Radical Resection in Entero-Pancreatic Neuroendocrine Tumors: Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence.

BACKGROUND: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date. OBJECTIVE: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence. PATIENTS AND METHODS: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model. RESULTS: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01). CONCLUSIONS: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.

[Pancreatic neuroendocrine tumors : Current treatment concepts]. / Neuroendokrine Tumoren des Pankreas : Aktuelle Therapiekonzepte.

The number of cases diagnosed as pancreatic neuroendocrine neoplasia (pNEN) is steadily increasing. The 2017 World Health Organization classification defines a new subgroup of morphologically well differentiated tumors with an elevated proliferation rate (Ki-67 over 20%) as neuroendocrine tumor (NET) G3. Due to the heterogeneity of pNEN regarding etiology (sporadic versus hereditary), symptoms (hormone syndrome versus non-functional tumor), and prognosis (ranging from benign behavior to highly malignant), multidisciplinary management by experienced physicians is required. This is especially true as the number of therapeutic options has increased, while we still lack comparative trials. This overview aims to summarize the multidisciplinary therapeutic options, their selection criteria and the recommendations of the new German S2k guideline.

Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer.

OBJECTIVE: Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery. DESIGN: Gemcitabine metabolites were analysed in LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation. RESULTS: Gemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2',2'-difluorodeoxycytidine-5'-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2',2'-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5'-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%. CONCLUSIONS: Our findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.

[Pancreatic ductal adenocarcinoma]. / Duktales Adenokarzinom des Pankreas.

Pancreatic ductal adenocarcinoma represents the most common malignant tumor of the pancreas. Despite substantial research efforts and gradual diagnostic and therapeutic improvements, its prognosis remains dismal. In accordance with the current German, European, and US guidelines, this CME-article provides a comprehensive review of the disease. In addition, selected up-to-date aspects of epidemiology, etiopathology, genetics, and basic principles of diagnostics and therapy including potential future therapeutic options are discussed.

Relevance of dihydropyrimidine-dehydrogenase and thymidylate-synthase in patients with pancreatic neuroendocrine neoplasms treated with 5-FU-based chemotherapy.

BACKGROUND: Chemotherapy with 5-FU and Streptozotocin (STZ) is recommended as first-line treatment in patients with metastatic pancreatic neuroendocrine neoplasms (PNEN). However, data about biomarkers involved in the 5-FU metabolism to predict response are still limited. OBJECTIVES: Evaluation of clinicopathological features and potential predictive and prognostic markers of patients with PNEN treated with 5-FU based regimens. PATIENTS AND METHODS: We retrospectively analyzed 41 patients with PNEN who were treated at the University Hospital Marburg between 2000 and 2013. Dihydropyrimidine-Dehydrogenase (DPD) and Thymidylate-Synthase (TS) expression was correlated with treatment response in 19 patients who had available tumour tissue and response data. The median overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. RESULTS: The median PFS in patients receiving 5-FU/STZ was 17 months with a median OS of 50 months. Objective response rate (ORR) and disease control rate (DCR) were 32% and 73%, respectively. Biochemical response (p = 0.005) and high DPD expression (p = 0.018) were predictive markers of response to 5-FU-based chemotherapy. Univariate analysis identified Ki-67 > 10%, no biochemical response, positive 5-HIAA levels and TS deficiency as independent risk factors for shorter PFS. Moreover, performance status (PS) ≥1 was an independent risk factors for impaired OS. CONCLUSIONS: DPD expression and biochemical response represent promising predictive biomarkers for response to 5-FU based chemotherapy. Moreover, Ki-67, PS and TS are independent prognostic markers of OS and PFS in patients with PNEN.

Refinement of screening for familial pancreatic cancer.

