[Diagnostics and clinical management of premalignant diseases of the pancreas]. / Diagnostik und klinisches Management prämaligner Erkrankungen des Pankreas.

Pancreatic cancer is one of the most aggressive solid tumors and still has a poor prognosis. A delayed diagnosis at advanced stages and a poor response to systemic treatment frequently make a curative treatment impossible. Therefore, the identification of high-risk patients and screening them regularly is the most promising approach to improve the prognosis. Chronic pancreatitis as well as neoplastic pancreatic cysts can greatly increase the risk of developing pancreatic cancer. Furthermore, familial syndromes and germline mutations also confer an increased risk for development of pancreatic cancer. This article provides an overview of the various premalignant diseases of the pancreas. The value of the various imaging modalities, such as magnetic resonance imaging and endosonography are particularly discussed as well as the screening interval and the indications for surgical treatment are explained.

Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.

BACKGROUND: Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial. METHODS: Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers. RESULTS: In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47-0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65-1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13-0.70). CONCLUSIONS: SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. CLINICAL TRIAL REGISTRATION: ISRCTN71070888; ClinialTrials.gov (NCT03529175).

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.

Detection of peripheral embolic consolidations using contrast-enhanced ultrasonography in patients with no evidence of pulmonary embolism on computed tomography: A pilot study.

AIM: To investigate the value of B-mode imaging and contrast-enhanced ultrasonography (CEUS) in patients with clinically suspected pulmonary embolism (PE) but no evidence of central PE on CT. METHODS: Between May 2004 and February 2015, we included in this retrospective study 19 patients with a risk profile for PE according to their Wells' score, sonographic patterns of peripheral embolic consolidations (EC) on B-mode-imaging and CEUS (ie, missing or inhomogeneous enhancement of the pleural lesions), and exclusion of central PE by CT within 1 week of CEUS. RESULTS: On B-mode imaging, 19 pleural defects presented as hypoechoic. The shape of EC was round in 2, wedge-shaped in 12, polygonal in 3, and presented as atelectasis in 2 cases. On CEUS, 5 of the defects demonstrated, at the arterial and parenchymal phase, a lack of enhancement, and 14 showed an inhomogeneous (mixed) enhancement with wedge-shaped peripheral areas of no contrast enhancement. A second radiologic evaluation of the CT scans revealed PE in two patients and lesions suspicious for malignancy in two other patients. CONCLUSIONS: Despite the lack of definite confirmation of peripheral and central PE on CT, peripheral pleural consolidations with no or inhomogeneous enhancement on CEUS, in combination with the risk profile for a PE, are highly suggestive of EC. If there is still some doubt, histologic confirmation is important to confirm EC and exclude malignancy. Thus, CEUS may close a potential diagnostic gap of small peripheral PE on CT. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:575-579, 2017.

[Spontaneous remission of HCV infection after autologous stem cell transplantation in a 58-year-old man]. / Spontane Remission einer HCV-Infektion nach autologer Stammzelltransplantation bei einem 58-jährigen Patienten.

We report about a 58-year-old man with a chronic and treatment-naive hepatitis C virus (HCV) infection of genotype 1b, who had undergone autologous stem cell transplantation twice due to multiple myeloma. Subsequently, a high-level viremic reactivation of an occult hepatitis B virus (HBV) infection and also a reverse seroconversion was observed. Furthermore, a sustained spontaneous remission of HCV infection was seen. Antiviral therapy of HBV infection was initiated with tenofovir. Seven months after therapy initiation, the patient acquired an "anti-HBc-only" status. Antiviral therapy with tenofovir is still continued. The patient is in a good clinical condition.

Sonographic patterns of renal lymphoma in B-mode imaging and in contrast-enhanced ultrasound (CEUS)--a retrospective evaluation.

