Shining a spotlight on sarcopenia and myosteatosis in liver disease and liver transplantation: Potentially modifiable risk factors with major clinical impact.

Muscle-wasting and disease-related malnutrition are highly prevalent in patients with chronic liver diseases (CLD) as well as in liver transplant (LT) candidates. Alterations of body composition (BC) such as sarcopenia, myosteatosis and sarcopenic obesity and associated clinical frailty were tied to inferior clinical outcomes including hospital admissions, length of stay, complications, mortality and healthcare costs in various patient cohorts and clinical scenarios. In contrast to other inherent detrimental individual characteristics often observed in these complex patients, such as comorbidities or genetic risk, alterations of the skeletal muscle and malnutrition are considered as potentially modifiable risk factors with a major clinical impact. Even so, there is only limited high-level evidence to show how these pathologies should be addressed in the clinical setting. This review discusses the current state-of-the-art on the role of BC assessment in clinical outcomes in the setting of CLD and LT focusing mainly on sarcopenia and myosteatosis. We focus on the disease-related pathophysiology of BC alterations. Based on these, we address potential therapeutic interventions including nutritional regimens, physical activity, hormone and targeted therapies. In addition to summarizing existing knowledge, this review highlights novel trends, and future perspectives and identifies persisting challenges in addressing BC pathologies in a holistic way, aiming to improve outcomes and quality of life of patients with CLD awaiting or undergoing LT.

CT-based screening of sarcopenia and its role in cachexia syndrome in pancreatic cancer.

Since computed tomography (CT) is a part of standard diagnostic protocol in pancreatic ductal adenocarcinoma (PDAC), we have evaluated the value of CT for sarcopenia screening in patients with PDAC, intending to expand the diagnostic value of tomographic studies. In our study, we included 177 patients with available CT images. Two groups were formed: Group 1 consisted of 117 patients with PDAC in various locations and stages and Group 2, or the control group, consisted of 60 "nominally healthy" patients with other somatic non-oncological diseases. The body mass index (BMI) was defined as a ratio of patient's weight to the square of their height (kg/m2). CT-based body composition analysis was performed using commercially available software with evaluation of sarcopenia using skeletal muscle index (SMI, cm2/m2). Based on the SMI values, sarcopenia was found in 67.5% of patients (79 out of 117) in the first patient group. It was found more frequently in males (42 out of 56; 75%) than in females (37 out of 61; 60.6%). Additionally, we observed a decrease in muscle mass (hidden sarcopenia) in 79.7% in patients with a normal BMI. Even in overweight patients, sarcopenia was found in 50% (sarcopenic obesity). In patients with reduced BMI sarcopenia was found in all cases (100%). Statistically significant difference of SMI between two groups was revealed for both sexes (p = 0,0001), with no significant difference between groups in BMI. BMI is an inaccurate value for the assessment of body composition as it does not reflect in the details the human body structure. As SMI may correlate with the prognosis, decreased muscle mass- especially "hidden" sarcopenia or sarcopenic obesity- should be reported. The use of CT-based evaluation of sarcopenia and sarcopenic obesity will allow for a better treatment response assessment in patients with cancer cachexia.

Evaluation and timing optimization of CT perfusion first pass analysis in comparison to maximum slope model in pancreatic adenocarcinoma.

For implementation, performance evaluation and timing optimization of CT perfusion first pass analysis (FPA) by correlation with maximum slope model (MSM) in pancreatic adenocarcinoma, dynamic CT perfusion acquisitions of 34 time-points were performed in 16 pancreatic adenocarcinoma patients. Regions of interest were marked in both parenchyma and carcinoma. FPA, a low radiation exposure CT perfusion technique, was implemented. Blood flow (BF) perfusion maps were calculated using FPA and MSM. Pearson's correlation between FPA and MSM was calculated at each evaluated time-point to determine optimum timing for FPA. Differences in BF between parenchyma and carcinoma were calculated. Average BF for MSM was 106.8 ± 41.5 ml/100 ml/min in parenchyma and 42.0 ± 24.8 ml/100 ml/min in carcinoma, respectively. For FPA, values ranged from 85.6 ± 37.5 ml/100 ml/min to 117.7 ± 44.5 ml/100 ml/min in parenchyma and from 27.3 ± 18.8 ml/100 ml/min to 39.5 ± 26.6 ml/100 ml/min in carcinoma, depending on acquisition timing. A significant difference (p value < 0.0001) between carcinoma and parenchyma was observed at all acquisition times based on FPA measurements. FPA shows high correlation with MSM (r > 0.90) and 94% reduction in the radiation dose compared to MSM. CT perfusion FPA, where the first scan is obtained after the arterial input function exceeds a threshold of 120 HU, followed by a second scan after 15.5-20.0 s, could be used as a potential imaging biomarker with low radiation exposure for diagnosing and evaluating pancreatic carcinoma in clinical practice, showing high correlation with MSM and the ability to differentiate between parenchyma and carcinoma.

