Remote ischemic preconditioning versus sham-control for prevention of anastomotic leakage after resection for rectal cancer (RIPAL trial): a pilot randomized controlled, triple-blinded monocenter trial.

PURPOSE: Remote ischemic preconditioning (RIPC) reportedly reduces ischemia‒reperfusion injury (IRI) in various organ systems. In addition to tension and technical factors, ischemia is a common cause of anastomotic leakage (AL) after rectal resection. The aim of this pilot study was to investigate the potentially protective effect of RIPC on anastomotic healing and to determine the effect size to facilitate the development of a subsequent confirmatory trial. MATERIALS AND METHODS: Fifty-four patients with rectal cancer (RC) who underwent anterior resection were enrolled in this prospectively registered (DRKS0001894) pilot randomized controlled triple-blinded monocenter trial at the Department of Surgery, University Medicine Mannheim, Mannheim, Germany, between 10/12/2019 and 19/06/2022. The primary endpoint was AL within 30 days after surgery. The secondary endpoints were perioperative morbidity and mortality, reintervention, hospital stay, readmission and biomarkers of ischemia‒reperfusion injury (vascular endothelial growth factor, VEGF) and cell death (high mobility group box 1 protein, HMGB1). RIPC was induced through three 10-min cycles of alternating ischemia and reperfusion to the upper extremity. RESULTS: Of the 207 patients assessed, 153 were excluded, leaving 54 patients to be randomized to the RIPC or the sham-RIPC arm (27 each per arm). The mean age was 61 years, and the majority of patients were male (37:17 (68.5:31.5%)). Most of the patients underwent surgery after neoadjuvant therapy (29/54 (53.7%)) for adenocarcinoma (52/54 (96.3%)). The primary endpoint, AL, occurred almost equally frequently in both arms (RIPC arm: 4/25 (16%), sham arm: 4/26 (15.4%), p = 1.000). The secondary outcomes were comparable except for a greater rate of reintervention in the sham arm (9 (6-12) vs. 3 (1-5), p = 0.034). The median duration of endoscopic vacuum therapy was shorter in the RIPC arm (10.5 (10-11) vs. 38 (24-39) days, p = 0.083), although the difference was not statistically significant. CONCLUSION: A clinically relevant protective effect of RIPC on anastomotic healing after rectal resection cannot be assumed on the basis of these data.

Robotic or laparoscopic repeat hepatectomy after open hepatectomy: a cohort study.

BACKGROUND: Repeat hepatectomies are technically complex procedures. The evidence of robotic or laparoscopic (= minimally invasive) repeat hepatectomies (MIRH) after previous open hepatectomy is poor. Therefore, we compared postoperative outcomes of MIRH vs open repeat hepatectomies (ORH) in patients with liver tumors after previous open liver resections. METHODS: Consecutive patients who underwent repeat hepatectomies after open liver resections were identified from a prospective database between April 2018 and May 2023. Postoperative complications were graded in line with the Clavien-Dindo classification. We stratified patients by intention to treat into MIRH or ORH and compared outcomes. Logistic regression analysis was performed to define variables associated with the utilization of a minimally invasive approach. RESULTS: Among 46 patients included, 20 (43%) underwent MIRH and 26 (57%) ORH. Twenty-seven patients had advanced or expert repeat hepatectomies (59%) according to the IWATE criteria. Baseline characteristics were comparable between the study groups. The use of a minimally invasive approach was not dependent on preoperative or intraoperative variables. All patients had negative resection margins on final histology. MIRH was associated with less blood loss (450 ml, IQR (interquartile range): 200-600 vs 600 ml, IQR: 400-1500 ml, P = 0.032), and shorter length of stay (5 days, IQR: 4-7 vs 7 days, IQR: 5-9 days, P = 0.041). Postoperative complications were similar between the groups (P = 0.298). CONCLUSIONS: MIRH is feasible after previous open hepatectomy and a safe alternative approach to ORH. (German Clinical Trials Register ID: DRKS00032183).

