ALK1 controls hepatic vessel formation, angiodiversity, and angiocrine functions in hereditary hemorrhagic telangiectasia of the liver.

BACKGROUND AND AIMS: In hereditary hemorrhagic telangiectasia (HHT), severe liver vascular malformations are associated with mutations in the Activin A Receptor-Like Type 1 ( ACVRL1 ) gene encoding ALK1, the receptor for bone morphogenetic protein (BMP) 9/BMP10, which regulates blood vessel development. Here, we established an HHT mouse model with exclusive liver involvement and adequate life expectancy to investigate ALK1 signaling in liver vessel formation and metabolic function. APPROACH AND RESULTS: Liver sinusoidal endothelial cell (LSEC)-selective Cre deleter line, Stab2-iCreF3 , was crossed with Acvrl1 -floxed mice to generate LSEC-specific Acvrl1 -deficient mice ( Alk1HEC-KO ). Alk1HEC-KO mice revealed hepatic vascular malformations and increased posthepatic flow, causing right ventricular volume overload. Transcriptomic analyses demonstrated induction of proangiogenic/tip cell gene sets and arterialization of hepatic vessels at the expense of LSEC and central venous identities. Loss of LSEC angiokines Wnt2 , Wnt9b , and R-spondin-3 ( Rspo3 ) led to disruption of metabolic liver zonation in Alk1HEC-KO mice and in liver specimens of patients with HHT. Furthermore, prion-like protein doppel ( Prnd ) and placental growth factor ( Pgf ) were upregulated in Alk1HEC-KO hepatic endothelial cells, representing candidates driving the organ-specific pathogenesis of HHT. In LSEC in vitro , stimulation or inhibition of ALK1 signaling counter-regulated Inhibitors of DNA binding (ID)1-3, known Alk1 transcriptional targets. Stimulation of ALK1 signaling and inhibition of ID1-3 function confirmed regulation of Wnt2 and Rspo3 by the BMP9/ALK1/ID axis. CONCLUSIONS: Hepatic endothelial ALK1 signaling protects from development of vascular malformations preserving organ-specific endothelial differentiation and angiocrine signaling. The long-term surviving Alk1HEC-KO HHT model offers opportunities to develop targeted therapies for this severe disease.

Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

One fits all: a highly sensitive combined ddPCR/pyrosequencing system for the quantification of microchimerism after hematopoietic and solid organ transplantation.

OBJECTIVES: A combined digital droplet PCR (ddPCR)/pyrosequencing assay system was developed that demonstrated advantages applicable to multiple qualitative and quantitative molecular genetic diagnostic applications. Data for characterizing this combined approach for hematologic stem cell transplantation (HSCT) and allele quantification from graft-derived cell-free (cf) DNA in solid organ transplantation (SOT) is presented. METHODS: ddPCR and pyrosequencing assays targeting 32 SNPs/markers were established. ddPCR results from 72 gDNAs of 55 patients after allogeneic HSCT and 107 plasma-cfDNAs of 25 liver transplant recipients were compared with established methods/markers, i.e. short-tandem-repeat PCR and ALT, respectively. RESULTS: The ddPCR results were in good agreement with the established marker. The limit of detection was 0.02 % minor allele fraction. The relationship between ddPCR and STR-PCR was linear with R2=0.98 allowing to transfer previously established clinical STR-PCR cut-offs to ddPCR; 50-fold higher sensitivity and a variation coefficient of <2 % enable the use of low DNA concentrations (e.g. pre-sorted cells). ddPCR detected liver allograft injury at least as sensitive as ALT suggesting that ddPCR is a reliable method to monitor the transplant integrity, especially when other biomarkers are lacking (e.g. kidney). CONCLUSIONS: Combining pyrosequencing for genotyping and ddPCR for minor allele quantification enhances sensitivity and precision for the patient after HSCT and SOT. The assay is designed for maximum flexibility. It is expected to be suitable for other applications (sample tracking, prenatal diagnostics, etc.).

