Faculty Bibliography

Pancreatic ductal adenocarcinoma (PDAC) is strikingly resistant to conventional therapeutic approaches. We previously demonstrated that the histone deacetylase-associated protein SIN3B is essential for oncogene-induced senescence in cultured cells. Here, using a mouse model of pancreatic cancer, we have demonstrated that SIN3B is required for activated KRAS-induced senescence in vivo. Surprisingly, impaired senescence as the result of genetic inactivation of Sin3B was associated with delayed PDAC progression and correlated with an impaired inflammatory response. In murine and human pancreatic cells and tissues, levels of SIN3B correlated with KRAS-induced production of IL-1alpha. Furthermore, evaluation of human pancreatic tissue and cancer cells revealed that Sin3B was decreased in control and PDAC samples, compared with samples from patients with pancreatic inflammation. These results indicate that senescence-associated inflammation positively correlates with PDAC progression and suggest that SIN3B has potential as a therapeutic target for inhibiting inflammation-driven tumorigenesis.

Transcriptional intermediary factor 1 gamma (Tif1gamma) (Ectodermin/PTC7/RFG7/TRIM33) is a transcriptional cofactor with an important role in the regulation of the TGFbeta pathway. It has been suggested that it competes with Smad2/Smad3 for binding to Smad4, or alternatively that it may target Smad4 for degradation, although its role in carcinogenesis is unclear. In this study, we showed that Tif1gamma interacts with Smad1/Smad4 complex in vivo, using both yeast two-hybrid and coimmunoprecipitation assays. We demonstrated that Tif1gamma inhibits transcriptional activity of the Smad1/Smad4 complex through its PHD domain or bromo-domainin pancreatic cells by luciferase assay. Additionally, there is a dynamic inverse relationship between the levels of Tif1gamma and Smad4 in benign and malignant pancreatic cell lines. Overexpression of Tif1gamma resulted in decreased level of Smad4. Both overexpression and knockdown of Tif1gamma resulted in growth inhibition in both benign and cancerous pancreatic cell lines, attributable to a G2-phase cell cycle arrest, but only knockdown of Tif1gamma reduces tumor cell invasiveness in vitro. Our study demonstrated that imbalanced expression of Tif1gamma results in inhibition of pancreatic ductal epithelial cell growth. In addition, knockdown of Tif1gamma may inhibit tumor invasion. These data suggest that Tif1gamma might serve as a potential therapeutic target for pancreatic cancer.

Background: PNETs (Pancreatic Neuroendocrine tumors) are infrequent in the context of tuberous sclerosis complex (TSC) in children. There is marked disease heterogeneity, challenging clinical presentation and a limited knowledge of underlying molecular mechanisms. Inactivating mutations in the two genes TSC1 and TSC2, which correspondingly encode for hamartin and tuberin, are pathognomonic for the disease. The upregulation of the phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) with cascade activation of mitogen-activated protein kinase (MAPK) and the mammalian target of rapamycin (mTOR) leads to uncontrolled cell proliferation and tumorigenesis. The association of TSC and PNET is not clearly defined. We describe a case of PNET in a toddler with TSC1. Case presentation: An asymptomatic male aged 3 years 10 months with a TSC1 was identified with a pancreatic mass. Clinical sequence of events: diagnosed at 3 months with epilepsy and 3 hypomelanotic lesions on trunk; delayed speech development; at 3 years: kidney angiomyolipomas/left cortical cyst; at 3 years 7 months: multiple small rhabdomyomas in the right/left ventricles, at 3 years 9 months: a subependymal giant cell astrocytoma (SGCA)/excision and at 4 years of age open enucleation of 1 cm pancreatic mass located near junction of body and tail. Endocrine study: Test NameValue Reference Range Gastrin, pg/mL 83 Fasting 3-4 hrs: 2-168 Neuron-Specific Enolase (NSE), Serum, ng/mL 8.9 0.0-12.5 Chromogranin A, nmol/L 2 0-5 Glucose, plasma, mg/dL 81 65-99 Insulin, ulU/mL 4 2.6-24.9 IGF-1, ng/mL 59 20-141 IGFBP3, ng/mL 1960 972-4123 Diagnostic study: Molecular study: exon 10 of the TSC1 gene has a heterozygous basechange mutation (c.989dupT, an abnormal TSC1 protein, hamartin - p.Ser331fs). Brain MRI: SGCA (2.3 cm). Histology: Grade I, single mitoses, immunostains (+) for GFAP (glial fibrillary acidic protein) and synaptophysin (neuroendocrine marker), increased MIB-1 proliferation index (10%) indicative of high activity of cell proliferation. SGCA in the setting of TSC1 is able to express GFAP. MRI abdomen with contrast: pancreatic body lesion 1.1 cm in diameter (interval change from 4 mm in 5 months). Pathology: 1.0 x 0.8 x 0.6 cm; pale tan-pink tumor. Histology: PNET, grade 2; 2 mitotic figures/10 hpf, the Ki-67 proliferation index is about 20%; diffuse positivity with chromogranin, synaptophysin and CD56 (membranous). Conclusions: Our case demonstrates that patients with TSC1 may develop SGCA and pancreatic nonsecretory tumor at an early age along with the typical clinical stigmata of this entity. PNETs express neuroendocrine markers, which are useful to differentiate functional vs nonfunctional tumors. Semi-annual/annual evaluation with abdominal MRI will be beneficial for identification of PNETs. Some evidence exists to support that PNETs are an associated feature of TSC and require further investigation