Ultra-sensitive CTC-based liquid biopsy for pancreatic cancer enabled by large blood volume analysis.

The limited sensitivity of circulating tumor cell (CTC) detection in pancreatic adenocarcinoma (PDAC) stems from their extremely low concentration in the whole circulating blood, necessitating enhanced detection methodologies. This study sought to amplify assay-sensitivity by employing diagnostic leukapheresis (DLA) to screen large blood volumes. Sixty patients were subjected to DLA, with a median processed blood volume of ~ 2.8 L and approximately 5% of the resulting DLA-product analyzed using CellSearch (CS). Notably, DLA significantly increased CS-CTC detection to 44% in M0-patients and 74% in M1-patients, yielding a 60-fold increase in CS-CTC enumeration. DLA also provided sufficient CS-CTCs for genomic profiling, thereby delivering additional genomic information compared to tissue biopsy samples. DLA CS-CTCs exhibited a pronounced negative prognostic impact on overall survival (OS), evidenced by a reduction in OS from 28.6 to 8.5 months (univariate: p = 0.002; multivariable: p = 0.043). Additionally, a marked enhancement in sensitivity was achieved (by around 3-4-times) compared to peripheral blood (PB) samples, with positive predictive values for OS being preserved at around 90%. Prognostic relevance of CS-CTCs in PDAC was further validated in PB-samples from 228 PDAC patients, consolidating the established association between CTC-presence and reduced OS (8.5 vs. 19.0 months, p < 0.001). In conclusion, DLA-derived CS-CTCs may serve as a viable tool for identifying high-risk PDAC-patients and aiding the optimization of multimodal treatment strategies. Moreover, DLA enables comprehensive diagnostic profiling by providing ample CTC material, reinforcing its utility as a reliable liquid-biopsy approach. This high-volume liquid-biopsy strategy presents a potential pathway for enhancing clinical management in this malignancy.

The Role of Adjuvant Therapy in Duodenal Adenocarcinoma and Intestinal Subtype Ampullary Carcinoma after Curative Resection.

OBJECTIVE: Defining the role of adjuvant therapy in duodenal adenocarcinoma (DAC) and intestinal subtype ampullary carcinoma (iAC). SUMMARY BACKGROUND DATA: DAC and iAC share a similar histological differentiation but the benefit of adjuvant therapy remains unclear. METHODS: Patients undergoing curative-intent surgical resection for DAC and iAC between 2010 and 2021 at five high-volume centers were included. Patient baseline, perioperative and long-term oncological outcomes were evaluated. Statistical testing was performed with SPSS 25 (IBM). RESULTS: A total of 136 patients with DAC and 171 with iAC were identified. Patients with DAC had more advanced tumors than those with iAC. Median overall survival (OS) in DAC patients was 101 months versus 155 months for iAC patients (P=0.098). DAC had a higher rate of local (14.1% vs. 1.2%, P<0.001) and systemic recurrence (30.4% vs. 3.5%, P<0.001). Adjuvant therapy failed to improve overall survival in all patients with DAC and iAC. For DAC, patients with perineural invasion, but not other negative prognostic factors had improved OS rates with adjuvant therapy (72 m vs. 44 m, P=0.044). IAC patients with N+ (190 m vs. 57 m, P=0.003), T3-4 (177 m vs. 59 m, P=0.050) and perineural invasion (150 m vs. 59 m, P=0.019) had improved OS rates with adjuvant therapy. CONCLUSION: While adjuvant therapy fails to improve OS in all patients with DAC and iAC in the current study, it improved overall survival in DAC patients with perineural invasion and in iAC patients with T3-4 tumors, positive lymph nodes, and perineural invasion.

An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND: Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS: 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS: A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION: Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app.

E-AHPBA-ESSO-ESSR Innsbruck consensus guidelines for preoperative liver function assessment before hepatectomy.