Lymphoepithelial cyst of the pancreas: can common imaging features help to avoid resection?

BACKGROUND: Differentiation of cystic pancreatic neoplasms remains a challenging task for radiologists regarding the main aim of identifying malignant and premalignant lesions. PURPOSE: The study aimed to compare the radiological features of lymphoepithelial cysts (LEC) with other cystic pancreatic lesions, which could help to differentiate them in order to avoid unnecessary resection. MATERIAL AND METHODS: We retrospectively reviewed 10 cases of resected and histopathologically confirmed LECs during a 12-year period with available imaging studies; 20 patients with mucinous cystic neoplasms (MCN), 20 patients with branch-duct intraductal papillary mucinous neoplasms (BD-IPMN), and 20 patients with serous cystic neoplasms (SCN) were selected to serve as control groups. Imaging findings as well as clinical data were analyzed. RESULTS: The following imaging morphology of LEC was identified: simple cystic appearance (20%) and mixed cystic-solid appearance (80%) with either a diffuse subsolid component (30%) or mural nodule(s) (50%). All lesions revealed exophytic location with a strong male predominance (9:1). MCNs occurred exclusively in middle-aged women, IPMN in both sexes showed slight male predominance (13:7), and SCN showed female predominance (5:15). Median patient age in LEC (48.5, IQR 47-54.5) was significantly younger compared to IPMN (p < 0.001) and SCN (p = 0.02). Unenhanced CT attenuation of LEC was higher than MCNs (p = 0.025) and IPMNs (p = 0.021), showing no significant difference to SCN (p = 0.343). CONCLUSION: The present study provides key radiological features of LEC for the differentiation from other cystic pancreatic lesions such as increased CT attenuation in the unenhanced phase, absence of a connection to the main pancreatic duct (MPD), and exophytic location. In addition to these imaging features, clinical data, such as male predominance in LEC, must be considered for the differentiation of cystic pancreatic lesions.

Subtyping of hepatocellular adenomas using Gd-EOB-DTPA: a qualitative and quantitative analysis.

BACKGROUND: The goal of medical imaging is not only to identify the entity "hepatocellular adenoma," but to detect typical magnetic resonance (MR) patterns of the subtypes so that lesions with a higher malignant transformation rate could be differentiated from those that should just be controlled. PURPOSE: To evaluate the differentiation between subtypes of hepatocellular adenomas using hepatobiliary specific contrast agent (Gd-EOB-DTPA) in MR imaging. MATERIAL/METHODS: A total of 11 patients with 39 lesions with histologically proven hepatocellular adenomas were evaluated. Of the, 34 were inflammatory hepatocellular adenomas (IHCA) and 5 were HNF1α adenomas. No ß-catenin-mutated adenoma was found. In all patients, a standard protocol considering the guidelines of the international consensus conference of Gd-EOB-DTPA was performed in a 1.5-T scanner. Besides a qualitative analysis of all sequences, we measured the quantitative signal intensity (SI) ratio in all examinations. RESULTS: Qualitative analysis showed that best sequences for differentiation of HNF1α adenomas from IHCA were T1-weighted (T1W) precontrast (P = 0.03) and portalvenous phase (P < 0.0001) as well as arterial phase (P = 0.002). All adenomas were hypointense in hepatobiliary phase (15 min). The quantitative analyses of the SI ratio and of lesion-to-liver contrast (LLC) ratio show statistically significant differences in T1W precontrast (SI: P = 0.035; LLC: P = 0.049) and portalvenous phase (SI: P = 0.002; LLC: P = 0.002). CONCLUSION: Subtyping of hepatocellular adenomas using Gd-EOB-DTPA is possible due to qualitative and quantitative analyses regarding T1W precontrast and portalvenous phase. In addition, the SI ratio and liver-to-lesion contrast ratio in the arterial phase gave additional qualitative information for differentiation.

