unnecessary cellular components and utilization of the breakdown components. Autophagy also plays an important role in tumor pathology. In this study, we detected autophagy protein light chain 3 (LC3) and X-linked inhibitor of apoptosis protein (XIAP) in hepatocellular carcinoma (HCC) tissue specimens to assess their role in HCC tumorigenesis and progression. We analyzed expression of LC3, XIAP, and Ki-67 proteins immunohistochemically in surgical specimen of 150 HCC and 136 nontumor hepatic tissues. The levels of LC3 and XIAP proteins were compared between tumor and nontumoral parenchyme. The data showed that LC3 expression was increased in HCC compared with nontumoral parenchyma. LC3 expression was significantly associated with male gender, large tumor size, advanced tumor stages, and worse relapse-free and overall survival (OS). In contrast, XIAP expression was associated with small tumor size, early tumor stage, and better relapse-free and OS. In contrast, XIAP expression was associated with small tumor size, early tumor stage, and better relapse-free and OS. Furthermore, expression of LC3 and XIAP was inversely associated in HCC tissue specimens. In conclusion, increase in autophagic LC3 activity and low XIAP expression could be useful to predict the worse HCC prognosis.

Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model.

The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening model in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops lung tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smoke-related lung tumors in the A/J mouse model using mRNA and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression interaction term analysis of lung tumors and surrounding non-tumorous parenchyma samples from animals that were exposed to either 300 mg/m3 MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis® (IPA®) indicated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism and a deregulation of potentially oncogenic miRNA in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA, which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene expression signature and show its utility in distinguishing between cigarette smoke-related and spontaneous lung tumors.

Acoustic structure quantification (ASQ): a new tool in sonographic examination of liver lesions in hepatic alveolar echinococcosis.

Qualitative and quantitative acoustic structure quantification (ASQ) is a new, noninvasive sonographic imaging method based on B-mode. This prospective clinical pilot study aims to answer the question whether delineation and measurement of liver lesions in hepatic alveolar echinococcosis (HAE) can be improved by ASQ. Furthermore, this is the first pilot study to explore how ASQ parameters in HAE lesions develop. A total of 24 patients (male=13/female=11, mean age=52years (16-85), mean disease duration=68months (1-334)) with HAE were examined with ASQ using a Toshiba Aplio 500 unit. ASQ parameters were measured in HAE liver lesions and in adjacent non-tumor parenchyma. Quantitative analysis was performed offline using ASQ quantification software. Subjectively parasitic tumors in HAE appear more prominent in color-coded ASQ imaging, but the size of lesions measured in ASQ mode does not differ from size measurements in B-mode. Median focal disturbance ratio (FD ratio) in lesions was 3 (0.1-3), compared with 0.5 (0.1-1.8) in surrounding liver parenchyma (p<0.0001). Statistical comparison of other ASQ parameters (mode, average, standard deviation) shows results that are similarly significant with p values between p<0.0001 and p<0.0018. ASQ is a promising sonographic method for examination and quantification of structural changes of liver parenchyma in HAE lesions.

Stereotactic Body Radiotherapy-Induced Arterial Hypervascularity of Non-Tumorous Hepatic Parenchyma in Patients with Hepatocellular Carcinoma: Potential Pitfalls in Tumor Response Evaluation on Multiphase Computed Tomography