BACKGROUND: Posthepatectomy liver failure (PHLF) contributes significantly to morbidity and mortality after liver surgery. Standardized assessment of preoperative liver function is crucial to identify patients at risk. These European consensus guidelines provide guidance for preoperative patient assessment. METHODS: A modified Delphi approach was used to achieve consensus. The expert panel consisted of hepatobiliary surgeons, radiologists, nuclear medicine specialists, and hepatologists. The guideline process was supervised by a methodologist and reviewed by a patient representative. A systematic literature search was performed in PubMed/MEDLINE, the Cochrane library, and the WHO International Clinical Trials Registry. Evidence assessment and statement development followed Scottish Intercollegiate Guidelines Network methodology. RESULTS: Based on 271 publications covering 4 key areas, 21 statements (at least 85 per cent agreement) were produced (median level of evidence 2- to 2+). Only a few systematic reviews (2++) and one RCT (1+) were identified. Preoperative liver function assessment should be considered before complex resections, and in patients with suspected or known underlying liver disease, or chemotherapy-associated or drug-induced liver injury. Clinical assessment and blood-based scores reflecting liver function or portal hypertension (for example albumin/bilirubin, platelet count) aid in identifying risk of PHLF. Volumetry of the future liver remnant represents the foundation for assessment, and can be combined with indocyanine green clearance or LiMAx® according to local expertise and availability. Functional MRI and liver scintigraphy are alternatives, combining FLR volume and function in one examination. CONCLUSION: These guidelines reflect established methods to assess preoperative liver function and PHLF risk, and have uncovered evidence gaps of interest for future research.

Liver surgery is an effective treatment for liver tumours. Liver failure is a major problem in patients with a poor liver quality or having large operations. The treatment options for liver failure are limited, with high death rates. To estimate patient risk, assessing liver function before surgery is important. Many methods exist for this purpose, including functional, blood, and imaging tests. This guideline summarizes the available literature and expert opinions, and aids clinicians in planning safe liver surgery.

[Robotic Left Hepatectomy Using the Glissonean Pedicle Approach for the Treatment of Caroli's Syndrome]. / Roboter-assistierte Hemihepatektomie links mittels Glissonean pedicle approach bei Caroli Syndrom.

BACKGROUND: Caroli's syndrome is a rare disease characterised by non-obstructive dilation of intrahepatic bile ducts, hepatic fibrosis, and an increased risk of developing cholangiocarcinoma. Minimally invasive liver resection has recently been increasingly adopted for the treatment of patients with localised Caroli's syndrome. However, robot-assisted liver resection for the treatment of Caroli's syndrome has not been published. MATERIALS AND METHODS: We report a case of a 72-year-old Asian female who was referred to our hospital with multifocal cystic dilation of liver segments II, III, and IV. She had no family history of congenital cysts. Her past medical history was uneventful except for an open appendectomy. The liver function tests were normal, with a negative echinococcus serology test. On MRI, the biliary anatomy at the hilum and right liver appeared to be regular. Therefore, a robotic left hepatectomy was carried out for the unilobar involvement of Caroli's syndrome using the Da Vinci Xi-system. RESULTS: We performed a Glissonean pedicle approach while preserving the caudate lobe. After removing surgical adhesions from the anterior abdominal wall using robotic scissors, a routine cholecystectomy was performed. An aberrant left hepatic artery arising from the left gastric artery was clipped and divided. The left portal pedicle was controlled after lowering the hilar plate. The ischemic demarcation line on the liver surface was followed after clamping the left pedicle, and parenchymal dissection was performed using Maryland bipolar forceps. A Pringle manoeuvre was not applied. The left pedicle and the left hepatic vein were transected using a GIA stapling device while the middle hepatic vein was preserved. Indocyanin green fluorescence imaging confirmed adequate perfusion of the remnant liver tissue including the caudate lobe. The specimen was placed in an extraction bag and removed via a Pfannenstiel incision. The total operation time was 239 min, including a total blood loss of 100 ml. The postoperative course was uneventful. The patient was discharged on postoperative day 5. On 6 months follow-up, the patient had normal liver function and no signs of recurrent disease. CONCLUSION: Robotic left hepatectomy using an extrahepatic Glissonean pedicle approach is technically feasible.