Celiac Axis Stenosis is an Underestimated Risk Factor for Increased Morbidity After Pancreatoduodenectomy.

OBJECTIVE: To assesses the prevalence and severity of CAS in patients undergoing PD/total pancreatectomy and its association with major postoperative complications after PD. SUMMARY OF BACKGROUND DATA: CAS may increase the risk of ischemic complications after PD. However, the prevalence of CAS and its relevance to major morbidity remain unknown. METHODS: All patients with a preoperative computed tomography with arterial phase undergoing partial PD or TP between 2014 and 2017 were identified from a prospective database. CAS was assessed based on computed tomography and graded according to its severity: no stenosis (<30%), grade A (30%-<50%), grade B (50%-≤80%), and grade C (>80%). Postoperative complications were assessed and uni- and multivariable risk analyses were performed. RESULTS: Of 989 patients, 273 (27.5%) had CAS: 177 (17.9%) with grade A, 83 (8.4%) with grade B, and 13 (1.3%) with grade C. Postoperative morbidity and 90-day mortality occurred in 278 (28.1%) patients and 41 (4.1%) patients, respectively. CAS was associated with clinically relevant pancreatic fistula ( P =0.019), liver perfusion failure ( P =0.003), gastric ischemia ( P =0.001), clinically relevant biliary leakage ( P =0.006), and intensive care unit ( P =0.016) and hospital stay ( P =0.001). Multivariable analyses confirmed grade B and C CAS as independent risk factors for liver perfusion failure; in addition, grade C CAS was an independent risk factor for clinically relevant pancreatic fistula and gastric complications. CONCLUSIONS: CAS is common in patients undergoing PD. Higher grade of CAS is associated with an increased risk for clinically relevant complications, including liver perfusion failure and postoperative pancreatic fistula. Precise radiological assessment may help to identify CAS. Future studies should investigate measures to mitigate CAS-associated risks.

Imaging features of intraductal tubulopapillary neoplasm of the pancreas and its differentiation from conventional pancreatic ductal adenocarcinoma.

Intraductal tubulopapillary neoplasms (ITPN) are rare pancreatic tumors (< 1% of exocrine neoplasms) and are considered to have better prognosis than classical pancreatic ductal adenocarcinoma (PDAC). The present study aimed to evaluate imaging features of ITPN in computed tomography (CT) and magnetic resonance (MR) imaging. We performed monocentric retrospective analysis of 14 patients with histopathologically verified ITPN, operated in 2003-2018. Images were available for 12 patients and were analysed independently by two radiologists, blinded to reports. Imaging features were compared to a matched control group consisting of 43 patients with PDAC, matched for sex and age. Histopathologic analysis showed invasive carcinoma component in all ITPN patients. CT-attenuation values of ITPN were higher in arterial and venous phases (62.3 ± 14.6 HU and 68 ± 15.6 HU) than in unenhanced phase (39.2 ± 7.9 HU), compatible with solid lesion enhancement. Compared to PDAC, ITPN lesions had significantly higher HU-values in both arterial and venous phases (arterial and venous phases, p < 0.001). ITPN were significantly larger than PDAC (4.1 ± 2.0 cm versus 2.6 ± 0.84 cm, p = 0.021). ITPN lesions were more often well-circumscribed (p < 0.002). Employing a multiple logistic regression analysis with forward stepwise method, higher HU density in the arterial phase (p = 0.012) and well-circumscribed lesion margins (p = 0.047) were found to be significant predictors of ITPN versus PDAC. Our study identified key imaging features for differentiation of ITPN and PDAC. Isodensity or moderate hypodensity and well-circumscribed margins favor the diagnosis of ITPN over PDAC. Being familiar with CT-features of these rare pancreatic tumors is essential for radiologists to accelerate the diagnosis and narrow the differentials.

Validation of the ISGLS classification of bile leakage after pancreatic surgery: A rare but severe complication.

