Clinical features and prediction of long-term survival after surgery for perihilar cholangiocarcinoma.

INTRODUCTION: The treatment of perihilar Cholangiocarcinoma (pCCA) poses specific challenges not only due to its high perioperative complication rates but also due its dismal long-term prognosis with only a few long-term survivors (LTS) among the patients. Therefore, in this analysis characteristics and predictors of LTS in pCCA patients are investigated. MATERIAL AND METHODS: In this single center analysis, patients undergoing curative-intent liver resection for pCCA between 2010 and 2022 were categorized into long-term and short-term survivors (STS) excluding perioperative mortality. Binary logistic regression was used to determine key differences between the groups and to develop a prognostic composite variable. This composite variable was subsequently tested in the whole cohort of surgically treated pCCA patients using Cox Regression analysis for cancer-specific survival (CSS). RESULTS: Within a cohort of 209 individuals, 27 patients were identified as LTS (median CSS = 125 months) and 55 patients as STS (median CSS = 16 months). Multivariable analysis identified preoperative portal vein infiltration (OR = 5.85, p = 0.018) and intraoperative packed red blood cell (PRBC) transfusions (OR = 10.29, p = 0.002) as key differences between the groups. A prognostic composite variable based on these two features was created and transferred into a Cox regression model of the whole cohort. Here, the composite variable (HR = 0.35, p<0.001), lymph node metastases (HR = 2.15, p = 0.001) and postoperative complications (HR = 3.06, p<0.001) were identified as independent predictors of CSS. CONCLUSION: Long-term survival after surgery for pCCA is possible and is strongly negatively associated with preoperative portal vein infiltration and intraoperative PRBC transfusion. As these variables are part of preoperative staging or can be modulated by intraoperative technique, the proposed prognostic composite variable can easily be transferred into clinical management to predict the oncological outcome of patients undergoing surgery for pCCA.

Partial liver resection alters the bile salt-FGF19 axis in patients with perihilar cholangiocarcinoma: Implications for liver regeneration.

BACKGROUND: Extended liver resection is the only treatment option for perihilar cholangiocarcinoma (pCCA). Bile salts and the gut hormone FGF19, both promoters of liver regeneration (LR), have not been investigated in patients undergoing resection for pCCA. We aimed to evaluate the bile salt-FGF19 axis perioperatively in pCCA and study its effects on LR. METHODS: Plasma bile salts, FGF19, and C4 (bile salt synthesis marker) were assessed in patients with pCCA and controls (colorectal liver metastases), before and after resection on postoperative days (PODs) 1, 3, and 7. Hepatic bile salts were determined in intraoperative liver biopsies. RESULTS: Partial liver resection in pCCA elicited a sharp decline in bile salt and FGF19 plasma levels on POD 1 and remained low thereafter, unlike in controls, where bile salts rose gradually. Preoperatively, suppressed C4 in pCCA normalized postoperatively to levels similar to those in the controls. The remnant liver volume and postoperative bilirubin levels were negatively associated with postoperative C4 levels. Furthermore, patients who developed postoperative liver failure had nearly undetectable C4 levels on POD 7. Hepatic bile salts strongly predicted hyperbilirubinemia on POD 7 in both groups. Finally, postoperative bile salt levels on day 7 were an independent predictor of LR. CONCLUSIONS: Partial liver resection alters the bile salt-FGF19 axis, but its derailment is unrelated to LR in pCCA. Postoperative monitoring of circulating bile salts and their production may be useful for monitoring LR.

Preoperative three-dimensional lung volumetry predicts respiratory complications in patients undergoing major liver resection for colorectal metastases.

