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INTRODUCTION: Neoadjuvant therapy may improve survival compared with upfront surgery in patients with resectable and borderline resectable pancreatic cancer, but high-quality evidence is lacking.METHODS: We systematically searched for randomised trials comparing neoadjuvant therapy with upfront surgery for resectable and borderline resectable pancreatic cancer published since database inception until December 2020. The primary outcome was overall survival (OS) by intention-to-treat with subgroup analyses for resectability status. Meta-analyses using a random-effects model were performed. Certainty of evidence was assessed using the GRADE approach.RESULTS: Seven trials with 938 patients were included. All trials included a neoadjuvant gemcitabine-based chemo(radio)therapy arm. None of the studies used adjuvant FOLFIRINOX. Neoadjuvant therapy improved OS (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.52-0.85; P = 0.001; I 2 = 46%) compared with upfront surgery. This represents an increase in median OS from 19 to 29 months. In the subgroup of resectable pancreatic cancer (i.e., venous contact ≤180°, no arterial contact), no statistically significant difference in OS was observed (HR 0.77, 95% CI 0.53-1.12; P = 0.18; I 2 = 20%). In the subgroup of borderline resectable pancreatic cancer (i.e. venous contact >180°, any arterial contact), neoadjuvant therapy improved OS (HR 0.61, 95% CI 0.44-0.85; P = 0.004; I 2 = 59%). The GRADE certainty of evidence was high for the outcome of OS. CONCLUSIONS: Neoadjuvant therapy improves OS compared with upfront surgery in patients with borderline resectable pancreatic cancer. More evidence is required on whether neoadjuvant therapy improves survival for patients with resectable pancreatic cancer.

Background The added value of radiotherapy following neoadjuvant FOLFIRINOX chemotherapy in patients with resectable or borderline resectable pancreatic cancer ((B)RPC) is unclear. The objective of this meta-analysis was to compare outcomes of patients who received neoadjuvant FOLFIRINOX alone or combined with radiotherapy. Methods A systematic literature search was performed in Embase, Medline (ovidSP), Web of Science, Scopus, Cochrane, and Google Scholar. The primary endpoint was pooled median overall survival (OS). Secondary endpoints included resection rate, R0 resection rate, and other pathologic outcomes. Results We included 512 patients with (B)RPC from 15 studies, of which 7 were prospective nonrandomized studies. In total, 351 patients (68.6%) were treated with FOLFIRINOX alone (8 studies) and 161 patients (31.4%) were treated with FOLFIRINOX and radiotherapy (7 studies). The pooled estimated median OS was 21.6 months (range 18.4–34.0 months) for FOLFIRINOX alone and 22.4 months (range 11.0–37.7 months) for FOLFIRINOX with radiotherapy. The pooled resection rate was similar (71.9% vs. 63.1%, p = 0.43) and the pooled R0 resection rate was higher for FOLFIRINOX with radiotherapy (88.0% vs. 97.6%, p = 0.045). Other pathological outcomes (ypN0, pathologic complete response, perineural invasion) were comparable. Conclusions In this meta-analysis, radiotherapy following neoadjuvant FOLFIRINOX was associated with an improved R0 resection rate as compared with neoadjuvant FOLFIRINOX alone, but a difference in survival could not be demonstrated. Randomized trials are needed to determine the added value of radiotherapy following neoadjuvant FOLFIRINOX in patients with (B)PRC.

Background: Microvascular invasion (MVI) is an established prognosticator in hepatocellular carcinoma (HCC). Histopathological growth patterns (HGPs) classify the invasive margin of hepatic tumors, with superior survival observed for the desmoplastic HGP. Our aim was to investigate non-cirrhotic HCC in light of MVI and the HGP. Methods: A retrospective cohort study was performed in resected non-cirrhotic HCC. MVI was assessed prospectively. The HGP was determined retrospectively, blinded, and according to guidelines. Overall and disease-free survival (OS, DFS) were evaluated by Kaplan–Meier and multivariable Cox regression. Results: The HGP was determined in 155 eligible patients, 55 (35%) featured a desmoplastic HGP. MVI was observed in 92 (59%) and was uncorrelated with HGP (64% vs 57%, p = 0.42). On multivariable analysis, non-desmoplastic and MVI-positive were associated with an adjusted HR [95%CI] of 1.61 [0.98–2.65] and 3.22 [1.89–5.51] for OS, and 1.59 [1.05–2.41] and 2.30 [1.52–3.50] for DFS. Effect modification for OS existed between HGP and MVI (p < 0.01). Non-desmoplastic MVI-positive patients had a 5-year OS of 36% (HR: 5.21 [2.68–10.12]), compared to 60% for desmoplastic regardless of MVI (HR: 2.12 [1.08–4.18]), and 86% in non-desmoplastic MVI-negative. Conclusion: HCCs in non-cirrhotic livers display HGPs which may be of prognostic importance, especially when combined with MVI.

Background The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling. Methods Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib). Results Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37–6.97) and 9.79 months (95% CI: 7.85–10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment. Conclusions Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population. Trial registration ClinicalTrials.gov Identifier: NCT01088815.