INTRODUCTION: Hepaticoenterostomy is an important step of reconstruction during hepatopancreatobiliary (HPB) surgery with a subsequent bile leakage rate of up to 5%. The International Study Group of Liver Surgery (ISGLS) proposed a severity grading system for defining bile leakage after HPB surgery, which has not been validated after pancreatic surgery in a large patient cohort. The present study aimed to validate the ISGLS definition for bile leakage in pancreatic surgery and to investigate the postoperative outcomes of bile leakage after pancreatic resections. MATERIALS AND METHODS: Data from the prospectively maintained database for pancreas surgery were extracted for any type of pancreatectomy with hepaticoenterostomy between 2006 and 2019. The severity of bile leakage was graded according to the ISGLS definition. The influence of our standardized hepaticoenterostomy technique and of the complexity of the surgical procedure on the rate of clinically relevant bile leakages (B and C) were assessed in three different timeframes. RESULTS: Bile leakage was detected in 152 of 5,300 patients (2.9%). Clinically relevant bile leakages included seventy patients with grade B and eighty-two patients with grade C bile leakages (46.1% and 53.9%, respectively). During the study period, the overall rate of bile leakage showed to be stable (from 3.5% to 2.4%). Patients with grade C bile leakage had a higher rate of postoperative wound infection (P < 0.001) and longer ICU stays and hospital stays compared to patients with grade B bile leakage (P = 0.03 and P < 0.001 respectively). These parameters were significantly higher in patients with late grade C bile leakage but were similar between patients with grade B bile leakage and early grade C bile leakage (<5th day POD). In the whole patients' cohort, the 90-day mortality rate was 3.2% (174/5,300), with a rate of 25% in patients with bile leakage (38/152). CONCLUSION: The ISGLS classification is a valid method for classifying postoperative bile leak after pancreas surgery. Standardization of our hepaticoenterostomy technique resulted in a stable rate of bile leakage. Although rare, bile leakage following pancreas surgery is a severe complication that has a major impact on patient outcomes and contributes significantly to morbidity and mortality, even in the absence of POPF.

Clinical effects and safety of different transarterial chemoembolization methods for bridging and palliative treatments in hepatocellular carcinoma.

PURPOSE: We assessed and compared clinical effects and safety endpoints of three methods of transarterial chemoembolization (TACE), conventional (cTACE), with drug-eluting beads (DEB-TACE), and with degradable starch microspheres (DSM-TACE), used in patients with hepatocellular carcinoma (HCC) in the bridging to liver transplant (LT) and the palliative setting. METHODS: In our center, 148 patients with HCC underwent 492 completed TACE procedures between 2008 and 2017 (158 for bridging to LT; 334 for palliative treatment) which we analyzed retrospectively. Of these procedures, 348 were DEB-TACE, 60 cTACE, and 84 DSM-TACE. RESULTS: The cTACE procedure revealed a significantly longer period of hospitalization (p = 0.02), increased occurrence of nausea (p = 0.025), and rise in alanine transaminase (ALT) levels (p = 0.001), especially in the palliative setting. In the bridging to LT cohort, these clinical endpoints did not reach statistical significance. CONCLUSIONS: The clinical safety of different TACE methods for HCC in both the palliative and the bridging to LT setting was equivalent. In the palliative setting, the cTACE procedure revealed an increased risk for adverse clinical effects such as nausea, elevation of ALT, and a prolonged period of hospitalization what might either be related to the systemic effects of the chemotherapeutic agent or to the differences in both collectives. Thus, further studies must be conducted on a larger number of TACE procedures to effectively explore the clinical side effects of the various TACE variants.

Therapeutic lymphography for persistent chyle leak after pancreatic surgery.

BACKGROUND: Chyle leak is a common complication following pancreatic surgery. After failure of conservative treatment, lymphography is one of the last therapeutic options. The objective of this study was to evaluate whether lymphography represents an effective treatment for severe chyle leak (International study Group on Pancreatic Surgery, grade C) after pancreatic surgery. METHODS: Patients with grade C chyle leak after pancreatic surgery who received transpedal or transnodal therapeutic lymphography between 2010 and 2020 were identified from a prospectively maintained database. Clinical success of the lymphography was evaluated according to percent decrease of drainage output after lymphography (>50% decrease = partial success; >85% decrease = complete success). RESULTS: Of the 48 patients undergoing lymphography, 23 had a clinically successful lymphography: 14 (29%) showed partial and 9 (19%) complete success. In 25 cases (52%) lymphography did not lead to a significant reduction of chyle leak. Successful lymphography was associated with earlier drain removal and hospital discharge [complete clinical success: 7.1 days (±4.1); partial clinical success: 12 days (±9.1), clinical failure: 19 days (±19) after lymphography; p = 0.006]. No serious adverse events were observed. CONCLUSION: Therapeutic lymphography is a feasible, safe, and effective option for treating grade C chyle leak after pancreatic surgery.

