Publications by authors named "Lars Grenacher"

68 Publications

Assessment of tissue perfusion of pancreatic cancer as potential imaging biomarker by means of Intravoxel incoherent motion MRI and CT perfusion: correlation with histological microvessel density as ground truth.

Cancer Imaging 2021 Jan 19;21(1):13. Epub 2021 Jan 19.

Clinic for Diagnostic and Interventional Radiology (DIR), Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120, Heidelberg, Germany.

Background/objectives: The aim of this study was to compare intravoxel incoherent motion (IVIM) diffusion weighted (DW) MRI and CT perfusion to assess tumor perfusion of pancreatic ductal adenocarcinoma (PDAC).

Methods: In this prospective study, DW-MRI and CT perfusion were conducted in nineteen patients with PDAC on the day before surgery. IVIM analysis of DW-MRI was performed and the parameters perfusion fraction f, pseudodiffusion coefficient D*, and diffusion coefficient D were extracted for tumors, upstream, and downstream parenchyma. With a deconvolution-based analysis, the CT perfusion parameters blood flow (BF) and blood volume (BV) were estimated for tumors, upstream, and downstream parenchyma. In ten patients, intratumoral microvessel density (MVD) and microvessel area (MVA) were analyzed microscopically in resection specimens. Correlation coefficients between IVIM parameters, CT perfusion parameters, and histological microvessel parameters in tumors were calculated. Receiver operating characteristic (ROC) analysis was performed for differentiation of tumors and upstream parenchyma.

Results: f significantly positively correlated with BF (r = 0.668, p = 0.002) and BV (r = 0.672, p = 0.002). There were significant positive correlations between f and MVD/ MVA (r ≥ 0.770, p ≤ 0.009) as well as between BF and MVD/ MVA (r ≥ 0.697, p ≤ 0.025). Correlation coefficients between f and MVD/ MVA were not significantly different from correlation coefficients between BF and MVD/ MVA (p ≥ 0.400). Moreover, f, BF, BV, and permeability values (PEM) showed excellent performance in distinguishing tumors from upstream parenchyma (area under the ROC curve ≥0.874).

Conclusions: The study shows that IVIM derived f and CT perfusion derived BF similarly reflect vascularity of PDAC and seem to be comparably applicable for the evaluation of tumor perfusion for tumor characterization and as potential quantitative imaging biomarker.

Trial Registration: DRKS, DRKS00022227, Registered 26 June 2020, retrospectively registered. https://www.drks.de/drks_web/navigate.do?navigationId=trial . HTML&TRIAL_ID=DRKS00022227.
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http://dx.doi.org/10.1186/s40644-021-00382-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816417PMC
January 2021

Evaluation of cross-sectional imaging features that aid in the differentiation of benign and malignant splenic lesions.

Eur J Radiol 2021 Mar 13;136:109549. Epub 2021 Jan 13.

Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany.

Purpose: This study aimed to investigate the role of cross-sectional imaging in differentiating between benign and malignant splenic lesions based on various imaging features.

Methods: Database of imaging reports from January 2015 to December 2017 were searched dedicatedly for "spleen" or "splenic" terms to identify patients with splenic lesions found either on CT or MRI. The study cohort consisted of patients who had available histological reports or had follow-up imaging for a minimum of one year. Patients were categorized into the benign subcohort if they did not have a history of extra-splenic malignancy, and had a splenic lesion(s) falling into one of these categories: benign histopathology on biopsy, stable size and enhancement, or decreased size on follow-up imaging. Those who had malignant histopathology on biopsy were included in the malignant subcohort. Various morphologic features and enhancement patterns of these lesions were carefully reviewed by two radiologists who were blinded to the final histopathologic diagnosis.

Results: We identified 161 patients (54 % males, mean age ± SD = 59.7 ± 15.4) including 124 (77 %) in the benign and 37 (23 %) in the malignant subcohort. Benign lesions were more likely to be cystic (21.7 % vs 2.7 %, p < 0.001), homogenous (59.7 % vs. 29.7 %, p = 0.001) and to demonstrate well-defined borders (69.3 % vs. 29.7 % p= <0.001). Malignant lesions had significantly larger diameter (median size: 15 vs 11 mm, p = 0.03). Restricted diffusion was not seen in any of the benign lesions; however, 50 % of malignant lesions demonstrated restricted diffusion (p = 0.003). Features such as lesion distribution, presence of calcification, splenomegaly and number of lesions were not significantly different between benign and malignant lesions.

Conclusion: Smaller lesion diameter, well-defined border and homogeneity favor benign nature of splenic lesions while restricted diffusion should raise suspicion for malignancy.
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http://dx.doi.org/10.1016/j.ejrad.2021.109549DOI Listing
March 2021

LI-RADS in the year 2020 - Are you already using it or still considering?

Rofo 2021 Feb 20;193(2):186-193. Epub 2020 Jul 20.

Institute for Diagnostic and Interventional Radiology, Brandenburg Medical School Theodor Fontane, Brandenburg a. d. Havel, Germany.

Purpose:  The working group for gastrointestinal and abdominal imaging within the German Radiological Society performed a nationwide online survey in order to assess the current status regarding the awareness and application of LI-RADS, a classification for evaluation of liver lesions in patients at risk.

Materials And Methods:  Using the website www.deutsches-krankenhausverzeichnis.de a list of hospitals was generated meeting the criteria internal medicine, gastroenterology, general and visceral surgery and radiology (n = 391). Randomly, 102 department directors were contacted, and asked to name one consultant and one resident from their department in order to participate in the survey. 177 potential participants were invited to fill out an approximately 10-minute online survey in the form of 17 questions regarding the awareness and application of LI-RADS. The results of the survey were analyzed by means of descriptive statistics.

Results:  77 participants were registered, which corresponds to a response rate of 43.5 %. 47 % of all participants were radiologists, 30 % surgeons and 23 % internal doctors/gastroenterologists, respectively, many with more than 13 years of professional experience (37.2 %). The majority of participants worked in a hospital with a focus (37.2 %) or a university hospital (29.1 %). Even though the majority of participants knows about or has heard of LI-RADS (73.2 %), only a minority uses the classification themselves (26 %) or within the context of tumor boards (19.2 %).

Conclusion:  The results of our survey demonstrate that LI-RADS is relatively known in Germany, the application however quite sparse. This is in contrast to the general desire and endeavor for more standardized reporting in radiology.

Key Points: · LI-RADS is not yet broadly implemented in clinical routine in Germany. · The sparse application is in contrast to the general desire for more standardized reporting in radiology. · Interdisciplinary education may support the propagation and use of the LI-RDAS classification.

Citation Format: · Ringe KI, Gut A, Grenacher L et al. LI-RADS in the year 2020 - Are you already using it or still considering? Fortschr Röntgenstr 2021; 193: 186 - 193.
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http://dx.doi.org/10.1055/a-1212-5915DOI Listing
February 2021

Structured Reporting of Solid and Cystic Pancreatic Lesions in CT and MRI: Consensus-Based Structured Report Templates of the German Society of Radiology (DRG).

Rofo 2020 Jul 2;192(7):641-656. Epub 2020 Jul 2.

Department of Radiology, Clemens-Hospital GmbH Münster, Germany.

Background:  Radiological reports of pancreatic lesions are currently widely formulated as free texts. However, for optimal characterization, staging and operation planning, a wide range of information is required but is sometimes not captured comprehensively. Structured reporting offers the potential for improvement in terms of completeness, reproducibility and clarity of interdisciplinary communication.