Background: Data on surgical outcomes of laparoscopic liver resection (LLR) versus open liver resection (OLR) of benign liver tumour (BLT) are scarce. This study aimed to provide a nationwide overview of postoperative outcomes after LLR and OLR of BLT. Methods: This was a nationwide retrospective study including all patients who underwent liver resection for hepatocellular adenoma, haemangioma and focal nodular hyperplasia in the Netherlands from 2014 to 2019. Propensity score matching (PSM) was applied to compare 30-day overall and major morbidity and 30-day mortality after OLR and LLR. Results: In total, 415 patients underwent BLT resection of whom 230 (55.4%) underwent LLR. PSM for OLR and LLR resulted in 250 matched patients. Median (IQR) length of stay was shorter after LLR than OLR (4 versus 6 days, 5.0–8.0, p < 0.001). Postoperative 30-day overall morbidity was lower after LLR than OLR (12.0% vs. 22.4%, p = 0.043). LLR was associated with reduced 30-day overall morbidity in multivariable analysis (aOR:0.46, CI:0.22–0.95, p = 0.043). Both 30-day major morbidity and 30-day mortality were not different. Conclusions: LLR for BLT is associated with shorter hospital stay and reduced overall morbidity and is preferred if technically feasible.

Background: Preoperative chemo- or chemoradiotherapy is recommended for borderline-resectable pancreatic cancer. The aim of this study was to determine the impact of preoperative therapy on surgical complications in patients with resected pancreatic cancer. Methods: This systematic review and meta-analysis included studies reporting on the rate of surgical complications after preoperative chemo- or chemoradiotherapy versus immediate surgery in pancreatic cancer patients. The primary endpoint was the rate of grade B/C POPF. Pooled odds ratios were calculated using random-effects models. Results: Forty-one comparative studies including 25,389 patients were included. Vascular resections were more often performed after preoperative therapy (29.4% vs. 15.7%, p < 0.001). Preoperative therapy was associated with a lower rate of grade B/C POPF as compared to immediate surgery (pooled OR 0.47, 95%CI 0.38–0.58). This reduction was mostly obtained by preoperative chemoradiotherapy (OR 0.46, 95%CI 0.29–0.73), but not by preoperative chemotherapy alone (OR 0.83, 95%CI 0.59–1.16). No difference was demonstrated for major morbidity, mortality, postpancreatectomy haemorrhage, delayed gastric emptying and overall morbidity. Conclusion: Preoperative chemo- and chemoradiotherapy in patients with pancreatic cancer appears to be safe with respect to POPF and other surgical complications as compared to immediate surgery. The reduced rate of POPF appears to be attributable to preoperative chemoradiation.

The impact of donor body mass index (BMI) on graft function outcomes in liver transplantation (LT) is still controversial. The aim of this study was to review the current evidence investigating the effect of donor BMI on outcomes in patients undergoing LT. A systematic review was performed to evaluate relevant outcomes such as the availability of data on donor BMI as well as graft and patient survival after LT. Screening of 901 articles resulted in 11 observational studies for data extraction. In adult deceased donor after brain death and living donor LT, donor BMI was not associatedwith graft and patient survival. However, high donor BMIwas associated with a higher chance of macrosteatosis besides a significantly higher incidence of declined livers. In pediatric LT, severe obesity in adult donors with BMI >= 35 was associated with graft loss and mortality, whereas obesity in pediatric donors was not associated with graft loss and mortality. Accordingly, donor BMI is not associated with long-term outcomes in adult patients undergoing LT. However, further research should be conducted to identify the effect of donor BMI on outcomes in LT. (C) 2020 The Author(s). Published by Elsevier Inc.

OBJECTIVE: The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. BACKGROUND: Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. METHODS: A total of 87 small primary PanNETs (

Curative-intent resection is the only treatment of perihilar cholangiocarcinoma (pCCA) offering patients the chance for long-term survival. Surgery generally requires an (extended) hemi-hepatectomy including the caudate lobe with resection of the extrahepatic bile duct and a regional lymph node dissection. pCCA is considered resectable when negative surgical margins can be obtained while safeguarding adequate vascular inflow to the future liver remnant.