Iodine concentration and tissue attenuation in dual-energy contrast-enhanced CT as a potential quantitative parameter in early detection of local pancreatic carcinoma recurrence after surgical resection.

PURPOSE: Due to the difficult differentiation from non-specific postoperative soft tissue formation (PSF), early diagnosis of pancreatic carcinoma recurrence remains challenging. Thus, we investigated the diagnostic potential of dual-energy (DE) contrast-enhanced CT. METHOD: After potentially curative pancreatic carcinoma resection, 31 consecutive patients with PSF were examined via DE perfusion CT, acquiring 34 images (80 kVp/140 kVp) every 1.5 s, as the initial purpose of this study was evaluating CT-Perfusion. Corresponding time points of arterial, pancreatic, and early venous phase were calculated from bolus trigger times in prior conventional CT. Iodine and 120 kVp-equivalent images were calculated. Regions of interest were placed in each soft tissue formation. Diagnosis of local recurrence was confirmed by regular follow-up or histopathology. RESULTS: Final diagnosis was local recurrence in 17 patients and non-specific PSF in 14 patients. Iodine concentrations in early venous phase were significantly higher in recurrent carcinoma than in non-specific PSF (1.47 mg/ml vs. 0.96 mg/ml, p = 0.007). In earlier contrast phases iodine concentrations tended to be higher, but not significantly. CT numbers in recurrent carcinoma in 120 kVp-equivalent images in venous phase were significantly higher, too (74HU vs 47HU, p = 0.002). ROC-curve analysis for iodine concentrations in early venous phase suggests a cut-off value of ≥ 1.55 mg/ml for local recurrence (AUC = 0.78, specificity = 1.0, sensitivity = 0.53) and for CT numbers in 120kVp-equivalent images a cut-off value of ≥ 57HU (AUC = 0.82, specificity = 0.82, sensitivity = 0.71). CONCLUSION: In difficult cases, measuring iodine concentrations or CT numbers in PSF in (early) venous phase DECT could be a valuable additional parameter for differentiating local recurrence from non-specific PSF.

Computed Tomography Perfusion Analysis of Pancreatic Adenocarcinoma using Deconvolution, Maximum Slope, and Patlak Methods - Evaluation of Diagnostic Accuracy and Interchangeability of Cut-Off Values.

PURPOSE: The goal of this study was to evaluate the diagnostic accuracy of perfusion computed tomography (CT) parameters obtained by different mathematical-kinetic methods for distinguishing pancreatic adenocarcinoma from normal tissue. To determine cut-off values and to assess the interchangeability of cut-off values, which were determined by different methods. MATERIALS AND METHODS: Perfusion CT imaging of the pancreas was prospectively performed in 23 patients. 19 patients with histopathologically confirmed pancreatic adenocarcinoma were included in the study. Blood flow (BF), blood volume (BV) and permeability-surface area product (PS) were measured in pancreatic adenocarcinoma and normal tissue with the deconvolution (BF, BV, PS), maximum slope (BF), and Patlak methods (BV, PS). The interchangeability of cut-off values was examined by assessing agreement between BF, BV, and PS measured with different mathematical-kinetic methods. RESULTS: Bland-Altman analysis demonstrated poor agreement between perfusion parameters, measured with different mathematical-kinetic methods. According to receiver operating characteristic (ROC) analysis, PS measured with the Patlak method had the significantly lowest diagnostic accuracy (area under ROC curve = 0.748). All other parameters were of high diagnostic accuracy (area under ROC curve = 0.940-0.997), although differences in diagnostic accuracy were not statistically different. Cut-off values for BF of ≤ 91.83 ml/100 ml/min and for BV of ≤ 5.36 ml/100 ml, both measured with the deconvolution method, appear to be the most appropriate cut-off values to distinguish pancreatic adenocarcinoma from normal tissue. CONCLUSION: Perfusion parameters obtained by different methods are not interchangeable. Therefore, cut-off values, which were determined using different methods, are not interchangeable either. Perfusion parameters can help to distinguish pancreatic adenocarcinoma from normal tissue with high diagnostic accuracy, except for PS measured with the Patlak method. KEY POINTS: · Perfusion CT parameters showed high diagnostic accuracy in differentiating between pancreatic adenocarcinoma and normal tissue.. · Only PS measured with the Patlak method showed a significantly lower diagnostic accuracy.. · Perfusion parameters measured with different mathematical-kinetic methods are not interchangeable.. · A specific cut-off value must be determined for each method and each perfusion parameter.. CITATION FORMAT: · Koell M, Klauss M, Skornitzke S et al. Computed Tomography Perfusion Analysis of Pancreatic Adenocarcinoma with the Deconvolution, Maximum Slope, and Patlak Methods - Evaluation of Diagnostic Accuracy and Interchangeability of Cut-Off Values. Fortschr Röntgenstr 2021; 193: 1062 - 1073.

