. Plate 1 (Figure 2-1) Primitive gut in a sagital section of a 4 weeks human embryo. Broken lines: limit between foregut, midgut and hindgut. . Plate 2 (Figure 2-3) Development of the in human embryos of 5(a), 6(b) and 7(c) weeks. Arrows indicate the sense of primitive intestine rotation around its longitudinal axis. Broken line: limit between foregut and midgut. . Plate 3 (Figure 2-4) Histologic structure of the adult pancreas: (a) ac acini, iL islets of langerhans, (b) a arteria, v vein, n nerve, (c) ild interlobular duct, Arrowheads ductal cilindric epithelia, Broken arrows litle interlobular ducts, Arrows basophilic ergastoplasm of acini.

. Plate 4 (Figure 3-1) Normal pancreatic tissue. Acinar cells arranged in lobules constitute the majority of the parenchyma. These cells have apical lightly eosinophilic cytoplasm due to the presence of zymogen granules and basophilia in the basal aspect of the cytoplasm. To aid in their secretory activity, the nuclei are polarized to the periphery and the cells are arranged in round units creating the acinus. In the left middle part of the field, an islet of Langerhans consisting of round collection of endocrine cells is represented. Endocrine cells have moderate amphophilic cytoplasm and nuclei with finely stippled chromatin pattern. In the right upper part of the field an intralobular duct lined by cuboidal-low columnar epithelium is seen. . Plate 5 (Figure 3-2) (a) Invasive ductal , macroscopic findings. A firm, sclerotic, poorly defined mass is seen in the head of the pancreas. The rounded pale structure (arrow) adjacent to the right lower border of the specimen represents a lymph node enlarged by metastatic adenocarcinoma. (b) Invasive ductal adenocarcinoma is characterized (and defined) by infiltrating tubular units embedded in desmoplastic stroma.

. Plate 6 (Figure 3-3) Invasive ductal adenocarcinoma, well differentiated. Well formed glandular structures lined by cuboidal cells closely mimic the non-neoplastic ducts. . Plate 7 (Figure 3-4) Invasive ductal adenocarcinoma, moderately differentiated. There is a greater degree of cytologic and nuclear atypia. Loss of polarity can be seen as well.

. Plate 8 (Figure 3-5) Invasive ductal adenocarcinoma showing perineural invasion. . Plate 9 (Figure 3-6) Vascular invasion of infiltrating ductal adenocarcinoma. Carcinoma cells line the luminal surface of vascular walls in such an organized and polarized fashion that they form a well-structured duct-like unit virtually indistinguishable from normal ducts or PanINs.

. Plate 10 (Figure 3-7) Isolated solitary ducts surrounded entirely by adipocytes without any accompanying islets, acini or other ducts are indicative of invasive carcinoma. This phenomenon of renegade ducts away from the main tumor is a peculiar manifestation of the insidious spread of pancreatic adenocarcinoma. . Plate 11 (Figure 3-8) Undifferentiated carcinoma with osteoclast-like giant cells. Non-neoplasic multinucleated giant cells of histiocytic origin are mixed with neoplastic mononuclear spindle shaped epitheloid cells. The mononuclear cells have hyperchromatic, occasionally bizarre nuclei.

. Plate 12 (Figure 3-9) Colloid carcinoma (mucinous non-cystic carcinoma) characterized by large amounts of mucin pools. Detached fragments of tumor cells can be observed in these pools. . Plate 13 (Figure 3-10) (a) PanIN-1B. In PanIN-1, the normal cuboidal to low columnar ductal epithelial cells are replaced by tall columnar cells containing abundant apical mucin. The nuclei are basally located. The epithelium can be relatively flat in PanIN-1A but papilla formation is well established in the PanIN-1B stage. (b) PanIN-2 usually is papillary. Cytologically, there is nuclear crowding, pseudo-stratification, loss of polarity, and enlarged nuclei. Mitoses are rare, but when present are not atypical. (c) PanIN-3 is characterized by severe cytologic atypia that is seen in full-blown carcinoma. Loss of polarity, nuclear irregularities and prominent (macro) nucleoli (inset) and mitoses, which may occasionally be abnormal, are usually prominent. . Plate 14 (Figure 3-11) Intraductal papillary mucinous (IPMN). Tall, exuberant papillary structures lined by columnar cells with abundant mucin and cigar-shaped nuclei filling and dilating the ducts (cystic transformation). The overall picture of the process is highly similar to that of villous adenomas of the colon. . Plate 15 (Figure 3-12) Mucinous cystadenoma (MCN). The lining is composed of tall columnar mucinous epithelium, surrounded by a cuff of distinctive hypercellular stroma, which shows all the characteristics of ovarian stroma.

. Plate 16 (Figure 3-13) Serous cystadenoma. Typical honeycomb (microcystic) pattern due to innumerable of various sizes. The lining of these cysts compose of low cuboidal epithelial cells with clear (glycogen-rich) cytoplasm showing distinctive uniform, round, small nuclei with homogenous, dense chromatin (inset). . Plate 17 (Figure 3-14) Pancreatic endocrine neoplasm. Uniform cells are arranged in nests and nuclear features show the characteristic clumped, ‘‘salt and pepper’’ chromatin pattern.

. Plate 18 (Figure 3-15) Acinar cell carcinoma. The tumor cells are highly atypical but at the same time fairly monotonous and round. They display markedly chromopholic cytoplasm, mostly reflecting the enzymatic granules and cytoplasmic organelles involved in their production. Single prominent nucleoli are also among the most distinctive histologic features of this tumor type. . Plate 19 (Figure 3-16) . The acinar component predominates in most pancreatoblastomas as seen here. The most distinctive and characteristic finding in this tumor type is the squamoid corpuscles, which are well defined nests of plump to spindle-shaped cells that form a vague fascicular or whorled pattern highly similar to the ‘‘morules’’ seen in other malignant tumors related to beta-catenin pathway alterations.