Simple Summary For patients with early-stage hepatocellular carcinoma, it is important to know whether liver transplantation offers a survival benefit over liver resection. Patients receiving transplantation often have different characteristics in terms of their cancer stage and liver function compared to those being resected. This makes a comparison of the two treatment modalities challenging. This article presents a comprehensive review of research articles comparing these two treatments and discusses their strengths and weaknesses. Furthermore, we suggest a new research design that uses a treatment guideline to help ensure that the groups are more comparable. Hereby, we enable future studies to assess whether liver transplantation offers a survival benefit over liver resection in patients that are eligible for both treatments. Abstract For patients presenting with hepatocellular carcinoma within the Milan criteria, either liver resection or liver transplantation can be performed. However, to what extent either of these treatment options is superior in terms of long-term survival is unknown. Obviously, the comparison of these treatments is complicated by several selection processes. In this article, we comprehensively review the current literature with a focus on factors accounting for selection bias. Thus far, studies that did not perform an intention-to-treat analysis conclude that liver transplantation is superior to liver resection for early-stage hepatocellular carcinoma. In contrast, studies performing an intention-to-treat analysis state that survival is comparable between both modalities. Furthermore, all studies demonstrate that disease-free survival is longer after liver transplantation compared to liver resection. With respect to the latter, implications of recurrences for survival are rarely discussed. Heterogeneous treatment effects and logical inconsistencies indicate that studies with a higher level of evidence are needed to determine if liver transplantation offers a survival benefit over liver resection. However, randomised controlled trials, as the golden standard, are believed to be infeasible. Therefore, we suggest an alternative research design from the causal inference literature. The rationale for a regression discontinuity design that exploits the natural experiment created by the widely adopted Milan criteria will be discussed. In this type of study, the analysis is focused on liver transplantation patients just within the Milan criteria and liver resection patients just outside, hereby ensuring equal distribution of confounders.

The “Warburg effect” describes a peculiar metabolic feature of many solid tumors, namely their increased glucose uptake and high glycolytic rates, which allow cancer cells to accumulate building blocks for the biosynthesis of macromolecules. During aerobic glycolysis, pyruvate is preferentially metabolized to lactate by the enzyme lactate dehydrogenase-A (LDH-A), suggesting a possible vulnerability at this target for small-molecule inhibition in cancer cells. In this study, we used FX11, a small-molecule inhibitor of LDH-A, to investigate this possible vulnerability in a panel of 15 patient-derived mouse xenograft (PDX) models of pancreatic cancer. Unexpectedly, the p53 status of the PDX tumor determined the response to FX11. Tumors harboring wild-type (WT) TP53 were resistant to FX11. In contrast, tumors harboring mutant TP53 exhibited increased apoptosis, reduced proliferation indices, and attenuated tumor growth when exposed to FX11. [18F]-FDG PET-CT scans revealed a relative increase in glucose uptake in mutant TP53 versus WT TP53 tumors, with FX11 administration downregulating metabolic activity only in mutant TP53 tumors. Through a noninvasive quantitative assessment of lactate production, as determined by 13C magnetic resonance spectroscopy (MRS) of hyperpolarized pyruvate, we confirmed that FX11 administration inhibited pyruvate-to-lactate conversion only in mutant TP53 tumors, a feature associated with reduced expression of the TP53 target gene TIGAR, which is known to regulate glycolysis. Taken together, our findings highlight p53 status in pancreatic cancer as a biomarker to predict sensitivity to LDH-A inhibition, with regard to both real-time noninvasive imaging by 13C MRS as well as therapeutic response. Cancer Res; 75(16); 3355–64. ©2015 AACR.

Purpose: The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently Experimental Design: We sequenced the exomes of eight PDACs from patients who survived ≥10 years. On the basis of the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs. Results: KRAS mutations were identified in 33 of 35 cancers (94%) from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in four of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared with available data from PDACs unselected for survival. Comparison of clinicopathologic features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade, or nodal disease did not preclude long-term survival. Conclusions: Our results suggest that in most patients, somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC. Clin Cancer Res; 21(8); 1944–50. ©2015 AACR.

Recent studies suggest that the telomere maintenance mechanism known as Alternative Lengthening of Telomeres (ALT) is relatively more common in specific glioma subsets and strongly associated with ATRX mutations. We retrospectively examined 116 high grade astrocytomas (32 pediatric glioblastomas, 65 adult glioblastomas,19 anaplastic astrocytomas) with known ALT status using tissue microarrays to identify associations with molecular and phenotypic features. Immunohistochemistry was performed using antibodies against ATRX, DAXX, p53 and IDH1 R132H mutant protein. EGFR amplification was evaluated by FISH. When focusing on histologic subtypes, almost half of fibrillary and gemistocytic astrocytomas (44%) demonstrated ALT. Conversely all gliosarcomas (n=4), epithelioid (n=2), giant cell (n=2) and adult small cell astrocytomas (n=7) were ALT negative. The ALT phenotype was positively correlated with the presence of round cells (p=0.002), microcysts (p

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, with most patients facing an adverse clinical outcome. Aberrant Notch pathway activation has been implicated in the initiation and progression of PDAC, specifically the aggressive phenotype of the disease. We used a panel of human PDAC cell lines as well as patient-derived PDAC xenografts to determine whether pharmacologic targeting of Notch pathway could inhibit PDAC growth and potentiate gemcitabine sensitivity. MRK-003, a potent and selective γ-secretase inhibitor, treatment resulted in the downregulation of nuclear Notch1 intracellular domain, inhibition of anchorage-independent growth, and reduction of tumor-initiating cells capable of extensive self-renewal. Pretreatment of PDAC cells with MRK-003 in cell culture significantly inhibited the subsequent engraftment in immunocompromised mice. MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) PDAC xenografts. A combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared with gemcitabine in 4 of 9 (44%) PDAC xenografts, reduced tumor cell proliferation, and induced both apoptosis and intratumoral necrosis. Gene expression analysis of untreated tumors indicated that upregulation of NF-κB pathway components was predictive of sensitivity to MRK-003, whereas upregulation in B-cell receptor signaling and nuclear factor erythroid-derived 2-like 2 pathway correlated with response to the combination of MRK-003 with gemcitabine. Our findings strengthen the rationale for small-molecule inhibition of Notch signaling as a therapeutic strategy in PDAC. Mol Cancer Ther; 11(9); 1999–2009. ©2012 AACR.