INTRODUCTION: Retrospective analysis of sonographic patterns of renal lymphoma in B-mode imaging and contrast-enhanced ultrasound (CEUS). PATIENTS/METHODS: From January 2000 to June 2014, 27 patients with clinical or histologically confirmed renal lymphoma were examined with B-mode imaging, followed by CEUS in 8 cases. RESULTS: In B-mode imaging renal lymphoma were hypoechoic in all 27 cases (100%). 9 patients (33.3%) had a bilateral, 18 (66.7%) patients had an unilateral lymphoma infiltration of the kidneys. 8 (29.6%) cases of small nodular, 5 (18.5%) cases of large nodular and 6 (22.2%) cases of perirenal lymphoma infiltration of the kidney were observed in B-mode imaging. Bulky-formation of renal lymphoma was detected in 6 (22.2%) patients and 2 (7.4%) patients had a diffuse lymphoma infiltration of the kidneys. In CEUS an arterial isoechoic enhancement was observed in 5 (62.5%)- and, an arterial hypoechoic enhancement was observed in 3 (37.5%) cases of renal lymphoma. A hypoechoic enhancement in the parenchymal phase was observed in 8 (100%) cases of renal lymphoma infiltration. CONCLUSION: In B-mode-imaging, nodular lymphoma infiltration of the kidneys is the most common of all renal lymphoma patterns in B-mode imaging. In CEUS, renal lymphoma presented an arterial iso- or hypoechoic enhancement, followed by a hypoechoic enhancement in the parenchymal phase. In regard to the differentiation of renal lymphoma to benign lesions of the kidney, CEUS may be helpful. However, the differentiation of renal lymphoma from other malignant lesions of the kidney like renal cell carcinoma is not feasible by CEUS.

CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling.

Many solid cancers including pancreatic ductal adenocarcinoma (PDAC) are characterized by an extensive stromal reaction that is accompanied by infiltrating tumor-associated macrophages (TAMs). The role of TAMs in malignant tumors is only partially understood. Previously, we identified the transcription factor CUX1 as an important mediator of tumor progression in PDAC. Interestingly, we found that CUX1 is highly expressed not only in tumor cells but also in TAMs. On the basis of these data, we aimed to elucidate the effects of CUX1 in TAMs in vitro and in vivo. We analyzed the effects of CUX1 on cytokine expression using overexpression and knockdown strategies. The cytokine regulation by CUX1 was further assessed by reporter assays, DNA pulldown experiments and chromatin-immunoprecipitation. CUX1 expression in TAMs was analyzed in human pancreatic cancer tissues and in a genetic mouse model. Immunohistochemical analysis revealed strong expression levels of CUX1 in a distinct subset of TAMs in human PDAC tissues. Furthermore, its expression increased during tumor progression in a genetic mouse model of PDAC. Profiling experiments showed that CUX1 downregulates several NF-κB-regulated chemokines such as CXCL10, which have been associated with M1 polarization and inhibition of angiogenesis and tumor progression. We could demonstrate that CUX1 interacts with NF-κB p65, leading to reduced binding of NF-κB p65 to the chemokine promoters. In addition, CUX1 reduces acetylation of NF-κB p65 at K310 by recruiting HDAC1. Functionally, CUX1 expression in TAMs antagonizes T-cell attraction and enhances angiogenesis in vitro. We identified CUX1 as an important modulator of the TAMs phenotype and function by modulating NF-κB-dependent cytokines.

Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo.

BACKGROUND: The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS(G12D); p53(R172H); pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism. METHODS: LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. RESULTS: In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates in vitro, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells in vitro, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition. CONCLUSIONS: GdPC is an important element of the intra-tumoural dFdC metabolic pathway in vivo.

nab-Paclitaxel: novel clinical and experimental evidence in pancreatic cancer.

The past few decades have seen virtually no treatment advances for patients with metastatic pancreatic cancer. Clinical hallmark features of pancreatic ductal adenocarcinoma (PDA) include late symptom onset, invasive growth, early liver and lymph node metastasis, and resistance to available chemotherapies. nab-Paclitaxel (Abraxane®) is generated through high-pressure homogenization of human albumin and conventional paclitaxel resulting in non-covalently bound, water-soluble albumin-paclitaxel particles with an approximate diameter of 130 nm. Results from the recently completed Metastatic Pancreatic Adenocarcinoma Trial (MPACT) (phase III trial) showed a significant survival benefit for patients treated with nab-paclitaxel in combination with gemcitabine, and this treatment regimen is currently being implemented in national and international guidelines for PDA patients. Therefore, this regimen provides a much needed vantage point of attack for this recalcitrant tumor offering potential new hope for our patients. Mechanisms such as stromal depletion, selective intratumoral accumulation, synergism with gemcitabine metabolism and secreted protein acidic and rich in cysteine (SPARC) mediated anti-tumor activity have been suggested for nab-paclitaxel. This review discusses the clinical and experimental advances of nab-paclitaxel in pancreatic cancer.

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.

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.