. Plate 20 (Figure 3-17) Solid pseudopapillary tumor. Prominent pseudopapillary growth pattern is seen most cases, and is a characteristic feature of this enigmatic tumor. . Plate 21 (Figure 4-1) Overview of pancreatic organogenesis. Schematics and photographs of embryonic pancreas depict development at stages indicated, from (a) bud evagination from the endoderm, (b) initiation of stratification or branching, (c) onset of the secondary transition, (d) exocrine and endocrine differentiation, and (e) the maturing anatomy of acinar, ductal and endocrine tissues and associated vasculature just prior to birth. Left panels depict the pancreatic epithelium at each stage (mesenchyme not shown). Note the alternative models for dense branching (left) versus stratification and microlumen formation (right) of the epithelium at 10.5 (B1) and 12.5 dpc (C1). Yellow, pancreatic epithelium; orange, multipotent precursor cells (MPCs); red, differentiating acini; light blue, newly emerged endocrine cells; dark blue, maturing endocrine cells. Middle panels show whole mount views of Pdx1-expressing (blue stain) dorsal and ventral pancreatic buds. At 12.5–15.5 dpc, the pancreas is associated with underlying and . Right panels show sections through Pdx1-expressing epithelium (blue stain) surrounded by pancreatic mesenchyme (pink eosin staining). a, aorta; ac, acini; d, duodenum; dp, dorsal pancreas; du, duct; ec, endocrine cord; m, mesenchyme; p, portal vein; pa, proacinus; st, stomach; te, tubular precursor epithelium; vp, ventral pancreas. . Plate 22 (Figure 4-4) Cell-cell signaling during pancreatic development. Developmental signaling depends on the proper spatiotemporal communication between embryonic tissues. Multiple sequential inductions between adjacent developing tissues are mediated by secreted or cell-tethered factors. During pancreatic bud development, sequential signals are produced by (1) the primitive streak during gastrulation (prior to the stage shown), which patterns the endoderm with a gradient of FGF4; (2) the notochord, which sends permissive signals (such as Fgf2 and activin-bB) that promote the pancreas domain; (3) the aorta, which provides endothelial signals (EC factors) required for Ptf1a induction, Pdx1 maintenance and first wave insulin expression; and (4) the lateral plate mesoderm, which produces Fgf10 and retinoic acid (RA) required for bud outgrowth. Reciprocally, structures such as the gut endoderm and somites produce VEGF, which is required for patterning the dorsal aorta. . Plate 23 (Figure 4-6) The branched pancreatic epithelium in the middle of the secondary transition of an embryonic mouse pancreas. A section through the dorsal pancreas at late 14.5 dpc with immunolocalization of the transcription factor Pdx1 (green) displays the pancreatic epithelium during the secondary transition. At this stage, most of the cells of the epithelial tubules containing islet and ductal precursors (yellow outlines) and pro-acini (white indicators around the periphery) have nuclear Pdx1. . Plate 24 (Figure 4-7) Multipotent precursors for acinar, ductal and islet cells initiate the secondary transition at epithelial tips. Yellow, precursors in the tubules for duct and islet cells. Orange, multipotent precursor cells (MPCs) [7]. Burnt orange, proacinar cells at the ends of branched tubules that have lost multipotency and committed to acinar differentiation. Red, differentiating acini that have revised their relationship with the terminal tubule cells, which will become centroacinar cells. Brown, domains in the tubules initiate ductal cell differentiation. Green nuclei, scattered cells in the tubules initiate Ngn3 expression. Green cells have escaped the epithelium and begun the islet cell developmental program. Light blue, differentiating endocrine cells that have initiated the synthesis of an islet hormone. Blue, clusters of differentiated islet cells. Arrows indicate the outward growth of the epithelia. Although the drawing depicts a uniform population of bipotent precursor cells (yellow, islet and duct potential), it is also possible that two discrete precursor populations are present, one for islet cells and one for ductal cells. . Plate 25 (Figure 4-8) A stereotypic model for the morphogenetic processes that generate islets centrally and acini peripherally. (a): A close-up view of the structure of Pdx1-expressing tubules, peritubular cords, and proacini from a section nearby that of > Fig. 4-6. Note the subset of cells located in the cell cords or the tubules in contact with the cords that have very high Pdx1; these may be cells committed selectively to the b-cell differentiation program [136]. Green, Pdx1; red, glucagon, which marks the majority of the differentiated endocrine cells at this stage (E14.5). (b): Diagram of the proposed developmental compartments of the post-MPC epithelium. Yellow, progenitors of islet and ductal cells retain the capacity for cell proliferation. Beige, committed ductal cell precursors. Orange (left), committed pro-acinar cells retain cell-proliferation and continuity with the tubular epithelium and have begun the synthesis of other digestive enzymes in addition to Cpa1. Red (right), differentiating acinar cells with low cell-replication capacity, ongoing cytodifferentiation and accumulation of secretory (zymogen) granules. The acinar cells have formed a cap engulfing the tubule end cells, which become the centroacinar cells of the mature acinus. Green-to-blue, islet precursors initiate the islet program via Ngn3 expression (green nuclei) and release from the tubule epithelium. The disposition of cell-cell junctions is not confirmed. Orthogonal/Asymmetric division model (upper): Parallel cell divisions are symmetric and generate equivalent daughter cells that remain in the epithelium. Orthogonal divisions (green) are asymmetric and retain one daughter in the epithelium with intracellular junctions intact and release the other. EMT model (lower): Pre-endocrine cells in the epithelium break intracellular junctions, acquire transient mesenchymal properties, migrate from the epithelium, congregate in clusters, re-establish epithelial cell properties, and differentiate. Inset left: pro-acinus with connecting tubule. Inset right: differentiating acinus with cap structure. . Plate 26 (Figure 5-1) Representative histologies of low-grade (a) and high-grade (b) PanINs, low-grade (c) and high-grade (d) IPMNs and low-grad (e) and high-grade (f) MCNs (H&E stainings). Note the prominent ovarian-type stroma beneath the epithelial layer in f. . Plate 27 (Figure 6-1) Examples of epigenetic-mediated tumor suppressor gene silencing. This cartoon depicts a model for various roles of chromatin dynamics in tumor suppressor gene silencing, participating in the phenotype. Several different mechanisms of epigenetic-mediated gene silencing can accomplish the same outcome of tumor suppressor gene silencing, including the HDAC system, polycomb proteins and HP1 proteins. For example, a sequence-specific transcription factor (ssTF) may recruit the Sin3a–HDAC complex to a target gene promoter. The recruitment of Sin3a–HDAC to the promoter facilitates the remodeling of surrounding chromatin with silencing marks, namely the deacetylation of histones. Removal of acetylation signals short-term repression of a target gene and in addition, primes the histone for receiving additional long-term silencing marks, such as methylation of K9 or K27 on histone H3, binding marks for HP1 and polycomb, respectively. The recruitment of HP1 to a gene promoter facilitates the further recruitment of the G9a methylase, which creates more methyl-K9 H3 silencing marks and thus, more HP1 binding sites. In addition, HP1 can recruit a DNA methyltransferase (Dnmt) to the promoter. In a similar manner for the polycomb group proteins, PRC1 recruitment results in the binding of the PRC2 complex, which contains the K27 H3 methylase EZH2. The PRC2 complex also is capable of recruiting the DNA methyltransferases. . Plate 28 (Figure 6-3) Dynamics of chromatin marks on promoters. The figure demonstrates three different promoter states of chromatin marks: active, ‘‘poised’’ and silenced (adapted from [44]). Nucleosomes encompassing the promoter region of a gene are shown. The numbers indicate the corresponding amino acid of the histone H3 tail. The orange circles represent the degree of methylation with multiple states possible for a given signal. For example, on active promoters, the chromatin marks are a signal of gene transcription, such as mono-, di- or tri-methylation of K4 of H3 and mono-methylation of H3-K9. Active promoters are also enriched in H3, H4, and H2A acetylation (not shown). On a ‘‘poised’’ promoter, a combination of active and repressive marks can leave genes ready for activation and forms a ‘‘bivalent domain.’’ The promoter regions of this type are enriched in the repressive trimethyl-K27 H3 mark, whereas the region around the transcription start is also enriched in the active trimethyl-K4 H3 mark. Finally, a silenced promoter contains inactive chromatin marks. These nucleosomes are enriched in H3-K9 tri- methylation (and sometimes di-methylation, not shown) and H3-K27 di- and tri-methylation. . Plate 29 (Figure 6-5) (a) The triple code hypothesis. This figure summarizes the integration of the well-known DNA-centric hypothesis for the establishment and maintenance of the cancer phenotype, which includes mutations and deletions, with changes in chromatin, signaled through the Histone Code, barcode and its subcodes, and alterations in nuclear structure to form what we call the ‘‘Triple Code Hypothesis.’’ This ‘‘Triple Code Hypothesis’’ has formed the basis of the more comprehensive progression model for , proposed in Fig. 77-5b. (b) Revised Comprehensive Progression Model for Pancreatic Cancer The model developed by Hruban and colleagues [1] was fundamental for expanding the work of many laboratories in the area of somatic genetics in pancreatic cancer to the point that today we understand the relationship between the morphological progression and mutations/deletion of important oncogenes and tumor suppressor pathways. However, the model cannot currently explain emerging knowledge on critical steps that occur between these mutations and even the potential cause of subsequent mutations and deletions. Most of these changes are epigenetic in nature with the underlying basic mechanisms of both, chromatin dynamics and nuclear shape. Thus, here, we propose a novel model for the progression of pancreatic cancer, which not only incorporates the elegant and extremely important data generated under the premise of the previous model but, in addition, formally includes chromatin-induced and miRNA-induced epigenetic changes, as well as other alterations caused by changes in nuclear shape. It is the hope that this model will serve as a compass to guide future experiments in these under-explored and yet crucial areas of knowledge. We believe that in the next 5 years, experiments aimed at addressing the contribution of these phenomena to pancreatic cancer progression and their potential translation to clinical applications will be among the most promising areas of our field. . Plate 30 (Figure 8-1) H&E staining with the typical trabecular pattern of a PET (here gastrinoma).