Multiple lines of evidence support a role for curcumin in cancer chemoprevention. Nonetheless, despite its reported efficacy and safety profile, clinical translation of curcumin has been hampered by low oral bioavailability, requiring infeasible ‘mega’ doses for achieving detectable tissue levels. We have engineered a polymeric nanoparticle encapsulated formulation of curcumin (NanoCurc) to harness its full therapeutic potential. In the current study, we assessed the chemoprevention efficacy of NanoCurc administered via direct intraductal (i.duc) injection in a chemical carcinogen-induced rodent mammary cancer model. Specifically, Sprague–Dawley rats exposed to systemic N-methyl-N-nitrosourea were randomized to receive either oral free curcumin at a previously reported ‘mega’ dose (200mg/kg) or by direct i.duc injection of free curcumin or NanoCurc, respectively, each delivering 168 µg equivalent of curcumin per rodent teat (a ~20-fold lower dose per animal compared to oral administration). All three chemoprevention modalities resulted in significantly lower mammary tumor incidence compared with control rats; however, there was no significant difference in cancer incidence between the oral dosing and either i.duc arms. On the other hand, mean tumor size, was significantly smaller in the i.duc NanoCurc cohort compared with i.duc free curcumin (P < 0.0001), suggesting the possibility of better resectability for ‘breakthrough’ cancers. Reduction in cancer incidence was associated with significant decrease in nuclear factor -κB activation in the NanoCurc treated mammary epithelium explants, compared to either control or oral curcumin-administered rats. Our studies confirm the potential for i.duc NanoCurc as an alternative to the oral route for breast cancer chemoprevention in high-risk cohorts.

A better molecular characterization of intraductal papillary mucinous neoplasm (IPMN), the most frequent cystic precursor lesion of pancreatic adenocarcinoma, may have a pivotal role in its early detection and in the development of effective therapeutic strategies. BRG1, a central component of the chromatin remodeling complex SWI/SNF regulating transcription, is inactive in several malignancies. In this study, we evaluate the Brg1 expression in intraductal papillary mucinous neoplasm to better understand its role in the pancreatic carcinogenesis. Tissue microarrays of 66 surgically resected IPMNs were immunolabeled for the Brg1 protein. Expression patterns were then correlated with clinicopathologic parameters. Normal pancreatic epithelium strongly immunolabeled for Brg1. Reduced Brg1 expression was observed in 32 (53.3%) of the 60 evaluable IPMN lesions and occurred more frequently in high-grade IPMNs (13 of 17 showed loss; 76%) compared to intermediate-grade (15 of 29 showed loss; 52%) and low-grade IPMNs (4 of 14 showed loss; 28%) (P = .03). A complete loss of Brg1 expression was observed in 5 (8.3%) of the 60 lesions. Finally, a decrease in Brg1 protein expression was furthermore found in a low-passage noninvasive IPMN cell line by Western blot analysis. We did not observe correlation between Brg1 expression and IPMN subtype or with location of the cyst. We provide first evidence that Brg1 expression is lost in noninvasive cystic precursor lesions of pancreatic adenocarcinoma.

Background The impact of nationwide centralization of pancreaticoduodenectomy (PD) on mortality is largely unknown. The aim of this study was to analyse changes in hospital volumes and in-hospital mortality after PD in the Netherlands between 2004 and 2009. Methods Nationwide data on International Classification of Diseases, ninth revision (ICD-9) code 5-526 (PD, including Whipple), patient age, sex and mortality were retrieved from the independent nationwide KiwaPrismant registry. Based on established cut-off points of annually performed PDs, hospitals were categorized as very low (fewer than 5), low (5–10), medium (11–19) or high (at least 20) volume. A subgroup analysis based on a cut-off age of 70 years was also performed. Results Some 2155 PDs were included. The number of hospitals performing PD decreased from 48 in 2004 to 30 in 2009 (P = 0·011). In these specific years, the proportion of patients undergoing PD in a medium- or high-volume centre increased from 52·9 to 91·2 per cent (P < 0·001). Nationwide mortality rates after PD decreased from 9·8 to 5·1 per cent (P = 0·044). The mortality rate during the 6-year period was 14·7, 9·8, 6·3 and 3·3 per cent in very low-, low-, medium- and high-volume hospitals respectively (P < 0·001). The difference in mortality between medium- and high-volume centres was statistically significant (P = 0·004). The volume–outcome relationship was not influenced by age (P = 0·467). The mortality rate after PD in patients aged at least 70 years was 10·4 per cent compared with 4·4 per cent in younger patients (P < 0·001). Conclusion With nationwide centralization of PD, the in-hospital mortality rate after this procedure decreased. Further centralization of PD is likely to decrease mortality further, especially in the elderly.