Method:  Interdisciplinary consensus finding of structured report templates for solid and cystic pancreatic tumors in computed tomography (CT) and magnetic resonance imaging (MRI) with representatives of the German Society of Radiology (DRG), German Society for General and Visceral Surgery (DGAV), working group Oncological Imaging (ABO) of the German Cancer Society (DKG) and other radiologists, oncologists and surgeons.

Results:  Among experts in the field of pancreatic imaging, oncology and pancreatic surgery, as well as in a public online survey, structured report templates were developed by consensus. These templates are available on the DRG homepage under www.befundung.drg.de and will be regularly revised to the current state of scientific knowledge by the participating specialist societies and responsible working groups.

Conclusion:  This article presents structured report templates for solid and cystic pancreatic tumors to improve clinical staging (cTNM, ycTNM) in everyday radiology.

Key Points:   · Structured report templates offer the potential of optimized radiological reporting with regard to completeness, reproducibility and differential diagnosis.. · This article presents consensus-based, structured reports for solid and cystic pancreatic lesions in CT and MRI.. · These structured reports are available open source on the homepage of the German Society of Radiology (DRG) under www.befundung.drg.de..

Citation Format: · Persigehl T, Baumhauer M, Baeßler B et al. Structured Reporting of Solid and Cystic Pancreatic Lesions in CT and MRI: Consensus-Based Structured Report Templates of the German Society of Radiology (DRG). Fortschr Röntgenstr 2020; 192: 641 - 655.
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http://dx.doi.org/10.1055/a-1150-8217DOI Listing
July 2020

MR defecography detects pelvic floor dysfunction in participants with chronic complete spinal cord injury.

Spinal Cord 2020 Feb 10;58(2):203-210. Epub 2019 Sep 10.

Spinal Cord Injury Center, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118, Heidelberg, Germany.

Study Design: A prospective single arm study.

Objectives: Previously we have demonstrated that magnetic resonance (MR) defecography is feasible in participants with complete spinal cord injury (SCI). The main aim of this study is to evaluate whether MR defecography can provide objective parameters correlating with the clinical manifestations of neurogenic bowel dysfunction (NBD) in participants with SCI.

Setting: A monocentric study in a comprehensive care university hospital Spinal Cord Injury Center.

Methods: Previously published MR defecography parameters (anorectal angle (ARA), hiatal descent (M-line) and hiatal width (H-line)) of twenty participants with SCI were now compared to a standardized clinical assessment of NBD. Descriptive statistics, correlations and t-tests for independent samples were calculated.

Results: The significantly higher values for the ARA at rest and M-line at rest in participants with SCI correlated with the clinical assessment of bowel incontinence. Furthermore, in nearly half of the investigated SCI cohort the normally positive difference between ARA, M-line and H-line at rest and during defecation became negative suggesting pelvic floor dyssynergia as a potential mechanism underlying constipation in people with complete SCI. In fact, these participants showed a more severe clinical presentation of NBD according to the total NBD score.

Conclusions: MR defecography provides objective parameters correlating with clinical signs of NBD, such as constipation and bowel incontinence. Therefore, MR defecography can support pathophysiology-based decision-making with respect to specific therapeutic interventions, which should help to improve the management of NBD.
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http://dx.doi.org/10.1038/s41393-019-0351-8DOI Listing
February 2020

A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer.

Oncoimmunology 2018;7(4):e1303584. Epub 2018 Jan 16.

Regensburg Center for Interventional Immunology (RCI), University Hospital Regensburg, Regensburg, Germany.

VXM01 is a first-in-kind orally applied tumor vaccine based on live attenuated typhi carrying an expression plasmid encoding VEGFR2, an antigen expressed on tumor vasculature and a stable and accessible target for anti-angiogenic intervention. A recent randomized, placebo-controlled, phase I dose-escalation trial in advanced pancreatic cancer patients demonstrated safety, immunogenicity and transient, T-cell response-related anti-angiogenic activity of four priming vaccinations applied within one week. We here evaluated whether monthly boost vaccinations are safe and can sustain increased frequencies of vaccine-specific T cells. Patients with advanced pancreatic cancer were randomly assigned at a ratio of 2:1 to priming with VXM01 followed by up to six monthly boost vaccinations, or placebo treatment. Vaccinations were applied orally at two alternative doses of either 10 colony-forming units (CFU) or 10 CFU, and concomitant treatment with standard-of-care gemcitabine during the priming phase, and any treatment thereafter, was allowed in the study. Immunomonitoring involved interferon-gamma (IFNγ) ELIspot analysis with long overlapping peptides spanning the entire VEGFR2 sequence. A total of 26 patients were treated. Treatment-related adverse events preferentially associated with VXM01 were decreases in lymphocyte numbers in the blood, increased frequencies of neutrophils and diarrhea. Eight out of 16 patients who received at least one boosting vaccination responded with pronounced, i.e. at least 3-fold, increase in VEGFR2-specific T cell response over baseline levels. In the VXM01 vaccination group, VEGFR2-specific T cells peaked preferentially during the boosting phase with an average 4-fold increase over baseline levels. In conclusion, prime/boost vaccination with VXM01 was safe and immunogenic and increased vaccine specific T cell responses compared with placebo treatment.
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http://dx.doi.org/10.1080/2162402X.2017.1303584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889207PMC
January 2018

3T MR-defecography-A feasibility study in sensorimotor complete spinal cord injured patients with neurogenic bowel dysfunction.

Eur J Radiol 2017 Jun 21;91:15-21. Epub 2017 Mar 21.

Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Electronic address:

Introduction: To investigate whether MR-defecography can be employed in sensorimotor complete spinal cord injury (SCI) subjects as a potential diagnostic tool to detect defecational disorders associated with neurogenic bowel dysfunction (NBD) using standard parameters for obstructed defecation.

Material And Methods: In a prospective single centre clinical trial, we developed MR-defecography in traumatic sensorimotor complete paraplegic SCI patients with upper motoneuron type injury (neurological level of injury T1 to T10) using a conventional 3T scanner. Defecation was successfully induced by eliciting the defecational reflex after rectal filling with ultrasonic gel, application of two lecicarbon suppositories and digital rectal stimulation. Examination was performed with patients in left lateral decubitus position using T2-weighted turbo spin echo sequence in the sagittal plane at rest (TE 89ms, TR 3220ms, FOV 300mm, matrix 512×512, ST 4mm) and ultrafast-T2-weighted-sequence in the sagittal plane with repeating measurements (TE 1.54ms, TR 3.51ms, FOV 400mm, matrix 256×256, ST 6mm). Changes of anorectal angle (ARA), anorectal descent (ARJ) and pelvic floor weakness were documented and measured data was compared to reference values of asymptomatic non-SCI subjects in the literature to assess feasibility.

Results: MR-defecography provides evaluable imaging sequences of the induced evacuation phase in SCI patients. Measurement results for ARA, ARJ, hiatal width (H-line) and hiatal descent (M-line) deviate significantly from reference values in the literature in asymptomatic subjects without SCI. The overall mean values in our study for SCI patients were: ARA (rest) 127.3°, ARA (evacuation) 137.6°, ARJ (rest) 2.4cm, ARJ (evacuation) 4.0cm, H-line (rest) 7.6cm, H-line (evacuation) 8.1cm, M-line (rest) 2.6cm, M-line (evacuation) 4.2cm.

Conclusions: MR-defecography is feasible in sensorimotor complete SCI patients. Individual MR-defecography findings may help to determine specific therapeutical options for respective patients suffering from severe NBD.
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http://dx.doi.org/10.1016/j.ejrad.2017.02.036DOI Listing
June 2017

Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer.