OBJECTIVE: Surveillance programmes are recommended for individuals at risk (IAR) of familial pancreatic cancer (FPC) to detect early pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC). However, the age to begin screening and the optimal screening protocol remain to be determined. METHODS: IAR from non-CDKN2A FPC families underwent annual screening by MRI with endoscopic ultrasonography (EUS) in board-approved prospective screening programmes at three tertiary referral centres. The diagnostic yield according to age and different screening protocols was analysed. RESULTS: 253 IAR with a median age of 48 (25-81) years underwent screening with a median of 3 (1-11) screening visits during a median follow-up of 28 (1-152) months. 134 (53%) IAR revealed pancreatic lesions on imaging, mostly cystic (94%), on baseline or follow-up screening. Lesions were significantly more often identified in IAR above the age of 45 years (p<0.0001). In 21 IAR who underwent surgery, no significant lesions (PDAC, pancreatic intraepithelial neoplasia (PanIN) 3 lesions, high-grade intraductal papillary mucinous neoplasia (IPMN)) were detected before the age of 50 years. Potentially relevant lesions (multifocal PanIN2 lesions, low/moderate-grade branch-duct IPMNs) occurred also significantly more often after the age of 50 years (13 vs 2, p<0.0004). The diagnostic yield of potentially relevant lesions was not different between screening protocols using annual MRI with EUS (n=98) or annual MRI with EUS every 3rd year (n=198) and between IAR screened at intervals of 12 months (n=180) or IAR that decided to be screened at ≥24 months intervals (n=30). CONCLUSIONS: It appears safe to start screening for PDAC in IAR of non-CDKN2a FPC families at the age of 50 years. MRI-based screening supplemented by EUS at baseline and every 3rd year or when changes in MRI occur appears to be efficient.

Key role of dual specificity kinase TTK in proliferation and survival of pancreatic cancer cells.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies with an overall 5-year survival rate of <5%. Despite significant advances in treatment of the disease during the past decade, the median survival rate (∼6 months) has hardly improved, warranting the need to identify novel targets for therapeutic approaches. METHODS: Quantitative real time PCR, western blot analyses and immunohistochemical staining of tissue microarrays were used to analyse the expression of TTK gene in primary PDAC tissues and cell lines. To inhibit TTK kinase expression in a variety of pancreatic cancer cell lines, RNA interference was used. Functional roles of this kinase in the context of PDAC were studied using cell proliferation, viability and anchorage-independent growth assays. Western blotting, fluorescence-activated cell sorting analyses and fluorescence microscopy were used to gain mechanistic insight into the functional effects. CONCLUSIONS: We show that the dual specificity kinase TTK (also known as Mps1), is strongly overexpressed in human PDAC. Functionally, cell proliferation was significantly attenuated following TTK knockdown, whereas apoptosis and necrosis rates were significantly increased. In addition, anchorage-independent growth, a hallmark of malignant transformation and metastatic potential, was strongly impaired in the absence of TTK gene function. Interestingly, immortalised normal pancreatic hTERT-HPNE cells were not affected by loss of TTK function. Mechanistically, these effects in cancer cells were associated with increased formation of micronuclei, suggesting that loss of TTK function in pancreatic cancer cells results in chromosomal instability and mitotic catastrophe. Taken together, our data show that TTK function is critical for growth and proliferation of pancreatic cancer cells, thus establishing this kinase as an interesting new target for novel therapeutic approaches in combating this malignancy.

[A 59-year-old patient with recurrent flushes and bland hepatic cyst]. / 59-jähriger Patient mit rezidivierendem Erröten bei blander Leberzyste.

A 59-year-old patient was admitted to hospital with recurrent flush symptoms and pathologically elevated 5-hydroxyindoleacetic acid (5-HIAA) levels in urine. A known cystic lesion of the liver which had been followed for years by ultrasound examinations and was regarded as a bland hepatic cyst was identified as a metastasis of a neuroendocrine neoplasm of the ileum. In two sequential surgical interventions the primary tumor with mesenteric lymph node metastases as well as the cystic liver metastasis could be resected. After surgical treatment an R1 situation at the mesenteric site and suspicious para-aortic lymph nodes remained. The long established treatment of factor-V Leiden mutation by anticoagulation with phenprocoumon was supplemented by deep subcutaneous injection of lanreotide autogel every 4 weeks. Currently, there is no evidence for progressive disease and the patient is without clinical signs of a carcinoid syndrome.

