The rate of cholangiocarcinoma in Caroli Disease A German multicenter study.

BACKGROUND: Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts. CD/CS are associated with cholangiocarcinoma (CCA). However, the true incidence of CCA is still unclear, although it may serve as an indication for surgery. In this paper, we analyzed (I) the incidence of CCA in German centers, (II) reviewed our single center population together with its clinical presentation and (III) performed a thorough literature review. METHODS: 17 large HPB-centers across Germany were contacted and their patients after surgical treatment due to CD/CS with histopathology were included. Medline search for all studies published in English or German literature was performed. Patients who underwent surgery at our department between 2012 and 2020 due to CD or CS were analyzed. RESULTS: In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients. In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%). Between 2012 and 2020, 1661 liver resections were performed at our department. 14 patients underwent surgery due to CD or CS. Histological examination showed synchronous cholangiocarcinoma in one patient. The literature review revealed a CCA-rate of 7,3% in large series, whereas in case reports a rate of 6,8% was found. CONCLUSION: There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised. As certain patients with CS require transplantation, treatment should not be guided by the relatively low rate of CCA but by the concomitant diseases that come along with hepatic failure.

Robotic-assisted total mesorectal excision (TME) for rectal cancer results in a significantly higher quality of TME specimen compared to the laparoscopic approach-report of a single-center experience.

AIM: Robotic surgery allows for a better visualization and more precise dissection especially in the narrow male pelvis and mid and lower third of the rectum. However, superiority to laparoscopic TME has yet to be proven. We therefore analyzed short-term outcomes of laparoscopic and robotic low anterior rectal resection for rectal cancer. PATIENTS AND METHODS: From 2011 to 2016, 44 robotic (RTME) and 41 laparoscopic (LTME) low anterior rectal resection with total mesorectal excision were performed at a single institution. Specimen quality was assessed and reported by an independent pathologist following international guidelines. RESULTS: The groups did not differ significantly regarding gender, age, ASA stage, BMI, and distance of the lower tumor margin from the anal verge. More patients in the RTME group underwent preoperative chemoradiation (43.2 vs. 19.5%, p = 0.019). The quality of the TME specimen was significantly better in the RTME group (complete/nearly complete/incomplete for RTME 97/0/3% and for LTME 78/17/5%, p = 0.03). The conversion rate tended to be lower in the RTME group (7 vs. 17%, p = 0.143). There was no difference in CRM positivity between the groups. CONCLUSION: Robotic surgery is safe and can improve the quality of TME for rectal cancer compared to laparoscopy. Any effect on long-term survival remains to be established.

MRI in mild pediatric traumatic brain injury: diagnostic overkill or useful tool?

PURPOSE: Magnetic resonance imaging (MRI) is a sensitive imaging tool which lacks the burden of ionizing radiation. It is not established as primary diagnostic tool in traumatic brain injury (TBI). The purpose of this study was to evaluate the usefulness of MRI as initial imaging modality in the emergency management of mild pediatric TBI. METHODS: Children (0-18 years, sub-divided in four age-groups) with mild TBI who received MRI in the emergency department were identified. Clinical characteristics and trauma mechanisms were evaluated retrospectively. Univariate and multivariate logistic regression analyses were used to identify clinical factors that might be indicative for trauma sequelae on MRI scans. RESULTS: An institutional case series of 569 patients (322 male/247 female; age < 18years; (GCS ≥ 13), who received MRI for mild TBI, was analyzed. Multi-sequence imaging (including T2, T2*, FLAIR, and diffusion-weighted sequences) was feasible without sedation in 96.8% of cases (sedation, 1.8%; general anesthesia, 1.4%). MRI revealed trauma-associated findings in 13% of all cases; incidental findings were detected in 4.7%. In our cohort, GCS deterioration, scalp hematoma, clinical signs of skull base fractures, and horseback riding accidents were related to structural trauma sequelae on MRI. CONCLUSIONS: MRI is a practical primary imaging tool for evaluating children with mild TBI in the emergency department. The presented analyses demonstrated that in our institution, MRI imaging is performed frequently in the emergency department. It resulted mostly in normal findings. This may reflect uneasiness of when to perform imaging in mild TBI and appears retrospectively as an "overdo." There are clinical factors that are more likely associated with MRI-positive findings. Their reliability has to be evaluated in prospective studies in order to formulate further decision rules of when to perform MRI imaging or not.