Colorectal liver metastases (CRLM) are the predominant factor limiting survival in patients with colorectal cancer and liver resection with complete tumor removal is the best treatment option for these patients. This study examines the predictive ability of three-dimensional lung volumetry (3DLV) based on preoperative computerized tomography (CT), to predict postoperative pulmonary complications in patients undergoing major liver resection for CRLM. Patients undergoing major curative liver resection for CRLM between 2010 and 2021 with a preoperative CT scan of the thorax within 6 weeks of surgery, were included. Total lung volume (TLV) was calculated using volumetry software 3D-Slicer version 4.11.20210226 including Chest Imaging Platform extension ( http://www.slicer.org ). The area under the curve (AUC) of a receiver-operating characteristic analysis was used to define a cut-off value of TLV, for predicting the occurrence of postoperative respiratory complications. Differences between patients with TLV below and above the cut-off were examined with Chi-square or Fisher's exact test and Mann-Whitney U tests and logistic regression was used to determine independent risk factors for the development of respiratory complications. A total of 123 patients were included, of which 35 (29%) developed respiratory complications. A predictive ability of TLV regarding respiratory complications was shown (AUC 0.62, p = 0.036) and a cut-off value of 4500 cm3 was defined. Patients with TLV < 4500 cm3 were shown to suffer from significantly higher rates of respiratory complications (44% vs. 21%, p = 0.007) compared to the rest. Logistic regression analysis identified TLV < 4500 cm3 as an independent predictor for the occurrence of respiratory complications (odds ratio 3.777, 95% confidence intervals 1.488-9.588, p = 0.005). Preoperative 3DLV is a viable technique for prediction of postoperative pulmonary complications in patients undergoing major liver resection for CRLM. More studies in larger cohorts are necessary to further evaluate this technique.

Managing hepatocellular carcinoma across the stages: efficacy and outcomes of stereotactic body radiotherapy : A retrospective study.

PURPOSE: Hepatocellular carcinoma (HCC) poses a unique challenge due to its predilection for developing on compromised livers, often limiting surgical options. Stereotactic body radiotherapy (SBRT) has emerged as a promising local treatment modality for HCC. This study aims to assess the effectiveness of SBRT in HCC patients not suitable for surgery, focusing on local control, optimal radiation dosing, and prognostic factors. METHODS: In this retrospective analysis, 52 HCC patients treated with SBRT were examined. The study assessed local control, progression-free survival (PFS), and overall survival (OS) while conducting dosimetric analyses. The relationship between mean liver dose and Child-Pugh score (CPS) progression was also explored. RESULTS: SBRT demonstrated 93.4% freedom from local progression (FFLP) at 12 months. Notably, a near minimum dose (D98%) below 61 Gy as an equivalent dose in 2­Gy fractions with α/ß 10 Gy (EQD2α/ß10) was associated with reduced FFLP (p-value 0.034). Logistic regression analysis revealed a dose-response relationship for FFLP and D98% with 95% and 98% probability of FFLP at a dose of 56.9 and 73.1 Gy, respectively. The study observed OS rates of 63.7% at 1 year and 34.3% at 3 years. Patients with portal vein tumor thrombus (PVTT) and larger tumors (≥ 37 cm3) experienced decreased PFS and OS. Multivariate analysis identified PVTT, larger tumor volume, and performance status as independent predictors of reduced OS. Notably, classical radiation-induced disease (cRILD) was absent, but nonclassical (nc) RILD occurred in 7.7% of patients. Regression analysis linked a mean EQD2α/ß3-8 dose to the liver (12.8-12.6) with a 10% likelihood of ncRILD. CONCLUSION: SBRT offers a compelling option for achieving high local control and promising survival outcomes in HCC. The study supports a radiation dose range of 61-73.1 Gy, coupled with a mean liver dose under 12.6-12.8 Gy as EQD2, to achieve favorable FFLP rates, with acceptable toxicity rates.

Preoperative predictors for non-resectability in perihilar cholangiocarcinoma.