Well-differentiated pancreatic neuroendocrine tumors (PanNETs) comprise ~1–3% of pancreatic neoplasms. Although long considered as reasonably benign lesions, PanNETs have considerable malignant potential, with a 5-year survival of ~65% and a 10-year survival of 45% for resected lesions. As PanNETs have a low incidence, they have been understudied, with few advances made until the completion of their exomic sequencing in the past year. In this Review, we summarize some of the latest insights into the genetics of PanNETs, and their probable implications in the context of prognosis and therapy. In particular, we discuss two genes (DAXX and ATRX) that have collectively been identified as mutated in >40% of PanNETs, and the biological and prognostic implications of these novel mutations. The identification of recurrent somatic mutations within the mTOR signaling pathway and the therapeutic implications for personalized therapy in patients with PanNETs are also discussed. Finally, this Review outlines state-of-the-art advances in the biology of PanNETs that are of emerging translational importance.

Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well-differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients.

Purpose: To identify a predictive molecular “signature” for sensitivity to retinoic acid in pancreatic cancer. Experimental Design: Fourteen patient-derived, low-passage pancreatic ductal adenocarcinoma (PDAC) lines with varied expression of fatty acid–binding protein 5 (FABP5) and cellular retinoic acid–binding protein 2 (CRABP2) were used to evaluate the response to all-trans retinoic acid (ATRA). Cell proliferation, apoptosis, and migration/invasion assays were used to measure the in vitro response. Tumor growth was monitored in subcutaneous xenografts in athymic nude mice for 4 weeks. Results: Response to ATRA was observed to be dependent upon differential expression of FABP5 versus CRABP2. Thus, elevated FABP5 expression was associated with minimal cytotoxicity and tumor growth inhibition and a paradoxical increase in migration and invasion. Conversely, CRABP2 expression in the absence of FABP5 was associated with significant tumor growth inhibition with ATRA, even in gemcitabine-resistant tumors. The ATRA-resistant phenotype of FABP5highCRABP2null cells could be circumvented by ectopic expression of CRABP2. Alternatively, reexpression of endogenous CRABP2 could be enabled in FABP5highCRABP2null PDAC lines by exposure to decitabine and trichostatin A, thereby relieving epigenetic silencing of the CRABP2 gene promoter. Immunohistochemical staining for FABP5 in archival human tissue microarrays identifies a subset of cases (13 of 63, ∼20%) which are negative for FABP5 expression and might be candidates for ATRA therapy. Conclusions: The widely used agent ATRA deserves a “second look” in PDAC, but needs to be targeted to patient subsets with biopsy-proven FABP5-negative tumors, or be combined with a chromatin-modifying agent to reexpress endogenous CRABP2. Clin Cancer Res; 18(1); 280–9. ©2011 AACR.

Cases of ischaemic brain damage have been reported in relatively healthy patients undergoing shoulder surgery in the beach chair position. Unrecognised cerebral hypoperfusion may have contributed to these catastrophic events, indicating that routine anaesthesia monitoring may not suffice. Near-infrared spectroscopy (NIRS) provides a non-invasive, continuous method to measure regional cerebral oxygen saturation (rScO2). The aim of this clinical investigation was to evaluate the prevalence of regional cerebral oxygen desaturation in patients undergoing shoulder surgery in the upright position during routine anaesthesia management. We also aimed to identify some causal factors for cerebral desaturation. Prospective, observational, blinded study. University hospital. Observation period from 19 05 2008 to 26 08 2008. Twenty consecutive adult patients presenting for elective shoulder surgery under general anaesthesia in the beach chair position were enrolled. Patients with clinically apparent neurological or cognitive dysfunction were excluded. Routine anaesthesia management and standard monitoring were used. The responsible anaesthesiologist was blinded to the rScO2 data and was not informed about the purpose of the study. The prevalence of cerebral oxygen desaturation was measured. With beach chair positioning, rScO2 decreased significantly from 79± to 57±9% on the left side and from 77±10 to 59±10% on the right side (P

More than 2% of adults harbor a pancreatic cyst, a subset of which progresses to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 ± 4.6, 27 ± 12, 16 ± 7.6, and 2.9 ± 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of the von Hippel–Lindau gene ( VHL ), a key component of the VHL ubiquitin ligase complex that has previously been associated with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43 , a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations but always contained mutations of CTNNB1 , previously demonstrated to inhibit degradation of the encoded protein (β-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.