Influence of mTOR-inhibitors and mycophenolic acid on human cholangiocellular carcinoma and cancer associated fibroblasts.

BACKGROUND: The incidence of Cholangiocellular Carcinoma (CCA) is increasing in the western world. The tumour has a high proportion of desmoplastic stroma and is correlated with a worse prognosis when cancer associated myofibroblasts (CAFs) are present. Recent studies showed promising results after liver transplantation (LTx) in non-resectable early stage CCA. Mycophenolic acid (MPA) and the mTor inhibitor Everolimus are used to prevent organ rejection but recently were shown to exhibit an antiproliferative effect on CCA-cells. Little is known about the influence of immunosuppressive drugs on tumour cell proliferation and migration after paracrine stimulation by CAFs. Moreover, it is still unknown, which signaling pathways are activated following these specific cell-cell interactions. METHODS: CCA cell lines HuCCT1 and TFK1 were utilized for the study. CAFs were derived from resected CCA cancer tissue. Cell viability was measured by the crystal violet assay and tumour cell invasion was quantified using a modified co-culture transmigration assay. Semiquantitative cytokine-expression was measured using a cytokine-array. Protein expression and phosphorylation of ERK, STAT3 and AKT was determined by Western-blot analysis. RESULTS: CCA cells treated with MPA exhibited a dose related decrease in cell viability in contrast to Cyclosporine A (CSA) treatment which had no effect on cell viability. Everolimus significantly inhibited proliferation at very low concentrations. The pro-invasive effect of CAFs in co-culture transmigration assay was significantly reduced by Everolimus at a concentration of 1nM (p = 0.047). In contrast, MPA and CSA showed no effect on tumour cell invasion. Treatment of CAFs with 1nM Everolimus showed a significant reduction in the expression of IL 8, IL 13, MCP1, MIF and Serpin E1. CCA-cells showed significant increases in phosphorylation of ERK, STAT3 and AKT under the influence of conditioned CAF-media. This effect was suppressed by Everolimus. CONCLUSIONS: The secretion of proinflammatory cytokines by CAFs may lead to increased activation of JAK/STAT3-, ERK- and AKT-signaling and increased migration of CCA-cells. Everolimus abrogates this effect and inhibits proliferation of CCA-cells even at low concentrations. LTx for non-resectable early stage CCA is currently performed in several clinical studies. Consistent with a role for common immunosuppressants in inhibiting tumour cell-proliferation and -invasion, our study indicates that a combination of standard therapies with Everolimus and MPA is a promising therapy option to treat CCA following LTx.

Mode of allocation and social demographic factors correlate with impaired quality of life after liver transplantation.

BACKGROUND: Health-related Quality of life (HRQoL) is a major goal of clinical management after liver transplantation (LTx). There is still disagreement on the effects of social-demographic factors and changes in the allocation system on HRQoL. The aim of this study was to evaluate the impact of social-demographic factors, mode of organ-allocation, waiting time and hepatocellular carcinoma (HCC) on HRQoL after LTx. METHODS: HRQoL was assessed using the EORTC-QLQ-C30 questionnaire, which was sent to 238 recipients. Investigated parameters included age, sex, distance to transplant center, follow-up at hospital, size of hometown, highest education, marital status, having children, background liver disease, waiting time, mode of allocation, HCC, hospitalization after LTx and diagnosis of malignancy after LTx. All evaluated parameters were entered into multivariate linear regression analysis. RESULTS: Completed questionnaire were returned by 73% of the recipients. After LTx, the HRQoL-function scales increased over time. Age, marital status, highest education, completed professional training, working status, job position, duration of waiting time to LTx, distance to transplant center, place offollow, HU-statuts, mode of organ allocation and duration of hospitalization were associated with significantly worse function- and significantly lower symptom scales. HCC as a primary disease did not affect HRQoL. CONCLUSIONS: Low HRQoL correlated significantly with MELD-based organ allocation, more than 28-day hospitalization, divorced status, lower education- and non-working status, higher distance to transplant center, follow up at transplant center, HU-status, shorter waiting time to LTx and younger age. Improvement of HRQoL after LTx may require clinical management of pain, psychotherapy and financial support.

