Faculty Bibliography

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-beta, PPARgamma, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-kappaB 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.

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 (SNR(est)) and ADC were measured in the right hepatic lobe (for b values of 50 and 500 s/mm(2)). SNR(est) 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 SNR(est) and ADC compared with patients without siderosis (p < 0.0001). SNR(est) at b = 50 s/mm(2) and b = 500 s/mm(2) 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.

The transition of chronic pancreatic fibroinflammatory disease to neoplasia is a primary example of the paradigm linking inflammation to carcinogenesis. However, the cellular and molecular mediators bridging these entities are not well understood. Because TLR4 ligation can exacerbate pancreatic inflammation, we postulated that TLR4 activation drives pancreatic carcinogenesis. In this study, we show that lipopolysaccharide accelerates pancreatic tumorigenesis, whereas TLR4 inhibition is protective. Furthermore, blockade of the MyD88-independent TRIF pathway is protective against pancreatic cancer, whereas blockade of the MyD88-dependent pathway surprisingly exacerbates pancreatic inflammation and malignant progression. The protumorigenic and fibroinflammatory effects of MyD88 inhibition are mediated by dendritic cells (DCs), which induce pancreatic antigen-restricted Th2-deviated CD4(+) T cells and promote the transition from pancreatitis to carcinoma. Our data implicate a primary role for DCs in pancreatic carcinogenesis and illustrate divergent pathways in which blockade of TLR4 signaling via TRIF is protective against pancreatic cancer and, conversely, MyD88 inhibition exacerbates pancreatic inflammation and neoplastic transformation by augmenting the DC-Th2 axis.

Objective: To report a case of sebaceoma of the auricle, and to discuss the differential diagnosis, histopathological features, surgical management and genetic associations of this entity. Methods: Case report and review of the medical literature. Results: A 79-year-old man presented with a slowly growing lesion of his auricle. Excision of the mass and histopathological review revealed a benign, basaloid, adnexal neoplasm consistent with sebaceoma. Due to its association with Muir-Torre syndrome and increased risk of visceral malignancy, the patient was followed closely for signs of malignancy. At 36 months post-excision, there were no signs of recurrence; thereafter, the patient continued to receive routine cancer surveillance follow up. Conclusion: Sebaceoma is a rarely encountered, benign, adnexal neoplasm which can occur in the head and neck. The treatment is surgical excision, and recurrence is rare. Sebaceoma can occur as part of Muir-Torre syndrome, and in these patients there is an increased risk of other sebaceous lesions and visceral malignancy; thus, genetic testing and surveillance should be strongly considered.

This study evaluates the performance of diffusion-weighted magnetic resonance imaging (DWI) for the detection of hepatocellular carcinoma (HCC) in pre-liver transplant patients, compared and combined to contrast-enhanced T1-weighted imaging (CE T1WI), using liver explant as the standard of reference. We included 52 patients with cirrhosis (M/F 40/12, mean age 56 y) who underwent DWI and CE T1WI within 90 days of liver transplantation. MR images were analyzed for HCC detection in 3 separate sessions by 2 independent observers: DW images (DW-set), CE T1 WI (CE-set), and all images together (All-set). Sensitivity, specificity, PPV, NPV, accuracy per-patient; and sensitivity, PPV per-lesion were calculated for each image set. 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); while specificity, PPV and accuracy were equivalent. Per-lesion sensitivity was significantly higher for CE-set vs. DW-set (59.0% vs. 43.8%, p=0.008, pooled data from 2 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 vs. 74.0% for CE-set, p=0.001). The addition of DWI to CE T1WI improved sensitivity for the more experienced observer. Conclusion: DWI is outperformed by CE T1WI for detection of HCC, but represents a reasonable alternative to CE T1WI for detection of HCC with a size above 2 cm. The addition of DWI to CE T1WI slightly increases the detection rate. (HEPATOLOGY 2012.).

Stromal responses elicited by early stage neoplastic lesions can promote tumor growth. However, the molecular mechanisms that underlie the early recruitment of stromal cells to sites of neoplasia remain poorly understood. Here, we demonstrate an oncogenic Kras(G12D)-dependent upregulation of GM-CSF in mouse pancreatic ductal epithelial cells (PDECs). An enhanced GM-CSF production is also observed in human PanIN lesions. Kras(G12D)-dependent production of GM-CSF in vivo is required for the recruitment of Gr1(+)CD11b(+) myeloid cells. The suppression of GM-CSF production inhibits the in vivo growth of Kras(G12D)-PDECs, and, consistent with the role of GM-CSF in Gr1(+)CD11b(+) mobilization, this effect is mediated by CD8(+) T cells. These results identify a pathway that links oncogenic activation to the evasion of antitumor immunity.