Multicenter phase II trial to investigate safety and efficacy of gemcitabine combined with cetuximab as adjuvant therapy in pancreatic cancer (ATIP).

BACKGROUND: To investigate whether addition of cetuximab to standard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer, specifically whether the rate of disease-free survival (DFS) at 18 months (primary end point) exceeds the previously reported 35% of gemcitabine alone. PATIENTS AND METHODS: Prospective, open-label, multicenter, nonrandomized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008. Gemcitabine and cetuximab were administered for 24 weeks. Secondary end points included overall survival (OS) and toxic effect. RESULTS: Seventy-three patients received cetuximab. Median DFS was 10.0 [95% confidence interval (CI) 8.9-13.6] months and the DFS rate at month 18 of 27.1% (16.7%-37.6%) was inferior to 35%. Median OS was 22.4 (18.2-27.9) months. Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 (median 14.7 versus 8.3 months, P = 0.073) and wild-type versus mutated K-Ras (median 11.5 versus 9.3 months, P = 0.57). Grade 3/4 toxic effects included neutropenia (11.0%), thrombopenia (7%), skin toxic effect (7%) and allergic reactions (7%). CONCLUSION: Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients. Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed.

Claudin-4 as therapeutic target in cancer.

BACKGROUND: Intercellular junctional complexes such as adherens junctions and tight junctions are critical regulators of cellular polarity, paracellular permeability and metabolic and structural integrity of cellular networks. Abundant expression analysis data have yielded insights into the complex pattern of differentially expressed cell-adhesion proteins in epithelial cancers and provide a useful platform for functional, preclinical and clinical evaluation of novel targets. SCOPE OF REVIEW: This review will focus on the role of claudin-4, an integral constituent of tight junctions, in the pathophysiology of epithelial malignancies with particular focus pancreatic cancer, and its potential applicability for prognostic, diagnostic and therapeutic approaches. MAJOR CONCLUSIONS: Claudin-4 expression is widely dysregulated in epithelial malignancies and in a number of premalignant precursor lesions. Although the functional implications are only starting to unravel, claudin-4 seems to play an important role in tumour cell invasion and metastasis, and its dual role as receptor of Clostridium perfringens enterotoxin (CPE) opens exciting avenues for molecular targeted approaches. GENERAL SIGNIFICANCE: Claudin-4 constitutes a promising molecular marker for prognosis, diagnosis and therapy of epithelial malignancies.

Successful selective internal radiotherapy (SIRT) in a patient with a malignant solid pseudopapillary pancreatic neoplasm (SPN).

Solid pseudopapillary neoplasms of the pancreas (SPNs, Gruber-Frantz-Tumor) are a rare entity representing 1-5% of all exocrine pancreatic tumors. The pseudocystic lesions preferentially affect young females <30 years, are mostly benign (∼90%) and normally present with unspecific symptoms. We describe the case of a 16-years-old Asian woman that was initially diagnosed with an SPN in the pancreatic head with mesenterial and hepatic metastases. After diagnosis, an extensive tumor resection was performed including pyloric-preserving pancreatic head resection followed by sequential resection of all hepatic metastases. After the patient was diagnosed with a hepatic recurrence and high intrahepatic tumor load, we chose a multimodal procedure and performed a selective internal radiotherapy (SIRT). Four years after SIRT and 10 years after initial diagnosis of metastatic SPN, the patient is in a good condition without any evidence for hepatic recurrence. This case represents a rare clinical course of a malignant and invasive SPN with an exceptionally long survival despite of high initial tumor burden. The selective internal radiotherapy is a suitable approach for inducing long-term remissions of the strongly vascularized liver metastases.

Prospective evaluation of duodenogastroesophageal reflux in gastroesophageal reflux disease patients refractory to proton pump inhibitor therapy.