Identification of liver-derived bone morphogenetic protein (BMP)-9 as a potential new candidate for treatment of colorectal cancer.

Colorectal cancer (CRC) is a high-incidence malignancy worldwide which still needs better therapy options. Therefore, the aim of the present study was to investigate the responses of normal or malignant human intestinal epithelium to bone morphogenetic protein (BMP)-9 and to find out whether the application of BMP-9 to patients with CRC or the enhancement of its synthesis in the liver could be useful strategies for new therapy approaches. In silico analyses of CRC patient cohorts (TCGA database) revealed that high expression of the BMP-target gene ID1, especially in combination with low expression of the BMP-inhibitor noggin, is significantly associated with better patient survival. Organoid lines were generated from human biopsies of colon cancer (T-Orgs) and corresponding non-malignant areas (N-Orgs) of three patients. The N-Orgs represented tumours belonging to three different consensus molecular subtypes (CMS) of CRC. Overall, BMP-9 stimulation of organoids promoted an enrichment of tumour-suppressive gene expression signatures, whereas the stimulation with noggin had the opposite effects. Furthermore, treatment of organoids with BMP-9 induced ID1 expression (independently of high noggin levels), while treatment with noggin reduced ID1. In summary, our data identify the ratio between ID1 and noggin as a new prognostic value for CRC patient outcome. We further show that by inducing ID1, BMP-9 enhances this ratio, even in the presence of noggin. Thus, BMP-9 is identified as a novel target for the development of improved anti-cancer therapies of patients with CRC.

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

BACKGROUND & AIMS: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. METHODS: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). RESULTS: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. LAY SUMMARY: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.

Impact of spleen preservation on the incidence of postoperative pancreatic fistula after distal pancreatectomy: Is less more?

BACKGROUND: Postoperative pancreatic fistula (POPF) remains a major complication after distal pancreatectomy (DP) with a significant impact on patients' quality of life. There is limited evidence that preservation of the spleen reduces the risk of POPF. Therefore, we aimed to investigate the impact of splenectomy on perioperative outcome. METHODS: Data from patients who underwent DP for malignant and benign disease at our institution between 2004 and 2021 were reviewed. Patients were grouped according to spleen preservation (SP-DP) and splenectomy (DPS). Intraoperative parameters and postoperative outcomes were compared between groups. Univariable and multivariable analyses were used to investigate factors that influence the occurrence of clinically relevant (cr)POPF. RESULTS: A total of 199 patients were included, of whom 61 (30.7%) patients underwent SP-DP. Patients who underwent SP-DP had a significantly lower rate of crPOPF (p = 0.022), shorter hospital stay (p = 0.003), and less readmissions (p = 0.012). On multivariate analysis, obesity (OR 2.88, p = 0.021), benign lesions (OR 2.35, p = 0.018), postoperative acute pancreatitis (OR 2.53, p = 0.028), and splenectomy (OR 2.83, p = 0.011) were independent risk factors associated with the onset of crPOPF. DISCUSSION: Preservation of the spleen reduces the risk of crPOPF in patients undergoing distal pancreatectomy for benign and malignant disease.

Quality assurance and quality control in surgical oncology.

Even though surgery has remained a key component within multi-disciplinary cancer care, the expectations have changed. Instead of serving as a modality to free a patient of a mass at all means and at the risk of high morbidity, modern cancer surgery is expected to provide adequate tumor clearance with lowest invasiveness. This review summarizes the evidence on quality assurance in surgical oncology and gives a comprehensive overview of quality improvement tools.

Minimally invasive mesohepatectomy for centrally located liver lesions-a case series.