Paracrine Interaction of Cholangiocellular Carcinoma with Cancer-Associated Fibroblasts and Schwann Cells Impact Cell Migration.

Although the Mitogen-activated protein kinase (MAPK) pathway is enriched in cholangiocarcinoma (CCA), treatment with the multityrosine kinase-inhibitor Sorafenib is disappointing. While cancer-associated fibroblasts (CAF) are known to contribute to treatment resistance in CCA, knowledge is lacking for Schwann cells (SC). We investigated the impact of stromal cells on CCA cells and whether this is affected by Sorafenib. Immunohistochemistry revealed elevated expression of CAF and SC markers significantly correlating with reduced tumor-free survival. In co-culture with CAF, CCA cells mostly migrated, which could be diminished by Sorafenib, while in SC co-cultures, SC predominantly migrated towards CCA cells, unaffected by Sorafenib. Moreover, increased secretion of pro-inflammatory cytokines MCP-1, CXCL-1, IL-6 and IL-8 was determined in CAF mono- and co-cultures, which could be reduced by Sorafenib. Corresponding to migration results, an increased expression of phospho-AKT was measured in CAF co-cultured HuCCT-1 cells, although was unaffected by Sorafenib. Intriguingly, CAF co-cultured TFK-1 cells showed increased activation of STAT3, JNK, ERK and AKT pathways, which was partly reduced by Sorafenib. This study indicates that CAF and SC differentially impact CCA cells and Sorafenib partially reverts these stroma-mediated effects. These findings contribute to a better understanding of the paracrine interplay of CAF and SC with CCA cells.

Phosphatidylethanol (PEth) for Monitoring Sobriety in Liver Transplant Candidates: Preliminary Results of Differences Between Alcohol-Related and Non-Alcohol-Related Cirrhosis Candidates.

BACKGROUND Monitoring sobriety is mandatory for liver transplant (LT) candidates with alcohol-related cirrhosis in Germany. Prior to listing, abstinence of 6 months is required. However, little is known about biomarker performance in alcohol-related cirrhosis. Routine testing of ethyl glucuronide in urine (uEtG) or hair (hEtG) is prone to manipulation or is unfeasible in anuria. Phosphatidylethanol (PEth) in dried-blood spots is a promising alternative. We compared PEth with routine parameters and self-reports in alcohol-related and non-alcohol-related cirrhosis at our transplant center. MATERIAL AND METHODS All patients received self-report questionnaires (AUDIT & TLFB). Blood, urine and hair samples, as well as PEth dried-blood spots were drawn at baseline. In addition, survival analyses were conducted. RESULTS Out of 66 patients, 53 were listed for LT and 13 were candidates not listed so far. An alcohol-use disorder was found in 25 patients. Positive results for uEtG, hEtG, and PEth were found in 5/65, 9/65, and 34/66 cases, respectively. PEth positivity was found in 52% of patients with alcohol-related cirrhosis, while 53% of patients with other liver diseases were positive. While uEtG, hEtG, and TLFB correlated with higher PEth values, active waiting list status was significantly correlated with negative PEth values. During the mean follow-up of 41.15 months, 23 patients were transplanted (34.9%). None of the biomarkers significantly predicted survival. CONCLUSIONS PEth can importantly assist abstinence monitoring in LT candidates due to its high validity and objectivity. The high percentage of patients with alcohol consumption in the non-alcoholic liver disease cohort underscores the importance of testing all transplant candidates.