PurposeTo evaluate temporal changes in contrast enhancement patterns of non-tumorous hepatic parenchyma with a focus on arterial hypervascularity on multiphase computed tomography (CT) in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT).MethodsWe retrospectively identified 61 patients who had undergone multiphase contrast-enhanced CT at one, three, and six months after SBRT. Irradiated versus non-irradiated liver parenchyma was delineated by cross-correlation with the dose-volume histogram of SBRT plan. Serial changes in the contrast enhancement patterns of the irradiated versus non-irradiated liver parenchyma were evaluated by two abdominal radiologists in consensus. We compared the frequency of the contrast enhancement patterns according to the follow-up period using the Fisher-Freeman-Halton exact test.ResultsThe irradiated non-tumorous hepatic parenchyma showed that the prevalence of arterial hypervascularity increased during the follow-up period (P<.01): 11.5% (7/61) in one, 45.9% (28/61) in three, and 54.1% (33/61) in six months. Contrast wash-out on the delayed phase was uncommon: 1.6% (1/61) in one, 3.3% (2/61) in three, and 0% in six months.ConclusionThe incidence of arterial hypervascularity of the irradiated hepatic parenchyma gradually increased until six months after SBRT, which could interfere with the accurate evaluation of treatment response. The lack of wash-out on the delayed phase in the hypervascular area would distinguish SBRT-related change from residual/recurred HCC.

Pancreatic adenocarcinoma: a pilot study of quantitative perfusion and diffusion-weighted breath-hold magnetic resonance imaging

To confirm the feasibility of breath-hold DCE-MRI and DWI at 3T to obtain the intra-abdominal quantitative physiologic parameters, K(trans), k ep, and ADC, in patients with untreated pancreatic ductal adenocarcinomas. Diffusion-weighted single-shot echo-planar imaging (DW-SS-EPI) and dynamic contrast-enhanced (DCE) MRI were used for 16 patients with newly diagnosed biopsy-proven pancreatic ductal adenocarcinomas. K(trans), k ep, and apparent diffusion coefficient (ADC) values of pancreatic tumors, non-tumor adjacent pancreatic parenchyma (NAP), liver metastases, and normal liver tissues were quantitated and statistically compared. Fourteen patients were able to adequately hold their breath for DCE-MRI, and 15 patients for DW-SS-EPI. Four patients had liver metastases within the 6 cm of Z axis coverage centered on the pancreatic primary tumors. K(trans) values (10(-3) min(-1)) of primary pancreatic tumors, NAP, liver metastases, and normal liver tissues were 7.3 ± 4.2 (mean ± SD), 25.8 ± 14.9, 8.1 ± 5.9, and 45.1 ± 15.6, respectively, k ep values (10(-2) min(-1)) were 3.0 ± 0.9, 7.4 ± 3.1, 5.2 ± 2.0, and 12.1 ± 2.8, respectively, and ADC values (10(-3) mm(2)/s) were 1.3 ± 0.2, 1.6 ± 0.3, 1.1 ± 0.1, and 1.3 ± 0.1, respectively. K(trans), k ep, and ADC values of primary pancreatic tumors were significantly lower than those of NAP (p < 0.05), while K(trans) and k ep values of liver metastases were significantly lower than those of normal liver tissues (p < 0.05). 3T breath-hold quantitative physiologic MRI is a feasible technique that can be applied to a majority of patients with pancreatic adenocarcinomas.

The role of biopsy of the nontumorous liver parenchyma in patients considered for partial resection of small hepatocellular carcinoma

We read with interest the article by Roayaie et al. reporting on resection of hepatocellular carcinoma (HCC) ≤2 cm in two Western centers.1 This elegant study shows that excellent results (e.g., up to 80% 5-year survival) can be achieved with adequate surgical resection in selected patients with small HCC. These results are in line with the study from our group published this year in HEPATOLOGY concerning potentially transplantable patients who were resected first in a strategy of salvage transplantation in cases of recurrence.2 In the context of organ shortage, we fully agree with the conclusion that resection should continue to be a first-line option in patients with preserved liver function.1 In addition to classical tumor factors, these two studies confirm that nonanatomic resection and presence of cirrhosis were associated with a higher risk of recurrence. In our series, for instance, 64% of the patients who did not experience recurrence after resection had stage 3 fibrosis. The feasibility of anatomic resection, which was independently associated with less recurrence, as well as postoperative morbidity, obviously depends upon the extent of underlying fibrosis. Although Roayaie et al. have shown that advances in the management of HCC could come from the underlying liver parenchyma, they do not mention the usefulness of preoperative biopsy of nontumorous liver parenchyma, to better select the optimal candidates for resection. The importance of nontumorous parenchyma is illustrated by the finding by the same group that gene expression signatures in the adjacent liver parenchyma, but not in the tumor, were highly correlated to recurrence and survival after resection.3 Overall, these data strongly suggest that in addition to tumor status, careful assessment of nontumorous liver parenchyma with preoperative biopsy of the nontumorous parenchyma should be incorporated in the decision-making of patients with small HCC who are potential candidates for resection.