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.

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 (MVDtumor) and microvessel area (MVAtumor) 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: ftumor significantly positively correlated with BFtumor (r = 0.668, p = 0.002) and BVtumor (r = 0.672, p = 0.002). There were significant positive correlations between ftumor and MVDtumor/ MVAtumor (r ≥ 0.770, p ≤ 0.009) as well as between BFtumor and MVDtumor/ MVAtumor (r ≥ 0.697, p ≤ 0.025). Correlation coefficients between ftumor and MVDtumor/ MVAtumor were not significantly different from correlation coefficients between BFtumor and MVDtumor/ MVAtumor (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 ftumor and CT perfusion derived BFtumor 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.

Epithelial-to-Mesenchymal Transition in Pancreatic Cancer is associated with Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging.

Purpose: This study aimed to evaluate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) as imaging biomarker for epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC). Methods: In forty-two patients, preoperative apparent diffusion coefficient (ADC) values of therapy-naive PDAC were compared with immunohistochemical expression profiles of the epithelial marker E-cadherin as well as mesenchymal transcription factors Runt-related transcription factor 2 (Runx2) and Zinc finger E-box-binding homeobox 1 (Zeb1), as determined by Allred immunoreactivity score. Results: We observed a significant positive rank correlation between the ADC and the E-cadherin Allred score (ρ = 0.553, p < 0.001) and significant negative rank correlations between the ADC and the Runx2 Allred score (ρ = -0.526, p < 0.001) as well as the Zeb1 Allred score (ρ = -0.710, p < 0.001). Compared to tumors with low ADC values < 1.3 µm2/s, tumors with ADC values ≥ 1.3 µm2/s had significantly higher Allred scores for E-cadherin (median, 4 versus 5; p < 0.001) and significantly lower Allred scores for Runx2 (median, 3 versus 2; p = 0.003) as well as Zeb1 (median, 4 versus 0; p < 0.001). Conclusion: In PDAC, tumor plasticity in terms of EMT is well reflected by ADC values from DW-MRI. In the near future, DW-MRI could be beneficial for identification of PDAC patients that might profit from personalized EMT-targeted therapies.

Diffusion Kurtosis Imaging-A Superior Approach to Assess Tumor-Stroma Ratio in Pancreatic Ductal Adenocarcinoma.

Extensive desmoplastic stroma is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor progression and to the relative resistance of tumor cells towards (radio) chemotherapy. Thus, therapies that target the stroma are under intense investigation. To allow the stratification of patients who would profit from such therapies, non-invasive methods assessing the stroma content in relation to tumor mass are required. In the current prospective study, we investigated the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI), a radiologic method that measures the random motion of water molecules in tissue, in the assessment of PDAC lesions, and more specifically in the desmoplastic tumor stroma. We made use of a sophisticated DW-MRI approach, the so-called diffusion kurtosis imaging (DKI), which possesses potential advantages over conventional and widely used monoexponential diffusion-weighted imaging analysis (cDWI). We found that the diffusion constant D from DKI is highly negatively correlated with the percentage of tumor stroma, the latter determined by histology. D performed significantly better than the widely used apparent diffusion coefficient (ADC) from cDWI in distinguishing stroma-rich (>50% stroma percentage) from stroma-poor tumors (≤50% stroma percentage). Moreover, we could prove the potential of the diffusion constant D as a clinically useful imaging parameter for the differentiation of PDAC-lesions from non-neoplastic pancreatic parenchyma. Therefore, the diffusion constant D from DKI could represent a valuable non-invasive imaging biomarker for assessment of stroma content in PDAC, which is applicable for the clinical diagnostic of PDAC.