INTRODUCTION: Explorative laparotomy without subsequent curative-intent liver resection remains a major clinical problem in the treatment of perihilar cholangiocarcinoma (pCCA). Thus, we aimed to identify preoperative risk factors for non-resectability of pCCA patients. MATERIAL AND METHODS: Patients undergoing surgical exploration between 2010 and 2022 were eligible for the analysis. Separate binary logistic regressions analyses were used to determine risk factors for non-resectability after explorative laparotomy due to technical (tumor extent, vessel infiltration) and oncological (peritoneal carcinomatosis, distant nodal or liver metastases)/liver function reasons. RESULTS: This monocentric cohort comprised 318 patients with 209 (65.7%) being surgically resected and 109 (34.3%) being surgically explored [explorative laparotomy: 87 (27.4%), laparoscopic exploration: 22 (6.9%)]. The median age in the cohort was 69 years (range 60-75) and a majority had significant comorbidities with ASA-Score ≥ 3 (202/318, 63.5%). Statistically significant (p < 0.05) risk factors for non-resectability were age above 70 years (HR = 3.76, p = 0.003), portal vein embolization (PVE, HR = 5.73, p = 0.007), and arterial infiltration > 180° (HR = 8.05 p < 0.001) for technical non-resectability and PVE (HR = 4.67, p = 0.018), arterial infiltration > 180° (HR = 3.24, p = 0.015), and elevated CA 19-9 (HR = 3.2, p = 0.009) for oncological/liver-functional non-resectability. CONCLUSION: Advanced age, PVE, arterial infiltration, and elevated CA19-9 are major risk factors for non-resectability in pCCA. Preoperative assessment of those factors is crucial for better therapeutical pathways. Diagnostic laparoscopy, especially in high-risk situations, should be used to reduce the amount of explorative laparotomies without subsequent liver resection.

Body composition is associated with postoperative complications in perihilar cholangiocarcinoma.

BACKGROUND: Perihilar cholangiocarcinoma (pCCA) is a malignant tumor of the hepatobiliary system which is still associated with a challenging prognosis. Postoperative complications play a crucial role in determining the overall prognosis of patients with pCCA. Changes in body composition (BC) have been shown to impact the prognosis of various types of tumors. Therefore, our study aimed to investigate the correlation between BC, postoperative complications and oncological outcome in patients with pCCA. METHODS: All patients with pCCA who underwent curative-intent surgery for pCCA between 2010 and 2022 were included in this analysis. BC was assessed using preoperative computed tomography and analyzed with the assistance of a 3D Slicer software. Univariate and multivariate binary logistic regression analyses were conducted to examine the relationship between BC and clinical characteristics including various measurements of postoperative complications and Cox regressions and Kaplan-Meier analysis to evaluate oncological risk factors in the study cohort. RESULTS: BC was frequently altered in patients undergoing curative-intent liver resection for pCCA (n = 204) with 52.5% of the patients showing obesity, 55.9% sarcopenia, 21.6% sarcopenic obesity, 48.5% myosteatosis, and 69.1% visceral obesity. In multivariate analysis, severe postoperative complications (Clavien-Dindo ≥3b) were associated with body mass index (BMI) (Odds ratio (OR) = 2.001, p = 0.024), sarcopenia (OR = 2.145, p = 0.034), and myosteatosis (OR = 2.097, p = 0.017) as independent predictors. Furthermore, sarcopenia was associated with reduced overall survival (OS) in pCCA patients (sarcopenia vs. no-sarcopenia, 21 months vs. 32 months, p = 0.048 log rank). CONCLUSIONS: BC is highly associated with severe postoperative complications in patients with pCCA and shows tendency to be associated impaired overall survival. Preoperative assessment of BC and interventions to improve BC might therefore be key to improve outcome in pCCA patients undergoing surgical therapy.

Time to surgery is not an oncological risk factor in patients with cholangiocarcinoma undergoing curative-intent liver surgery.