Background context Many animal species and an overwhelming variety of procedures that produce an experimental scoliosis have been reported in the literature. However, varying results have been reported on identical procedures in different animal species. Furthermore, the relevance of experimental animal models for the understanding of human idiopathic scoliosis remains questionable. Purpose To give an overview of the procedures that have been performed in animals in an attempt to induce experimental scoliosis and discuss the characteristics and significance of various animal models. Study design Extensive review of the literature on experimental animal models in scoliosis research. Methods MEDLINE electronic database was searched, focusing on parameters concerning experimental scoliosis in animal models. The search was limited to the English, French, and German languages. Results The chicken appeared to be the most frequently used experimental animal followed by the rabbit and rat. Additionally, scoliosis has been induced in primates, goats, sheep, pigs, cows, dogs, and frogs. Procedures widely varied from systemic to local procedures. Conclusions Although it has been possible to induce scoliosis-like deformities in many animals through various ways, this always required drastic surgical or systemic interventions, thus making the relation to human idiopathic scoliosis unclear. The basic drawback of all used models remains that no animal resembles the upright biomechanical spinal loading condition of man, with its inherent rotational instability of certain spinal segments. The fundamental question remains what the significance of these animal models is to the understanding of human idiopathic scoliosis.

Pancreatic neuroendocrine tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase complex, and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain-associated protein) and ATRX (α thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.

The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival.

Approximately 45% of sporadic well-differentiated pancreatic neuroendocrine tumors harbor mutations in either ATRX (alpha thalassemia/mental retardation X-linked) or DAXX (death domain-associated protein). These novel tumor suppressor genes encode nuclear proteins that interact with one another and function in chromatin remodeling at telomeric and peri-centromeric regions. Mutations in these genes are associated with loss of their protein expression and correlate with the alternative lengthening of telomeres phenotype. Patients with multiple endocrine neoplasia-1 (MEN-1) syndrome, genetically defined by a germ line mutation in the MEN1 gene, are predisposed to developing pancreatic neuroendocrine tumors and thus represent a unique model for studying the timing of ATRX and DAXX inactivation in pancreatic neuroendocrine tumor development. We characterized ATRX and DAXX protein expression by immunohistochemistry and telomere status by telomere-specific fluorescence in situ hybridization in 109 well-differentiated pancreatic neuroendocrine lesions from 28 MEN-1 syndrome patients. The study consisted of 47 neuroendocrine microadenomas (

Hereditary diffuse gastric cancer is an autosomal dominant cancer syndrome characterized by highly penetrant diffuse gastric cancer. It is caused by germ line mutations in CDHI, encoding the cell-cell adhesion protein E-cadherin. Pancreatic ductal adenocarcinoma is one of the most dismal malignancies in humans. Although absent E-cadherin expression in pancreatic ductal adenocarcinoma is related to a higher tumor grade and a worse prognosis, there have been no reports of pancreatic ductal adenocarcinoma associated with hereditary diffuse gastric cancer. Here, we describe a patient with hereditary diffuse gastric cancer who was subsequently diagnosed with pancreatic ductal adenocarcinoma. To investigate if the previously identified CDHI germ line mutation initiated pancreatic ductal adenocarcinoma development, we performed mutational and proteomic analyses. We conclude that the pancreatic ductal adenocarcinoma did not occur in the context of the germ line CDHI mutation but rather appeared as a sporadic event. Immunohistochemistry ultimately proved to be the most valuable tool of investigation as persistent CDHI staining in the pancreatic ductal adenocarcinoma unequivocally revealed E-cadherin expression. (C) 2012 Elsevier Inc. All rights reserved

The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.

Acinar cell carcinoma is a rare non-ductal neoplasm of the pancreas with poorly defined molecular genetic features. Recently, biallelic inactivation of LKB1 was described in an acinar cell carcinoma of a Peutz-Jeghers patient carrying a heterozygous germline LKB1 mutation, and inhibition of mTOR signaling resulted in partial remission of the tumor. To explore the potential of mTOR inhibitors in sporadic acinar cell carcinoma, the LKB1 gene was investigated in five sporadic acinar cell carcinomas by sequence analysis, methylation analysis and mRNA expression. In addition, microsatellite instability and methylation of a number of tumor suppressor genes were investigated and KRAS, TP53, CDKN1A, SMAD4 and CTNNB1 were studied by mutation analysis and immunohistochemistry. No mutations, deletions or promoter hypermethylation of LKB1 were found in any of the sporadic acinar cell carcinomas, and mRNA expression of LKB1 was not altered. Amplifications at chromosome 20q and 19p were found in 100 and 80% of the cases, respectively. In addition, hypermethylation of one or more tumor suppressor genes was found in 80% of cases. One case harbored a TP53 mutation, and expression of SMAD4 and CTNNB1 was altered in one case each. No KRAS mutations or microsatellite instability were found. To conclude, no evidence for a role for LKB1 in tumorigenesis of sporadic pancreatic acinar cell carcinoma was found. However, copy number variations and hypermethylation were found in a majority of cases. Molecular pathways involved in acinar cell carcinoma-tumorigenesis differ from those involved in ductal pancreatic neoplasms. Further studies are needed to increase our understanding of molecular pathogenesis of acinar cell carcinoma, which may eventually result in development of new therapeutic targets.

Pancreatic cancer is an almost universally lethal disease and despite extensive research over the last decades, this has not changed significantly. Nevertheless, much progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) suggesting that different therapeutic strategies based on these new insights are forthcoming. Increasing focus exists on designing the so-called targeted treatment strategies in which the genetic characteristics of a tumor guide therapy. In the past, the focus of research was on identifying the most frequently affected genes in PDAC, but with the complete sequencing of the pancreatic cancer genome the focus has shifted to defining the biological function that the altered genes play. In this paper we aimed to put the genetic alterations present in pancreatic cancer in the context of their role in signaling pathways. In addition, this paper provides an update of the recent advances made in the development of the targeted treatment approach in PDAC.

