[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.

Study protocol P-MAPS: microbiome as predictor of severity in acute pancreatitis-a prospective multicentre translational study.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disorder that causes a considerable economic health burden. While the overall mortality is low, around 20% of patients have a complicated course of disease resulting in increased morbidity and mortality. There is an emerging body of evidence that the microbiome exerts a crucial impact on the pathophysiology and course of AP. For several decades multiple clinical and laboratory parameters have been evaluated, and complex scoring systems were developed to predict the clinical course of AP upon admission. However, the majority of scoring systems are determined after several days and achieve a sensitivity around 70% for early prediction of severe AP. Thus, continued efforts are required to investigate reliable biomarkers for the early prediction of severity in order to guide early clinical management of AP patients. METHODS: We designed a multi-center, prospective clinical-translational study to test whether the orointestinal microbiome may serve as novel early predictor of the course, severity and outcome of patients with AP. We will recruit 400 AP patients and obtain buccal and rectal swabs within 72 h of admission to the hospital. Following DNA extraction, microbiome analysis will be performed using 3rd generation sequencing Oxford Nanopore Technologies (ONT) for 16S rRNA and metagenomic sequencing. Alpha- and beta-diversity will be determined and correlated to the revised Atlanta classification and additional clinical outcome parameters such as the length of hospital stay, number and type of complications, number of interventions and 30-day mortality. DISCUSSION: If AP patients show a distinct orointestinal microbiome dependent on the severity and course of the disease, microbiome sequencing could rapidly be implemented in the early clinical management of AP patients in the future. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04777812.

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).

Spontaneous and Traumatic Splenic Rupture: Retrospective Clinical, B-Mode and CEUS Analysis in 62 Patients.

INTRODUCTION: Both B-mode ultrasound and contrast-enhanced ultrasound (CEUS) are well established procedures when diagnosing traumatic splenic ruptures (TSR). To date, there are no data about CEUS patterns in spontaneous splenic ruptures (SSR). It remains unknown whether TSR and SSR differ with respect to clinical characteristics, B-mode and CEUS characteristics. PATIENTS AND METHODS: Between 12/2003 and 2/2010, n=33 SSRs and n=29 TSRs were diagnosed in a tertiary referral center. All patients were examined with B-mode and CEUS, and clinical data and the outcome were retrospectively analyzed. RESULTS: Patients with SSR were significantly older than patients with TSR (62 years vs. 44 years; p=0.01). The 4-week mortality was significantly higher in SSR than in TSR (36% vs. 0%; p=0.001). No differences between the grading of TSR and SSR could be shown in B-mode or in CEUS. Notably, CEUS was significantly superior to B-mode with respect to the grading of splenic ruptures (p=0.01). Therefore, therapeutic management was influenced by CEUS. CONCLUSION: There are differences between SSR and TSR, especially concerning clinical data (age, course of disease and mortality). Regarding the sonographic pattern, SSR and TSR show identical grading. When splenic rupture is suspected, CEUS should always be performed to identify patients at risk who require interventional procedures.

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.

[Incidental findings in abdominal ultrasound. Characteristics and clinical interpretation]. / Zufallsbefunde in der Abdomensonographie: Charakteristika und klinische Interpretation.

Abdominal ultrasound is a common diagnostic procedure in internal medicine. The correct interpretation of incidental findings can be difficult at times and often results in expensive and sometimes invasive follow-up examinations. Therefore, detailed knowledge of incidental findings on abdominal ultrasound is of utmost clinical and economical importance. Incidental findings are often benign, however, an accurate evaluation and correct diagnosis is crucial for the subsequent clinical management. To this end B-mode ultrasonography is complemented by color flow Doppler sonography and contrast-enhanced ultrasonography to add dynamic information on blood flow and vessel formation. This article presents frequent incidental findings of the major abdominal organs and vessels, and describes the sonographic and clinical management to find the correct diagnosis.

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.

Combined lung-sound and reflux-monitoring: a pilot study of a novel approach to detect nocturnal respiratory symptoms in gastro-oesophageal reflux disease.

BACKGROUND: Increased prevalence of respiratory symptoms has been commonly reported in patients with gastro-oesophageal reflux disease (GERD). AIM: To introduce a novel Lung-Sound-Monitoring device that allows simultaneous measurement of both nocturnal respiratory symptoms and episodes of acidic and biliary refluxes. METHODS: Nocturnal respiratory symptoms (coughing and wheezing) were continuously recorded in 20 healthy subjects and 30 reflux patients with respiratory symptoms in parallel to combined pH-monitoring and Bilitec measurement. RESULTS: Analysis could be completed in 20 healthy subjects and in 25 patients with reflux. A clear temporal correlation to reflux phases was detected in 49% of coughing and 41% of wheezing events, respectively. Moreover, 89% of the coughing and 100% of the wheezing events succeeded reflux episodes. Finally, the technique was capable of assessing a statistically significant difference between patients and controls regarding the occurrence of these symptoms. CONCLUSIONS: Our pilot study establishes the Lung-Sound-Monitoring system as a unique tool to measure objectively the temporal correlation between gastroesophageal reflux and the appearance of respiratory symptoms. It represents a useful technique to identify patients with respiratory symptoms due to reflux, and therefore allows one to determine and quantify the impact of therapeutic interventions such as antireflux therapy on respiratory symptoms.