IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; andoften but not always-elevated serum IgG4 concentrations. An international symposium on IgG4-related The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4 þ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

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Hedgehog signalling-an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer-may also be an important mediator in human pancreatic carcinoma [1][2][3][4][5][6][7][8] . Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.Sonic hedgehog (SHH) is misexpressed in human adenocarcinoma and its precursor lesions. SHH expression was determined using in situ hybridization to detect SHH messenger RNA and immunohistochemistry (IHC) to detect the protein with an antibody directed against Competing interests statementThe authors declare that they have no competing financial interests. . Pancreatic tissues were obtained from 20 specimens resected for pancreatic cancer. Control pancreatic tissues with no evidence of abnormality or autolysis upon histological evaluation were obtained from autopsy specimens or from pancreatic resections for trauma. In normal adult human pancreata, no SHH was detected in the islets, acini or ductal epithelium (Fig. 1a). However, evaluation of pancreata from patients with adenocarcinoma reveals that SHH is aberrantly expressed in 70% of specimens. Normal ductal epithelium does not express detectable levels of SHH (Fig. 1b); however, as the ductal epithelium shows increasing degrees of atypia, PanIN-1 to -3 ( Fig. 1c-e), a higher expression of SHH is observed. SHH expression is also detected in the malignant epithelium of adenocarcinoma samples (Fig. 1f). This expression pattern was also confirmed by our in situ hybridization for SHH mRNA ( Supplementary Fig. 1). NIH Public AccessLoss of regulation in this pathway has been implicated in several human cancers 10,11 . Thus in order to determine the potential role of SHH misexpression in the adult human pancreas, pancreata from transgenic mice (gift of H. Edlund) in which Shh misexpression was driven by the pancreatic-specific Pdx-1 promoter were histologically and immunohistochemically analysed.A total of four pancreata from three-week-old Pdx-Shh mice were histologically evaluated by a gastro...

The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.VEGF has a crucial role in physiological and pathological angiogenesis 1-3 . Although VEGF blockade, alone or in combination with cytotoxic therapies, is being tested in a number of

Hippo-Lats-Yorkie signaling regulates tissue overgrowth and tumorigenesis in Drosophila. We show that the Mst1 and Mst2 protein kinases, the mammalian Hippo orthologs, are cleaved and constitutively activated in the mouse liver. Combined Mst1/2 deficiency in the liver results in loss of inhibitory Ser127 phosphorylation of the Yorkie ortholog, Yap1, massive overgrowth, and hepatocellular carcinoma (HCC). Reexpression of Mst1 in HCC-derived cell lines promotes Yap1 Ser127 phosphorylation and inactivation, and abrogates their tumorigenicity. Notably, Mst1/2 inactivates Yap1 in liver through an intermediary kinase distinct from Lats1/2. Approximately 30% of human HCCs show low Yap1(Ser127) phosphorylation and a majority exhibit loss of cleaved, activated Mst1. Mst1/2 inhibition of Yap1 is an important pathway for tumor suppression in liver relevant to human HCC. Significance The pathways that regulate quiescence and tumor suppression in the liver have not been fully elucidated. We show that the Mst1 and Mst2 kinases are tumor suppressors and regulators of liver size in adults and that negative regulation of the transcriptional coactivator, Yap1, is central to Mst1/2 tumor suppressor function. Loss of both Mst1 and Mst2 is sufficient to initiate hepatocyte proliferation, resulting in dramatic liver overgrowth, resistance to pro-apoptotic stimuli, and the development of HCC. Mst1 and Mst2 promote phosphorylation of Yap1 and thereby suppress its oncogenic activity. Mst1/2 regulation of Yap1 is tissue-specific and, in the liver, involves an Mst1/2-regulated Yap1 kinase distinct from Lats1/2. Significantly, the Mst-Yap1 pathway is disrupted in a substantial fraction of human HCCs.

Steatohepatitis is associated with an increased 90-day mortality after hepatic surgery. In patients with hepatic CRM, the chemotherapy regimen should be carefully considered because the risk of hepatotoxicity is significant.