Renal histologic parameters influencing postoperative renal function in renal cell carcinoma patients.

BackgroundPre-existing non-neoplastic renal diseases or lesions may influence patient renal function after tumor removal. However, its description is often neglected or omitted in pathologic reports. To determine the incidence and clinical significance of non-neoplastic lesions, we retrospectively examined renal tissues obtained during 85 radical nephrectomies for renal cell carcinoma.MethodsOne paraffin-embedded tissue block from each case containing a sufficient amount of non-tumorous renal parenchyma was cut and processed with hematoxylin and eosin and periodic acid-Schiff methods. Non-neoplastic lesions of each histological compartment were semi-quantitatively and quantitatively evaluated.ResultsAmong the various histologic lesions found, tubular atrophy, arterial intimal thickening, and glomerulosclerosis were the most common (94.1%, 91.8%, and 88.2%, respectively). Glomerulosclerosis correlated with estimated glomerular filtration rate at the time of surgery, as well as at 1- and 5-years post-surgery (p=.0071), but tubulointerstitial fibrosis or arterial fibrous intimal thickening did not. Post-hoc analysis revealed that glomerulosclerosis of more than 20% predicted post-operative renal function. However, its significance disappeared when gender and age were considered.ConclusionsIn conclusion, non-neoplastic lesions, especially with regard to glomerulosclerosis percentage, should be described in pathology reports to provide additional information on renal function decline.

Hepatocellular carcinoma in a non-cirrhotic patient with Wilson's disease

We report the exceptional case of hepatocellular carcinoma in a non-cirrhotic patient, whose Wilson's disease was diagnosed at the unusual age of 58 years. The liver histology revealed macrovesicular steatosis with fibrosis, but no cirrhosis. The disease was treated with D-penicillamine for 3 years until acute discomfort in the right upper quadrant led to detection of multifocal hepatocellular carcinoma, which was successfully resected. The histological examination confirmed the malignant nature of the 4 lesions, which were classified according to Edmondson and Steiner as poorly differentiated hepatocellular carcinoma grade 3. The non-tumoral parenchyma showed 80% steatosis with ballooned cells, lobular inflammation, septal fibrosis but no cirrhosis. Hepatocellular carcinoma is rare in Wilson's disease, especially in the absence of cirrhosis. The literature's 28 published cases are reviewed and the contributory role of copper in the hepatocarcinogenic process is discussed.

Solid Pancreatic Lesions: Characterization by Using Timing Bolus Dynamic Contrast-enhanced MR Imaging Assessment—A Preliminary Study

To assess the feasibility of postprocessing dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging timing bolus data by using a three-dimensional radial gradient-echo technique with k-space-weighted image contrast (KWIC) for the characterization of solid pancreatic diseases. This retrospective study was approved by the institutional review board, and informed consent was waived. A total of 45 patients suspected of having biliary or pancreatic disease underwent pancreatic MR examination with a 3.0-T imager with a low-dose (2 mL gadopentetate dimeglumine) timing bolus by using the radial KWIC technique. There were 24 patients with pancreatic cancers, eight with pancreatic neuroendocrine tumors (PNETs), three with chronic pancreatitis, and 10 with a normal pancreas. By using a dedicated postprocessing software program for DCE MR imaging, the following perfusion parameters were measured for tumor and nontumorous parenchyma: volume transfer coefficient (K(trans)) and extracellular extravascular volume fraction; the rate constant (k(ep)) and initial area under the concentration curve in 60 seconds (iAUC) were then generated. The perfusion parameters acquired on DCE MR images were compared among the groups by using the analysis of variance test. K(trans), k(ep), and iAUC values in patients with pancreatic cancer (0.042 min(-1) ± 0.023 [standard deviation], 0.761 min(-1) ± 0.529, and 2.841 mmol/sec ± 1.811, respectively) were significantly lower than in patients with a normal pancreas (0.387 min(-1) ± 0.176, 6.376 min(-1) ± 2.529, and 7.156 mmol/sec ± 3.414, respectively) (P < .05 for all). In addition, k(ep) values of PNETs and normal pancreas also differed (P < .0001), and K(trans), k(ep), and iAUC values of pancreatic cancers and PNETs differed significantly (P < .0001, P = .038, and P < .0001, respectively). Results of timing bolus DCE MR imaging with the radial KWIC sequence from routine examinations can be postprocessed to yield potentially useful perfusion parameters for the characterization of pancreatic diseases.