Successful transplantation of four kidney grafts from two small pediatric donors with anuric acute renal failure into adult recipients.

BACKGROUND: Kidneys from infants with anuric acute kidney injury (AKI) only rarely get accepted for transplantation despite encouraging data that such kidneys can have very good long-term outcome. METHODS: We report the transplantation of four kidney grafts from two pediatric donors (3 and 4 years) with anuric acute kidney injury as single kidneys into four adult recipients. RESULTS: All grafts gained function within 14 days posttransplantation, only one recipient needed dialysis after transplantation. None of the recipients suffered from surgical complications. One month after transplantation, all recipients were free of dialysis. Estimated glomerular filtration rates (eGFR) 3 months after transplantation were 37, 40, 50, and 83 mL/min/1.73 m2 . eGFR increased further through month 6, reaching 45, 50, 58, and 89 mL/min/1.73 m2 . CONCLUSION: These cases highlight the feasibility of successful transplantation of single pediatric kidney grafts into adult recipients despite anuric AKI of the donor.

[Liver Resections Can Be Safely Performed in Cirrhotic Patients after Careful Patient Selection]. / Leberresektionen können bei vorsichtiger Patientenselektion auch in Zirrhose sicher durchgeführt werden.

BACKGROUND: Hepatocellular Carcinoma (HCC) is the most frequent malignant primary liver tumour in a cirrhotic liver. Liver transplantation and resection are the only curative treatment options in compensated liver cirrhosis, but liver resections are associated with increased perioperative morbidity and mortality. PATIENTS: We identified 108 cirrhotic patients, who underwent liver resections at the University Hospital of Mainz between January 2008 and December 2019. During the same period, 185 liver resections were performed for HCC in non-cirrhotic livers. Furthermore, 167 liver resections served as control group, which were performed for colorectal liver metastases (CRLM) with comparable extent of resection to HCC in cirrhotic livers. Preoperatively, we assessed the Charlson Comorbidity Index (CCI), MELD and Child scores in addition to the general patient characteristics. Perioperative morbidity was graded according to the Clavien-Dindo classification. Resections of HCC in cirrhosis and liver metastases were additionally compared by a matched-pair analysis. RESULTS: The three groups were comparable in age. Preoperative liver function was best in patients with CRLM (p < 0.001). Resections for HCC in non-cirrhotic livers were more extended than in cirrhotic livers (p < 0.001). The overall morbidity (Clavien/Dindo stage III - IV) was higher after resections in cirrhotic livers than in CRLM resections (p = 0.026). Postoperative mortality was comparably low in all three groups (2.2%). Neither MELD nor Child score was predictive for postoperative morbidity or mortality (area under the curve: AUC < 0.6, each). Preoperative CCI was predictive for postoperative mortality (AUC = 0.78). CONCLUSIONS: Liver resections in cirrhotic livers are feasible after adequate patient selection and limitation of the extent of surgery. Comorbidities additionally increase the postoperative mortality in addition to impaired liver function and should therefore always be included into the preoperative assessment of patients undergoing liver surgery.

Fully automated AI-based splenic segmentation for predicting survival and estimating the risk of hepatic decompensation in TACE patients with HCC.