Indication of Liver Transplantation for Hepatocellular Carcinoma Should Be Reconsidered in Case of Microvascular Invasion and Multilocular Tumor Occurrence.

Liver transplantation (LT) is routinely performed for hepatocellular carcinoma (HCC) in cirrhosis without major vascular invasion. Although the adverse influence of microvascular invasion is recognized, its occurrence does not contraindicate LT. We retrospectively analyzed in our LT cohort the significance of microvascular invasion on survival and demonstrate bridging procedures. At our hospital, 346 patients were diagnosed with HCC, 171 patients were evaluated for LT, and 153 were listed at Eurotransplant during a period of 11 years. Among these, 112 patients received LT and were included in this study. Overall survival after 1, 3 and 5 years was 86.3%, 73.9%, and 67.9%, respectively. Microvascular invasion led to significantly reduced overall (p = 0.030) and disease-free survival (p = 0.002). Five-year disease-free survival with microvascular invasion was 10.5%. Multilocular tumor occurrence with simultaneous microvascular invasion revealed the worst prognosis. In our LT cohort, predominant bridging treatment was transarterial chemoembolization (TACE) and the number of TACE significantly correlated with poorer overall survival after LT (p = 0.028), which was confirmed in multiple Cox regression analysis for overall and disease-free survival (p = 0.015 and p = 0.011). Microvascular tumor invasion is significantly associated with reduced prognosis after LT, which is aggravated by simultaneous occurrence of multiple lesions. Therefore, indication strategies for LT should be reconsidered.

Inferior Vena Cava Constriction After Liver Transplantation Is a Severe Complication Requiring Individually Adapted Treatment: Report of a Single-Center Experience.

BACKGROUND Reports on vena cava occlusion after liver transplantation (LT) are rare, but this finding represents a severe complication in the early postoperative period. In the context of the complex presentation of a patient after LT, symptoms are often misinterpreted and can be subtle. MATERIAL AND METHODS In our cohort of 138 LTs performed between 2014 and 2017 at our University's Transplantation Department, 117 transplantations were valid for further analysis after exclusion of pediatric transplantations and transplants with primary non-function grafts. In 101 cases (73%), patients received a deceased-donor full-size organ. Living-donor LT was performed in 8 patients (6.4%) and 8 patients (6.4%) received a split graft. We report on 6 patients who had inferior vena cava (IVC) occlusion and summarize the treatment choices. RESULTS In our series, patients with positive findings (age 38-70 years) received an orthotopic full-size deceased-donor graft with end-to-end IVC anastomosis. In the subsequent period, imaging revealing IVC occlusion was done on a follow-up basis (n=2), due to dyspnea (n=1), and for progressive ascites (n=2). In 3 cases, a thrombus was found. We give detailed information on our treatment options from interventional treatment to transcardial thrombus removal and anastomosis augmentation. CONCLUSIONS IVC constriction and subsequent thrombosis are severe complications after LT that require individually adapted treatment in specialized centers. Since patients often present with subclinical symptoms, vascular diagnosis should be performed early to detect caval anastomosis pathologies. Despite regular ultrasonography, we favor CT and cavography for subsequent quantification. We also review the literature on IVC occlusion after LT.

The Impact of Robotics in Learning Roux-en-Y Gastric Bypass: a Retrospective Analysis of 214 Laparoscopic and Robotic Procedures : Robotic Vs. Laparoscopic RYGB.