Impact of cytolysis following transarterial chemoembolization for hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is increasingly used as a treatment of hepatocellular carcinoma. Cytolysis, which may occur within days following the procedure is due to either necrosis of the tumour or of the non-tumoral parenchyma. Therefore it may influence either tumour response or liver function or both. We evaluated the impact of cytolysis after TACE on tumour response, incidence of hepatobiliary complications and overall survival. We conducted a retrospective analysis of 157 patients with liver disease who underwent 271 treatments for hepatocellular carcinoma. Cytolysis was defined as an increase of AST value above 100 IU/L with at least doubling of the baseline value. The associations between cytolysis and radiologic tumor response two months following each treatment and adverse hepatobiliary events were estimated using generalized estimating equations models. Comparison of 18 months survival after a first treatment of chemoembolization between the groups with and without cytolysis was performed using the proportional hazards model. Cytolysis occurred in 198 out of 271 cases and was associated with a favourable radiological response (OR 1.90, 1.03-3.54) at two months compared to non-cytolysis with no difference in the occurrence of adverse hepatobiliary events. The adjusted hazard ratio for overall survival was 1.33 times greater in the group with cytolysis compared to non-cytolysis (0.45-3.90). The occurrence of cytolysis was associated with a favorable radiological response, but had no impact on short-term adverse events and on survival at 18 months.

MiR-210 expression in tumor tissue and in vitro effects of its silencing in renal cell carcinoma

Renal cell carcinoma (RCC) is the most common neoplasm of adult kidney accounting for about 3% of adult malignancies. MicroRNAs (miRNAs) are a class of naturally occurring, short non-coding RNAs that regulate gene expression at the post-transcriptional level. We determined global miRNA expression profiles of RCC and parallel renal parenchyma tissues by using quantitative reverse transcriptase-polymerase chain reaction-based TaqMan low-density arrays. Afterward, we validated the difference in miR-210 expression levels on the larger group of RCC patients (35 RCC versus 10 non-tumorous parenchyma samples). Functional in vitro experiments were performed on ACHN and CAKI-2 RCC cell lines transfected with miRNA-210 inhibitor. Cell viability, apoptosis, cell cycle, scratch wound migration assay, and invasion assay (xCELLigence) were performed. We have identified original ccRCC-specific miRNA signature in clinical samples (73 miRNAs were significantly downregulated and five miRNAs upregulated (P < 0.003)). Increased expression levels of miR-210 in RCC tumor tissue were independently validated. We observed decreased viability of ACHN and CAKI-2 cells and accumulation of CAKI-2 in G2 phase of cell cycle after silencing of miR-210 expression. Downregulation of miR-210 also reduced the migratory and invasive potential of ACHN metastatic RCC cells. Moreover, we showed downregulation of HIF1a protein in both cell lines after miR-210 silencing indicating participation of miR-210 in hypoxic processes of RCC not only through regulation of its target mRNAs but also by indirect regulation of HIF1a. To our knowledge, this is the first report to show miR-210 regulatory effects on cell migration, invasive potential, and HIF1a protein in RCC cells.

