Benchmarks and Geographic Differences in Gallbladder Cancer Surgery: An International Multicenter Study.

BACKGROUND: High-quality surgery plays a central role in the delivery of excellent oncologic care. Benchmark values indicate the best achievable results. We aimed to define benchmark values for gallbladder cancer (GBC) surgery across an international population. PATIENTS AND METHODS: This study included consecutive patients with GBC who underwent curative-intent surgery during 2000-2021 at 13 centers, across seven countries and four continents. Patients operated on at high-volume centers without the need for vascular and/or bile duct reconstruction and without significant comorbidities were chosen as the benchmark group. RESULTS: Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) were included in the benchmark group. These were predominantly women (n = 174, 71%) and had a median age of 64 years (interquartile range 57-70 years). In the benchmark group, 50 patients (20%) experienced complications within 90 days after surgery, with 20 patients (8%) developing major complications (Clavien-Dindo grade ≥ IIIa). Median length of postoperative hospital stay was 6 days (interquartile range 4-8 days). Benchmark values included ≥ 4 lymph nodes retrieved, estimated intraoperative blood loss ≤ 350 mL, perioperative blood transfusion rate ≤ 13%, operative time ≤ 332 min, length of hospital stay ≤ 8 days, R1 margin rate ≤ 7%, complication rate ≤ 22%, and rate of grade ≥ IIIa complications ≤ 11%. CONCLUSIONS: Surgery for GBC remains associated with significant morbidity. The availability of benchmark values may facilitate comparisons in future analyses among GBC patients, GBC surgical approaches, and centers performing GBC surgery.

Protocol of the RACB study: a multicenter, single-arm, prospective study to evaluate the efficacy of resection of initially unresectable hepatocellular carcinoma with atezolizumab combined with bevacizumab.

BACKGROUND: Although the standard therapy for advanced-stage hepatocellular carcinoma (HCC) is systemic chemotherapy, the combination of atezolizumab and bevacizumab (atezo + bev) with a high objective response rate may lead to conversion to resection in patients with initially unresectable HCC. This study aims to evaluate the efficacy of atezo + bev in achieving conversion surgery and prolonged progression-free survival (PFS) for initially unresectable HCC. METHODS: The RACB study is a prospective, single-arm, multicenter, phase II trial evaluating the efficacy of combination therapy with atezo + bev for conversion surgery in patients with technically and/or oncologically unresectable HCC. The main eligibility criteria are as follows: (1) unresectable HCC without a history of systemic chemotherapy, (2) at least one target lesion based on RECIST ver. 1.1, and (3) a Child‒Pugh score of 5-6. The definition of unresectable tumors in this study includes macroscopic vascular invasion and/or extrahepatic metastasis and massive distribution of intrahepatic tumors. Patients will be treated with atezolizumab (1200 mg/body weight) and bevacizumab (15 mg/kg) every 3 weeks. If the patient is considered resectable on radiological assessment 12 weeks after initial chemotherapy, the patient will be treated with atezolizumab monotherapy 3 weeks after combination chemotherapy followed by surgery 3 weeks after atezolizumab monotherapy. If the patient is considered unresectable, the patient will continue with atezo + bev and undergo a radiological assessment every 9 weeks until resectable or until disease progression. The primary endpoint is PFS, and the secondary endpoints are the overall response rate, overall survival, resection rate, curative resection rate, on-protocol resection rate, and ICG retention rate at 15 min after atezo + bev therapy. The assessments of safety and quality of life during the treatment course will also be evaluated. The number of patients has been set at 50 based on the threshold and the expected PFS rate at 6 months after enrollment of 40% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.80. The enrollment and follow-up periods will be 2 and 1.5 years, respectively. DISCUSSION: This study will elucidate the efficacy of conversion surgery with atezo + bev for initially unresectable HCC. In addition, the conversion rate, safety and quality of life during the treatment course will also be demonstrated. TRIAL REGISTRATION: This study is registered in the Japan Registry of Clinical Trials (jRCTs051210148, January 7, 2022).

Clinically relevant model of oxaliplatin-induced sinusoidal obstruction syndrome.