. Plate 31 (Figure 8-9) Necrolytic migratory erythema in a patient with a malignant glucagonoma. . Plate 32 (Figure 9-2) Immunohistochemical characterization of intestinal-type versus pancreaticobiliary-type ampullary carcinomas: Intestinal-type carcinomas are positive for mucin-2 (MUC2) and cytokeratin-20 (CK20) (left column), whereas pancreaticobiliary-type carcinomas are positive for mucin-1 (MUC1) and cytokeratin-7 (CK7) (right column), as detected immunohistochemically by specific antibodies. The intestinal-type ampullary cancer histologically resembles duodenal carcinomas, the hepatobiliary-type is similar to distal -duct carcinomas. Courtesy of Prof. G. Klo¨ppel, Dept. of Pathology, University of Kiel, Germany. . Plate 33 (Figure 10-3) Adenocarcinoma, intestinal type. The tumor is composed of complexed glands lined by atypical cells. Note the typical luminal inflammation. (Reprinted from Mino and Lauwers, [14].)

. Plate 34 (Figure 10-4) Adenocarcinoma, pancreatobiliary type. The tumor is composed of simple malignant glands lined by low columnar cells. Note the markedly atypical nuclei and the surrounding desmoplasia. (Reprinted from Mino and Lauwers, [14].) . Plate 35 (Figure 11-1) The histology of normal human pancreas, CP, PDAC and PanIN1. Low magnification (20) and high (60) magnification micrographs are shown for normal pancreas (a,b), CP (c,d), PDAC (e,f) and PanIN1 lesions (g,h). The similarity in histology between CP and PDAC are obvious. In the normal pancreas the majority of the organ is occupied with mature pancreatic acinar cells. Normal ducts possess a narrow surrounding of stroma. Islets are also observed. In CP and PDAC the acinar cells are displaced by an abundant stroma. These two diseases can be difficult to distinguish for an untrained person. The PanIN1 lesions display a pronounced increase in stroma compared to normal ducts. . Plate 36 (Figure 12-2) Tumor formation in NOD/SCID mice injected with highly tumorigenic CD44þ CD24þ ESAþ pancreatic cancer cells. (a) H & E staining of the tumor generated from CD44þ CD24þ ESAþcells in NOD/SCID mice (right panel) has similar histologic features to the corresponding patient’s primary (left panel). Magnification 200X. (b) Expression of the differentiation markers S100P (top two panels) and stratifin (bottom two panels) is similar in tumors derived from CD44þ CD24þ ESAþpancreatic cancer stem cells in NOD/SCID and the corresponding primary tumor form the patient. Antibody localization was performed using horseradish peroxidase, with dark brown staining indicating the presence of the specific antigen. . Plate 37 (Figure 15-2) ErbB dimers: There are nine possible signaling ErbB dimer combinations. Monomers of ErbB1 (purple), ErbB3 (pink), and ErbB4 (blue) change conformation with ligand binding (light blue) such that the DD becomes available and the monomer forms a dimer. Upon dimerization with all ErbB monomers except ErbB3, tyrosines in the C-terminal tail become phosphorylated (yellow) by the dimerization partner. ErbB2 (green) does not bind ligand and has a constitutively available DD. The kinase domain of ErbB3 is inactive, thus ErbB3 cannot phosphorylate its dimerization partner; however, ErbB3 can be phosphorylated. The phosphorylated tyrosines bind and activate intracellular proteins with SH2 and PTB domains. Shown on top are the possible activated ErbB homodimers (ErbB1, ErbB2, and ErbB4), and on bottom the activated heterodimers. . Plate 38 (Figure 15-3) ERB signaling pathways: EGF receptor activation initiates a diverse array of cellular pathways via dimerization (represented by the light blue cylinders in the cell membrane). Each receptor dimer recruits different SH2-containing effector proteins triggering distinct signaling pathways, culminating in cellular responses such as cell proliferation or apoptosis. The activated receptor complexes with the adaptor protein, Grb2, which is coupled to the guanine nucleotide releasing factor, SOS1. This Grb2-SOS1 complex can either directly bind to receptor phosphotyrosine sites or indirectly through SHC. As a result of these interactions, SOS is localized in close proximity to RAS, allowing for Ras activation. Subsequently, the ERK and JNK signaling pathways are activated, which ultimately lead to the activation of transcription factors, such as c-fos, AP-1, and Elk-1, that promote gene expression and contribute to cell proliferation. In addition, in response to EGFR activation, JAK kinases activate STAT-1 and STAT-3 transcription factors, contributing to further proliferative signaling. Protein kinase C (PKC) is also activated via phosphatidylinositol signaling (PIP2 to PIP3) and calcium release, which serves as another node of EGF signaling. See text for further details. . Plate 39 (Figure 15-4) Downstream RAS signaling: After receptor activation (represented by the light blue cylinders in the cell membrane), RAS activation is regulated by the cycle of hydrolysis of bound GTP. The activated receptor signals to a guanine nucleotide exchange factor, such as SOS1 (see > Fig. 15-3), which then ejects GDP from RAS to allow RAS to bind free GTP to become active. Opposing this activation are the GTPase-activating proteins (GAPs), which stimulate the endogenous GTPase of RAS, thereby creating inactive RAS-GDP. Although PI3K can be activated via its recruitment to ErbB receptors, PI3K can also be activated by RAS directly. Activation of PI3K results in not only activation of AKT and its downstream effectors (see > Fig. 15-6) to mediate cell survival, but an increase in PtdIns(3,4,5)P3 at the plasma membrane as well. This leads to the activation of the Rho family of small GTPases, Rho, Rac1, and Cdc42 via recruitment of GEFs to the plasma membrane. . Plate 40 (Figure 15-5) PTEN regulation of phosphoinositide 3-kinase (pi3k) signaling: Upon activation via receptor signaling (represented by the light blue cylinders in the cell membrane), the main substrate of PI3K is phosphoinositide (4,5) bisphosphate (PIP2). Phosphorylation of PIP2 by PI3K generates PtdIns(3,4,5)P3 (PIP3). PIP3 and its 5’-dephosphorylation product, PIP2, are important second messengers that promote cell survival, cell growth, protein synthesis, mitosis, and motility. Cell survival, mitosis, and protein synthesis are all promoted via PI3K-dependent activation of the PDK-1/AKTpathway. Importantly, PTEN is a tumor suppressor gene that is able to dephosphorylate PIP3 in order to regulate this process. Since the activation of AKT is regulated via its phosphorylation by PDK-1, along with integrin-linked kinase (ILK), inactivation of PTEN permits constitutive and unregulated activation of the AKT pathway. In addition to regulating the AKT signaling pathway, PTEN also inhibits EGF-induced SHC phosphorylation to suppress the MAP kinase signaling cascade. Thus, inactivation of PTEN also facilitates the constitutive and unregulated signaling of MAP kinase, lending to an increase in cell growth. . Plate 41 (Figure 15-6) AKT and its downstream effectors: As shown in > Fig. 15-3, EGFR activation results in direct or indirect activation of PI3K. AKT is located downstream of PI3K and, therefore, functions as a key effector of ERB signaling. Activated AKT promotes cell survival through via inhibition of apoptosis by phosphorylating the Bad component of the Bad/Bcl-XL complex. This phosphorylation causes Bad to dissociate from the Bad/Bcl-XL complex through binding to 14-3-3. In addition, AKT triggers activation of IKK-a that ultimately leads to NFkB activation and cell survival. AKT also regulates cell growth through its effects on the mTOR pathway, as well as cell cycle and cell proliferation through its actions on GSK3b, resulting in inhibition of cyclin D1, and MDM2, thus indirectly inhibiting p53. . Plate 42 (Figure 18-1) The Notch signaling pathway. The figure illustrates the key events in the Notch signaling pathway. Ligands of the delta and jagged families expressed on an adjacent signal-sending cell initiate the signal through Notch receptor recognition on the signal-receiving cell (a). This interaction between receptor and ligand leads to a cascade of proteolytic cleavages of the Notch receptor, beginning with metalloprotease cleavage just outside the membrane (b). This proteolytic step facilitates the subsequent intramembrane cleavage of Notch by the g-secretase complex (c) to release the Notch intracellular domain (NICD) from the membrane. The NICD then translocates to the nucleus (d) and enters into a transcriptional activation complex with the transcription factor CSL along with co-activators, including Mastermind-like proteins (Maml) and CBP/p300, thereby activating transcription of target genes (e). . Plate 43 (Figure 18-2) The human Notch receptors. Schematic diagram of the structural domain features of the human Notch receptors 1–4. The arrows mark the approximate locations of the cleavage sites for the ADAM metalloprotease and g-secretase for release of the NICD. The double line represents the cellular membrane. The legend box identifies the graphic representation of each structural feature. . Plate 44 (Figure 18-3) The human DSL ligands. Schematic diagram of the structural domain features of the human DSL ligands for Notch with the double line representing the cellular membrane. The legend box identifies the graphic representation of each structural feature. . Plate 45 (Figure 20-1) Histological and molecular sequence of events in the evolution of PanIN to PDA. . Plate 46 (Figure 23-1) Immunofluorescence analysis of pancreatic stellate cells for specific activation markers and extracellular proteins: (a) The typical activation marker for PSC; intracytoplasmic alpha-smooth muscle actin filaments appear red while the DAPI stained nucleus appears blue, 400x magnification. (b) The actin cytoskeleton of the PSC appears green while the perinuclear vimentin filaments appear red, and the DAPI stained nucleus appears blue, 400x magnification. (c) Activated PSC express high levels of PDGF-2 receptor (green), 200x magnification. When the PSC are activated they produce significant amounts of (d) collagen type-I (green), 200x magnification, (e) fibronectin (green), 100x magnification, and (f) periostin (green), 200x magnification. . Plate 47 (Figure (23-2) Expression of Hypoxia-inducible factor-1 as a marker tissue hypoxia in pancreatic cancer: Hypoxia-inducible factor-1 is a transcription factor that responds to changes in available oxygen in the cellular environment. It is the master regulator of hypoxic responses. The alpha subunit of HIF-1 undergoes a rapid degradation by the proteasome under normoxic conditions. In hypoxic conditions however, HIF-1 degradation is inhibited, resulting in the accumulation of the transcription factor (brown staining). In pancreatic cancer, HIF-1 expression assessed by immunohistochemistry, not only increases in the cancer cells (a, arrows, 200x magnification), but also in the stellate cells found in the immediate vicinity of them cells as well as in the areas of peritumoral chronic pancreatitis like changes (b, 200x magnification) clearly demonstrating the reduction of tissue oxygenation.