Rabbit retinas were treated with laser coagulations of low intensity, using five different wavelengths. After coagulation (1, 4 and 28 days), the retinas were stained for GABA, using a direct biotinavidin-horseradish peroxidase immunocytochemical method. These time intervals were chosen with regard to the existing knowledge of retinal repair. The staining for GABA was increased in the inner plexiform layer at the centre of the lesions at days 1 and 4 after coagulation. At the margins of the lesions, cells in the ganglion cell layer showed strong staining and cells in the amacrine cell layer showed cuffing, independent of the wavelength used. On day 28, a regression of the hyperstaining was noted. Some possible pathophysiological mechanisms are discussed.

Aims: The aim of this study is to investigate psychometric properties of the Client Satisfaction Questionnaire (CSQ-8) in a Dutch substance abuse population. Methods: The CSQ-8 and the Mental Health Thermometer (the standard Dutch satisfaction instrument) were sent to 927 patients of a Dutch substance abuse treatment centre. (response rate 28.3%; n = 262). Data were compared on several variables (i.e., age, gender, ethnicity, treatment type). For a subgroup of responders (n = 84), data were compared with pre-treatment problem severity and treatment need (the European Addiction Severity Index). Findings: Both internal consistency and concurrent validity were found to be high. Only treatment type had significant effects on CSQ-8 satisfaction scores. Scores were negatively skewed. Conclusion: The CSQ-8 is as suitable an instrument to be used in addict populations, as it is in other populations.

Purpose Essential blepharospasm can be associated with apraxia of eyelid opening and is characterized by the inability to initiate the act of eyelid elevation even after cessation of orbicularis spasms. Current therapies such as botulinum toxin injections, orbicularis resection, or neurectomy may be unsuccessful or have undesired side effects. Methods Frontalis suspension was used to treat 13 consecutive patients with apraxia and blepharospasm during a 4-year interval. Follow-up ranged from 16 months to 55 months. To improve the aesthetic outcome, an upper blepharoplasty was done at the same time as the frontalis suspension in 7 cases. Results Good or excellent functional results were obtained in 10 of 13 patients. In 6 of these patients, the spasm disappeared completely. Therapy was unsuccessful in 1 patient, and in 2 patients blepharospasm recurred after 9 months. Conclusion Patients with blepharospasm and apraxia of eyelid opening may benefit from a frontalis suspension operation, which can be considered minimally invasive and reversible.

Background and Aim: Tumor cells depend on metabolic alterations for their continued growth and survival, and such changes make cancer cells peculiarly addicted to the rapacious uptake of glucose. The Warburg effect is such a metabolic feature of cancers that helps to preferentially metabolize pyruvate via glycolytic pathway to lactate by lactate dehydrogenase A (LDHA). Our recent findings indicated that LDHA is required not only for tumor initiation but for tumor maintenance and progression (Le et al., PNAS, 2010). Here, we investigated the therapeutic potential of LDHA inhibition in pancreatic cancer, and attempt to delineate the factors responsible for tumor response. Methods: We evaluated the in vivo efficacy of FX11, a small molecule inhibitor of LDHA, in a panel of pancreatic cancer xenografts with annotated mutational status. Non-invasive quantitative assessment of lactate production was measured by real-time hyperpolarization experiments with 1-13C-labeled pyruvate using a DNP polarizer (HyperSense). [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET) combined with computed tomography (CT) imaging was conducted to evaluate the effect of FX11 treatment on glucose metabolism. Liquid chromatography - mass spectrometry (LC-MS) was used to quantify the tumor metabolites. Ki-67 and TUNEL staining were performed to determine the effect of FX11 treatment on apoptosis and tumor cell proliferation. Results: p53-deficient pancreatic cancer xenografts showed higher baseline metabolic activity and FX11 treatment down-regulated the tumor metabolic activity. Real-time imaging of pyruvate to lactate conversion using nuclear magnetic resonance (NMR) spectroscopy revealed that FX11 treatment inhibits pyruvate to lactate conversion in p53-deficient pancreatic cancer xenografts. Importantly, p53 promotes the expression of TP53-induced glycolysis regulator (TIGAR) and loss of p53 in tumors results in reduced TIGAR levels. The metabolic profiles of p53-deficient versus p53-proficient pancreatic cancer xenografts were remarkably different. FX11 treatment attenuates tumor progression, induces apoptosis and reduces tumor cell proliferation, preferentially in p53-deficient pancreatic cancer xenografts. Conclusions: Because the Warburg effect is characteristic of virtually all cancers and p53 is frequently mutated in vast majority of human cancers, our finding that p53, a key regulator of glycolysis and a major factor deciding the therapeutic outcome of targeting the Warburg effect may have broad clinical implications. Our findings may help to identify patient subsets that may be particularly responsive to LDHA targeted agents in clinical trials. Acknowledgement: Stand Up To Cancer-AACR Dream Team Translational Cancer Research Grant No. SU2C-AACR DT0509. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-61. doi:1538-7445.AM2012-LB-61