BACKGROUND: Resection of centrally located liver lesions remains a technically demanding procedure. To date, there are limited data on the effectiveness and safety of minimally invasive mesohepatectomy for benign and malignant lesions. It was therefore the objective of this study to evaluate the perioperative outcomes of minimally invasive mesohepatectomy for liver tumors at a tertiary care hospital. METHODS: Consecutive patients who underwent a minimally invasive anatomic mesohepatectomy using a Glissonean pedicle approach from April 2018 to November 2021 were identified from a prospective database. Demographics, operative details, and postoperative outcomes were analyzed using descriptive statistics for continuous and categorical variables. RESULTS: A total of ten patients were included, of whom five patients had hepatocellular carcinoma, one patient had cholangiocarcinoma, three patients had colorectal liver metastases, and one patient had a hydatid cyst. Two and eight patients underwent robotic-assisted and laparoscopic resections, respectively. The median operative time was 393 min (interquartile range (IQR) 298-573 min). Conversion to laparotomy was required in one case. The median lesion size was 60 mm and all cases had negative resection margins on final histopathological analysis. The median total blood loss was 550 ml (IQR 413-850 ml). One patient had a grade III complication. The median length of stay was 7 days (IQR 5-12 days). Time-to-functional recovery was achieved after a median of 2 days (IQR 1-4 days). There were no readmissions within 90 days after surgery. CONCLUSION: Minimally invasive mesohepatectomy is a feasible and safe approach in selected patients with benign and malignant liver lesions.

Intraoperative Increase of Portal Venous Pressure is an Immediate Predictor of Posthepatectomy Liver Failure After Major Hepatectomy: A Prospective Study.

OBJECTIVES: The aim of this study was to assess intraoperative changes of hepatic macrohemodynamics and their association with ascites and posthepatectomy liver failure (PHLF) after major hepatectomy. SUMMARY OF BACKGROUND DATA: Large-scale ascites and PHLF remain clinical challenges after major hepatectomy. No study has concomitantly evaluated arterial and venous liver macrohemodynamics in patients undergoing liver resection. METHODS: Portal venous pressure (PVP), portal venous flow (PVF), and hepatic arterial flow (HAF) were measured intraoperatively pre- and postresection in 67 consecutive patients with major hepatectomy (ie, resection of ≥3 liver segments). A group of 30 patients with minor hepatectomy served as controls. Liver macrohemodynamics and their intraoperative changes (ie, Δ) were analyzed as predictive biomarkers of ascites and PHLF using Fisher exact, t test, or Wilcoxon rank sum test for univariate and logistic regression for multivariate analyses. RESULTS: Major hepatectomy increased PVP by 26.9% (P = 0.001), markedly decreased HAF by 40.7% (P < 0.001), and slightly decreased PVF by 13.4% (P = 0.011). Minor resections had little effects on hepatic macrohemodynamics. There was no significant association of liver macrohemodynamics with ascites. While middle hepatic vein resection caused higher postresection PVP after right hepatectomy (P = 0.04), the Pringle maneuver was associated with a significant PVF (P = 0.03) and HAF reduction (P = 0.03). Uni- and multivariate analysis revealed an intraoperative PVP increase as an independent predictor of PHLF (P = 0.025). CONCLUSION: Intraoperative PVP kinetics serve as independent predictive biomarker of PHLF after major hepatectomy. These data highlight the importance to assess intraoperative dynamics rather than the pre- and postresection PVP values.

Infrahepatic Inferior Vena Cava Clamping does not Increase the Risk of Pulmonary Embolism Following Hepatic Resection.

BACKGROUND: Infrahepatic inferior vena cava (IVC) clamping reduces central venous pressure. However, controversies remain regarding its impact on postoperative complications, particularly, the incidence of postoperative pulmonary embolism (PE). The aim of the study was to determine the impact of IVC clamping on the incidence of PE in patients undergoing hepatectomy. METHODS: A pooled analysis of five prospective trials on patients who underwent hepatic resection over a period of 10 years was performed. Patients with infrahepatic IVC clamping were compared to patients without infrahepatic IVC clamping. Outcomes were studied by univariate and multivariate analyses. RESULTS: Of 505 included patients, 141 patients had IVC clamping and 364 patients served as control group. The rate of postoperative PE was comparable between groups (3% vs. 3%; P = 0.762), as were postoperative morbidity (P = 0.932), bile leakage (P = 0.272), posthepatectomy hemorrhage (P = 0.095), and posthepatectomy liver failure (P = 0.605), respectively. No clinicopathological and intraoperative risk factors were found to predict the onset of PE. Subgroup analyses of patients with major hepatectomy and vascular resections confirmed no adverse perioperative outcomes to be associated with IVC clamping. CONCLUSIONS: Infrahepatic IVC clamping does not increase the incidence of postoperative PE.