. Plate 48 (Figure 23-3) The impact of a hostile microenvironment on cancer cell behavior: Reduction of blood circulation not only results in hypoxia but also in a reduction of the nutrients. In response to their microenvironment, cancer cell show significant morphologic and behavioral changes. When pancreatic cancer cells are kept in high nutrient containing medium in a Boyden chamber to assess their invasiveness (a, 200x magnification), they preserve their rounded shape and invade moderately. In contrast, when the nutrient content of the medium is decreased, cancer cells undergo significant morphological changes (b, 200x magnification) similar to those of epithelial-mesenchymal transition and become highly invasive. . Plate 49 (Figure 27-1) (a and b) Necrolytic migratory erythema is characterized by a figurative eruption with erosions and a rapid centrifugal progression.

. Plate 50 (Figure 27-2) (a and b) Erythema nodosum is characterized by subcutaneous nodules on the surfaces of the legs. . Plate 51 (Figure 28-1) (a) Normal pancreatic acinar tissue (red arrows) with a small pancreatic duct (blue arrow). (b) PanIN-1 in lower right (blue arrow) with adjacent loss of pancreatic tissue and replacement by adipose tissue (black arrows). (c) Areas of fibrosis (blue arrows) with loss of acinar tissue but retention of islets (red arrow). (d) High power field of a High grade PanIN (PanIN-2) with visible mitoses (green arrows). . Plate 52 (Figure 29-7) A 18 year old male with jaundice and pancreatitis. (a) Coronal MIP images show increased FDG activity in the region of the pancreas (arrow). (b) Coronal fused PET-CT image show increased diffuse FDG uptake in the pancreas (arrow). . Plate 53 (Figure 33-2) The end-of-life trajectory in advanced pancreatic cancer.

. Plate 54 (Figure 35-3) Aspects of EUS guided rendezvous procedures are shown. The image to the left demonstrates EUS guided access to a left intrahepatic with guidewire passage through the papilla and coiled within the duodenum as may be necessary following failed endoscopic retrograde cholangiography. Doing so, allow subsequent transpapillary drainage (right, top). When transpapillary drainage cannot be achieved, then hepaticogastrostomy with stent placement through the stomach to an intrahepatic bile duct provides an alternative means of drainage (right, bottom). . Plate 55 (Figure 35-6) Illustration demonstrates needle placement adjacent and anterior to the lateral aspect of the aorta at the level of the celiac trunk when performing standard celiac plexus neurolysis.

. Plate 56 (Figure 35-7) Linear EUS images of celiac ganglia revealing hypoechoic oval or almond shaped structures with irregular margins. Central echo rich strands or foci may be present, and echo poor threads are usually seen arising from ganglia. . Plate 57 (Figure 38-1) IMRT volumes of the treatment plan and response post-treatment in two patients. Patient 1 (a, c, e) shows regression of the involved lymph node from the hepatic artery and celiac axis. Before treatment (a), after treatment (b), treatment plan with isodose lines (c) are shown. Note that only focal areas of gastrointestinal mucosa <5 cc are treated to the 63 Gy dose. Patient 2 (b, d, f) shows regression from SMA. Before treatment (b), after treatment (d), treatment plan with isodose lines (f) are shown. Arrows highlight area of disease regression. The nested GTV surrounding the vascular margin is taken to 63 Gy and is well away from the duodenum (white isodose line, e and f). A larger volume is taken to 50.4 Gy (blue isodose line, e and f). . Plate 58 (Figure 40-6) Porto-mesenteric confluence resection and reconstruction using an external iliac vein graft. PV: portal vein, SMV: superior mesenteric vein, JV: jejunal vein, SMA: superior mesenteric artery, CHA: common hepatic artery, LRV: left renal vein, G: external iliac vein graft. Arrows indicate proximal and distal anastomosis of the interposed iliac vein graft.