Leiomyosarcomas are smooth muscle-derived tumors generally found intra-abdominally in the retoperitoneum, mesentery, or omentum. Only approximately 5% of these tumors originate from vessel wall smooth muscle. Those derived from the splenic vein are exceedingly rare, with only one previously published case in the literature. We present a second case of leiomyosarcoma of the splenic vein in a 58-year-old woman with 2 months of epigastric pain. A distal pancreatectomy was performed to include the tumor found centered in the splenic vein at the splenic and portal vein confluence and growing into the pancreas in the body on the posterior aspect. A saphenous vein patch was used for reconstruction.

OBJECTIVE: The purposes of this study were to describe the spectrum of cross-sectional imaging findings of pathologically proven hepatoportal sclerosis and to compare the features of advanced and nonadvanced hepatoportal sclerosis. MATERIALS AND METHODS: Eighteen patients with a histopathologic diagnosis of hepatoportal sclerosis who had concurrent MRI or CT images participated in the study. The following imaging features were assessed: presence of liver nodularity and liver lesions, portal vein patency, presence and degree of portal hypertension, liver volume, and caudate-to-right lobe ratio. These features were compared between patients who underwent transplant and those who did not. RESULTS: The 18 patients (11 men and one boy, six women; mean age, 46.5 years) had hepatoportal sclerosis confirmed with liver biopsy (14 patients) or explant (four patients). Fourteen patients underwent contrast-enhanced MRI, and five underwent CT. The imaging findings were as follows: liver surface nodularity, five patients (all four transplant, one nontransplant) (p = 0.0016); evidence of portal hypertension, 17 patients; increased caudate-to-right lobe ratio, 16 patients; high periportal signal intensity on T2-weighted images, six patients; portal vein occlusion with cavernous transformation, five patients. The transplant patients had smaller pretransplant liver volume than did nontransplant patients (p < 0.04). CONCLUSION: Hepatoportal sclerosis is characterized by caudate lobe hypertrophy and right hepatic lobe atrophy, preserved liver volume, and lack of the liver nodularity associated with portal hypertension. In advanced cases, liver nodularity and atrophy produce an imaging appearance indistinguishable from that of cirrhosis.

Purpose: To evaluate the ability of magnetization transfer (MT) contrast-prepared magnetic resonance (MR) imaging to help distinguish healthy from cirrhotic liver by using a spectrum of MT pulse frequency offsets. Materials and Methods: This HIPAA-compliant prospective study was approved by the institutional review board. Written informed consent was obtained from all subjects. After optimization of the MT sequence by using agar phantoms with protein concentrations ranging from 0% to 4%, 20 patients with cirrhosis and portal hypertension and 20 healthy volunteers with no known liver disease underwent liver MR imaging that included eight separate breath-hold MT contrast sequences, each performed by using a different MT pulse frequency offset (range, 200-2500 Hz). Regions of interest were then placed to calculate the MT ratio for the liver, fat, and muscle in the volunteer group and for the liver in the cirrhosis group. Results: MT ratio increased with decreasing MT pulse frequency offset for each of the four phantoms and the assessed in vivo tissues, consistent with previous reports. At all frequency offsets, MT ratio increased with increasing phantom protein concentration. In volunteers, at frequency offsets greater than 400 Hz, the MT ratio was significantly greater for muscle (range, 34.4%-54.9%) and significantly lower for subcutaneous fat (range, 10.3%-12.6%), compared with that for the liver (range, 22.8%-46.9%; P < .001 all comparisons). However, the MT ratio was nearly identical between healthy (range, 26.0%-80.0%) and cirrhotic livers (range, 26.7%-81.2%) for all frequency offsets (P = .162-.737), aside from a minimal difference in MT ratio of 1.7% at a frequency offset of 2500 Hz (22.8% in healthy liver vs 24.5% in cirrhotic liver) that was not significant when the Bonferroni correction was applied (P = .015). Conclusion: Findings of this study confirm the ability of the MT contrast-prepared sequence to help distinguish substances of varying protein concentration and suggest that MT imaging is unlikely to be of clinical utility in differentiating healthy and cirrhotic livers. (c) RSNA, 2011

Neuroendocrine tumors of the pancreas are rare in children. They usually occur in the setting of genetic syndromes such as multiple endocrine neoplasia type 1, von Hippel-Lindau disease, and neurofibromatosis 1. These tumors have also been reported in the tuberous sclerosis complex (TSC), but the incidence is low in comparison with other syndromes. Only 9 cases have been described to date, and it is not yet well understood if any connection exists between TSC and pancreatic endocrine tumors. TSC is characterized by mutations in TSC1 and TSC2 genes, which activate the AKT-mTOR oncogenic cascade. Recent molecular studies in pancreatic endocrine tumors showed activation of the same pathway, which points toward a common molecular pathway between these two entities. We present a case of well-differentiated neuroendocrine carcinoma of the pancreas in a child with TSC and discuss the genetic aspects of this disease