J Nanobiotechnology 2016 Dec 19;14(1):81. Epub 2016 Dec 19.

Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Functionalized nanoparticles (NPs) are one promising tool for detecting specific molecular targets and combine molecular biology and nanotechnology aiming at modern imaging. We aimed at ligand-directed delivery with a suitable target-biomarker to detect early pancreatic ductal adenocarcinoma (PDAC). Promising targets are galectins (Gal), due to their strong expression in and on PDAC-cells and occurrence at early stages in cancer precursor lesions, but not in adjacent normal tissues.

Results: Molecular probes (10-29 AA long peptides) derived from human tissue plasminogen activator (t-PA) were selected as binding partners to galectins. Affinity constants between the synthesized t-PA peptides and Gal were determined by microscale thermophoresis. The 29 AA-long t-PA-peptide-1 with a lactose-functionalized serine revealed the strongest binding properties to Gal-1 which was 25-fold higher in comparison with the native t-PA protein and showed additional strong binding to Gal-3 and Gal-4, both also over-expressed in PDAC. t-PA-peptide-1 was selected as vector moiety and linked covalently onto the surface of biodegradable iron oxide nanoparticles (NPs). In particular, CAN-doped maghemite NPs (CAN-Mag), promising as contrast agent for magnetic resonance imaging (MRI), were selected as magnetic core and coated with different biocompatible polymers, such as chitosan (CAN-Mag-Chitosan NPs) or polylactic co glycolic acid (PLGA) obtaining polymeric nanoparticles (CAN-Mag@PNPs), already approved for drug delivery applications. The binding efficacy of t-PA-vectorized NPs determined by exposure to different pancreatic cell lines was up to 90%, as assessed by flow cytometry. The in vivo targeting and imaging efficacy of the vectorized NPs were evaluated by applying murine pancreatic tumor models and assessed by 1.5 T magnetic resonance imaging (MRI). The t-PA-vectorized NPs as well as the protease-activated NPs with outer shell decoration (CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1) showed clearly detectable drop of subcutaneous and orthotopic tumor staining-intensity indicating a considerable uptake of the injected NPs. Post mortem NP deposition in tumors and organs was confirmed by Fe staining of histopathology tissue sections.

Conclusions: The targeted NPs indicate a fast and enhanced deposition of NPs in the murine tumor models. The CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1 interlocking steps strategy of NPs delivery and deposition in pancreatic tumor is promising.
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http://dx.doi.org/10.1186/s12951-016-0236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5168863PMC
December 2016

Intraductal papillary mucinous neoplasms of the pancreas: radiological predictors of malignant transformation and the introduction of bile duct dilation to current guidelines.

Br J Radiol 2016 9;89(1061):20150853. Epub 2016 Mar 9.

1 Radiology Department, University Hospital Heidelberg, Heidelberg, Germany.

Objective: To evaluate the current guidelines as a model to predict malignancy and to determine further radiological predictors of malignancy in intraductal papillary mucinous neoplasms (IPMNs).

Methods: 384 patients who had undergone a pancreatic operation with the pathological diagnosis of IPMN as well as applicable pre-operative imaging (CT/MRI) were included in the study. Images were evaluated retrospectively in consensus by two radiologists, using a standardized checklist. Descriptive statistics, binary logistic regression and receiver operator curve analysis were performed to assess the International Consensus Guidelines and other radiological predictors of clinical malignancy (defined as carcinoma in situ and invasive carcinoma).

Results: The best independent predictors of malignancy (n = 191) were solid components [odds ratio (OR) 3.98], parenchymal atrophy with main pancreatic duct dilation 5-9 mm (OR: 5.1) and common bile duct (CBD) dilation (OR: 31.26). >96% of all cases with CBD dilation were malignant IPMNs (positive-predictive value 96.4%; negative-predictive value 63.1%). Analysis of the current guidelines showed a diagnostic improvement with the addition of CBD dilation on determining the malignancy of IPMNs (sensitivity 82.2%/86.9%; specificity 72.7%/74.6%). Subanalysis of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs; n = 168) also resulted in a diagnostic improvement with the addition of CBD dilation (sensitivity 28.6%/45.2%; specificity 92.9%/92.1%). The best independent predictors of malignancy for BD-IPMNs were parenchymal atrophy (OR: 4.00) and CBD dilation (OR: 29.3). Frequency analysis revealed that even small BD-IPMNs had already undergone malignant transformation (≤1 cm: 15%; 1-2 cm: 26%; 2-3 cm: 20%) with about 10% of those having a dilated bile duct.

Conclusion: CBD dilation was a significant positive predictor of malignancy in IPMNs regardless of their size.

Advances In Knowledge: Introduction of CBD dilation as a radiological predictor for malignancy might increase the diagnostic accuracy of current imaging-based guidelines.
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http://dx.doi.org/10.1259/bjr.20150853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985463PMC
September 2016

CT-based compartmental quantification of adipose tissue versus body metrics in colorectal cancer patients.

Eur Radiol 2016 Nov 6;26(11):4131-4140. Epub 2016 Feb 6.

Department of Diagnostic and Interventional Radiology, University Hospital, Heidelberg, Germany.

Purpose: While obesity is considered a prognostic factor in colorectal cancer (CRC), there is increasing evidence that not simply body mass index (BMI) alone but specifically abdominal fat distribution is what matters. As part of the ColoCare study, this study measured the distribution of adipose tissue compartments in CRC patients and aimed to identify the body metric that best correlates with these measurements as a useful proxy for adipose tissue distribution.

Materials And Methods: In 120 newly-diagnosed CRC patients who underwent multidetector computed tomography (CT), densitometric quantification of total (TFA), visceral (VFA), intraperitoneal (IFA), retroperitoneal (RFA), and subcutaneous fat area (SFA), as well as the M. erector spinae and psoas was performed to test the association with gender, age, tumor stage, metabolic equivalents, BMI, waist-to-height (WHtR) and waist-to-hip ratio (WHR).

Results: VFA was 28.8 % higher in men (p<0.0001) and 30.5 % higher in patients older than 61 years (p<0.0001). WHtR correlated best with all adipose tissue compartments (r=0.69, r=0.84, p<0.0001) and visceral-to-subcutaneous-fat-ratio (VFR, r=0.22, p=<0.05). Patients with tumor stages III/IV showed significantly lower overall adipose tissue than I/II. Increased M. erector spinae mass was inversely correlated with all compartments.

Conclusion: Densitometric quantification on CT is a highly reproducible and reliable method to show fat distribution across adipose tissue compartments. This distribution might be best reflected by WHtR, rather than by BMI or WHR.

Key Points: • Densitometric quantification of adipose tissue on CT is highly reproducible and reliable. • Waist-to-height ratio better correlates with adipose tissue compartments and VFR than BMI or waist-to-hip ratio. • Men have higher a higher visceral fat area than women. • Patients older than 61 years have higher visceral fat area. • Patients with tumor stages III/IV have significantly lower adipose tissue than those in stages I/II.
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http://dx.doi.org/10.1007/s00330-016-4231-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587125PMC
November 2016

Fluid collection after distal pancreatectomy: a frequent finding.

HPB (Oxford) 2016 Jan 18;18(1):35-40. Epub 2015 Nov 18.

Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Electronic address:

Background: Fluid collections (FC) at the resection margin of the pancreatic stump after distal pancreatectomy (DP) are common radiological findings in follow-up scans. No recommendations exist regarding the management of such findings. The aim was to characterise incidence, risk factors, clinical impact and therapy of FC.

Method: Data of 209 patients who underwent DP between 07/2009 and 06/2011 were prospectively collected and analysed, regarding follow-up CT or MRI scan findings of FC at the resection margin. FC was defined as a cyst-like lesion >1 cm in diameter.

Results: A follow-up with at least two cross-sectional images was available in 159/209 patients. In the first postoperative control, 68 patients showed an FC (43%). FC size was classified as <5 cm (n = 38 pat.), 5-10 cm (n = 24 pat.) and >10 cm (n = 6 pat.). 20 patients (30%) showed clinical symptoms. Six patients (9%) required specific treatment, all other FC showed spontaneous regression. No correlation with stump closure techniques or preceding postoperative pancreatic fistula was found (4/68 patients, 6%). Multivariate analysis revealed standard resections as the only significant factor for FC.

Conclusions: FCs at the resection margin after DP are frequent and harmless findings. Therapeutic interventions are required in only 9% of all FC patients.
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http://dx.doi.org/10.1016/j.hpb.2015.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750236PMC
January 2016

Precancerous Lesions and Carcinoma of the Pancreas.

Viszeralmedizin 2015 Feb 3;31(1):53-7. Epub 2015 Feb 3.

Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.

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http://dx.doi.org/10.1159/000375245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582694PMC
February 2015

IVIM DW-MRI of autoimmune pancreatitis: therapy monitoring and differentiation from pancreatic cancer.

Eur Radiol 2016 Jul 8;26(7):2099-106. Epub 2015 Oct 8.

Department of Radiology, University Hospital Basel, Basel, Switzerland.

Objectives: To evaluate IVIM DW-MRI for changes in IVIM-derived parameters during steroid treatment of autoimmune pancreatitis (AIP) and for the differentiation from pancreatic cancer (PC).

Methods: Fifteen AIP-patients, 11 healthy patients and 20 PC-patients were examined with DWI-MRI using eight b-values (50, 100, 150, 200, 300, 400, 600, 800). 12 AIP-patients underwent follow-up examinations during treatment. IVIM-parameters and ADC800-values were tested for significant differences and an ROC analysis was performed.

Results: The perfusion fraction f was significantly lower in patients with AIP at the time of diagnosis (10.5 ± 4.3 %) than in patients without AIP (20.7 ± 4.3 %). In AIP follow-up, f increased significantly to 17.1 ± 7.0 % in the first and 21.0 ± 4.1 % in the second follow up. In PC, the f-values were lower (8.2 ± 4.0 %, n.s.) compared to initial AIP and were significantly lower compared to first and second follow-up examination. In the ROC-analysis AUC-values for f were 0.63, 0.88 and 0.98 for differentiation of PC from initial, first and second follow up AIP-examination.

Conclusions: The found differences in f between AIP, AIP during steroid treatment and pancreatic cancer suggest that IVIM-diffusion MRI could serve as imaging biomarker during treatment in AIP-patients and as a helpful tool for differentiation between PC and AIP.

Key Points: • MRI is used for follow-up examinations during therapy in AIP-patients • IVIM-DWI-MRI offers parameters which reflect perfusion and true diffusion • IVIM-parameters are helpful for differentiation between AIP and pancreatic cancer • IVIM-parameters could serve as an imaging biomarker during steroid treatment.
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http://dx.doi.org/10.1007/s00330-015-4041-4DOI Listing
July 2016

Cyst Features and Risk of Malignancy in Intraductal Papillary Mucinous Neoplasms of the Pancreas: Imaging and Pathology.

Viszeralmedizin 2015 Feb;31(1):31-7

Department of Medicine A, University Medicine, Ernst Moritz Arndt University, Greifswald, Germany.

Background: Intraductal papillary mucinous neoplasms (IPMNs) display diverse macroscopic, histological, and immunohistochemical characteristics with typical morphological appearance in magnetic resonance imaging. Depending on those, IPMNs may show progression into invasive carcinomas with variable frequency. Overall, IPMN-associated invasive carcinomas are found in about 30% of all IPMNs, revealing phenotpyes comparable with conventional ductal adenocarcinomas or mucinous (colloid) carcinomas of the pancreas. In Sendai-negative side-branch IPMNs, however, the annual risk of the development of invasive cancer is 2%; thus, risk stratification with regard to imaging and preoperative biomarkers and cytology is mandatory.

Methods And Results: The present study addresses the radiological and interventional preoperative measures including histological features to determine the risk of malignancy and the prognosis of IPMNs.

Conclusion: While preoperative imaging largely relies on the detection of macroscopic features of IPMNs, which are associated with a divergent risk of malignant behavior, in resected specimens the determination of the grade of dysplasia and the detection of an invasive component are the most important features to estimate the prognosis of IPMNs.
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http://dx.doi.org/10.1159/000375254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433136PMC
February 2015

Correlation of Histological Vessel Characteristics and Diffusion-Weighted Imaging Intravoxel Incoherent Motion-Derived Parameters in Pancreatic Ductal Adenocarcinomas and Pancreatic Neuroendocrine Tumors.

Invest Radiol 2015 Nov;50(11):792-7

From the *Department of Diagnostic and Interventional Radiology, and †Institute of Pathology, University of Heidelberg, Heidelberg, Germany; ‡Department of Medical and Biological Informatics, DKFZ, Heidelberg, Germany; §Department of Surgery, University of Heidelberg, Heidelberg, Germany; ∥Diagnostic Munich, Munich, Germany; and ¶Department of Radiology, University of Basel, Basel, Switzerland.

Objective: To investigate the correlation between intravoxel incoherent motion (IVIM) model-derived parameters and histologically determined microvascularity in pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine tumors (PNETs).

Materials And Methods: From April 2013 to May 2014, 42 patients with malignant pancreatic tumors were prospectively examined with diffusion-weighted imaging (DWI) magnetic resonance imaging using a breath-hold variant with 9 b values (0-800 seconds/mm). Intravoxel incoherent motion parameters were extracted from 2 types of volumes of interest (VOIs), one VOI encompassing the total tumor volume (TTV) and another VOI corresponding to the histological regional tumor location (RTV). In 36 PDACs and 6 PNETs, microvessel analysis was performed based on representative tissue sections from the resected tumor tissue, and microvessel density (MVD) as well as microvessel area were calculated. We performed a Pearson-correlation test to study the relationship between IVIM-derived and histology-derived parameters.

Results: The DWI-IVIM-derived flowing blood volume fraction f was significantly lower in PDACs compared to PNETs (9.9% ± 5.4% vs 15.5% ± 5.2%; P < 0.0001), the diffusion coefficient D was significantly higher (1.2 ± 0.18 × 10 vs 1.03 ± 0.15 × 10 mm/s; P = 0.001). There was no significant difference in the pseudodiffusion coefficient D* (44.9 ± 52.9 ×10 vs 53.8 ± 51.2 × 10 mm/s). Microvessel density was significantly lower in PDACs (36.8 ± 25.9/mm vs 80.0 ± 26.1/mm; P = 0.0005) compared to PNETs. When derived from the RTV, the flowing blood volume fraction f and MVD of PDACs and PNETs showed excellent correlation (r = 0.85). The correlation using the TTV was moderate (0.64). f (RTV and TTV) and microvessel area showed moderate correlation (r = 0.54/0.47).