Patient-Derived Organoids of Cholangiocarcinoma.

Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient-derived organoid culture as well as a protocol for the transition of 3D organoid lines to 2D cell lines. Tissue samples of non-cancer bile duct and cholangiocarcinoma were obtained during surgical resection. Organoid lines were generated following a standardized protocol. 2D cell lines were generated from established organoid lines following a novel protocol. Subcutaneous and orthotopic patient-derived xenografts were generated from CC organoid lines, histologically examined, and treated using standard CC protocols. Therapeutic responses of organoids and 2D cell lines were examined using standard CC agents. Next-generation exome and RNA sequencing was performed on primary tumors and CC organoid lines. Patient-derived organoids closely recapitulated the original features of the primary tumors on multiple levels. Treatment experiments demonstrated that patient-derived organoids of cholangiocarcinoma and organoid-derived xenografts can be used for the evaluation of novel treatments and may therefore be used in personalized oncology approaches. In summary, this study establishes cholangiocarcinoma organoids and organoid-derived cell lines, thus expanding translational research resources of cholangiocarcinoma.

Core needle biopsy versus incisional biopsy for differentiation of soft-tissue sarcomas: A systematic review and meta-analysis.

BACKGROUND: Controversies exist regarding the biopsy technique of choice for the accurate diagnosis of soft-tissue sarcoma (STS). The objective of this systematic review and meta-analysis was to compare the diagnostic accuracy of core needle biopsy (CNB) versus incisional biopsy (IB) in STS with reference to the final histopathological result. METHODS: Studies regarding the diagnostic accuracy of CNB and IB in detecting STS were searched systematically in the MEDLINE and EMBASE databases. Estimates of sensitivity and specificity with associated 95% CIs for diagnostic accuracy were calculated. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2). RESULTS: A total of 17 studies comprising 2680 patients who underwent 1582 CNBs and 241 IBs with subsequent tumor resection met the inclusion criteria. The sensitivity and specificity of CNB and IB to detect the dignity of lesions were 97% (95% CI, 95%-98%) and 99% (95% CI, 97%-99%), respectively, and 96% (95% CI, 92%-99%) and 100% (95% CI, 94%-100%), respectively. Estimates of the sensitivity and specificity of CNB and IB to detect the STS histotype were 88% (95% CI, 86%-90%) and 77% (95% CI, 72%-81%), respectively, and 93% (95% CI, 87%-97%) and 65% (95% CI, 49%-78%), respectively. Patients who underwent CNB had a significantly reduced risk of complications compared with patients who underwent IB (risk ratio, 0.14; 95% CI, 0.03-0.56 [P ≤ .01). Quality assessment of studies revealed a high risk of bias. CONCLUSIONS: CNB has high accuracy in diagnosing the dignity of lesions and STS histotype in patients with suspected STS with fewer complications compared with IB. Therefore, CNB should be regarded as the primary biopsy technique.

Cholangitis following biliary-enteric anastomosis: A systematic review and meta-analysis.