BACKGROUND: Proximal Roux-en-Y gastric bypass is commonly used to manage obesity, performed using laparoscopic or robot-assisted minimally invasive surgery. As the prevalence of robotic bariatric surgery increases, further data is required to justify its use. METHODS: This was a large, retrospective analysis of prospectively recorded data for Roux-en-Y gastric bypass (RYGB) procedures performed using laparoscopic (LRYGB) or robotic (RRYGB; da Vinci Xi system, Intuitive Surgical Sàrl) surgery between January 2016 and March 2019. The surgical techniques did not differ apart from different trocar placements. Data collected included patient characteristics before and after RYGB, operative outcomes and complications. RESULTS: In total, 114 RRYGB and 108 LRYGB primary surgeries were performed. There were no significant differences between the groups, apart from a significantly shorter duration of surgery (116.9 vs. 128.9 min, respectively), lower C-reactive protein values at days 1 (31.1 vs. 44.1 mg/l) and 2 (50.3 vs. 77.8 mg/l) after the intervention, and overall complication rate (4.4 vs. 12.0%, Clavien-Dindo classification II-V) with RRYGB compared with LRYGB. There was a lower hemoglobin value in the postoperative course after RRYGB (12.1 vs. 12.6 g/dl, day 2). CONCLUSIONS: In our experience, robotic RYGB has proven to be safe and efficient, with a shorter duration of surgery and lower rate of complications than laparoscopic RYGB. RRYGB is easier to learn and seems safer in less experienced centers. Increasing experience with the robotic system can reduce the duration of surgery over time. Further studies with higher evidence level are necessary to confirm our results.

Low Postoperative Levels of C-Reactive Protein Are an Early Predictor for an Uncomplicated Course After Bariatric Surgery: A Retrospective, Validated Cohort Study.

BACKGROUND: Bariatric surgery is popularly used to treat or prevent morbidity in severely obese patients. Severe complications are rare, but their early detection has a significant impact on clinical outcomes. We aimed to determine whether blood tests in the first few postoperative days are reliable predictors for complications. METHODS: We retrospectively analyzed 1073 patients who underwent laparoscopic bariatric surgery between 2009 and 2018 at our center. Clinical outcome was correlated with postoperative serum C-reactive protein (CRP), white blood cell count, and vital signs, analyzed using a receiver operating characteristic (ROC) curve. A total of 570 procedures between 2009 and 2015 were used to calculate the best cutoff values (calculation group), which were validated with 330 different patients operated upon between 2016 and 2018 (validation group). RESULTS: Twenty-four patients (4.2%) developed anastomotic or staple-line leakages in the calculation group. The ROC curve showed a good reliability for CRP levels on day 2 (area under the ROC curve=0.86); the highest Youden index existed for a cutoff of 119 mg/L. White blood cell count and heart rate were poor predictors. Even though several characteristics differed in the validation cohort, test quality of the cutoff was high (sensitivity, 71.4%; specificity, 94.9%; positive predictive value, 23.8%; negative predictive value, 99.3%). The prediction was excellent especially for leakages appearing on days 2 to 9 (sensitivity 100.0%, negative predictive value 100%). Leakages from day 10 were rare and prediction poor (sensitivity 0%). CONCLUSIONS: A CRP level on day 2 <120 mg/L is a good predictor of a postoperative course without leakage, even though the predictive value goes down for late-appearing events. An earlier CRP measurement added no predictive benefit. The cutoff value was validated in an internal cohort and could be applied to different populations.

Identifying patients with an unfavorable prognosis in early stages of colorectal carcinoma.

BACKGROUND: In recent years, the concept of liquid biopsy diagnostics in detection and progress monitoring of malignant diseases gained significant awareness. We here report on a semi-quantitative real-time cytokeratin 20 RT-PCR-based assay, for detecting circulating tumor cells within a fraction of peripheral blood mononuclear cells in colorectal cancer patients. METHODS: In total, 381 patients were included. Prior to surgical tumor resection, a peripheral blood sample was drawn. Mononuclear cells were isolated by Ficoll centrifugation and a cytokeratin 20 qRT-PCR assay was performed. Quantitative PCR data was assessed regarding histopathological characteristics and patients´ clinical outcome. RESULTS: A cut-off value was determined at ≥ 2.77 [EU]. Stratifying patients by this cut-off, it represents a statistically highly significant prognostic marker for both the overall and disease-free survival in the entire cohort UICC I-IV (both p<0.001) and in early tumor stages UICC I+II (overall survival p=0.003 and disease-free survival p=0.005). In multivariate analysis, the cut-off value stands for an independent predictor of significantly worse overall and disease-free survival (p=0.035 and p=0.047, respectively). CONCLUSION: We successfully established a highly sensitive real-time qRT-PCR assay by which we are able to identify colorectal cancer patients at risk for an unfavorable prognosis in UICC I and II stages.