. Plate 59 (Figure 41-2) Typical microscopical appearance of pancreatic ductal adenocarcinoma. This poorly differentiated tumor consists of atypical glandular structures and solid cords embedded in a dense (desmoplastic) stroma, which confers the tumor its typical grey-whitish color and hard consistency. . Plate 60 (Figure 41-3) Processing of specimens according to a standardized protocol. (a) Schematic representation of the circumferential soft tissue margins of a pancreaticoduodenectomy specimen. See text for explanations. (b) Fresh or, like in this case, fixed specimens are inked according to a defined color code that allows an easy identification of the soft tissue margins on the cut sections. With kind permission from Esposito I, Kleeff J, Bergmann F, Reiser C, Herpel E, Friess H, Schirmacher P, Bu¨ chler MW: Most pancreatic cancer resections are R1 resections. Ann Surg Oncol 2008;15:1651–1660, Springer Science + Business Media, > Fig. 41-1. . Plate 61 (Figure 41-4) Axial sectioning of pancreaticoduodenectomy specimens. (a) Schematic representation of the sectioning method. Reproduced with permission from Verbeke CS. Resection margins and R1 rates in pancreatic cancer – are we there yet? Histopathology 2008;52(7):787–796, Blackwell Publishing. (b) After inking, the specimens are sliced perpendicular to the long axis of the duodenum. All relevant anatomical structures, the tumor and the soft tissue margins can be easily identified on the cut specimen. With kind permission from Esposito I, Kleeff J, Bergmann F, Reiser C, Herpel E, Friess H, Schirmacher P, Bu¨ chler MW: Most pancreatic cancer resections are R1 resections. Ann Surg Oncol 2008;15:1651–1660, Springer Science + Business Media, > Fig. 41-2. . Plate 62 (Figure 41-5) Examples of microscopic incomplete resection. Presence of cancer cells within 1 mm from a resection margin, either as direct (a) or as perineural (b) spreading is considered R1. Red arrows indicate the margin, green arrows the cancer cells. With kind permission from Esposito I, Kleeff J, Bergmann F, Reiser C, Herpel E, Friess H, Schirmacher P, Bu¨ chler MW: Most pancreatic cancer resections are R1 resections. Ann Surg Oncol 2008;15:1651–1660, Springer Science + Business Media, > Fig. 41-3.

a

b . Plate 63 (Figure 47-2) Serous cystadenoma comprised of cuboidal cells with papillary projections of the epithelia.

. Plate 64 (Figure 47-6) Histologic finding of a solitary nodule in a main duct IPMN. Index

A BMi–1, 324–326, 328 Ablative anti-tumor therapies, 882–886 Body mass index, 5, 8 Abundant protein removal, 515, 516, 518 Borderline resectable, 1094, 1095, 1097, 1101–1102, Acanthosis nigricans, 656, 657 1104, 1105, 1109–1122 Acinar, 41–43, 55, 58–60, 62–64 – disease, 628, 632–635, 644, 645 Acinar development, 94, 97, 99, 100 – tumors, 712, 725 Acini, 31–36 BRCA1, 569, 578, 583, 591 Adenosquamous, 42, 49 BRCA2, 569, 578, 580–583, 586, 587, 589–592, A disintegrin and metalloprotease (ADAM), 444, 446, 1328–1329 450 Brush cytology, 840, 842–845, 853 Adjuvant , 1051–1072 Adjuvant regional therapy, 1065 C Adjuvant therapy, 276–277, 627–631, 633, 634, 643, 645 CA19–9, 631, 635, 645, 678–679, 681, 682, 690, 844 – non-randomized trials, 1084, 1087–1088 CA242, 679–680 – prospective trials, 1081–1086 Cachexia, 652–654, 668, 823, 827–829, 834 – rationale, 1080–1088 CAM 17.1, 680 Advanced, 913–942 Capecitabine, 1053, 1058 Akrokeratosis paraneoplastica, 657 Carbohydrate, 14 AKT, 390, 393–399 CD24, 319–323, 325–328 Alcohol, 5, 10–11, 14, 15, 17, 18 CD44, 319–323, 325–328 Allergy, 16 CD133, 319, 320, 323, 326–328 Allogeneic vaccine, 1301–1303 cdk inhibitor, 344–345 Alpha cell (A cell), 32 CDKN2A, 568, 570, 582, 584, 591 Ampullary cancer, 233–250 CEACAM1, 681–682 Ampullary tumors, 258–261, 273, 280 Celiac plexus and ganglia neurolysis, 871–878 Anaphase promoting complex (APC), 338, 340, 568, 569, Celiac plexus block, 904, 905, 908 580, 582, 587, 591 Cell cycle, 333–364 Anaplastic, 42, 62 Cell cycle checkpoints, 348, 359 Anatomy, 733–737, 739, 740, 742, 752, 757 Cell differentiation, 81, 91, 92, 96, 98, 102, 103 Aneuploidy, 340, 349, 354, 355 Cell surface markers, 318, 320, 323 Angiogenesis, 442, 446–449 Centroacinar, 74, 93, 96–98, 100, 109 Autoantibodies, 1189, 1192 Centrosomes, 340, 355 Autoimmunoantibody, 527 CHEK, 1329–1330 Autologous vaccine, 1287, 1301 Chemoradiation, 914, 935–938, 940–942 Autologous vein grafting, 1002, 1011 Chemoradiotherapy, 1059, 1061–1063, 1067, 1072 Chemotherapy, 327–329, 913–942, 1051–1072 B Cholangiography, 840 Bayesian analysis, 1182 Cholangitis, 840, 845–849, 853 Bcl–2, 372–374 Chromatin, 144–163 Bcl-xl, 373, 374, 376 Chromosomal gains/losses, 178–180 Beta cell (B cell), 32, 33, 1272, 1278, 1283, 1288, 1292 Chromosomal territory, 152, 153 Bile duct drainage, 861–868 Chronic pancreatitis, 285–307, 743–748, 1179–1183, Biological behavior, 1049 1185, 1187, 1192 Biomarkers, 510–512, 515, 516, 521, 523, 526, 529, 530, Cigarette smoking, 5, 7, 9, 17 1211–1226, 1229, 1230 Cilia, 404, 405, 414, 415 Biopsy, 778, 787, 788 Circulating DNA, 1213–1214, 1223 1386 Index