Intraoperative evaluation of hepatic artery blood flow during pancreatoduodenectomy (HEPARFLOW): Protocol of an exploratory study.

INTRODUCTION: Pancreatoduodenectomy is the treatment of choice for a range of benign and malignant diseases. The pancreatic head must be separated from its supplying vessels, especially the gastroduodenal artery, during this operation. However, dissection of the gastroduodenal artery can disturb blood supply to the liver and result in liver ischemia. There is currently no well-established algorithm to evaluate and ensure sufficient blood flow in patients with altered hepatic artery blood flow. To address this important issue, this study aims to establish a basis for assessing liver blood supply during pancreatoduodenectomy. Furthermore, factors influencing arterial blood flow and related postoperative complications will be evaluated. METHODS AND ANALYSIS: The HEPARFLOW study is a single institutional single-arm prospective exploratory observational clinical trial. All consecutive patients undergoing elective partial or total pancreatoduodenectomy will be screened for inclusion until 100 patients are enrolled. Blood flow in the proper hepatic artery, gastroduodenal artery, portal vein, and additional vessels supplying the liver will be measured during pancreatoduodenectomy using Doppler flowmetry. All patients will be followed up for 90 days after surgery. At each visit, standard clinical data, postoperative complications and mortality will be recorded. DISCUSSION: This will be the first study to prospectively assess intraoperative flow rates of the hepatic artery and portal vein to evaluate liver blood supply during pancreatoduodenectomy. The preoperative and intraoperative factors influencing blood flow in the hepatic arteries will be identified. This study may also reveal the hemodynamic and clinical relevance of a compression of the celiac axis during pancreatoduodenectomy. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of the University of Heidelberg (S-073/2018). The results will be published in a peer-reviewed journal and will be presented at medical meetings.

Applicability of scoring systems predicting outcome of transarterial chemoembolization for hepatocellular carcinoma.

PURPOSE: Several scoring systems have been proposed to predict the outcome of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). However, the application of these scores to a bridging to transplant setting is poorly validated. Evaluation of the applicability of prognostic scores for patients undergoing TACE in palliative intention vs. bridging therapy to liver transplantation (LT) is necessary. METHODS: Between 2008 and 2017, 148 patients with HCC received 492 completed TACE procedures (158 for bridging to transplant; 334 TACE procedures in palliative treatment intention at our center and were analyzed retrospectively. Scores (ART, CLIP, ALBI, APRI, SNACOR, HAP, STATE score, Child-Pugh, MELD, Okuda and BCLC) were calculated and evaluated for prediction of overall survival. ROC analysis was performed to assess prediction of 3-year survival and treatment discontinuation. RESULTS: In patients receiving TACE in palliative intention most scores predicted OS in univariate analysis but only mSNACOR score (p = 0.006), State score (p < 0.001) and Child-Pugh score (p < 0.001) revealed statistical significance in the multivariate analysis. In the bridging to LT cohort only the BCLC score revealed statistical significance (p = 0.002). CONCLUSIONS: Clinical usability of suggested scoring systems for TACE might be limited depending on the individual patient cohorts and the indication. Especially in patients receiving TACE as bridging to LT none of the scores showed sufficiently applicability. In our study Child-Pugh score, STATE score and mSNACOR score showed the best performance assessing OS in patients with TACE as palliative therapy.

The Microarchitecture of Pancreatic Cancer as Measured by Diffusion-Weighted Magnetic Resonance Imaging Is Altered by T Cells with a Tumor Promoting Th17 Phenotype.