BACKGROUND: Cholangitis is a serious biliary complication following biliary-enteric anastomosis (BEA). However, the rate of cholangitis in the postoperative period and its associated risk factors are inconclusive. The objective of this systematic review and meta-analysis was to assess the onset and risk factors of cholangitis after biliary-enteric reconstruction in literature. METHODS: MEDLINE, EMBASE, and Cochrane databases were searched systematically to identify studies reporting about cholangitis following biliary-enteric anastomosis. Meta-analyses were performed for risk factors using random effects model with odds ratio (OR) and 95% confidence interval (95 %CI) as effect measures. Study quality was assessed by the MINORS (methodological index for non-randomized studies) criteria. RESULTS: 28 studies involving 6904 patients were included in the study. The pooled rate for postoperative cholangitis (POC) was 10% (95 %CI: 8 %-13%) with studies reporting about an early- and late-onset of cholangitis. Male sex (OR 2.08; 95 %CI: 1.33-3.24; P = 0.001), postoperative hepatolithiasis (OR 137.19; 95 %CI: 29.00-648.97; P < 0.001) and postoperative anastomotic stricture (OR 178.29; 95 %CI: 68.64-463.11; P < 0.001) were associated with a higher risk of a late-onset of POC with a pooled rate of 8% (95 %CI: 6 %-11%) after a median time interval of 12 months. The quality of the included studies was low to moderate. CONCLUSION: Cholangitis is a frequent complication after BEA. Consensus definition and prospective trials are required to assess optimal therapeutic strategies. We proposed a standardized definition and grading of POC to enable comparisons between future studies.

Definition and severity grading of postoperative lymphatic leakage following inguinal lymph node dissection.

PURPOSE: Lymphatic complications occur frequently after radical inguinal lymph node dissection (RILND). The incidence of lymphatic leakage varies considerably among different studies due to the lack of a consistent definition. The aim of the present study is to propose a standardized definition and grading of different types of lymphatic leakage after groin dissection. METHODS: A bicentric retrospective analysis of 82 patients who had undergone RILND was conducted. A classification of postoperative lymphatic leakage was developed on the basis of the daily drainage output, any necessary postoperative interventions and reoperations, and any delay in adjuvant treatment. RESULTS: In the majority of cases, RILND was performed in patients with inguinal metastases of malignant melanoma (n = 71). Reinterventions were necessary in 15% of the patients and reoperations in 32%. A new classification of postoperative lymphatic leakage was developed. According to this definition, grade A lymphatic leakage (continued secretion of lymphatic fluid from the surgical drains without further complications) occurred in 13% of the patients, grade B lymphatic leakage (persistent drainage for more than 10 postoperative days or the occurrence of a seroma after the initial removal of the drain that requires an intervention) in 28%, and grade C lymphatic leakage (causing a reoperation or a subsequent conflict with medical measures) in 33%. The drainage volume on the second postoperative day was a suitable predictor for a complicated lymphatic leakage (grades B and C) with a cutoff of 110 ml. CONCLUSION: The proposed definition is clinically relevant, is easy to employ, and may serve as the definition of a standardized endpoint for the assessment of lymphatic morbidity after RILND in future studies.

Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer.

Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1-/- mice), Ly6Chigh monocytes (CCR2-/- mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2-induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2-induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.

Randomized clinical trial of BioFoam® Surgical Matrix to achieve hemostasis after liver resection.

BACKGROUND: Topical agents were designed to facilitate hemostasis during hepatic resection. The aim of this prospective randomized controlled clinical trial was to evaluate the effectiveness and safety of BioFoam® Surgical Matrix for achieving hemostasis after open hepatic resection. METHODS: This was a prospective, randomized controlled monocentric trial of patients undergoing elective open liver resection between December 2015 and September 2017. The primary endpoint was time-to-complete hemostasis. RESULTS: A total of 101 patients were enrolled in this trial, giving 51 patients in the BioFoam® group and 50 patients in the control group (without use of BioFoam®). Time-to-complete hemostasis was significantly reduced in the BioFoam® group (156 ± 129 versus 307 ± 264 s; P = 0.001). There were no significant differences in postoperative bile leaks (n = 6 (12%) vs. n = 5 (10%); P = 0.776), postoperative morbidity (n = 37 (73%) vs. n = 40 (80%); P = 0.482) or mortality (n = 3 (6%) vs. n = 1 (2%); P = 0.618) between groups. CONCLUSION: BioFoam® is a safe topical agent for achieving faster hemostasis during hepatic resection, however, the true clinical relevance of this finding needs to be further evaluated. ClinicalTrials.gov ID NCT02612220.