Surgical resection is the only option to achieve long-term survival in cholangiocellular carcinoma (CCA). Due to limitations of health care systems and unforeseeable events, e.g., the COVID pandemic, the time from diagnosis to surgery (time-to-surgery (TTS)) has gained great interest in malignancies. Thus, we investigated whether TTS is associated with the oncological outcome in patients who underwent surgery for CCA. A cohort of 276 patients undergoing curative-intent surgery for intrahepatic and perihilar CCA excluding individuals with neoadjuvant therapy and perioperative mortality between 2010 and 2021 were eligible for analysis. Patients were grouped according to TTS (≤ 30; 31-60; 61-90; > 90 days) and compared by Kruskal-Wallis-analysis. Survival was compared using Kaplan-Meier analysis and characteristics associated with cancer-specific survival (CSS), recurrence-free survival (RFS) and overall survival (OS) using Cox regressions. The median CSS was 39 months (3-year-CSS = 52%, 5-year-CSS = 42%) and the median RFS 20 months (3-year-CSS = 38%, 5-year-CSS = 33%). In univariable Cox regressions, TTS was not associated with CSS (p = 0.971) or RFS (p = 0.855), respectively. A grouped analysis with respect to TTS (≤ 30 days, n = 106; 31-60 days, n = 134; 61-90 days, n = 44; > 90 days, n = 29) displayed a median CSS of 38, 33, 51 and 41 months and median RFS of 17, 22, 28 and 20 months (p = 0.971 log rank; p = 0.520 log rank). No statistical difference regarding oncological risk factors were observed between the groups. This study is the first comprehensive analysis of TTS in CCA patients. Within a representative European cohort, TTS was not associated with earlier tumor recurrence or reduced CCS.

Laparoscopic Living donor liver transplantation in irresectable intrahepatic cholangiocarcinoma in primary sclerosing cholangitis associated liver cirrhosis.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor and usually associated with a poor oncological prognosis. The current gold standard is the surgical resection of the tumor with subsequent adjuvant therapy. However, in case of irresectability e.g. in case of liver cirrhosis, a palliative treatment regime is conducted.This report demonstrates the case of an irresectable iCCA in liver cirrhosis due to primary sclerosing cholangitis (PSC) treated by living-donor liver transplantation (LDLT) facilitated by minimal invasive donor hepatectomy. No postoperative complications were observed in the donor and the donor was released on the 6th postoperative day. Further, after a follow-up of 1.5 years, no disease recurrence was detected in the recipient.According to the recent international literature, liver transplantation can be evaluated in case of small solitary iCCA (< 3 cm) in cirrhosis. Less evidence is provided for transplantation in advanced tumors which are surgically not resectable due to advanced liver disease or infiltration of major vessels, however some reports display adequate long-term survival after strict patient selection. The selection criteria comprise the absence of distant metastases and locoregional lymph node metastases as well as partial remission or stable disease after neoadjuvant chemotherapy. Due to no established graft allocation for iCCA in Germany, LDLT is currently the best option to realize transplantation in these patients. Developments in the last decade indicate that LDLT should preferentially be performed in minimal invasive manner (laparoscopic or robotic) as this approach is associated with less overall complications and a shorter hospitalization. The presented case illustrates the possibilities of modern surgery and the introduction of transplant oncology in the modern therapy of patients combining systemic therapy, surgical resection and transplantation to achieve optimal long-term results in patients which were initially indicated for palliative treatment.

Impact of Altered Body Composition on Clinical and Oncological Outcomes in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma is a common primary liver tumor with limited treatment options and poor prognosis. Changes in body composition (BC) have been shown to affect the prognosis of various types of tumors. Therefore, our study aimed to investigate the correlation between BC and clinical and oncological outcomes in patients with iCCA. All patients with iCCA who had surgery from 2010 to 2022 at our institution were included. We used CT scans and 3D Slicer software to assess BC and conducted logistic regressions as well as Cox regressions and Kaplan-Meier analyses to investigate associations between BC and clinical variables with focus on postoperative complications and oncological outcomes. BC was frequently altered in iCCA (n = 162), with 53.1% of the patients showing obesity, 63.2% sarcopenia, 52.8% myosteatosis, 10.1% visceral obesity, and 15.3% sarcopenic obesity. The multivariate analysis showed no meaningful association between BC and perioperative complications. Myosteatosis was associated with reduced overall survival (OS) in iCCA patients (myosteatosis vs. non-myosteatosis, 7 vs. 18 months, p = 0.016 log rank). Further, the subgroup analysis revealed a notable effect in the subset of R0-resected patients (myosteatosis vs. non-myosteatosis, 18 vs. 32 months, p = 0.025) and patients with nodal metastases (myosteatosis vs. non-myosteatosis, 7 vs. 18 months, p = 0.016). While altered BC is not associated with perioperative outcomes in iCCA, myosteatosis emerges as a prognostic factor for reduced OS in the overall and sub-populations of resected patients.