Therapeutic targeting of apoptotic pathways: novel aspects in pancreatic cancer.

Pancreatic cancer constitutes one of the most aggressive tumours with a 5-year survival rate of less than 5%. It is characterized by a high degree of resistance to apoptosis which is associated by high expression levels of multiple prosurvival proteins of the extrinsic and intrinsic apoptosis signalling cascades. This review focuses on current knowledge of apoptotic pathways involved in pancreatic cancer and mechanisms of resistance to apoptosis, including alterations in the death receptor and mitochondrial pathways, as well as anti-apoptotic effects of NF-kB and Akt signalling and the impact of histone-modifying enzymes such as histondeacetylases (HDAC). Furthermore, the therapeutic implications of modulating pro-survival pathways by specific inhibitors investigated in preclinical and clinical trials will be discussed.

[Contrast enhanced sonographic patterns of hepatic candidiasis]. / Kontrastunterstützte sonografische Befunde bei hepatischer Candidiasis.

PURPOSE: B-mode ultrasound (US) of hepatic candidiasis (HC) shows an uncharacteristic pattern. The aim of this study is to display the pattern of HC by performing contrast-enhanced ultrasound (CEUS). PATIENTS AND METHODS: Between May 2006 and June 2008 HC was diagnosed in 12 patients (4 female, 8 male) by clinical and sonographic findings. The underlying diseases were acute leukemia (n = 10), aplastic anemia (n = 1), and testicular cancer (n = 1) in either the state of complete remission (n = 10) or relapse (n = 2). Due to neutropenic fever after chemotherapy all of the patients had received antifungal therapy. When HC was diagnosed all patients were afebrile and in a recovered hematological constitution. Additional diagnostic procedures were histological examination (n = 5), computed tomography (n = 8) and sonographic follow-up examinations (n = 12). All patients were examined with B-mode US and CEUS. RESULTS: In B-mode US the lesions were hypoechoic (n = 12), multiple (n = 10) and > 1 cm (n = 8) as well as > 2 cm (n = 4) in diameter. During CEUS no enhancement of contrast media in the centre of the lesions was seen in all cases during both phases. Additionally, in the arterial phase, the lesions showed no rim enhancement (n = 3) (type I), an isoechoic rim enhancement (n = 5) (type II), or a hyperechoic rim enhancement (n = 4) (type III). During sonographic follow-up a complete regression of the lesions (n = 9) or a stable disease (n = 2) was seen. One patient died due to a relapse. CONCLUSION: The CEUS pattern of HC is variable but characteristic. Therefore, CEUS should be performed in all patients with suspected HC.

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.

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.

Increased Duodeno-Gastro-Esophageal Reflux (DGER) in symptomatic GERD patients with a history of cholecystectomy.

BACKGROUND: Duodenal-Gastro-Esophageal Reflux (DGER) represents an independent risk factor for the development of complicated Gastro-esophageal-reflux-disease (GERD) and Barrett's esophagus. Clinical and epidemiological data suggest a potential association between cholecystectomy (CCE) and augmented bile reflux. METHODS: 132 patients (67 women, 65 men, median age 55) with typical symptoms of GERD were enrolled in the study and divided in cholecystectomized (CCE-group: n = 107) and non- cholecystectomized (nCCE-group: n = 25) patients. Standardized clinical work-up of patients included combined esophageal 24 h pH-measurement and Bilitec 2000 esophageal manometry and upper endoscopy. RESULTS: In the statistical analysis no differences between the cholecystectomized group (CCE-group, n = 25) and the patients without cholecystectomy (nCCE-group, n = 107) could be observed in quantity or quality of reflux symptoms. Furthermore, neither acid reflux nor severity of inflammation and frequency of Barrett's esophagus significantly differed between the nCCE and CCE-group. However, the percentage of patients with pathological DGER were significantly higher in the CCE-group as compared to the nCCE-group (76 vs. 55 %, p < 0.01). Moreover, the CCE-group revealed significant higher levels of pathological DGER compared to the nCCE-group (15.5 % +/- 14.1 vs. 8.6 % +/- 15.4; p < 0.05). CONCLUSION: To conclude, our data provide first evidence of elevated DGER after CCE in patients with typical clinical symptoms of GERD using the Bilitec device. Both the frequency and the extent of DGER was significantly increased in the CCE-group. Prospective studies are urgently needed to elucidate the impact of CCE on DGER in patients with clinical symptoms of a reflux disease.