MDCT findings after hepatic chemoembolization with DC-beads: What the radiologist needs to know

Transcatheter arterial chemoembolization with drug-eluting beads (TACE-DC-beads) is a new local treatment for primary or metastatic liver tumors. Despite technical efforts to achieve highly selective embolization of the tumor-supplying vessels, small, or large insults to the non-tumorous parenchyma are inevitably induced by the embolic materials or procedure itself. Parenchymal changes following TACE-DC-beads include bile duct injuries (bile duct dilatation, periportal edema, and bilomas), obliteration of intrahepatic portal vein branches, hypodense ill-defined areas, and perilesional parenchymal enhancement. The radiologist must be familiar with the changes induced by this treatment in order to distinguish therapeutic effect and collateral findings from complications and residual or recurrent tumor.

Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma

ObjectiveOur objective was to evaluate the levels of miR-210 in tumor and serum samples of conventional renal cell cancer (cRCC) patients to explore whether circulating miR-210 in serum can be used as a biomarker for the detection of cRCC. MethodsThe paired samples from primary cRCC tumors and adjacent non-tumoral renal parenchyma were collected from 32 patients with cRCC. Serum samples were obtained from 68 patients with a cRCC before surgery, 10 samples after one week of surgery, and 42 healthy individuals were included in this study. Real-time PCR was used to measure the microRNA level. The expression of miRNAs was normalized using the dCT method. Expression levels of miR-210 were compared using the Mann–Whitney U test or Wilcoxon test. Diagnostic performance of serum miR-210 level was calculated by using the receiver operating characteristic (ROC) curve. ResultsThe average miR-210 level was higher in primary cRCC tissues than in normal tissue (p=0.004). For serum samples, the average level of miR-210 was significantly higher in cRCC patients than in controls (p<0.001). The serum miR-210 level yielded an AUC (the areas under the ROC curve) of 0.874 with a sensitivity of 81.0% and a specificity of 79.4%. Furthermore, the average serum level of miR-210 was significantly decreased in the patients one week after the operation (p=0.001). ConclusionSerum mi-210 may have a potential as a novel noninvasive biomarker for the detection of cRCC.

Expression and function of heme oxygenase-1 in human gastric cancer

Heme oxygenase-1 (HO-1) potently influences tumor growth and metastasis. To date, no study has been performed on HO-1 expression pattern and its clinicopathological significance in human gastric cancer (GC) cases. In this study, the expression of HO-1 in human GC tissues (n = 74) and matched non-tumoral adjacent parenchyma (n = 46) was investigated by immunohistochemistry. The correlation of HO-1 with the clinicopathological characteristics was analyzed. Results showed that HO-1 was expressed in 62 GC tissues from 74 cases (83.8%), which is significantly higher than non-tumoral adjacent parenchyma (20/46, 43.8%, P < 0.05). A high HO-1 expression rate showed a close association with well/moderate histological differentiation and negative lymph node metastasis (P < 0.05). The expression of matrix metallopeptidase 9 (MMP9) and vascular endothelial growth factor A (VEGF-A) as well as chemosensitivity to cisplatin of MKN-45 cell lines with genetically altered HO-1 status were then determined by realtime polymerase chain reaction and 3-(4,5 dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), respectively. Whether the induction or inhibition of HO-1 by cobalt-protoporphyrin-IX (CoPP) or zinc-protoporphyrin-IX (ZnPP) could affect the sensitivity of MKN-45 cells to cisplatin was also studied. Results showed that the expression of MMP9 and VEGF-A were up-regulated in MKN-45 cells overexpressing HO-1, and down-regulated in HO-1 interfered cells. HO-1 overexpression could lead to an increased resistance to cisplatin, whereas down-regulation of HO-1 expression by siRNA or chemical inhibition of HO-1 could lead to increased chemosensitivity to cisplatin in MKN-45 cells. HO-1 may have multiple effects on protection against carcinogenesis and progression in GC.