Survival after combined resection and ablation is not inferior to that after resection alone, in patients with four or more colorectal liver metastases.

PURPOSE: Colorectal liver metastases (CRLM) are the predominant factor limiting survival in patients with colorectal cancer. Multimodal treatment strategies are frequently necessary to achieve total tumor elimination. This study examines the efficacy of liver resection combined with local ablative therapy in comparison to liver resection only, in the treatment of patients with ≥ 4 CRLM. METHODS: This retrospective cohort study was conducted at the University Hospital RWTH Aachen, Germany. Patients with ≥ 4 CRLM in preoperative imaging, who underwent curative resection between 2010-2021, were included. Recurrent resections and deaths in the early postoperative phase were excluded. Ablation modalities included radiofrequency or microwave ablation, and irreversible electroporation. Differences in overall- (OS) and recurrence-free-survival (RFS) between patients undergoing combined resection-ablation vs. resection only, were examined. RESULTS: Of 178 included patients, 46 (27%) underwent combined resection-ablation and 132 (73%) resection only. Apart from increased rates of adjuvant chemotherapy in the first group (44% vs. 25%, p = 0.014), there were no differences in perioperative systemic therapy. Kaplan-Meier and log-rank test analyses showed no statistically significant differences in median OS (36 months for both, p = 0.638) or RFS (9 months for combined resection-ablation vs. 8 months, p = 0.921). Cox regression analysis showed a hazard ratio of 0.891 (p = 0.642) for OS and 0.981 (p = 0.924) for RFS, for patients undergoing resection only. CONCLUSION: For patients with ≥ 4 CRLM, combined resection-ablation is a viable option in terms of OS and RFS. Therefore, combined resection-ablation should be considered for complete tumor clearance, in patients with multifocal disease.

Value of prognostic scoring systems in the era of multimodal therapy for recurrent colorectal liver metastases.

BACKGROUND: Various predictive scoring systems have been developed to estimate outcomes of patients undergoing surgery for colorectal liver metastases (CRLM). However, data regarding their effectiveness in recurrent CRLM (recCRLM) are very limited. METHODS: Patients who underwent repeat hepatectomy for recCRLM at the University Hospital RWTH Aachen, Germany from 2010 to 2021 were included. Nine predictive scoring systems (Fong's, Nordlinger, Nagashima, RAS mutation, Tumor Burden, GAME, CERR, and Glasgow Prognostic score, Basingstoke Index) were evaluated by likelihood ratio (LR) χ2, linear trend (LT) χ2 and Akaike Information Criterion (AIC) for their predictive value regarding overall survival (OS) and recurrence free survival (RFS). RESULTS: Among 150 patients, median RFS was 9 (2-124) months with a 5-year RFS rate of 10%. Median OS was 39 (4-131) months with a 5-year OS rate of 32%. For RFS and OS, the Nagashima score showed the best prognostic ability (LT χ2 3.00, LR χ2 9.39, AIC 266.66 and LT χ2 2.91, LR χ2 20.91, 290.36). DISCUSSION: The Nagashima score showed the best prognostic stratification to predict recurrence as well as survival, and therefore might be considered when evaluating patients with recCRLM for repeat hepatectomy.

An MRI Deep Learning Model Predicts Outcome in Rectal Cancer.