OBJECTIVES: Splenic volume (SV) was proposed as a relevant prognostic factor for patients with hepatocellular carcinoma (HCC). We trained a deep-learning algorithm to fully automatically assess SV based on computed tomography (CT) scans. Then, we investigated SV as a prognostic factor for patients with HCC undergoing transarterial chemoembolization (TACE). METHODS: This retrospective study included 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020. A convolutional neural network was trained and validated on the first 100 consecutive cases for spleen segmentation. Then, we used the algorithm to evaluate SV in all 327 patients. Subsequently, we evaluated correlations between SV and survival as well as the risk of hepatic decompensation during TACE. RESULTS: The algorithm showed Sørensen Dice Scores of 0.96 during both training and validation. In the remaining 227 patients assessed with the algorithm, spleen segmentation was visually approved in 223 patients (98.2%) and failed in four patients (1.8%), which required manual re-assessments. Mean SV was 551 ml. Survival was significantly lower in patients with high SV (10.9 months), compared to low SV (22.0 months, p = 0.001). In contrast, overall survival was not significantly predicted by axial and craniocaudal spleen diameter. Furthermore, patients with a hepatic decompensation after TACE had significantly higher SV (p < 0.001). CONCLUSION: Automated SV assessments showed superior survival predictions in patients with HCC undergoing TACE compared to two-dimensional spleen size estimates and identified patients at risk of hepatic decompensation. Thus, SV could serve as an automatically available, currently underappreciated imaging biomarker. KEY POINTS: • Splenic volume is a relevant prognostic factor for prediction of survival in patients with HCC undergoing TACE, and should be preferred over two-dimensional surrogates for splenic size. • Besides overall survival, progression-free survival and hepatic decompensation were significantly associated with splenic volume, making splenic volume a currently underappreciated prognostic factor prior to TACE. • Splenic volume can be fully automatically assessed using deep-learning methods; thus, it is a promising imaging biomarker easily integrable into daily radiological routine.

How to Handle Arterial Conduits in Liver Transplantation? Evidence From the First Multicenter Risk Analysis.

OBJECTIVE: The aims of the present study were to identify independent risk factors for conduit occlusion, compare outcomes of different AC placement sites, and investigate whether postoperative platelet antiaggregation is protective. BACKGROUND: Arterial conduits (AC) in liver transplantation (LT) offer an effective rescue option when regular arterial graft revascularization is not feasible. However, the role of the conduit placement site and postoperative antiaggregation is insufficiently answered in the literature. STUDY DESIGN: This is an international, multicenter cohort study of adult deceased donor LT requiring AC. The study included 14 LT centers and covered the period from January 2007 to December 2016. Primary endpoint was arterial occlusion/patency. Secondary endpoints included intra- and perioperative outcomes and graft and patient survival. RESULTS: The cohort was composed of 565 LT. Infrarenal aortic placement was performed in 77% of ACs whereas supraceliac placement in 20%. Early occlusion (≤30 days) occurred in 8% of cases. Primary patency was equivalent for supraceliac, infrarenal, and iliac conduits. Multivariate analysis identified donor age >40 years, coronary artery bypass, and no aspirin after LT as independent risk factors for early occlusion. Postoperative antiaggregation regimen differed among centers and was given in 49% of cases. Graft survival was significantly superior for patients receiving aggregation inhibitors after LT. CONCLUSION: When AC is required for rescue graft revascularization, the conduit placement site seems to be negligible and should follow the surgeon's preference. In this high-risk group, the study supports the concept of postoperative antiaggregation in LT requiring AC.

Urinary ethyl glucuronide (uEtG) as a marker for alcohol consumption in liver transplant candidates: a real-world cohort.

BACKGROUND: In order to reduce alcohol relapse after liver transplantation (LT), the German national guidelines for waiting-list maintenance and organ allocation demand a minimum 6-month period of alcohol abstinence pre-LT, confirmed by measuring urinary ethyl glucuronide (uEtG). METHODS: Between January 2015 and June 2016, uEtG was measured at least once in 339 cirrhotic patients with an indication for LT at the University Medical Center Mainz. uEtG was measured with an enzyme-linked immunosorbent assay (ELISA) screening test (cutoff value: 500 µg/L). For uEtG values ≥ 500 µg/L, liquid chromatography-mass spectrometry (LC-MS/MS) was performed as a confirmatory assay. Data were collected prospectively in a transplant database. RESULTS: Of the 339 potential liver transplant candidates, uEtG was negative in 86.4 %. Most patients were male (64.3 %), with an average age of 56.42 ±â€Š10.1 years. In the multivariate analysis, mean corpuscular volume (p = 0.001), urinary creatinine (p = 0.001), gamma-glutamyl transferase (p = 0.001), and hemoglobin (p = 0.003) were significantly associated with a positive uEtG test result. The sensitivity of the ELISA screening test was 100 % for uEtG values > 2000 µg/L, as confirmed by LC-MS/MS. CONCLUSION: uEtG is an effective parameter to reveal alcohol consumption by patients on the waiting list for LT. The sensitivity of the ELISA is excellent for uEtG values > 2000 µg/L, for which LC-MS/MS confirmation could be omitted.