Conclusions: Intravoxel incoherent motion-derived flowing blood volume fraction f and MVD demonstrate an excellent correlation with histological tumor features in PDAC and PNET. Consequently, IVIM DWI may serve as noninvasive marker of tumor vascularity in different types of pancreatic neoplasms.
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http://dx.doi.org/10.1097/RLI.0000000000000187DOI Listing
November 2015

Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial.

Oncoimmunology 2015 Apr 16;4(4):e1001217. Epub 2015 Mar 16.

Translational Immunology; National Center for Tumor Diseases ; Heidelberg, Germany.

VEGFR-2 is expressed on tumor vasculature and a target for anti-angiogenic intervention. VXM01 is a first in kind orally applied tumor vaccine based on live, attenuated Salmonella bacteria carrying an expression plasmid, encoding VEGFR-2. We here studied the safety, tolerability, T effector (Teff), T regulatory (Treg) and humoral responses to VEGFR2 and anti-angiogenic effects in advanced pancreatic cancer patients in a randomized, dose escalation phase I clinical trial. Results of the first 3 mo observation period are reported. Locally advanced or metastatic, pancreatic cancer patients were enrolled. In five escalating dose groups, 30 patients received VXM01 and 15 placebo on days 1, 3, 5, and 7. Treatment was well tolerated at all dose levels. No dose-limiting toxicities were observed. Salmonella excretion and salmonella-specific humoral immune responses occurred in the two highest dose groups. VEGFR2 specific Teff, but not Treg responses were overall increased in vaccinated patients. We furthermore observed a significant reduction of tumor perfusion after 38 d in vaccinated patients together with increased levels of serum biomarkers indicative of anti-angiogenic activity, VEGF-A, and collagen IV. Vaccine specific Teff responses significantly correlated with reductions of tumor perfusion and high levels of preexisting VEGFR2-specific Teff while those showing no antiangiogenic activity had low levels of preexisting VEGFR2 specific Teff, showed a transient early increase of VEGFR2-specific Treg and reduced levels of VEGFR2-specific Teff at later time points - pointing to the possibility that early anti-angiogenic activity might be based at least in part on specific reactivation of preexisting memory T cells.
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http://dx.doi.org/10.1080/2162402X.2014.1001217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485742PMC
April 2015

Correlation of quantitative dual-energy computed tomography iodine maps and abdominal computed tomography perfusion measurements: are single-acquisition dual-energy computed tomography iodine maps more than a reduced-dose surrogate of conventional computed tomography perfusion?

Invest Radiol 2015 Oct;50(10):703-8

From the Clinic of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany.

Objectives: Study objectives were the quantitative evaluation of whether conventional abdominal computed tomography (CT) perfusion measurements mathematically correlate with quantitative single-acquisition dual-energy CT (DECT) iodine concentration maps, the determination of the optimum time of acquisition for achieving maximum correlation, and the estimation of the potential for radiation exposure reduction when replacing conventional CT perfusion by single-acquisition DECT iodine concentration maps.

Materials And Methods: Dual-energy CT perfusion sequences were dynamically acquired over 51 seconds (34 acquisitions every 1.5 seconds) in 24 patients with histologically verified pancreatic carcinoma using dual-source DECT at tube potentials of 80 kVp and 140 kVp. Using software developed in-house, perfusion maps were calculated from 80-kVp image series using the maximum slope model after deformable motion correction. In addition, quantitative iodine maps were calculated for each of the 34 DECT acquisitions per patient. Within a manual segmentation of the pancreas, voxel-by-voxel correlation between the perfusion map and each of the iodine maps was calculated for each patient to determine the optimum time of acquisition topt defined as the acquisition time of the iodine map with the highest correlation coefficient. Subsequently, regions of interest were placed inside the tumor and inside healthy pancreatic tissue, and correlation between mean perfusion values and mean iodine concentrations within these regions of interest at topt was calculated for the patient sample.

Results: The mean (SD) topt was 31.7 (5.4) seconds after the start of contrast agent injection. The mean (SD) perfusion values for healthy pancreatic and tumor tissues were 67.8 (26.7) mL per 100 mL/min and 43.7 (32.2) mL per 100 mL/min, respectively. At topt, the mean (SD) iodine concentrations were 2.07 (0.71) mg/mL in healthy pancreatic and 1.69 (0.98) mg/mL in tumor tissue, respectively. Overall, the correlation between perfusion values and iodine concentrations was high (0.77), with correlation of 0.89 in tumor and of 0.56 in healthy pancreatic tissue at topt. Comparing radiation exposure associated with a single DECT acquisition at topt (0.18 mSv) to that of an 80 kVp CT perfusion sequence (2.96 mSv) indicates that an average reduction of Deff by 94% could be achieved by replacing conventional CT perfusion with a single-acquisition DECT iodine concentration map.

Conclusions: Quantitative iodine concentration maps obtained with DECT correlate well with conventional abdominal CT perfusion measurements, suggesting that quantitative iodine maps calculated from a single DECT acquisition at an organ-specific and patient-specific optimum time of acquisition might be able to replace conventional abdominal CT perfusion measurements if the time of acquisition is carefully calibrated. This could lead to large reductions of radiation exposure to the patients while offering quantitative perfusion data for diagnosis.
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http://dx.doi.org/10.1097/RLI.0000000000000176DOI Listing
October 2015

Influence of Different Neoadjuvant Chemotherapy Regimens on Response, Prognosis, and Complication Rate in Patients with Esophagogastric Adenocarcinoma.

Ann Surg Oncol 2015 Dec 22;22 Suppl 3:S905-14. Epub 2015 May 22.

Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Background: Perioperative chemotherapy improves survival in patients with advanced esophagogastric cancer, but the optimal treatment regimen remains unclear. More intensive chemotherapy may improve outcome, but also increase toxicity and complications.

Methods: A total of 843 patients were included in this retrospective study and stratified in 4 groups: doublet therapy with cisplatin or oxaliplatin and 5-fluorouracil (groups A/B) or triplet therapy with additional epirubicin or taxane (groups C/D). The influence of the different neoadjuvant chemotherapy regimens on response, prognosis, and complications was assessed.

Results: Clinical and pathological response were associated with longer overall survival (OS; p < 0.001). No significant differences regarding response or OS were found, but there was a trend toward better outcome in group D (taxane-containing triplet). In the subgroup of 669 patients with adenocarcinomas of the esophagogastric junction (AEG), patients who had received taxane-containing regimens had a significantly longer OS (p = 0.037), but taxane use was not an independent factor in multivariate analysis. Triple therapy with taxanes did not result in a higher complication rate or postoperative mortality.

Conclusions: Although no superior neoadjuvant chemotherapy regimen was identified for patients with esophagogastric adenocarcinoma, taxane-containing regimens should be further investigated in randomized trials, especially in patients with AEG tumors.
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http://dx.doi.org/10.1245/s10434-015-4617-xDOI Listing
December 2015

Hypodense liver lesions in patients with hepatic steatosis: do we profit from dual-energy computed tomography?

Eur Radiol 2015 Dec 17;25(12):3567-76. Epub 2015 May 17.

Department of Diagnostic and Interventional Radiology (DIR), University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Purpose: To evaluate dual-energy CT (DECT) imaging of hypodense liver lesions in patients with hepatic steatosis, having a high incidence in the general population and among cancer patients receiving chemotherapy.