Background Deep learning (DL) models can potentially improve prognostication of rectal cancer but have not been systematically assessed. Purpose To develop and validate an MRI DL model for predicting survival in patients with rectal cancer based on segmented tumor volumes from pretreatment T2-weighted MRI scans. Materials and Methods DL models were trained and validated on retrospectively collected MRI scans of patients with rectal cancer diagnosed between August 2003 and April 2021 at two centers. Patients were excluded from the study if there were concurrent malignant neoplasms, prior anticancer treatment, incomplete course of neoadjuvant therapy, or no radical surgery performed. The Harrell C-index was used to determine the best model, which was applied to internal and external test sets. Patients were stratified into high- and low-risk groups based on a fixed cutoff calculated in the training set. A multimodal model was also assessed, which used DL model-computed risk score and pretreatment carcinoembryonic antigen level as input. Results The training set included 507 patients (median age, 56 years [IQR, 46-64 years]; 355 men). In the validation set (n = 218; median age, 55 years [IQR, 47-63 years]; 144 men), the best algorithm reached a C-index of 0.82 for overall survival. The best model reached hazard ratios of 3.0 (95% CI: 1.0, 9.0) in the high-risk group in the internal test set (n = 112; median age, 60 years [IQR, 52-70 years]; 76 men) and 2.3 (95% CI: 1.0, 5.4) in the external test set (n = 58; median age, 57 years [IQR, 50-67 years]; 38 men). The multimodal model further improved the performance, with a C-index of 0.86 and 0.67 for the validation and external test set, respectively. Conclusion A DL model based on preoperative MRI was able to predict survival of patients with rectal cancer. The model could be used as a preoperative risk stratification tool. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Langs in this issue.

The 3q Oncogene SEC62 Predicts Response to Neoadjuvant Chemotherapy and Regulates Tumor Cell Migration in Triple Negative Breast Cancer.

In the absence of targeted treatment options, neoadjuvant chemotherapy (NACT) is applied widely for triple-negative breast cancer (TNBC). Response to NACT is an important parameter predictive of oncological outcomes (progression-free and overall survival). An approach to the evaluation of predictive markers enabling therapy individualization is the identification of tumor driver genetic mutations. This study was conducted to investigate the role of SEC62, harbored at 3q26 and identified as a driver of breast cancer pathogenesis, in TNBC. We analyzed SEC62 expression in The Cancer Genome Atlas database, and immunohistologically investigated SEC62 expression in pre- and post-NACT tissue samples from 64 patients with TNBC treated at the Department of Gynecology and Obstetrics/Saarland University Hospital/Homburg between January 2010 and December 2018 and compared the effect of SEC62 on tumor cell migration and proliferation in functional assays. SEC62 expression dynamics correlated positively with the response to NACT (p ≤ 0.01) and oncological outcomes (p ≤ 0.01). SEC62 expression stimulated tumor cell migration (p ≤ 0.01). The study findings indicate that SEC62 is overexpressed in TNBC and serves as a predictive marker for the response to NACT, a prognostic marker for oncological outcomes, and a migration-stimulating oncogene in TNBC.

Time to surgery is not an oncological risk factor in HCC patients undergoing liver resection.

PURPOSE: Given limitations of the health care systems in case of unforeseeable events, e.g., the COVID pandemic as well as trends in prehabilitation, time from diagnosis to surgery (time to surgery, (TTS)) has become a research issue in malignancies. Thus, we investigated whether TTS is associated with oncological outcome in HCC patients undergoing surgery. METHODS: A monocentric cohort of 217 patients undergoing liver resection for HCC between 2009 and 2021 was analyzed. Individuals were grouped according to TTS and compared regarding clinical characteristics. Overall survival (OS) and recurrence-free survival (RFS) was compared using Kaplan-Meier analysis and investigated by univariate and multivariable Cox regressions. RESULTS: TTS was not associated with OS (p=0.126) or RFS (p=0.761) of the study cohort in univariate analysis. In multivariable analysis age (p=0.028), ASA (p=0.027), INR (0.016), number of HCC nodules (p=0.026), microvascular invasion (MVI; p<0.001), and postoperative complications (p<0.001) were associated with OS and INR (p=0.005), and number of HCC nodules (p<0.001) and MVI (p<0.001) were associated with RFS. A comparative analysis of TTS subgroups was conducted (group 1, ≤30 days, n=55; group 2, 31-60 days, n=79; group 3, 61-90 days, n=45; group 4, >90 days, n=38). Here, the median OS were 62, 41, 38, and 40 months (p=0.602 log rank) and median RFS were 21, 26, 26, and 25 months (p=0.994 log rank). No statistical difference regarding oncological risk factors were observed between these groups. CONCLUSION: TTS is not associated with earlier tumor recurrence or reduced overall survival in surgically treated HCC patients.