Background: Pancreatic ductal adenocarcinoma (PDA) has the highest mortality rate of any cancer type. The 5-year survival rate of 5% remained largely unchanged in the last three decades. The paucity of breakthroughs in treatment regimens and continued poor survival demonstrates an acute need for improvement in therapy for this lethal malignancy. Mounting evidence suggest that sustained re-activation of Notch signaling pathway contributes to the initiation, progression and maintenance of PDA. Recently, Notch signaling has been linked to the viability of putative tumor initiating cancer stem cell populations in pancreatic cancer. PF-03084014 is a selective γ-secretase inhibitor developed by Pfizer. The present study was conducted to determine the effect of PF-03084014 monotherapy and in combination with gemcitabine (GEM) to suppress tumor progression and prevent metastatic spread in preclinical models of pancreatic cancer. Methods: NOTCH-1 gene expression was determined in a panel of 30 human pancreatic cancer xenografts by Affymetrix gene array. We investigated the efficacy of PF-03084014 and in combination with GEM in subcutaneously (s.c) implanted as well as orthotopic models of pancreatic cancer. We also determined the treatment effect on putative pancreatic cancer stem cell (CSC) populations. TUNEL and Ki-67 staining were performed to determine whether the therapy induce apoptosis and suppresses tumor cell proliferation. Results: A combination of PF-03084014 and GEM is highly effective in producing durable tumor regression compared to GEM in subcutaneously implanted pancreatic cancer xenografts. Tumor re-growth curves plotted after 4 weeks of drug treatment demonstrate that the effect of the combination therapy is longer lasting than that of GEM. Notably, in a highly aggressive Panc265 orthotopic model, PF-03084014 and GEM combination was effective in controlling the primary tumor growth as well as preventing metastatic dissemination to organs as compared to GEM treatment. Flow cytometry of sorted tumor cells from Panc215 (after 4 weeks of treatment) showed that GEM treatment was not capable of diminishing the CSC pool as compared to the vehicle treated mice. However, PF-03084014 alone, and the combination of GEM with PF-03084014 resulted in a 3.72 and 3.04-fold decrease in CD24+CD44+ tumor cells compared with GEM treatment, respectively. TUNEL and Ki-67 staining demonstrated that combination therapy induced apoptosis and suppresses cell proliferation. Conclusions: The findings presented here provide strong rationale for the clinical investigation on notch inhibition as a chemotherapeutic strategy to combat pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3262. doi:1538-7445.AM2012-3262

Background: Metastasis and drug resistance are the major causes of mortality in patients with pancreatic ductal adenocarcinoma (PDA). Once developed, the progression of PDA metastasis is virtually unstoppable with current therapies. Accumulating evidence suggests important roles for the receptor tyrosine kinase AXL in cancer progression, invasion, metastasis, drug resistance, and patient mortality. Given the critical influence of metastasis on the clinical history of PDA, we hypothesize that pharmacological inhibition of AXL might inhibit tumor growth and prevent PDA metastasis. Methods: We investigated the AXL expression in a panel of human pancreatic cancer xenografts using Affymetrix gene array as well as qRT-PCR. We conducted a comprehensive preclinical trial to determine whether AXL targeted monotherapy, and in combination with gemcitabine, was effective in blocking PDA tumor progression and metastasis using subcutaneous as well as orthotopic pancreatic cancer models. Results: R428, a potent selective small molecule inhibitor of AXL, inhibited proliferation of pancreatic cancer cell lines in a concentration-dependent manner. A combination of R428 with gemcitabine could significantly inhibit primary tumor growth compared to gemcitabine treated mice. Notably, R428 alone and in combination with gemcitabine was remarkably effective in preventing the development of metastasis to organs and lymph nodes as compared to gemcitabine treatment in a highly aggressive orthotopic model. Conclusions: The data presented here provide strong evidence for the therapeutic development of AXL inhibitors as anti-metastatic agents in pancreatic cancer. A combination treatment of R428 and gemcitabine was highly effective in controlling the primary tumor growth and preventing metastatic spread. The novel therapeutic approach tested here has potential therapeutic implications for improving the current standard of care for PDA patients and to contribute towards making PDA a more manageable disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2546. doi:10.1158/1538-7445.AM2011-2546

Invasive ductal adenocarcinoma of the pancreas remains an almost universally lethal disease. Despite strenuous research efforts, the prognosis of the disease has not improved in the past decades. However, knowledge of pancreatic tumorigenesis and the identification and characterization of the precursor lesions that give rise to invasive pancreatic cancer have dramatically improved. This, coupled with the finding that it takes almost two decades for a pancreatic cell with an initial mutation to develop into a metastatic pancreatic cancer provides hope for the early detection of curable pancreatic neoplasms. We present a review of established precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms (including intraductal oncocytic papillary neoplasm and intraductal tubulopapillary neoplasm), and mucinous cystic neoplasm.