Methods: One hundred and five patients with hepatic steatosis (liver parenchyma <40 HU) underwent contrast-enhanced DECT with reconstruction of pure iodine (PI), optimum contrast (OC), 80 kVp, and 120 kVp-equivalent data sets. Image noise (IN), lesion to liver signal to noise (SNR) and contrast to noise (CNR) ratios were quantitatively analysed; image quality was rated on a 5-point scale (1, excellent; 2, good; 3, fair; 4, poor; 5, non-diagnostic) by two independent reviewers.

Results: In 21 patients with hypodense liver lesions, IN was lowest in PI followed by 120 kVp-equivalent and OC, and highest in 80 kVp. SNR was highest in PI (1.30), followed by 120 kVp-equivalent (0.72) and 80 kVp (0.63), and lowest in OC (0.55). CNR was highest in 120 kVp-equivalent (4.95), followed by OC (4.55) and 80 kVp (4.14), and lowest in PI (3.63). The 120 kVp-equivalent series exhibited best overall qualitative image score (1.88), followed by OC (1.98), 80 kVp (3.00) and PI (3.67).

Conclusion: In our study, the 120 kVp-equivalent series was best suited for visualization of hypodense lesions within steatotic liver parenchyma, while using DECT currently seems to offer no additional diagnostic advantage.

Key Points: • Hepatic steatosis has high incidence in the general population and following chemotherapy. • Hypodense liver lesions can be obscured by steatotic liver parenchyma in CT. • Low kV p -CT shows no advantage in detecting hypodense lesions in steatotic livers. • Additional DECT image information does not improve visualization of hypodense lesions in steatosis. • 120 kV p -equivalent imaging yields best quantitative and qualitative image analysis results.
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http://dx.doi.org/10.1007/s00330-015-3772-6DOI Listing
December 2015

Association of angiogenic factors with prognosis in esophageal cancer.

BMC Cancer 2015 Mar 13;15:121. Epub 2015 Mar 13.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Despite multimodal therapy esophageal cancer often presents with poor prognosis. To improve outcome, tumor angiogenesis and anti-angiogenic therapeutic agents have recently gained importance. However, patient subgroups who benefit from anti-angiogenic therapy are not yet defined. In this retrospective exploratory study we investigated 9 angiogenic factors in patients' serum and tissue samples with regard to their association with clinicopathological parameters, prognosis and response in patients with locally advanced preoperatively treated esophageal cancer.

Methods: From 2007 to 2012 preoperative serum and corresponding tumor tissue (n = 54), only serum (n = 20) or only tumor tissue (n = 4) were collected from esophageal squamous cell carcinoma (SCC) (n = 34) and adenocarcinoma of the esophagogastric junction (AEG) (n = 44) staged cT3/4NanyM0/x after preoperative chemo(radio)therapy. Angiogenic cytokine levels in both tissue and serum were measured by multiplex immunoassay.

Results: Median survival in all patients was 28.49 months. No significant difference was found in survival between SCC and AEG (p = 0.90). 26 patients were histopathological responders. Histopathological response was associated with prognosis (p = 0.05). Angiogenic factors were associated with the following clinicopathological factors: tumor tissue expression of Angiopoietin-2 and Follistatin was higher in SCC compared to AEG (p = 0.022 and p = 0.001). High HGF and Follistatin expression in the tumor tissue was associated with poor prognosis in all patients (p = 0.037 and p = 0.036). No association with prognosis was found in the patients' serum. Neither patients' serum nor tumor tissue showed an association between angiogenic factors and response to neoadjuvant therapy.

Conclusion: Two angiogenic factors (HGF and Follistatin) in posttherapeutic tumor tissue are associated with prognosis in esophageal cancer patients. Biological differences of AEG and SCC with respect to angiogenesis were evident by the different expression of 2 angiogenic factors. Results are promising and should be pursued prospectively, optimally sequentially pre- and posttherapeutically.
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http://dx.doi.org/10.1186/s12885-015-1120-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362831PMC
March 2015

Outcome, complications, and mortality of an intrathoracic anastomosis in esophageal cancer in patients without a preoperative selection with a risk score.

Langenbecks Arch Surg 2015 Jan 20;400(1):9-18. Epub 2014 Nov 20.

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, INF 110, 69120, Heidelberg, Germany,

Background: Esophagectomy for esophageal cancer remains a challenge with relatively high morbidity. We analyzed outcome, complications, and mortality after abdominothoracic esophagectomy with intrathoracic anastomosis. No routine preoperative risk stratification was performed.

Methods: One hundred eighty-seven consecutive patients (105 AEG I, 21 AEG II, 58 SCC, and 3 other entities) underwent standardized right abdominothoracic esophagectomy with intrathoracic anastomosis and two field lymphadenectomy between 2003 and 2009. Reconstruction was performed mostly with a gastric tube (n = 126) or a fundus rotation gastroplasty (n = 57). Seventy-four patients underwent neoadjuvant treatment (36 patients chemotherapy; 38 patients chemoradiotherapy).

Results: Postoperative morbidity was high (73.2 %). Ninety-two patients (49.2 %) suffered from surgical complications, 50 patients had major (26.7 %), and 42 minor (22.5 %) complications. Thirty-day mortality was 9/187 (4.8 %) while in-hospital mortality was doubled with 9.6 %. Six of 19 of the patients died without surgical complications. Preoperative treatment did not increase morbidity or mortality. Surgical complications with subsequent death were tracheobronchial fistula (2/3), ischemia of the gastric tube (3/6), anastomotic leakage (6/30), chylothorax (1/6), and intraoperative bleeding from the aorta (1/1). The median overall survival was 25.0 months. The occurrence of surgical or medical complications did not influence overall survival. In multivariate analysis, cT-category, pN-category, R-category, and re-intubation were independent prognostic factors.

Conclusions: Abdominothoracic esophagectomy with intrathoracic anastomosis without preoperative patient selection is associated with a high risk for complications and subsequent death but ranges still within the upper range of published data. Strict patient selection is accepted to reduce postoperative morbidity and mortality but excludes a subgroup of patients from potentially curative resection.
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http://dx.doi.org/10.1007/s00423-014-1257-8DOI Listing
January 2015

International comparison of the German evidence-based S3-guidelines on the diagnosis and multimodal treatment of early and locally advanced gastric cancer, including adenocarcinoma of the lower esophagus.

Gastric Cancer 2015 Jul 7;18(3):550-63. Epub 2014 Sep 7.

University Medical Center Mainz, Mainz, Germany,

Background: Clinical guidelines are essential in implementing and maintaining nationwide stage-specific diagnostic and therapeutic standards. In 2011, the first German expert consensus guideline defined the evidence for diagnosis and treatment of early and locally advanced esophagogastric cancers. Here, we compare this guideline with other national guidelines as well as current literature.

Methods: The German S3-guideline used an approved development process with de novo literature research, international guideline adaptation, or good clinical practice. Other recent evidence-based national guidelines and current references were compared with German recommendations.

Results: In the German S3 and other Western guidelines, adenocarcinomas of the esophagogastric junction (AEG) are classified according to formerly defined AEG I-III subgroups due to the high surgical impact. To stage local disease, computed tomography of the chest and abdomen and endosonography are reinforced. In contrast, laparoscopy is optional for staging. Mucosal cancers (T1a) should be endoscopically resected "en-bloc" to allow complete histological evaluation of lateral and basal margins. For locally advanced cancers of the stomach or esophagogastric junction (≥T3N+), preferred treatment is preoperative and postoperative chemotherapy. Preoperative radiochemotherapy is an evidence-based alternative for large AEG type I-II tumors (≥T3N+). Additionally, some experts recommend treating T2 tumors with a similar approach, mainly because pretherapeutic staging is often considered to be unreliable.