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.

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.

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 (DeltaADC) 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+/-0.39x10mm/s (p=0.042); post-TACE ADC 1.34+/-0.36 vs. 1.92+/-0.47 (p=0.0008). There was no difference in DeltaADC values. CONCLUSION: This preliminary data suggests that pre-TACE tumor ADC can be used to predict HCC response to TACE.

AIM: To identify retrospectively potential associations between apparent diffusion coefficient (ADC) values of pancreatic adenocarcinoma and tumour grade as well as other pathological features, using histopathological assessment from the Whipple procedure as the reference standard. MATERIALS AND METHODS: Thirty patients with pancreatic adenocarcinoma underwent magnetic resonance imaging (MRI) including diffusion-weighted imaging with b-values of 0 and 500 s/mm before the Whipple procedure. Two radiologists independently recorded the ADC values of the tumour and benign pancreas for all cases. ADC values were compared with histopathological findings following the Whipple procedure. RESULTS: The intra-class correlation coefficient was 0.689 for benign pancreas and 0.695 for tumours, indicating good inter-reader agreement for ADC values. The mean ADC value was significantly lower in tumours than in benign pancreas for both readers (reader 1: 1.74 +/- 0.34 x 10 mm/s versus 2.08 +/- 0.48 x 10 mm/s, respectively, p = 0.006; reader 2: 1.69 +/- 0.41 x 10 mm/s versus 2.11 +/- 0.54 x 10 mm/s, respectively, p < 0.001). However, there was no significant difference in mean ADC between poorly and well/moderately differentiated tumours for either reader (reader 1: 1.69 +/- 0.36 x 10 mm/s versus 1.78 +/- 0.33 x 10 mm/s, respectively, p = 0.491; reader 2: 1.62 +/- 0.33 x 10 mm/s versus 1.75 +/- 0.49 x 10 mm/s, respectively, p = 0.405). The area under the curve (AUC) for differentiation of poorly and well/moderately differentiated tumours was 0.611 and 0.596 for readers 1 and 2, respectively, and was not significantly better than an AUC of 0.500 for either reader (p >/= 0.306). In addition, ADC was not significantly different for either reader between tumours with stage T3 versus stage T1/T2, between tumours with and without metastatic peri-pancreatic lymph nodes, or between tumours located in the pancreatic head versus other pancreatic regions (p >/= 0.413). CONCLUSION: No associations between ADC values of pancreatic adenocarcinoma and tumour grade or other adverse pathological features were observed.

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.

OBJECTIVES: The objective was to perform ex vivo evaluation of non-Gaussian diffusion kurtosis imaging (DKI) for assessment of hepatocellular carcinoma (HCC), including presence of treatment-related necrosis, using fresh liver explants. METHODS: Twelve liver explants underwent 1.5-T magnetic resonance imaging using a DKI sequence with maximal b-value of 2000 s/mm(2). A standard monoexponential fit was used to calculate apparent diffusion coefficient (ADC), and a non-Gaussian kurtosis fit was used to calculate K, a measure of excess kurtosis of diffusion, and D, a corrected diffusion coefficient accounting for this non-Gaussian behavior. The mean value of these parameters was measured for 16 HCCs based upon histologic findings. For each metric, HCC-to-liver contrast was calculated, and coefficient of variation (CV) was computed for voxels within the lesion as an indicator of heterogeneity. A single hepatopathologist determined HCC necrosis and cellularity. RESULTS: The 16 HCCs demonstrated intermediate-to-substantial excess diffusional kurtosis, and mean corrected diffusion coefficient D was 23% greater than mean ADC (P=.002). HCC-to-liver contrast and CV of HCC were greater for K than ADC or D, although these differences were significant only for CV of HCCs (P