Opinions and use of neoadjuvant therapy for resectable, borderline resectable, and locally advanced pancreatic cancer: international survey and case-vignette study.

BACKGROUND: Several new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC), but the support for their use for resectable, borderline resectable and locally advanced PDAC is unclear. METHODS: A survey was distributed to the members of the European-African Hepato-Pancreato Biliary Association (E-AHPBA) and the pancreas group of the European Organization for Research and Treatment of Cancer (EORTC) regarding 1) definitions of local resectability, 2) indications for neoadjuvant therapy and 3) case-vignettes regarding the resectability and treatment of PDAC. RESULTS: In total, 114 participants from 37 countries were registered. About 35% of respondents, each, were of the opinion that borderline resectability is defined by any venous tumor contact and venous involvement < 180° or > 180°, respectively. The majority (75.4%) of participants believed that borderline resectable PDAC has a high risk for R1 resection and that neoadjuvant therapy might increase the R0-resection rate (79.8%) and improve oncological patient selection (84.2%). Chemotherapy was regarded useful to convert locally advanced to resectable PDAC by 55.7% of respondents. In the cases with resectable, borderline resectable, and locally advanced PDAC, 10 (8.8%), 78 (68.4%), 55 (48.2%) of participants would start with chemotherapy, respectively. CONCLUSIONS: Although definitions for borderline resectability differ among European surgeons, there seems to be a rather strong support for preoperative chemotherapy in PDAC aiming at minimizing R1 resections while increasing resection rates.

Surgical therapy of primary hepatic angiosarcoma.

BACKGROUND: Primary hepatic angiosarcoma (PHA) is a rare tumor entity. Radical surgical resection is currently considered the best treatment choice. The aim of this analysis is to report our experience with surgery for PHA. METHODS: All resections of PHA from 01/2002 until 06/2017 were identified from our prospective institutional database. All cases were re-confirmed by a second pathologist. We analyzed completeness of resection, overall (OS) and disease-free survival (DFS). RESULTS: Nine patients with PHA underwent hepatic resection. Median follow-up after surgery was 15.5 months (range: 3-144). At last follow-up 4/9 patients were alive, three of them without recurrence 15, 21 and 144 months after surgery. Five patients developed PHA recurrence. Four of these died 3 to 17 months after surgery. One patient with PHA recurrence is alive 15 months after surgery. Another patient without PHA recurrence died 59 months after surgery from pancreatic cancer. Median OS and DFS after resection was 18 months (range: 3-144 months) and 10 months (range: 2-144 months), respectively. After R-0 resection (n = 8), the median OS and DFS was 59 and 11 months. CONCLUSIONS: Resection of PHA is the only approach to achieve complete tumor removal and offers a chance for long-term survival and should be evaluated in cases of PHA.

Hepatitis E virus genotype 3 is a common finding in liver-transplanted patients undergoing liver biopsy for elevated liver enzymes with a low De Ritis ratio and suspected acute rejection: A real-world cohort.