Conclusions: The German S3 guideline represents an up-to-date European position with regard to diagnosis, staging, and treatment recommendations for patients with locally advanced esophagogastric cancer. Effects of perioperative chemotherapy versus chemoradiotherapy are still to be investigated for adenocarcinoma of the cardia and the lower esophagus.
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http://dx.doi.org/10.1007/s10120-014-0403-xDOI Listing
July 2015

A systematic review of localization, surgical treatment options, and outcome of insulinoma.

Pancreas 2014 Jul;43(5):675-86

From the Departments of *General, Visceral, and Transplantation Surgery, †Radiology, and ‡Anesthesiology, University of Heidelberg, Heidelberg, Germany.

Objective: Insulinoma with an incidence of 0.4% is a rare pancreatic tumor. Preserving surgery is the treatment of choice. Exact localization is necessary to plan the appropriate approach. This article gives an overview on localization and surgical strategies for treatment of insulinoma.

Methods: In this systematic review, 114 articles with 6222 cases of insulinoma were reviewed with emphasis on localization techniques and surgical treatment.

Results: Insulinoma happens mostly in the fifth decade of life, with a higher incidence in men. They occur mostly sporadic (94%), benign (87%), and single (90%). Insulinomas are mostly smaller than 20 mm (84%). The tumors are distributed almost equally in the pancreas.

Conclusions: Computed tomography is routinely used as first choice preoperatively. Intraoperative inspection, palpation, and sonography were applied with high success rate. Intraoperative sonography is considered as the most reliable technique. Enucleation is the most administered type of surgery (56%). Different types of resection include distal pancreatectomy (32%), Whipple procedure (3%), and subtotal pancreatectomy (<3%). Despite the development of laparoscopy, open approach is the favorite method (90%). The most common surgical complication is fistula. The mortality rate of open approach was higher (4 vs 0%). Despite high cure rate, recurrence of insulinoma occurs in 7% after surgery.
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http://dx.doi.org/10.1097/MPA.0000000000000110DOI Listing
July 2014

Post-therapeutic response evaluation by a combination of endoscopy and CT scan in esophagogastric adenocarcinoma after chemotherapy: better than its reputation.

Gastric Cancer 2015 Apr 11;18(2):314-25. Epub 2014 Apr 11.

Department of Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany,

Background: Neoadjuvant chemotherapy is an accepted standard of care for locally advanced esophagogastric cancer. As only a subgroup benefits, a response-based tailored treatment would be of interest. The aim of our study was the evaluation of the prognostic and predictive value of clinical response in esophagogastric adenocarcinomas.

Methods: Clinical response based on a combination of endoscopy and computed tomography (CT) scan was evaluated retrospectively within a prospective database in center A and then transferred to center B. A total of 686/740 (A) and 184/210 (B) patients, staged cT3/4, cN0/1 underwent neoadjuvant chemotherapy and were then re-staged by endoscopy and CT before undergoing tumor resection. Of 184 patients, 118 (B) additionally had an interim response assessment 4-6 weeks after the start of chemotherapy.

Results: In A, 479 patients (70%) were defined as clinical nonresponders, 207 (30%) as responders. Median survival was 38 months (nonresponders: 27 months, responders: 108 months, log-rank, p < 0.001). Clinical and histopathological response correlated significantly (p < 0.001). In multivariate analysis, clinical response was an independent prognostic factor (HR for death 1.4, 95% CI 1.0-1.8, p = 0.032). In B, 140 patients (76%) were nonresponders and 44 (24%) responded. Median survival was 33 months, (nonresponders: 27 months, responders: not reached, p = 0.003). Interim clinical response evaluation (118 patients) also had prognostic impact (p = 0.008). Interim, preoperative clinical response and histopathological response correlated strongly (p < 0.001).

Conclusion: Preoperative clinical response was an independent prognostic factor in center A, while in center B its prognostic value could only be confirmed in univariate analysis. The accordance with histopathological response was good in both centers, and interim clinical response evaluation showed comparable results to preoperative evaluation.
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http://dx.doi.org/10.1007/s10120-014-0367-xDOI Listing
April 2015

Is preoperative chemotherapy followed by surgery the appropriate treatment for signet ring cell containing adenocarcinomas of the esophagogastric junction and stomach?

Ann Surg Oncol 2014 May 14;21(5):1739-48. Epub 2014 Jan 14.

Department of Surgery, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany,

Background: Recent data suggest primary resection as the preferable approach in patients with signet ring cell gastric cancer (SRC). The aim of our retrospective exploratory study was to evaluate the influence of SRC on prognosis and response in esophagogastric adenocarcinoma treated with neoadjuvant chemotherapy.

Methods: A total of 723 locally advanced esophagogastric adenocarcinomas (cT3/4 N any) documented in a prospective database from two academic centers were classified according to the WHO definition for SRC (more than 50 % SRC) and analyzed for their association with response and prognosis after neoadjuvant treatment.

Results: A total of 235 tumors (32.5 %) contained SRC. Median survival of SRC was 26.3 compared with 46.6 months (p < 0.001) for non-SRC. SRC were significantly associated with female gender, gastric localization, advanced ypT and R1/2 categories, and lower risk of surgical complications and anastomotic leakage (each p < 0.001). Clinical (21.1 vs. 33.7 %, p = 0.001) and histopathological response (less than 10 % residual tumor: 16.3 vs. 28.9 %, p < 0.001) were significantly less frequent in SRC. Clinical response (p = 0.003) and complete histopathological response (pCR) (3.4 %) (p = 0.003) were associated with improved prognosis in SRC. Clinical response, surgical complications, ypTN categories, but not SRC were independent prognostic factors in forward Cox regression analysis in R0 resected patients. Risk of peritoneal carcinomatosis was increased (p < 0.001), while local (p = 0.015) and distant metastases (p = 0.02) were less frequent than in non-SRC.

Conclusions: Prognosis of SRC is unfavorable. Although response to neoadjuvant chemotherapy is rare in SRC, it is associated with improved outcome. Thus, chemotherapy might not generally be abandoned in SRC. A stratification based on SRC should be included in clinical trials.
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http://dx.doi.org/10.1245/s10434-013-3462-zDOI Listing
May 2014

Complications in CT-guided procedures: do we really need postinterventional CT control scans?

Cardiovasc Intervent Radiol 2014 Feb 19;37(1):241-6. Epub 2013 Jun 19.

Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany,

Purpose: The aim of this study is twofold: to determine the complication rate in computed tomography (CT)-guided biopsies and drainages, and to evaluate the value of postinterventional CT control scans.

Methods: Retrospective analysis of 1,067 CT-guided diagnostic biopsies (n = 476) and therapeutic drainages (n = 591) in thoracic (n = 37), abdominal (n = 866), and musculoskeletal (ms) (n = 164) locations. Severity of any complication was categorized as minor or major. To assess the need for postinterventional CT control scans, it was determined whether complications were detected clinically, on peri-procedural scans or on postinterventional scans only.

Results: The complication rate was 2.5 % in all procedures (n = 27), 4.4 % in diagnostic punctures, and 1.0 % in drainages; 13.5 % in thoracic, 2.0 % in abdominal, and 3.0 % in musculoskeletal procedures. There was only 1 major complication (0.1 %). Pneumothorax (n = 14) was most frequent, followed by bleeding (n = 9), paresthesia (n = 2), material damage (n = 1), and bone fissure (n = 1). Postinterventional control acquisitions were performed in 65.7 % (701 of 1,067). Six complications were solely detectable in postinterventional control acquisitions (3 retroperitoneal bleeds, 3 pneumothoraces); all other complications were clinically detectable (n = 4) and/or visible in peri-interventional controls (n = 21).