Circulating tumor cells, 1213 Duodenal gastrinoma, 202, 211, 213–216 Clinical algorithm, 1105 Duodenal lumen stenting, 867–870 Clinical staging, 1096, 1103 Duodenal stenting, 902, 907, 908 c-Myc, 343, 345, 347, 352, 354, 355, 357–361, 363, 364 Duodenal tumors, 263–264, 269, 272 Coactivator, 147–148 Colloid, 49, 50, 53, 55, 64, 65 E Comparative genomic hybridization (CGH), 177, 178, Early detection, 136, 137 184, 185, 191, 460, 463 Embryonic patterning, 72, 73, 75, 80, 83, 86, 93, 95, 96, Computed tomography (CT), 1211, 1212, 1227, 1229 101, 104–106, 108 CONKO–001, 1057, 1058, 1067, 1068, 1071 Embryonic stem cells, 472, 481 Corepressor, 147–148, 160 Endocrine, 29, 31–33, 36, 37, 41–43, 55–60, 62–66 CT diagnosis of pancreatic adenocarcinoma, 707, 725 – syndrome, 660 Cyclin, 343, 344 – tumor, 652, 653, 657, 661, 665–666 Cyclin dependent kinase (cdk), 341, 342, 356 Endoderm, 28, 29, 36, 72, 73, 79–81, 83–88, 91, 106, 108 Cyclophosphamide, 1285, 1292, 1293, 1295, 1302, 1307, Endoluminal ultrasound (EUS), 1211, 1212, 1226–1229 1311 Endoplasmic reticulum stress, 1330–1332 Cystic, 42, 51, 52, 54–56, 58, 61–65 Endoscopic drainage, 898 Cystic lesions of pancreas, 710 Endoscopic retrograde cholangiopancreatography Cytology, 778, 779 (ERCP), 840, 842, 844, 852, 853, 973, 1212, 1226, 1227 Endoscopic ultrasound, 209 D Endosonography, 765 Delamination, 103–106, 109 End-to-end anastomosis, 998–1000, 1002, 1003 Delayed gastric emptying, 980, 983, 986, 988–989 End-to-side anastomosis, 1001 Delta, 443–446, 449 EORTC 40891, 1059 Delta cell (D cell), 33 Epidemiology, 4–5 Dendritic cells, 1271, 1272, 1287, 1297, 1313, 1314 Epidermal growth factor (EGF), 388–389 Depression, 821–823 Epigenetics, 143–165 Dermatomyositis, 655, 658 Epithelial-to-mesenchymal transition (EMT), 75, 102, Desmoplastic, 44, 47, 58, 63–65 105, 461, 463, 465, 467, 1322, 1323, 1332 Development, 27–37, 388, 394, 397–400, 442, 448–452 Erythema nodosum, 655–656 Diabetes, 5, 8–10, 17, 18, 1155, 1164, 1168 ESPAC–1, 1056–1058, 1061, 1068–1071 Diabetes mellitus, 655, 660–668 EUROPAC, 1207, 1209, 1211, 1226–1229 Diagnosis, 259, 262, 265–274, 280, 733, 737, 743–749, EUS vs. MDCT in size evaluation, 711 751, 753, 754, 757 Exocrine, 31–33, 36, 37 – staging, 780–787 Expression profiling, 498, 499, 501, 503–505 Diagnostic markers, 678–684, 688 Extended lymphadenectomy, 972, 983, 991 Dietary fat, 12 Extended surgery, 998 Differential diagnosis, 764, 773, 775–776, 778, 779, 793 Extracellular matrix, 296, 300 Differential in-gel electrophoresis (DIGE), 520–521 Dimerization, 389–394 F Dissection protocol, 1017, 1024–1026 Familial adenomatous polyposis (FAP), 568, 569, 580, Distal bile duct cancer, 235, 236, 245–247, 249, 250 591 Distal common bile duct tumors, 261–263, 265, 270, 273, Familial multiple mole melanoma (FAMMM), 568, 591 280 Familial pancreatic cancer (FPC), 582, 586, 587, 589–590, Distal pancreatectomy, 975, 976, 980–984, 986, 988, 991 1205, 1207, 1226–1229 DNA damage response, 348–354 Fanconi anaemia, 569, 580, 582, 587, 591 DNA methylation, 155–160, 1177, 1180, 1181, Fasting test, 205 1186–1187, 1190 F cell (PP cell), 31, 33, 37 DNA microarrays, 498, 505 Fever, 652, 654–655, 659, 668 DNA replication, 336–339, 341–343, 348, 350, 355 Fibrosis, 288, 290, 291, 294–297, 299, 301, 303, 305 Double duct sign, 840, 841 Fine needle aspirates, 1177, 1181, 1189, 1191 Drug resistance, 458, 460, 464, 467 Fine needle aspiration, 841, 843 Ductal, 40–56, 58–60, 62, 64, 65 Flow cytometry, 319 Ductal development, 96, 100–101 5-Fluorouracil, 1052, 1054 Ducts system, 36 Follistatin, 31 Duodenal cancer, 233–250 Forceps biopsy, 841–843 Index 1387

G Immunotherapy, 1260–1262, 1269–1314 Gastric outlet obstruction, 846, 847, 851, 853, 900–903, Inflammation, 288, 294, 301–305, 307, 412 907–909 Inflammatory cells, 536–540, 544, 547, 556 Gastrinoma, 202, 203, 207, 211–216, 222, 223, 228, 603, Inflammatory mediators, 294, 303 605–609, 618 Insulinoma, 201–211, 225, 228 Gastrinoma triangle, 211–231 Intensity modulated radiotherapy (IMRT), 960–962, Gastroparesis, 823–826, 829, 830, 834 964, 966, 967 Gemcitabine, 458, 461, 463–467, 914–942, 1053, 1054, Inter-tumoral heterogeneity, 458 1057–1059, 1062, 1064, 1065, 1071, 1072 Intestinal-type, 235, 236, 238–240, 243–245, 249 Gene-environment interaction, 12 Intraductal, 42, 49, 50, 52, 58, 64 Gene expression, 291–293, 296, 303, 304, 306 Intraductal papillary mucinous papillary neoplasm Gene expression profiling, 459, 463, 464, 466, 467 (IPMN), 121, 131–134, 137, 680, 681, 685–687, 1126, Gene therapy, 1237–1263, 1331, 1332 1128, 1130–1137, 1177–1179, 1182, 1187, 1188, 1191 Genetic instability, 172, 177–185 Intraepithelial, 50–51, 64 Genome, 1184–1189, 1192 Islet development, 83, 93, 105 Genome-wide allelotyping, 177 Isobaric tags for relative and absolute quantification GITSG 9173, 1062 (iTRAQ), 518, 521, 523–524, 529 Gli, 404, 405, 407, 409–411 Isotope-coded affinity tag (ICAT), 521–524, 529 Glucagonoma, 203, 207, 217–218, 228 Glycemic index, 14 J Glycogen synthase kinase 3 (GS3K), 396 Jagged, 443, 445, 447 Growth factors, 172, 175, 185–188 Japan Pancreas Society (JPS) staging, 1036–1038, 1042 Growth patterns, 1047, 1049 Johns Hopkins, 1225–1227 Guidelines, 1154–1160, 1165 K H K-Ras, 353, 356–363, 370, 374–376, 380, 567–571, 578, Heavy ion therapy, 683, 844, 1177, 1180, 1184, 1185 Hedgehog, 76, 79, 87, 88, 108, 324–326, 378–380, 403–416, 1324–1326 L Helicobacter pylori, 14, 15 Laparoscopic cholecystojejunostomy, 896 Hepatitis B, 14, 15 Laparoscopic pancreatic left resection, 1142, 1143 Hepatobiliary-type, 239, 245 Laparoscopic pancreatic surgery, 1144, 1148, 1149 Hepatocyte growth factor (HGF), 1326–1328, 1332 Laparoscopic ultrasound, 801–809 Hereditary pancreatitis (HP), 572, 584–586, 588, 589, Laparoscopy, 801–809 592 LigAmp, 1216 Hereditary syndrome, 5–7 Ligand, 388–391, 397, 399, 442–447, 449, 450 Hes, 446, 448–449 Liver metastases of PET, 220, 222, 224, 225 Heterochromatin protein 1 (HP1), 148, 150, 157, Locally advanced disease, 628, 636, 637, 639, 644 159–160, 162 Locally injected anti-tumor therapies, 878–882 Histogenesis, 28 Loss of heterozygosity (LOH), 173, 175–177, 182, Histone chaperones, 149, 151–152 184–186 Histone code, 149–151, 154, 159 Loyer criteria vascular involvement, 712, 714 Histone deacetylase (HDAC), 147, 148, 157, 158, 162 Lu criteria vascular involvement, 713–715 HNPCC, breast ovarian syndrome, 569 Lymphatic invasion, 1049 Hypermethylation, 684 Lymph node, 1037–1039, 1046 Lymph node ratio, 1027 I Image-guided radiotherapy (IGRT), 963 M Imaging, 1204, 1211–1213, 1221, 1225–1230 Macrophage inhibitory cytokine 1 (MIC–1), 678, 681, Imaging technology, 959 688 Imapct of FDG-PET in management, 724 Magnetic resonance cholangiopancreatography (MRCP), Immune checkpoint, 1273, 1276–1279, 1281, 1282, 1285, 738–742, 744–746, 748, 749, 757 1290, 1294, 1295, 1309–1310, 1313 Malignant vs. benign cystic pancreatic lesions, 710 Immune tolerance, 1273–1283, 1297, 1299, 1300, 1303, Meat, 12, 18 1308, 1309, 1313 Medullary, 50 Immunoediting, 1273 Mesenchyme, 29, 31, 48, 62–63 1388 Index