AIM: Sinusoidal obstruction syndrome (SOS) induced by oxaliplatin-including chemotherapies (OXCx) is associated with impaired hepatic reserve and higher morbidity after hepatic resection. However, in the absence of an appropriate animal experimental model, little is known about its pathophysiology. This study aimed to establish a clinically relevant reproducible model of FOLFOX-induced SOS and to compare the clinical/histopathological features between the clinical and animal SOS settings. METHODS: We performed clinical/pathological analyses of colorectal liver metastasis (CRLM) patients who underwent hepatectomy with/without preoperative treatment of FOLFOX (n = 22/18). Male micro-minipigs were treated with 50% of the standard human dosage of the FOLFOX regimen. RESULTS: In contrast to the monocrotaline-induced SOS model in rats, hepatomegaly, ascites, congestion, and coagulative necrosis of hepatocytes were absent in patients with CRLM with OXCx pretreatment and OXCx-treated micro-minipigs. In parallel to CRLM cases with OXCx pretreatment, OXCx-challenged micro-minipigs exhibited deteriorated indocyanine green clearance, morphological alteration of liver sinusoidal endothelial cells, and upregulated matrix metalloproteinase-9. Using our novel porcine SOS model, we identified the hepatoprotective influence of recombinant human soluble thrombomodulin in OXCx-SOS. CONCLUSIONS: With distinct differences between monocrotaline-induced rat SOS and human/pig OXCx-SOS, our pig OXCx-SOS model serves as a preclinical platform for future investigations to dissect the pathophysiology of OXCx-SOS and seek preventive strategies.

Liver stiffness measured by virtual touch quantification predicts the occurrence of posthepatectomy refractory ascites in patients with hepatocellular carcinoma.

PURPOSE: This study assessed the significance of measuring liver stiffness using virtual touch quantification before hepatectomy to predict posthepatectomy refractory ascites. METHODS: A total of 267 patients with hepatocellular carcinoma who underwent hepatectomy were prospectively analyzed. Liver stiffness was defined as the median value of the virtual touch quantification (Vs; m/s) by acoustic radio-force-impulse-based virtual touch. RESULTS: A multivariate analysis showed that Vs and the aspartate aminotransferase-to-platelet ratio index were independent risk factors for postoperative refractory ascites (odds ratio = 3.27 and 3.08, respectively). The cutoff value for Vs was 1.52 m/s (sensitivity: 59.5%, specificity: 88.6%) as determined by the analysis of the receiver-operating characteristic curve, and the area under the receiver-operating characteristic curve was 0.79. The cutoff value for the aspartate aminotransferase-to-platelet ratio was 0.952 (sensitivity: 65.5%, specificity: 82.9%), and the area under the receiver-operating characteristic curve was 0.75. CONCLUSIONS: Vs is an independent risk factor for refractory ascites after hepatectomy. The measurement of liver stiffness by virtual touch quantification before hepatectomy can help estimate the risk of postoperative refractory ascites. Nonsurgical treatments should be considered for the management of patients who are at high risk for refractory ascites.

Conditional Recurrence-Free Survival after Oncologic Extended Resection for Gallbladder Cancer: An International Multicenter Analysis.

BACKGROUND: Data to guide surveillance following oncologic extended resection (OER) for gallbladder cancer (GBC) are lacking. Conditional recurrence-free survival (C-RFS) can inform surveillance. We aimed to estimate C-RFS and identify factors affecting conditional RFS after OER for GBC. PATIENTS AND METHODS: Patients with ≥ T1b GBC who underwent curative-intent surgery in 2000-2018 at four countries were identified. Risk factors for recurrence and RFS were evaluated at initial resection in all patients and at 12 and 24 months after resection in patients remaining recurrence-free. RESULTS: Of the 1071 patients who underwent OER, 484 met the inclusion criteria; 290 (60%) were recurrence-free at 12 months, and 199 (41%) were recurrence-free at 24 months. Median follow-up was 24.5 months for all patients and 47.21 months in survivors at analysis. Five-year RFS rates were 47% for the overall population, 71% for patients recurrence-free at 12 months, and 87% for the patients without recurrence at 24 months. In the entire cohort, the risk of recurrence peaked at 8 months. T3-T4 disease was independently associated with recurrence in all groups: entire cohort [hazard ratio (HR) 2.16, 95% confidence interval (CI) 1.49-3.13, P < 0.001], 12-month recurrence-free (HR 3.42, 95% CI 1.88-6.23, P < 0.001), and 24-month recurrence-free (HR 2.71, 95% CI 1.11-6.62, P = 0.029). Of the 125 patients without these risk factors, only 2 had recurrence after 36 months. CONCLUSION: C-RFS improves over time, and only T3-T4 disease remains a risk factor for recurrence at 24 months after OER for GBC. For all recurrence-free survivors after 36 months, the probability of recurrence is similar regardless of T category or disease stage.

Low level of postoperative plasma antithrombin III is associated with portal vein thrombosis after liver surgery.