SMAD4 is inactivated in the majority of pancreatic ductal adenocarcinomas (PDAC) with concurrent mutational inactivation of the INK4A/ARF tumor suppressor locus and activation of the KRAS oncogene. Here, using genetically engineered mice, we determined the impact of SMAD4 deficiency on the development of the pancreas and on the initiation and/or progression of PDAC-alone or in combination with PDAC-relevant mutations. Selective SMAD4 deletion in the pancreatic epithelium had no discernable impact on pancreatic development or physiology. However, when combined with the activated KRAS G12D allele, SMAD4 deficiency enabled rapid progression of KRAS G12D -initiated neoplasms. While KRAS G12D alone elicited premalignant pancreatic intraepithelial neoplasia (PanIN) that progressed slowly to carcinoma, the combination of KRAS G12D and SMAD4 deficiency resulted in the rapid development of tumors resembling intraductal papillary mucinous neoplasia (IPMN), a precursor to PDAC in humans. SMAD4 deficiency also accelerated PDAC development of KRAS G12D INK4A/ARF heterozygous mice and altered the tumor phenotype; while tumors with intact SMAD4 frequently exhibited epithelial-to-mesenchymal transition (EMT), PDAC null for SMAD4 retained a differentiated histopathology with increased expression of epithelial markers. SMAD4 status in PDAC cell lines was associated with differential responses to transforming growth factor-␤ (TGF-␤) in vitro with a subset of SMAD4 wild-type lines showing prominent TGF-␤-induced proliferation and migration. These results provide genetic confirmation that SMAD4 is a PDAC tumor suppressor, functioning to block the progression of KRAS G12D -initiated neoplasms, whereas in a subset of advanced tumors, intact SMAD4 facilitates EMT and TGF-␤-dependent growth.[Keywords: Smad4; pancreatic cancer; epithelial-to-mesenchymal transition mouse models; TGF-␤] Supplemental material is available at http://www.genesdev.org. PDAC (pancreatic ductal adenocarcinoma) ranks as the fourth leading cause of cancer mortality in the United States and carries a median survival of <6 mo (Li et al. 2004). Hallmarks of this disease include the infiltration of the tumor with a proliferative stroma (desmoplasia), early invasion and metastasis, and pronounced genomic instability (Solcia et al. 1995). PDAC is characterized by a highly recurrent pattern of genetic lesions consisting of activating mutations of KRAS and inactivation of INK4A (via mutation, deletion, or promoter methylation) in virtually all cases, inactivation of the p53-ARF pathway in ∼87% of cases (including tumors with deletions of the INK4A/ARF locus), and SMAD4 inactivation in ∼53% (Hansel et al. 2003). Hence, SMAD4 status can be considered as a distinguishing molecular feature of two major classes of PDAC. Significant ongoing efforts are being directed toward the elucidation of how specific signature mutations contribute to the genesis and progression of PDAC and influence its tumor biological features.

H epatic resection and liver transplantation are aggressive, extirpative approaches to the treatment of selected patients for hepatocellular carcinoma (HCC) and are the only known potentially curative treatment options for this disease. Resection and transplantation are largely complimentary, not competing, treatments-resection for patients with preserved liver function and transplantation for patients with compromised liver function. Within each group, selection of patients for surgical therapy is currently based on morphologic criteria such as size, number of tumors, and degree of underlying liver disease.After resection, long-term survival can be expected in patients with solitary tumors regardless of size, especially when underlying fibrosis is minimal. 1 In fact, size has no significant impact on survival when microscopic vascular invasion is absent, as survival after resection of T1 tumors larger than 10 cm in diameter is similar to survival following resection of T1 tumors less than 5 cm. 1 Similarly, long-term survival can be expected when multiple tumors without vascular invasion are completely resected. 1 The establishment of strict morphologic criteria has significantly impacted the outcome after liver transplantation for HCC. Before the adoption of these criteria for transplantation, results with liver transplantation were poor. Recurrence rates ranged from 60% to 70%, 2,3 and the 5-year survival rate was less than 30%. 4,5 Since the implementation of more stringent selection criteria, survival rates after liver transplantation have been similar to those after resection for Abbreviations: HCC, hepatocellular carcinoma; AFP, alpha-fetoprotein; HR, hazard ratio; FNA, fine-needle aspiration.