Meta-analysis, 1052, 1053, 1062, 1067–1070 NGN3, 30, 36, 81, 87, 92, 95, 96, 98, 100–106, 108 Metastasis, 321, 326, 329, 404, 408, 413, 896, 901, 907, NOD/SCID mice, 318–320, 322 909 Non-functioning PET, 202, 203, 220, 222, 223 Metastatic disease, 627, 628, 630–634, 637–639, Non-pancreatic periampullary tumors, 272, 276, 277, 641, 644 280 Methylation, 1215, 1216, 1219–1226, 1230 Notch, 76, 79, 80, 91–93, 96, 97, 99, 100, 102, 103, 108, Methylation specific PCR, 1186 378, 379, 441–452 Methyltransferase, 148, 158, 161 Notch intracellular domain (NICD), 443, 444, 446, 447 MGMT, 574 Notochord, 28, 30 Microarrays, 172, 186, 188–191 NSAID, 16, 17 Microenvironment, 287, 288, 291–293, 298, 299, N staging with CT and PET-CT, 715, 716 301–304, 306, 307, 536–538, 541, 542, 544, 547–550, Nuclear factor kappa B (NFκB), 373, 374, 376–379, 555, 556, 1273, 1278, 1279, 1281–1283, 1293–1295, 1320–1322 1313 Nuclear shape, 144, 152–161, 163 MicroRNA (miRNA), 144, 154, 156, 160–161, 163, 678, Nucleosome remodeling machines, 150–151 686–687, 692, 1177, 1188–1189, 1192 Nucleus, 152, 153, 161 Minimal invasive pancreatic surgery, 1145, 1149 Mismatch Repair, 569, 580, 582, 591 O Mitochondrial DNA markers, 686 Obesity, 8–9, 17 Mitogen-activated protein kinase (MAPK), 390, 394 Obstructive jaundice, 896, 897, 903, 907–909 Mitosis, 335–340, 343, 344, 346–349, 355 Occupation, 9, 15–17 Molecular diagnosis, 501, 505 Oncogenes, 172, 177, 178, 185–188, 191 Molecular imaging, 1191 Oncological pancreatic resection, 1142 Molecular pathology, 233–250 Oncolytic virus, 1241, 1247, 1256, 1258, 1262 Molecular progression of pancreatic cancer, Osteopontin, 681, 682, 688 Molecular signaling, 29 Monoclonal antibody, 1279, 1283, 1294, 1296 P Monoclonal antibody therapy, 397, 398 p16, 344, 348, 352, 354, 356, 359, 364, 568, 570, 582, 584, Morbidity and mortality, 998, 1002–1004, 1008 591, 844 Morphogenesis, 36, 441–452 p53, 345, 348, 350, 353–355, 357, 359–361, 364, 568, 591, MRI, 733–737, 741–746, 748, 749, 751–753, 755–757 592, 683–685, 844 M staging with CT and PET-CT, 716, 718–719 Pain mTOR, 394, 396, 398, 399 – intractable, 820, 834 MUC1, 680–681 – management, 904, 905 Mucinous, 42, 43, 49, 50, 52, 54, 55, 58, 64, 65 Palladin, 568, 578, 580, 582, 586, 590 – cystic lesions, 1126, 1129, 1136 Palliation, 845–853 – cystic neoplasm, 121, 134–135, 137 Palliative, 914, 927, 940, 941 Multidetector computed tomography, 973 – bypass, 906, 907 Multidisciplinary management, 627, 640, 644 – care, 816, 819, 821 Multiple endocrine neoplasia type–1 (MEN–1), 172–175, – drainage, 898 603–613, 618, 619 – pancreatoduodenectomy, 906 Mutant K-Ras, 294, 295, 301 Pancreas, 27–37, 1096, 1099, 1102 Mutation, 1177, 1180, 1181, 1184–1186 – adenocarcinoma, 1111, 1112, 1115, 1117, 1119, Myasthenia gravis, 657, 658 1120 – surgery, 1096, 1103 N Pancreas-specific promoters, 491 National Pancreatic Cancer Registry in Japan, 1036, Pancreatic cancer, 4–18, 119–138, 317–329, 387–400, 1039–1048 441–452, 651–668, 676–692, 731–757, 763–794, Necrolytic migratory erythema, 655, 656, 666 802–804, 807, 808, 895–909, 997–1011, 1015–1032, Neoadjuvant therapy, 271, 276–277, 632, 634, 635, 1093–1106, 1154–1168, 1176–1192 1065–1067, 1116 Pancreatic cancer registry, 1155, 1167 Neoadjuvant treatment, 1093–1106 Pancreatic cystic lesions, 1126, 1137 Nerve plexus, 1037, 1038, 1047, 1048, 1050 Pancreatic ductal adenocarcinoma, 1055, 1067 Neurofibromatosis, 615–618 Pancreatic endocrine tumors (PETs), 172–191 Neurofibromatosis type–1 (NF1), 172, 173, 176, 188 Pancreatic fistula, 986–988 Neuromuscular paraneoplastic syndrome, 658 Pancreatic gastrinoma, 211, 213, 215–216 Index 1389