BACKGROUND: Hepatitis E virus (HEV) infection is a potential reason for elevated liver enzymes after liver transplantation (LT). Our aim was to analyze a real-world cohort of LT patients, who underwent liver biopsy for elevated transaminases and suspected acute rejection, to evaluate frequency of post-transplant HEV infection. PATIENTS: Data from 160 liver biopsies were analyzed. Seventy-one patients were biopsied on schedule after LT without elevated liver enzymes. A subgroup of 25 patients with elevated liver enzymes and suspected rejection was chosen for further analysis. Patient demographics and data were retrieved from a clinical database, patients' charts, and reports. RESULTS: Hepatitis E virus infection was diagnosed in five of 25 patients with suspected acute rejection (20%). HEV genotype 3 was detected in three of the five HEV-infected patients. Patients with HEV infection showed higher ALT levels (P = 0.014), lower De Ritis ratio (P = 0.021), and more frequent glucocorticoid therapy (P = 0.012) compared to HEV-negative patients. CONCLUSION: We found a rate of 20% HEV infections in LT patients undergoing liver biopsy for elevated liver enzymes and suspected acute rejection. These data indicate the necessity for HEV testing in all LT patients with elevated liver enzymes and suspected acute rejection.

Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study.

Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP- (11 Val30Met, 13 nonVal30Met) and 23 DR-patients. DR symptoms referred to post-DLT only, while those of FAP patients were both pre- and post-transplantation. Symptoms of TTR-amyloidosis in Val30Met and Non-Val30Met patients pre- and post-LT were similarly distributed. Biopsy-proven de novo amyloidosis occurred in 4/23 DR after a mean observation of 10 years. Analysis for manifestations of amyloidosis only included patients with available 5-year follow-up data (n = 13 FAP, n = 12 DR). Compared to Val30Met FAP patients pre-LT, Val30Met DR patients had better NCV (P = 0.04) and HRV (P = 0.015). In the Non-Val30Met group no differences were found between DR and FAP patients pre-LT. TTR-amyloidosis symptoms showed no differences in FAP patients pre- and 5 years post-LT, irrespective of Val30Met status. In DR patients, de novo amyloidosis occurred earlier than expected. Therefore, recipients for DLT need to be carefully selected and followed.

Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy in the Treatment of Colorectal Liver Metastases: Current Scenario.

Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has expanded the surgical armamentarium for patients with advanced and bilateral colorectal liver metastases. However, the enthusiasm that the medical fraternity had about ALPPS was hampered by a high mortality rate and early and frequent tumor recurrence. While surgical safety has improved, mainly due to technical refinements and a better patient selection, the oncological value in the face of early tumor recurrence remains unclear. The only randomized controlled trial on ALPPS versus two-stage hepatectomy (TSH) so far confirmed that ALPPS led to higher resectability with comparable perioperative complication rate, but oncological outcome was not measured. Robust data regarding long-term outcome are still missing. TSH and ALPPS might be complementary strategies for the resection of colorectal liver metatsases (CRLM) with ALPPS being reserved for patients with no other surgical option, that is, after failed portal vein embolization or those with an extremely small future liver remnant. In other words, ALPPS can be considered a supplementary tool and a last resort in the liver surgeon's hand to offer resectability in otherwise nonresectable CRLM. In these individual cases, and always embedded into a multimodal treatment setting, ALPPS may offer a chance of complete tumor removal and prolonged survival and even a chance for cure.

Pringle maneuver increases the risk of anastomotic leakage after colonic resection in rats.