Diffusion-weighted magnetic resonance imaging (DW-MRI) is a diagnostic tool that is increasingly used for the detection and characterization of focal masses in the abdomen, among these, pancreatic ductal adenocarcinoma (PDAC). DW-MRI reflects the microarchitecture of the tissue, and changes in diffusion, which are reflected by changes in the apparent diffusion coefficient (ADC), are mainly attributed to variations in cellular density, glandular formation, and fibrosis. When analyzing the T cell infiltrates, we found an association of a tumor-promoting subpopulation, characterized by the expression of interleukin (IL) 21 and IL26, with high ADC values. Moreover, the presence of IL21+ and IL26+ positive T cells was associated with poor prognosis. Pancreatic cancers-but not healthy pancreatic tissue-expressed receptors for IL21 and IL26, a finding that could be confirmed in pancreatic cell lines. The functionality of these receptors was demonstrated in pancreatic tumor cell lines, which showed phosphorylation of ERK1/2 and STAT3 pathways in response to the respective recombinant interleukins. Moreover, in vitro data showed an increased colony formation of tumor cells. In summary, our data showed an association of IL21+ and IL26+ immune cell infiltration, increased ADC, and aggressive tumor disease, most likely due to the activation of the key cancer signaling pathways ERK1/2 and STAT3 and formation of tumor colonies.

Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging in Pancreatic Cancer is Associated with Tumor Hypoxia.

Hypoxia is a hallmark of pancreatic cancer (PDAC) due to its compact and extensive fibrotic tumor stroma. Hypoxia contributes to high lethality of this disease, by inducing a more malignant phenotype and resistance to radiation and chemotherapy. Thus, non-invasive methods to quantify hypoxia could be helpful for treatment decisions, for monitoring, especially in non-resectable tumors, or to optimize personalized therapy. In the present study, we investigated whether tumor hypoxia in PDAC is reflected by diffusion-weighted magnetic resonance imaging (DW-MRI), a functional imaging technique, frequently used in clinical practice for identification and characterization of pancreatic lesions. DW-MRI assesses the tissue microarchitecture by measuring the diffusion of water molecules, which is more restricted in highly compact tissues. As reliable surrogate markers for hypoxia, we determined Blimp-1 (B-lymphocyte induced maturation protein), a transcription factor, as well as vascular endothelial growth factor (VEGF), which are up-regulated in response to hypoxia. In 42 PDAC patients, we observed a close association between restricted water diffusion in DW-MRI and tumor hypoxia in matched samples, as expressed by high levels of Blimp-1 and VEGF in tissue samples of the respective patients. In summary, our data show that DW-MRI is well suited for the evaluation of tumor hypoxia in PDAC and could potentially be used for the identification of lesions with a high hypoxic fraction, which are at high risk for failure of radiochemotherapy.

Volume changes of the pancreatic head remnant after distal pancreatectomy.

BACKGROUND: Little is known about pancreatic regeneration in humans after surgical resection. We examined pancreatic head volume changes after distal pancreatectomy. METHODS: Using computed tomography or magnetic resonance imaging volumetry, we assessed volume changes of the pancreatic head remnant in 67 patients at defined time points (3, 6, 9, and 12 months) after distal pancreatectomy. A volume increase of >1 cm³ was defined as hypertrophy, a decrease of >1 cm³ as atrophy, and alterations of ±1 cm³ were considered as unchanged. Volumetry results were correlated with clinical patient data, histology, and immunohistochemistry for the pancreatic regeneration markers Pax4, Ghrelin, cholecystokinin receptor A, and cholecystokinin receptor B of the resection margin. RESULTS: Of 67 patients, 33 patients (49%) exhibited a hypertrophy of the pancreatic head remnant with a median increase of 5.08 cm³, 26 patients (39%) showed an atrophy, and in 8 patients (12%) pancreatic volume remained unchanged. No correlation of preoperative, postoperative, and new-onset diabetes with hypertrophy or atrophy was found. In patients with ductal adenocarcinoma, hypertrophy occurred less frequently compared to patients with other pathologies (38% vs 63%; P = .04). In patients with ductal adenocarcinoma, hypertrophy was associated with significantly shorter survival. Patients with a postoperative hypertrophy that did not suffer from ductal adenocarcinoma displayed significantly less fibrosis at the resection margin compared to patients with a postoperative atrophy and pancreatic ductal adenocarcinoma patients. Immunohistochemical staining revealed no differential expression of the tested regeneration markers in hypertrophy versus atrophy. CONCLUSION: This study demonstrates volume changes of the pancreatic head remnant after distal pancreatectomy. Clinical and functional significance and underlying molecular mechanisms in humans remain unclear.