Pancreatic intraepithelial neoplasia (PanIN), 119–138, Protein microarray, 528 408–415, 1178–1180, 1182, 1187, 1191 Proteomics, 509–530, 1179, 1190–1192 Pancreatic juice, 510, 512, 520, 521, 523, 525–527, 529, Protodifferentiated state, 82, 88, 89, 91–93 1177, 1180–1182, 1185, 1186, 1190, 1191, 1212, 1214, Proton therapy, 964–966 1217–1229 Pseudomyasthenia, 657, 658 Pancreatic neoplasm, Pseudotumor, 63 Pancreaticoduodenal neuroendocrine tumors (PET), Ptf1a, 82, 86, 88, 92–94, 96, 97, 99–101, 105, 448, 449 603–607, 611–618 Pancreaticoduodenectomy, 1094 Q Pancreaticogastrostomy, 979, 980 Quality of life, 816–818, 821, 823, 828, 829, 832 Pancreaticojejunostomy, 979 Pancreatic surgery, 1144, 1148, 1149 R Pancreatic tissue, 510, 512, 521, 523 Rac, 393, 397 Pancreatitis, 5–7, 10, 11, 14, 17, 18, 412–415, 429–430, Radiographic staging, 1095, 1103 772, 773, 775–780, 789, 791 Randomised controlled trial, 1053–1064, 1071 Pancreatoblastoma, 42, 58–60 Ras, 390, 392–399 Pancreatoduodenectomy, 906, 998, 1002, 1007, 1008, R-classification, 1028 1011 Real time PCR, 1215 PanIN lesions, 290, 291 Receptor, 388–395, 397–400, 443–447, 450, 451 Papillary, 42, 49, 51–54, 58, 61, 64 Recurrent disease diagnosis, CT and PET-CT, 720 Papillary mucinous neoplasm, 1164–1165, 1168 Regulatory T cells, 1273, 1276, 1279–1280, 1293, 1313 Paraneoplastic syndrome, 651–668 Resectability, 1110–1112, 1114, 1115, 1117, 1118, 1122 Partial pancreatoduodenectomy, 976–981, 983 Resectable disease, 628–635, 638, 644, 645 Particle beam therapy, 964–966 Resected specimen, 1046 Pathological reporting, 1015–1032 Resection, 257, 261, 262, 264, 265, 268, 269, 271–280 Pathology, 257–265, 274 Resection margins, 1016, 1017, 1019–1022, 1024–1027, Pax6, 30, 31 1031, 1097 Pdx1, 73, 79, 82, 85–88, 91–98, 100–103, 105, 108 Restriction fragment length polymorphism (RFLP), Periampullary cancer, 235–249 1214, 1217, 1219 Perineural invasion, 1038, 1049 Retinoic acid, 80, 86, 88, 108 Peritoneal spread, 716–717 Rho, 393, 397 PET-CT diagnosis of pancreatic adenocarcinoma, RNA polymerase, 145–147, 164 707–710 Role of laparoscopy, 631, 637–639 Phosphorylation, 389, 390, 394–397 RTOG 9704, 1064, 1071 PI3K/AKT/mTOR, 188, 189 PI3 kinase, 390, 395 S Polycomb, 148, 150, 151, 157–160, 162, 163 Screening, 604–606, 612, 613, 615, 616, 618, 619, 773, Polyneuropathy, 657, 658 780, 793, 1176, 1181–1183, 1192 Portal vein resection, 998, 1003, 1005, 1007, 1008, 1011 Secondary developmental transition, 83, 90, 94 Positron emission tomography (PET), 1212, 1225, 1230 γ–Secretase, 443, 444, 446, 450–452 Postoperative survival, 1003, 1008 Secretin test, 212, 216 Post processing in CT, 714 Serous, 42, 54–56 ppENK, 1220, 1221, 1224, 1225 Serous cystadenomas, 1126–1128, 1136 Practice points, 1105 Serrate, 444–446 Precursor lesions, 119–138 Serum, 510, 512, 515–520, 523, 525–529 Preinvasive, 50–55, 65 SH2 domain, 393, 395 Pre-operative chemotherapy, Signaling, 387–400, 442, 443, 445–452 Pre-operative radiation, 1096–1098 Signet ring, 42, 50 Preoperative therapy, 1115, 1117–1122 Single nucleotide polymorphisms (SNPs), 177, 178 Primary developmental transition, 83, 88–90, 108 Single-strand conformational polymorphism analysis Primary hyperparathyroidism, 603, 606 (SSCP), 1214, 1219 Primary xenografts, 467 Site-specific recombinase enzymes, 482, 491 Prognosis, 1016, 1017, 1027 Size of pancreatic tumors, 710–711, 719 Prognostic significance, FDG PET, 719 Smad4, 419–433 Progression model, pancreatic cancer, 143–165 Solid pseudopapillary, 42, 61, 65 Promoter, 145–152, 154, 156, 158–162 Somatostatinoma, 203, 219–220, 228 1390 Index

Somatostatin receptor scintigraphy (SRS), 206, 207, 213, Tuberous sclerosis complex (TSC), 172, 173, 176, 188, 220, 221, 223 189 Sonic hedgehog, 28–30 Tumor antigen, 1271–1273, 1276, 1277, 1281, 1283, 1286, Specificity protein 1, 1322–1323 1287, 1289, 1290, 1300, 1301, 1308, 1309 Stable isotope labeling with amino acids in cell culture Tumor development, 297, 300 (SILAC), 521, 524–525, 529 Tumorigenesis, 301, 302, 304 Staging, 749–757 Tumor markers, 840, 842, 844–845 – biopsy, 801–809 Tumor necrosis factor-related apoptosis-inducing ligand – grading, 1018, 1019, 1021, 1026, 1031 (Trail), 376, 377 Stellate cells, 287, 295–297, 300, 305, 307, 378, 536, 537, Tumorsphere, 321, 323 539–547, 550, 551, 553, 556–559 Tumor-stromal interactions, 370, 378, 380, 381, 459, 460, Stem cells, 317–329 463, 466, 467 Stent Tumor suppressor genes (TSGs), 172, 177, 178, 182, – biliary, 845–848, 851–853 185–188, 190, 191 – duodenal, 851 Tumor vessel, 841 – polyethylene stents metallic, 846, 849–851 Two dimensional gel electrophoresis, 518–520, 529 – self-expandable metallic, 849 Tyrosine kinase, 390, 397, 400 Stereotactic body radiotherapy, 958, 961–964 Tyrosine kinase receptors, 172, 187–188, 191 STK11, 568, 582, 587, 591 Strengths and pitfalls, FDG-PET, 721–722 U Stricture, 840–847, 849, 853, 854 UICC staging, 1036–1040, 1042 Stroma, 287–294, 297, 298, 301, 304–307, 406–408, 411, Ultrastructure, 34 414, 415, 535–559, 1049, 1179, 1180, 1188 Undifferentiated, 42, 48 Superior mesenteric vein resection, 1002 Unresectable periampullary cancer, 902 Surface enhanced laser desorption ionization (SELDI), 524–527 V Surgical biliary bypass, 898, 902, 903, 907, 908 Vaccine, 1269–1314 Survival, 261, 266, 273, 276–280, 1019 Vascular boost, 961 Vascular endothelial growth factor (VEGF), 446–448, 452 T Vascular involvement, 705, 707, 710–716, 725 Targeted therapy, 1320, 1332 Vascular resection, 972, 984–985 T cell, 1271–1282, 1284–1290, 1292–1295, 1297–1304, Vector, 1239, 1242–1245, 1248, 1249, 1252–1256, 1308–1314 1260–1263 Telomerase, 687–688, 1225–1226 Vegetable intake, 13 Therapeutic response markers, 689–690 Venous invasion, 1049 Therapeutics, 328, 329 Venous reconstruction, 999, 1011 Thompson procedure, 612 Vipoma, 203, 216–218, 228 Thoracoscopic splanchnicectomy, 904, 905 Von-Hippel-Lindau (VHL) disease, 172, 175–176, 182, Tissue polypeptide specific antigen (TPS), 682 186, 191, 613–615 TNM, 1036, 1042 – classification, 1016, 1019, 1024, 1029, 1031 W – staging, 705–706, 725 Whipple, Total pancreatectomy, 982–983, 991 WHO classification, 1021, 1030 Tp53, 566, 568, 570, 582 Wnt, 76, 79, 83, 84, 91, 92, 97, 104, 108, 378, 379 Transcription, 144–153, 157, 159, 162, 164, 388, 392, 394, 396, 443, 444, 446, 448, 449, 452 X Transcription factor, 76–79, 81–85, 88, 91–93, 95, 99, Xenografts, 320, 327, 328, 458, 459, 464, 466, 467 100, 102, 108 Xiap, 373, 374, 376 Transdifferentiation, 449, 450 Transforming growth factor beta (TGF-β), 76, 419–433, Z 446, 447, 1323–1324, 1326 Zollinger-Ellison syndrome (ZES), 201, 211–214, 216, Transgenic mice, 294, 299, 304, 458, 459, 466 603, 606 Translational research, 128, 129 Zymogen, 31–36 T staging, CT and PET-CT, 711–712, 715