BACKGROUND: Many centers use the Pringle's maneuver during liver resections. Since this maneuver might impair healing of bowel anastomoses, we evaluated its influence on the healing of colonic anastomosis in rats. METHODS: Male Wistar rats underwent median laparotomy and sigmoid resection with end-to-end anastomosis under inhalation anesthesia. Thereafter, rats received a 25 minutes Pringle's maneuver (PM, group 1) or were kept under anesthesia for the same period of time (group 2). The anastomotic bursting pressure (BP) was measured on postoperative days (POD) 3, 6 and 9. Hematoxylin and Eosin (H&E) staining was used for histopathological evaluation of the anastomosis. The Mann-Whitney U and χ2 -tests were used, p<0.05 values were considered significant. RESULTS: All animals (n=48) lost body weight (BW) until POD3 (95.2% vs. 85.7%, p=0.003), and BW remained lower after PM (106.2% vs. 92.8%, p=0.001). The anastomotic BP was lower in group 1 compared to group 2 on POD 3 (116mmHg vs. 176.28mmHg, p=0.001), POD 6 (182.8mmHg vs. 213mmHg, p=0.029) and POD 9 (197.2mmHg vs. 251.7mmHg, p=0.009), and mortality was higher in group 1 (1 vs. 7, p=0.022). CONCLUSIONS: Pringle's maneuver increases anastomotic complications in rats. Therefore, a Pringle's maneuver should be avoided during simultaneous liver and colorectal surgery.

Quantitative assessment of washout in hepatocellular carcinoma using MRI.

BACKGROUND: Arterial hyperenhancement and washout on computed tomography and magnetic resonance imaging (MRI) are described by all major guidelines as specific criteria for non-invasive diagnosis of hepatocellular carcinoma (HCC). However, publications on the quantitative assessment of washout in MRI are lacking. Therefore, we evaluated a method for quantitatively measuring and defining washout in MRI in order to determine a cutoff value that allows objective HCC diagnosis. METHODS: We analyzed all patients who underwent liver transplantation for cirrhosis or liver resection for HCC at our institution between 2003 and 2014. Washout was quantitatively investigated by placing a 25-mm2 region of interest (ROI) over each nodule and two 25-mm2 ROIs over adjacent liver parenchyma. The percentage signal ratio (PSR = 100 × ratio of signal intensity of adjacent liver to that of the lesion) was calculated for each series in both groups. Accordingly, this quantitative measurement was compared to a qualitative approach. RESULTS: A total of 16 hypervascularized non-HCC nodules and 69 HCC nodules were identified. Interobserver reliability was reasonably good for the measurement of PSRs and readers showed a substantial agreement for the qualitative assessment. In the HCC group, the median PSR was 116.2 at equilibrium and 112.9 in the delayed phase. In the non-HCC group, the median PSR was 93.8 at equilibrium and 96.0 in the delayed phase. Receiver operating characteristic analysis indicated areas under the curve of 0.902 (p < 0.001) and 0.873 (p < 0.001) at equilibrium and in the delayed phase. PSR values of 102 at equilibrium and 101.5 in the delayed phase led to the highest Youden's index of 0.82 and 0.77, respectively. These PSR cutoffs yielded sensitivities of 82 and 77 %, respectively, with specificities of 100 %. The sensitivity for the qualitative assessment of washout was 88 and 93 % and the specificity was 48 and 56 %. For the classification of HCC, sensitivity yielded 95 and 97 % and specificity was 68 and 56 %, respectively. CONCLUSION: Quantitatively measuring HCC washout in MRI is easy and reproducible. It can objectify and support diagnosis of HCC. However, the quantitative measurement of washout can only serve as one of several components of HCC assessment.

Visceral artery aneurysms: Incidence, management, and outcome analysis in a tertiary care center over one decade.