Conclusion: Complications in CT-guided interventions are rare. Of these, thoracic interventions had the highest rate, while pneumothoraces and bleeding were most frequent. Most complications can be detected clinically or peri-interventionally. To reduce the radiation dose, postinterventional CT controls should not be performed routinely and should be restricted to complicated or retroperitoneal interventions only.
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http://dx.doi.org/10.1007/s00270-013-0673-4DOI Listing
February 2014

Dynamic contrast-enhanced computed tomography to assess antitumor treatment effects: comparison of two contrast agents with different pharmacokinetics.

Invest Radiol 2013 Oct;48(10):715-21

MR and CT Contrast Media Research, Bayer Healthcare, 178 13353 Berlin, Germany.

Objective: Dynamic contrast-enhanced computed tomography (CT) is a sensitive method to evaluate functional changes of the tumor microvasculature after antitumor therapy by monitoring the kinetics of the contrast agent (CA) passage. Therefore, the pharmacokinetic properties of the CA possess a central role: iodinated x-ray CAs are small molecules that distribute rapidly within the extravascular extracellular space, whereas larger macromolecular compounds have a prolonged vascular phase and a restricted volume of distribution. The aim of this animal study was to compare the x-ray CA iopromide and the experimental gadolinium-based dendrimeric Gadomer in the assessment of early therapy response after a single dose of the novel multikinase inhibitor regorafenib.

Materials And Methods: For the study, an experimental GS9L rat glioma model was used. For each CA, the animals were divided randomly into a therapy (n = 8) and a placebo group (n = 4). All animals underwent a baseline CT and a second examination 24 hours after therapy with regorafenib (10 mg/kg body weight, oral) and placebo, respectively. The CAs were administered intravenously at a dosage of 0.5 g I or Gd per kg body weight and dynamic CT scans (80 kV, 160 mAseff, no table feed) of the tumor region were performed up to 404 seconds post injection (p.i.). Image evaluation was done by analyzing tumor time-density curves, the area under the curve (AUC), and the results of the 2-compartment Patlak modeling.

Results: Significant differences in the time-density curves, the AUC, and the Patlak transfer constant (Ktrans) were observed 24 hours after the regorafenib therapy but not after the placebo treatment. The treatment effects visualized with iopromide were most pronounced at early time points (<100 seconds p.i.), whereas imaging with Gadomer was most effective at a later time window (300-404 seconds p.i.). Comparable reductions of the AUC to 0.69 ± 0.12 (iopromide) and 0.76 ± 0.11 (Gadomer) were found 24 hours after the therapy. A significant higher Ktrans was detected with iopromide (14.3 ± 2.7 mL per 100 mL/min) compared with Gadomer (1.8 ± 0.2 mL per 100 mL/min). However, the relative reduction in Ktrans to 67% ± 11% (iopromide) and to 68% ± 7% (Gadomer) 24 hours after the therapy was similar.

Conclusions: Dynamic contrast-enhanced CT detects early treatment effects on tumor microvasculature after a single dose of regorafenib, independently of the used CA. Gadomer showed a later optimal imaging window than iopromide did. However, the efficacy of Gadomer- and iopromide-enhanced imaging is equivalent. The results demonstrate the potential of dynamic contrast-enhanced CT using clinically available x-ray CA in the assessment of early treatment response after administration of novel antitumor therapeutic agents.
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http://dx.doi.org/10.1097/RLI.0b013e318290cafbDOI Listing
October 2013

Fibrosis and pancreatic lesions: counterintuitive behavior of the diffusion imaging-derived structural diffusion coefficient d.

Invest Radiol 2013 Mar;48(3):129-33

Department of Diagnostic and Interventional Radiology, Faculty of Medicine Mannheim, University of Heidelberg, Germany.

Introduction: Stroma reaction leading to fibrosis is the most characteristic histopathological feature of both pancreatic carcinoma and chronic pancreatitis with increased fibrosis compared with healthy pancreatic tissue and further increased fibrosis during radiochemotherapy. Recent studies using intravoxel incoherent motion-derived parameters did not show differences for structural diffusion constant D between these 2 diseases. The aim of this study was to verify the hypothesis that D correlates with the histopathological grade of fibrosis in pancreatic lesions.

Materials And Methods: We included 15 patients with histopathologically proven pancreatic carcinoma and 9 patients with histopathologically proven focal chronic pancreatitis. Diffusion-weighted magnetic resonance imaging was performed using 10 b values between 25 and 800 s/mm² before surgery. We calculated the apparent diffusion coefficient and the intravoxel incoherent motion-derived parameters D and f within tumors and focal chronic pancreatitis. The resected tissue was evaluated with regard to the grade of fibrosis.

Results: Fourteen patients were found to have moderate fibrosis and 10 patients had severe fibrosis. The difference between the D values for the moderate and severe fibrosis was significant with mean (SD) D value of 1.02 × 10⁻³ (0.48 × 10⁻³ mm/s) and mean (SD) D of 1.22 × 10⁻³ (0.76 × 10⁻³) mm²/s. There were no significant differences for the f and ADC values.

Conclusions: Contrary to our hypothesis, D rises from moderate to severe fibrosis. It seems that cellular complexes surrounded by fibrosis provide more structural limitations than does fibrosis alone. Our data suggest that D is not intuitively related to the degree of fibrosis. Compared with healthy tissue, D is reduced in moderate fibrosis but increases when severe fibrosis is present.
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http://dx.doi.org/10.1097/RLI.0b013e31827ac0f1DOI Listing
March 2013

Re-resection for isolated local recurrence of pancreatic cancer is feasible, safe, and associated with encouraging survival.

Ann Surg Oncol 2013 Mar 12;20(3):964-72. Epub 2012 Dec 12.

Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.

Background: Local recurrence of pancreatic cancer occurs in 80% of patients within 2 years after potentially curative resections. Around 30% of patients have isolated local recurrence (ILR) without evidence of metastases. In spite of localized disease these patients usually only receive palliative chemotherapy and have a short survival.

Purpose: To evaluate the outcome of surgery as part of a multimodal treatment for ILR of pancreatic cancer.

Methods: All consecutive operations performed for suspected ILR in our institution between October 2001 and October 2009 were identified from a prospective database. Perioperative outcome, survival, and prognostic parameters were assessed.

Results: Of 97 patients with histologically proven recurrence, 57 (59%) had ILR. In 40 (41%) patients surgical exploration revealed metastases distant to the local recurrence. Resection was performed in 41 (72%) patients with ILR, while 16 (28%) ILR were locally unresectable. Morbidity and mortality were 25 and 1.8% after resections and 10 and 0% after explorations, respectively. Median postoperative survival was 16.4 months in ILR versus 9.4 months in metastatic disease (p < 0.0001). In ILR median survival was significantly longer after resection (26.0 months) compared with exploration without resection (10.8 months, p = 0.0104). R0 resection was achieved in 18 patients and resulted in 30.5 months median survival. Presence of metastases, incomplete resection, and high preoperative CA 19-9 serum values were associated with lesser survival.

Conclusions: Resection for isolated local recurrence of pancreatic cancer is feasible, safe, and associated with favorable survival outcome. This concept warrants further evaluation in other institutions and in randomized controlled trials.
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http://dx.doi.org/10.1245/s10434-012-2762-zDOI Listing
March 2013