Long-term quality of life after endovac-therapy in anastomotic leakages after esophagectomy.

BACKGROUND: Endoluminal vacuum therapy (EVT) has been successfully established with promising survival rates in the treatment of anastomotic leakages after esophagectomy. It is still unclear how this therapy affects health related quality of life (HRQOL). METHODS: HRQOL was prospectively assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) questionnaire. Assessment was carried out prior to surgery, after discharge, 6 months and 12 months after surgery. We compared HRQOL after EVT (n=23) to patients without anastomotic leakages as a control group (n=50). Investigated parameters included age, sex, and localization of anastomosis, number of EVT sessions, length of ICU and hospital stay, therapy failure, anastomotic stricture, tumour stage, neoadjuvant and adjuvant treatment, sepsis. RESULTS: After esophagectomy HRQOL increased within 12 months. Compared to patients without leakages the EVT-group showed significantly better HRQOL-scores for pain, social and emotional functioning after discharge and 6 months after surgery. In the long-term follow up HRQOL was comparable between the groups. After EVT age, advanced tumour stage, tumour recurrence, anastomotic strictures, length of ICU and hospital stay and length of EVT had a significant influence on HRQOL. CONCLUSIONS: EVT is a promising therapeutic option in leakages after esophagectomy. In the long-term, HRQOL of EVT-treated patients is comparable to patients, who did not suffer from postsurgical leakages.

Cognitive Evaluation in Liver Transplant Patients Under Calcineurin Inhibitor Maintenance Therapy.

BACKGROUND: Neurological disorders due to calcineurin inhibitor (CNI) treatment pose a well-known problem after liver transplantation (LTx). In this study, the impact of CNIs on cognitive functioning during maintenance therapy was analyzed. A possible improvement of cognitive functioning, compliance and health-related quality of life (HRQoL) after conversion to a once-daily tacrolimus formulation was prospectively assessed. METHODS: In a cross-section analysis cognitive functioning of living donors (LD), waiting list patients and LTx patients was tested using a 4 times trail making test (4-TTMT). In a further investigator-initiated trial a possible improvement of cognitive functioning, HRQoL and compliance after conversion to the once-daily tacrolimus formulation was prospectively assessed over 1 year. HRQoL was assessed using an EORTC-QLQ C30 questionnaire and patient's compliance was assessed by the Basel Assessment of Compliance with Immunosuppressive Medication Scales questionnaire. Correlated data were sex, age, time after surgery, liver disease, model of end-stage liver disease score, creatinine, CNI type, and CNI trough levels. RESULTS: Two hundred eleven patients were included in this cross-section analysis. Twenty-seven patients agreed to participate in the investigator-initiated trial. LTx patients completed the 4-TTMT slower than living donor patients and faster than waiting list patients. Patients with twice daily cyclosporine A (CSA) formulation needed longer to finish the 4-TTMT than patients with the once-daily tacrolimus formulation. After drug conversion of a twice-daily CNI formulation to a once-daily tacrolimus formulation, CSA-treated patients needed longer to improve their cognitive functioning. HRQoL and compliance did not improve after drug conversion. CONCLUSIONS: Patients with once-daily tacrolimus formulation had a better psychomotor speed than CSA-treated patients. The conversion to once-daily tacrolimus formulation significantly improved cognitive functioning, but had no impact on HRQoL or compliance.