BACKGROUND: Duodenogastroesophageal reflux (DGER) is considered an independent risk factor for complicated reflux disease (gastroesophageal reflux disease; GERD). However, the role of DGER in GERD patients refractory to proton pump inhibitors (PPI) remains poorly understood. METHODS: 85 patients with clinical reflux symptoms and a history of ineffective response to PPIs were enrolled in the study. Patients with elevated reflux measurement (pH and/or Bilitec measurement; n = 47) received pantoprazole 80 mg for 8 weeks. Clinical outcome was defined as response (≤2 symptoms/week) or nonresponse (≥3 symptoms/week). RESULTS: Of the 47 patients with elevated reflux measurement, 30 were classified as responders and 17 as nonresponders. Treatment with pantoprazole resulted in a significant reduction of acidic reflux in both PPI responders and PPI nonresponders. In contrast, DGER was only significantly reduced in the PPI responder group (22.8 ± 22.8 vs. 6.6 ± 10.8%; p < 0.05) but not in the PPI nonresponder group (24.5 ± 18.6 vs. 22.2 ± 12.7%; p > 0.05). CONCLUSIONS: The presented study firstly describes that nonresponsiveness to PPI is associated with a limited effect of PPIs on reducing DGER. Thus, persistent DGER may play a key role in mediating reflux symptoms refractory to high-dose PPIs.

[Hereditary neuroendrocrine tumors. Multiple endocrine neoplasia type 1 and 2]. / Hereditäre neuroendokrine Tumoren. Multiple endokrine Neoplasien Typ 1 und 2.

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal-dominant hereditary disease characterized by the occurrence of tumors of the parathyroids, duodenum and/or pancreas, and anterior pituitary. The syndrome is caused by germline mutations of the MEN1 tumor suppressor gene. The identification of the causative mutations is of paramount importance for the long-term management of affected individuals and their relatives. Multiple endocrine neoplasia type 2 (MEN2) is less frequent than MEN1 and represents a cancer syndrome caused by autosomal-dominant inherited mutations of the RET proto-oncogene, and displays a genotype-phenotype correlation of remarkable clinical relevance. Major components of MEN-2 comprise medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism. Since 25-30% of patients with MTC display a hereditary background, genetic testing is indicated once MTC is diagnosed. Occurrence of MTC can be avoided by prophylactic thyroidectomy in early childhood in gene carriers. Early diagnosis and therapy of simultaneous pheochromocytoma avoids the development of complications caused by acute or chronic hypertension.

Listeria monocytogenes-induced bacterial peritonitis caused by contaminated cheese in a patient with haemochromatosis.

Infections with Listeria monocytogenes can present clinically with a wide range of different organ manifestations such as gastroenteritis, meningoencephalitis or osteomyelitis, posing a serious threat, particularly to immunocompromised patients. We present the case of a 76-year-old female patient with advanced liver disease due to underlying haemochromatosis, who was admitted to the hospital with increasing abdominal pain. She was diagnosed with spontaneous bacterial peritonitis caused by infection with Listeria monocytogenes, which she had acquired after consuming contaminated cheese from a local supermarket chain. To the best of our knowledge, this is the first case to describe Listeria-induced spontaneous bacterial peritonitis in a patient with haemochromatosis. Both end-stage liver disease and hereditary haemochromatosis on their own impair the local and systemic immune response, thereby representing predisposing factors for acquiring Listeria monocytogenes infection. This case demonstrates a rare organ manifestation of Listeria monocytogenes infection, which can be life-threatening if not diagnosed and treated adequately, and underlines the need to identify possible sources of infection in order to apply measures to prevent the further spread of the contaminated food.

CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer.