Successful Transplantation of a Liver from a Donor with HELLP Syndrome Undergoing Hypothermic Oxygenated Machine Perfusion (HOPE) Prior to Implantation.

BACKGROUND Liver transplantation (LT) has become the treatment of choice for patients with end-stage liver disease (ESLD). The organ shortage forced clinicians to use livers from donors with certain risk factors, so-called extended-criteria donor (ECD) organs. Hypothermic oxygenated machine perfusion (HOPE) is an alternative to conventional static cold storage and reduces early allograft injury in ECD organs. In this article we present the case of a 45-year-old man with hepatitis B virus (HBV)-associated cirrhosis and hepatocellular carcinoma (HCC) who underwent successful liver transplantation supported by pretransplant hypothermic oxygenated machine perfusion (HOPE) from a 34-year-old extended-criteria donor (ECD) with hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. CASE REPORT Liver transplantation was scheduled for a 45-year-old man with hepatocellular carcinoma (HCC) due to hepatitis B virus-induced liver cirrhosis. The organ donor was a 34-year-old woman who had developed intracerebral hemorrhage and brain death due to HELLP syndrome after delivery. Compared to the day of admission to the intensive care unit, a decrease in the donor's transaminases was observed prior to organ procurement. Before transplantation, HOPE was conducted after regular back-table preparation of the graft. LT was performed according to the standard surgical techniques and a standardized immunosuppressive regimen was conducted. In the post-transplant period, transaminases peaked directly after the operation and normalized after 1 week. No major surgical complications occurred. The patient was discharged after a 24-day hospital stay with normal liver function. CONCLUSIONS This case report supports the benefits of using HOPE in ECD organs and it should be considered in livers of donors with HELLP syndrome to improve post-transplant outcome.

Optical coherence tomography combined with convolutional neural networks can differentiate between intrahepatic cholangiocarcinoma and liver parenchyma ex vivo.

PURPOSE: Surgical resection with complete tumor excision (R0) provides the best chance of long-term survival for patients with intrahepatic cholangiocarcinoma (iCCA). A non-invasive imaging technology, which could provide quick intraoperative assessment of resection margins, as an adjunct to histological examination, is optical coherence tomography (OCT). In this study, we investigated the ability of OCT combined with convolutional neural networks (CNN), to differentiate iCCA from normal liver parenchyma ex vivo. METHODS: Consecutive adult patients undergoing elective liver resections for iCCA between June 2020 and April 2021 (n = 11) were included in this study. Areas of interest from resection specimens were scanned ex vivo, before formalin fixation, using a table-top OCT device at 1310 nm wavelength. Scanned areas were marked and histologically examined, providing a diagnosis for each scan. An Xception CNN was trained, validated, and tested in matching OCT scans to their corresponding histological diagnoses, through a 5 × 5 stratified cross-validation process. RESULTS: Twenty-four three-dimensional scans (corresponding to approx. 85,603 individual) from ten patients were included in the analysis. In 5 × 5 cross-validation, the model achieved a mean F1-score, sensitivity, and specificity of 0.94, 0.94, and 0.93, respectively. CONCLUSION: Optical coherence tomography combined with CNN can differentiate iCCA from liver parenchyma ex vivo. Further studies are necessary to expand on these results and lead to innovative in vivo OCT applications, such as intraoperative or endoscopic scanning.

Expression of Checkpoint Molecules in the Tumor Microenvironment of Intrahepatic Cholangiocarcinoma: Implications for Immune Checkpoint Blockade Therapy.