OBJECTIVES: To evaluate the incidence, management, and outcome of visceral artery aneurysms (VAA) over one decade. METHODS: 233 patients with 253 VAA were analyzed according to location, diameter, aneurysm type, aetiology, rupture, management, and outcome. RESULTS: VAA were localized at the splenic artery, coeliac trunk, renal artery, hepatic artery, superior mesenteric artery, and other locations. The aetiology was degenerative, iatrogenic after medical procedures, connective tissue disease, and others. The rate of rupture was much higher in pseudoaneurysms than true aneurysms (76.3% vs.3.1%). Fifty-nine VAA were treated by intervention (n = 45) or surgery (n = 14). Interventions included embolization with coils or glue, covered stents, or combinations of these. Thirty-five cases with ruptured VAA were treated on an emergency basis. There was no difference in size between ruptured and non-ruptured VAA. After interventional treatment, the 30-day mortality was 6.7% in ruptured VAA compared to no mortality in non-ruptured cases. Follow-up included CT and/or MRI after a mean period of 18.0 ± 26.8 months. The current status of the patient was obtained by a structured telephone survey. CONCLUSIONS: Pseudoaneurysms of visceral arteries have a high risk for rupture. Aneurysm size seems to be no reliable predictor for rupture. Interventional treatment is safe and effective for management of VAA. KEY POINTS: • Diagnosis of visceral artery aneurysms is increasing due to CT and MRI. • Diameter of visceral arterial aneurysms is no reliable predictor for rupture. • False aneurysms/pseudoaneurysms and symptomatic cases need emergency treatment. • Interventional treatment is safe and effective.

Amount of ascites impacts survival in patients with hepatocellular carcinoma undergoing transarterial chemoembolization advocating for volumetric assessment.

Preliminary work has shown that portal hypertension plays a key role for the prognosis in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Specifically, the presence of ascites appears to be a strong negative predictor for these patients. However, it remains unclear whether different ascites volumes influence prognosis. Therefore, the aim of this work was to investigate the influence of different ascites volumes on survival for patients with HCC undergoing TACE. A total of 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020 were included. In patients with ascites, the fluid was segmented, and the volume quantified by slice-wise addition using contrast-enhanced CT imaging. Median overall survival (OS) was calculated and univariate and multivariate Cox regression analysis has been performed. Ascites was present in 102 (31.9%) patients. Ascites volume as continuous variable was significantly associated with an increased hazard ratio in univariate analysis (p < 0.001) and remained an independent predictor of impaired median OS in multivariate analysis (p < 0.001). Median OS without ascites was 17.1 months, and therefore significantly longer than in patients with ascites (6.4 months, p < 0.001). When subdivided into groups of low and high ascites volume in relation to the median ascites volume, patients with low ascites volume had a significantly longer median OS (8.6 vs 3.6 months, p < 0.001). Ascites in patients with HCC undergoing TACE is strongly associated with a poor prognosis. Our results show that not only the presence but also the amount of ascites is highly relevant. Therefore, true ascites volume as opportunistic quantitative biomarker is likely to impact clinical decision-making once automated solutions become available.

A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del).

About 10-15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha (PDGFRA) (wt-GISTs). These tumors are currently defined by having no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene. Until now, the analysis of further exons is not recommended. However, we have previously published a report on a KIT exon 8 germline mutation, which was associated with familial GIST and mastocytosis. We therefore investigated whether KIT exon 8 mutations might also occur in sporadic GIST. We screened a cohort of 145 wt-GISTs from a total of 1351 cases from our registry for somatic mutations in KIT exon 8. Two primary GISTs with an identical exon 8 mutation (p.D419del) were detected, representing 1.4% of all the cases analyzed. Based on all GISTs from our registry, the overall frequency of KIT exon 8 mutations was 0.15%. The first tumor originating in the small bowel of a 53-year-old male patient had mostly a biphasic spindled-epithelioid pattern with a high proliferative activity (14 mitoses/50 HPF) combined with a second low proliferative spindle cell pattern (4/50 HPF). The patient developed multiple peritoneal metastases 29 months later. The second case represented a jejunal GIST in a 67-year old woman who is relapse-free under adjuvant imatinib treatment. We conclude that about 1-2% of GISTs being classified as 'wild type' so far might, in fact, carry KIT mutations in exon 8. Moreover, this mutational subtype was shown to be activating and imatinib sensitive in vitro. We therefore propose that screening for KIT exon 8 mutations should become a routine in the diagnostic work-up of GIST and that patients with an exon 8 mutation and a significant risk for tumor progression should be treated with imatinib.