BACKGROUND AND AIMS: The transcription factor CUX1 is known as a regulator of cell differentiation and cell cycle progression. Previously, CUX1 was identified as a modulator of invasiveness in various cancers. Based on expression profiles suggesting a role for CUX1 in mediating chemoresistance, the aim of this study was to characterise the effect of CUX1 on apoptosis as well as its regulation by signalling pathways modulating drug resistance in pancreatic cancer. METHODS: The effect of CUX1 on TRAIL- (tumour necrosis factor-related apoptosis-inducing ligand) and drug-induced apoptosis was analysed using overexpression and knock-down strategies. Regulation of CUX1 by phosphatidylinositol-3-kinase (PI3K)/Akt signalling was examined at the mRNA and protein level. The effect of CUX1 knock-down by nanoparticle-complexed small interfering RNA (siRNA) in vivo was analysed in a murine xenograft model. Furthermore, CUX1 RNA and protein expression was evaluated in human pancreatic cancer and adjacent normal tissues. RESULTS: Knock-down of CUX1 resulted in significantly enhanced TRAIL- and drug-induced apoptosis, associated with increased PARP (poly ADP-ribose polymerase) cleavage and caspase activity. Vice versa, overexpression of CUX1 inhibited apoptosis. CUX1 expression was induced by activation of Akt/protein kinase B signalling, and decreased by PI3K inhibitors. The antiapoptotic effect of CUX1 was associated with upregulation of BCL2 and downregulation of tumour necrosis factor alpha. CUX1 was significantly overexpressed in pancreatic cancers, as analysed by in situ hybridisation and immunohistochemistry. In vivo, silencing of CUX1 by intratumourally administered polyethylenimine-complexed siRNA led to reduced tumour growth and increased apoptosis in pancreatic cancer xenografts. CONCLUSION: CUX1 was identified as an important mediator of tumour cell survival in pancreatic cancer in vitro and in vivo.

[Current aspects of the pathology and differentiation of extranodal marginal zone B-cell lymphoma, MALT-Type, and gastrointestinal diffuse large B-cell lymphoma]. / Aktuelle molekular-zytogenetische Aspekte zur Pathologie und Differenzierung von extranodalen Marginalzonen B-Zell-Lymphomen vom MALT-Typ und gastrointestinalen diffusen grosszelligen B-Zell-Lymphomen.

The marginal zone B-cell lymphoma, MALT-type (MZBL, MT) is a low-grade B-cell lymphoma which is predominantly localised in the stomach with a typical morphology and cytogenetic pattern. The coexistence of a diffuse large B-cell lymphoma (DLBCL) with an MZBL, MT in the gastrointestinal tract is defined as a composite lymphoma (ComL) and represents a fascinating model of lymphoma progression. In this review we focus on current aspects regarding the molecular characterisation of MZBL, MT and gastrointestinal DLBCL and their mutual relationships.

Contrast-enhanced ultrasound pattern of splenic metastases - a retrospective study in 32 patients.

PURPOSE: To characterize the pattern of contrast-enhanced ultrasonography (CEUS) in splenic metastases compared to standard B-mode ultrasonography. MATERIALS AND METHODS: Between January 2004 and March 2009, about 50,000 abdominal ultrasound examinations were performed, and n = 279 (< 0.6 %) of focal splenic lesions were detected of which n = 32 (11.5 %) were highly suggestive for splenic metastases of various solid tumors. The number of lesions, size, echogenicity, rim appearance, presence of halo sign and necrosis were recorded via B-mode sonography. Contrast enhancement was determined in the arterial phase (5 - 30 sec) and parenchymal phase (3 - 5 min). B-mode sonography and CEUS were compared in terms of the visibility of splenic metastases. All data was evaluated retrospectively. RESULTS: On B-mode sonography lesions were solitary n = 18 (56 %), multiple n = 14 (44 %), < 2 cm n = 11 (34 %), > or = 2 cm n = 21 (66 %), hypoechoic n = 14 (44 %), isoechoic n = 12 (38 %) and hyperechoic n = 6 (19 %), with regular rim appearance n = 27 (84 %), and with irregular rim appearance n = 5 (16 %). During the arterial phase CEUS lesions were hypoechoic n = 21 (66 %), isoechoic n = 2 (6 %), hyperechoic n = 1 (3 %) and complex n = 8 (25 %). During the parenchymal phase lesions were hypoechoic n = 24 (75 %) and complex n = 8 (25 %). CEUS provided improved visualization of splenic metastases in n = 12 (38 %) cases. CONCLUSION: CEUS of splenic metastases is characterized by reduced contrast enhancement in both the arterial and the parenchymal phase in most cases. Moreover, CEUS improved the visualization of splenic metastases in about 40 % of cases in comparison to standard B-mode sonography.

Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.

OBJECTIVE: Familial pancreatic cancer (FPC) accounts for approximately 3% of all pancreatic cancer (PC) cases. It has been suggested that high-risk individuals (HRIs) should be offered a screening programme. AIM: To evaluate the diagnostic yield of a prospective screening programme in HRIs from families with FPC over a period of 5 years. METHODS: HRIs of families with FPC of the National German Familial Pancreatic Cancer Registry (FaPaCa) were counselled and enrolled in a prospective, board-approved PC screening programme. Screening included clinical examination, laboratory tests, endoscopic ultrasound (EUS) and MRI with magnetic resonance cholangiopancreaticography (MRCP) and MR angiography. RESULTS: Between June 2002 and December 2007, 76 HRIs of families with FPC took part in the screening programme with a total of 182 examination visits. Twenty-eight patients revealed abnormalities in EUS (n = 25) and/or MR/MRCP (n = 12). In 7 patients fine needle aspiration cytology was performed. Operative pancreatic explorations were performed in 7 individuals, resulting in limited resections in 6 cases. Histopathological examination of the resected specimens showed serous oligocystic adenomas (n = 3), pancreatic intraepithelial neoplasia 1 (PanIN1) lesions with lobular fibrosis (n = 1), PanIN2 lesions (n = 1) and PanIN1 lesion plus a gastric type intraductal papillary mucinous neoplasm (IPMN) (n = 1). CONCLUSIONS: In FPC an EUS/MR/MRCP-based screening programme leads to the detection of potential precursor lesions of PC. However, the yield of an extensive screening programme is low, especially since the tumourigenic value of low grade PanIN lesions is not yet defined. Taking into account the enormous psychological stress for the tested individual and the high costs, a general PC screening in HRIs is not justified.

CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models.

BACKGROUND: CD147 (basigin, EMMPRIN) is a multifunctional, highly conserved glycoprotein enriched in pancreatic ductal adenocarcinomas (PDACs) which is associated with poor prognosis in many malignancies. The role of CD147 in pancreatic cancer, however, remains elusive. METHODS AND RESULTS: Silencing of CD147 by RNA interference (RNAi) reduced the proliferation rate of MiaPaCa2 and Panc1 cells. CD147 is required for the function and expression of the monocarboxylate transporters MCT1 and MCT4 that are expressed in human PDAC cells as demonstrated by real-time reverse transcription-PCR (RT-PCR) as well as immunohistology. MCT1 and MCT4 are the natural transporters of lactate, and MiaPaCa2 cells exhibited a high rate of lactate production, which is characteristic for the Warburg effect, an early hallmark of cancer that confers a significant growth advantage. Further induction of lactate production by sodium azide in MiaPaCa2 cells increased MCT1 as well as MCT4 expression. CD147 silencing inhibited the expression and function of MCT1 and MCT4 and resulted in an increased intracellular lactate concentration. Addition of exogenous lactate inhibited cancer cell growth in a dose-dependent fashion. In vivo, knock-down of CD147 in MiaPaCa2 cells by inducible short hairpin RNA (shRNA)-mediated CD147 silencing reduced invasiveness through the chorioallantoic membrane of chick embryos (CAM assay) and inhibited tumourigenicity in a xenograft model in nude mice. CONCLUSION: The function of CD147 as an ancillary protein that is required to sustain the expression and function of MCT1 and MCT4 is involved in the association of CD147 expression with the malignant potential of pancreatic cancer cells exhibiting the Warburg effect.