Background: The tumor microenvironment (TME) in cholangiocarcinoma (CCA) influences the immune environment. Checkpoint blockade is promising, but reliable biomarkers to predict response to treatment are still lacking. Materials and Methods: The levels of checkpoint molecules (PD-1, PD-L1, PD-L2, LAG-3, ICOS, TIGIT, TIM-3, CTLA-4), macrophages (CD68), and T cells (CD4 and CD8 cells) were assessed by multiplexed immunofluorescence in 50 intrahepatic cases. Associations between marker expression, immune cells, and region of expression were studied in the annotated regions of tumor, interface, sclerotic tumor, and tumor-free tissue. Results: ICCA demonstrated CD4_TIM-3 high densities in the tumor region of interest (ROI) compared to the interface (p = 0.014). CD8_PD-L1 and CD8_ICOS densities were elevated in the sclerotic tumor compared to the interface (p = 0.011 and p = 0.031, respectively). In a multivariate model, high expression of CD8_PD-L2 (p = 0.048) and CD4_ICOS_TIGIT (p = 0.011) was associated with nodal metastases. Conclusions: High densities of PD-L1 were more abundant in the sclerotic tumor region; this is meaningful for the stratification of immunotherapy. Lymph node metastasis correlates with CD4_ICOS_TIGIT co-expression and CD8_PD-L2 expression, indicating the checkpoint expression profile of patients with a poor prognosis. Also, multiple co-expressions occur, and this potentially suggests a role for combination therapy with different immune checkpoint targets than just PD-1 blockade monotherapy.

Co-chaperones of the Human Endoplasmic Reticulum: An Update.

In mammalian cells, the rough endoplasmic reticulum (ER) plays central roles in the biogenesis of extracellular plus organellar proteins and in various signal transduction pathways. For these reasons, the ER comprises molecular chaperones, which are involved in import, folding, assembly, export, plus degradation of polypeptides, and signal transduction components, such as calcium channels, calcium pumps, and UPR transducers plus adenine nucleotide carriers/exchangers in the ER membrane. The calcium- and ATP-dependent ER lumenal Hsp70, termed immunoglobulin heavy-chain-binding protein or BiP, is the central player in all these activities and involves up to nine different Hsp40-type co-chaperones, i.e., ER membrane integrated as well as ER lumenal J-domain proteins, termed ERj or ERdj proteins, two nucleotide exchange factors or NEFs (Grp170 and Sil1), and NEF-antagonists, such as MANF. Here we summarize the current knowledge on the ER-resident BiP/ERj chaperone network and focus on the interaction of BiP with the polypeptide-conducting and calcium-permeable Sec61 channel of the ER membrane as an example for BiP action and how its functional cycle is linked to ER protein import and various calcium-dependent signal transduction pathways.

Calcification of the visceral aorta and celiac trunk is associated with renal and allograft outcomes after deceased donor liver transplantation.

PURPOSE: Atherosclerosis affects clinical outcomes in the setting of major surgery. Here we aimed to investigate the prognostic role of visceral aortic (VAC), extended visceral aortic (VAC+), and celiac artery calcification (CAC) in the assessment of short- and long-term outcomes following deceased donor orthotopic liver transplantation (OLT) in a western European cohort. METHODS: We retrospectively analyzed the data of 281 consecutive recipients who underwent OLT at a German university medical center (05/2010-03/2020). The parameters VAC, VAC+, or CAC were evaluated by preoperative computed tomography-based calcium quantification according to the Agatston score. RESULTS: Significant VAC or CAC were associated with impaired postoperative renal function (p = 0.0016; p = 0.0211). Patients with VAC suffered more frequently from early allograft dysfunction (EAD) (38 vs 26%, p = 0.031), while CAC was associated with higher estimated procedural costs (p = 0.049). In the multivariate logistic regression analysis, VAC was identified as an independent predictor of EAD (2.387 OR, 1.290-4.418 CI, p = 0.006). Concerning long-term graft and patient survival, no significant difference was found, even though patients with calcification showed a tendency towards lower 5-year survival compared to those without (VAC: 65 vs 73%, p = 0.217; CAC: 52 vs 72%, p = 0.105). VAC+ failed to provide an additional prognostic value compared to VAC. CONCLUSION: This is the first clinical report to show the prognostic role of VAC/CAC in the setting of deceased donor OLT with a particular value in the perioperative phase. Further studies are warranted to validate these findings. CT computed tomography, OLT orthotopic liver transplantation.