PURPOSE: Although decreased antithrombin-III (AT-III) is a risk factor for portal vein thrombosis (PVT) in patients with liver cirrhosis, the association between postoperative PVT and postoperative AT-III levels is unknown in patients undergoing hepatectomy. METHODS: Patients who underwent hepatectomy between 2015 and 2018 were retrospectively analyzed. Postoperative PVT was assessed on CT at days 6-9 after hepatectomy. One-to-one propensity score (PS) matching was used to match the baseline characteristics. RESULTS: Of the 295 patients included in this analysis, 19 patients (6.4%) were diagnosed with postoperative PVT. The AT-III level on postoperative day (POD) 3 predicted postoperative PVT with a sensitivity/specificity of 74%/59% (AUC, 0.644; cut-off value, 60%; p = 0.032). Multivariate analysis revealed that AT-III levels ≤ 60% on POD3 (OR, 3.01; 95% CI 1.02-8.89; p = 0.046), cirrhosis (OR, 5.88; 95% CI 1.92-18.0; p = 0.002) and right-sided hepatectomy (OR, 4.16; 95% CI 1.45-11.9; p = 0.0079) were significant risk factors for postoperative PVT. After PS matching, 56 patients with and without AT-III supplementation were analyzed. The two groups had a similar incidence of PVT (p = 0.489). CONCLUSIONS: Patients with AT-III levels ≤ 60% on POD3 should be carefully followed up regarding postoperative PVT. Our results did not support the efficacy of routine AT-III supplementation for the prophylaxis of postoperative PVT.

Characteristics of atypical large well-differentiated hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma?

BACKGROUND: Hepatocellular carcinoma (HCC) de-differentiation is thought to correlate with size, therefore well-differentiated HCC ≥3 cm are considered rare and not fully understood. METHODS: Patients who underwent hepatectomy for HCC between 1998-2016 were retrospectively analyzed. Patient's characteristics and recurrence-free (RFS) and overall (OS) survival were compared between those with atypical- (well-differentiated-HCC ≥3 cm) and typical-HCC (moderate-to-poorly-differentiated HCC ≥3 cm). RESULTS: Of 176 patients included in this study, 37 (21%) had atypical-HCC. Patients with atypical-HCC were less likely to be Asian ethnicity (3% vs. 17%, p = 0.062), have lower rate of viral infection (14% vs. 43%, p = 0.003), cirrhosis (8% vs. 27%, p = 0.015). The tumors were less likely to demonstrate vascular invasion (30% vs. 59%, p = 0.002), and were associated with a lower alpha-fetoprotein level (3.5 ng/ml vs. 33.2 ng/ml, p < 0.001). Patients with atypical-HCC had a longer RFS (5-y RFS: 58.3% vs. 35.7%, p = 0.016) and OS (5-y OS: 79.1% vs 53.3%, p = 0.029) as compared to those with typical-HCC following univariate analysis, however this did not appear following multivariate analysis. CONCLUSION: Patients with atypical-HCC have different characteristic in terms of epidemiology, etiology, cirrhosis and vascular invasion as compared to typical-HCC. The etiology of atypical-HCC may be non-alcoholic fatty liver disease-related and/or malignant transformation of hepatocellular adenoma.

Middle Hepatic Vein Roadmap for a Safe Laparoscopic Right Hepatectomy.

BACKGROUND: When performing a right hepatectomy, the middle hepatic vein (MHV) should guide the parenchymal transection. MHV hotspots for bleeding can be anticipated when applying the previously developed MHV Roadmap to a minimally invasive approach.1 This video demonstrates application of the MHV Roadmap to perform a safe laparoscopic right hepatectomy. PATIENT: A 44-year-old woman with a solitary and large breast cancer liver metastasis in the right liver was considered for a laparoscopic right hepatectomy following an excellent response to neoadjuvant chemotherapy. The MHV anatomy was reconstructed using automated vascular reconstruction software (Synapse, Fuji) ahead of surgery. TECHNIQUE: With the patient in the French position, the hilar vessels are exposed and the inflow is controlled. Parenchymal transection begins along the demarcation line.2,3 The constant relationship between the portal bifurcation and the V5 ventral and dorsal allows for easy intraparenchymal identification of the MHV. The parenchymal transection is performed in a convex fashion to optimize exposure of the MHV. Using MHV guidance, the parenchymal transection is continued and V8 is safely identified. The operation is completed with division of the anterior fissure and right hepatic vein. CONCLUSION: Outlining the MHV anatomy according to the MHV Roadmap preoperatively helps to anticipate hotspots of bleeding. Guidance along the MHV through the parenchymal transection allows for early identification of tributaries, thereby preventing injury and remnant liver ischemia.

Long-term survival after post-hepatectomy liver failure for colorectal liver metastases.

BACKGROUND: While post-hepatectomy liver failure (PHLF) accurately predicts short-term mortality, its role in prognosticating long-term overall survival (OS) remains unclear. METHODS: Patients who underwent hepatectomy for colorectal liver metastases (CRLM) after portal vein embolization during 1999-2015 were evaluated retrospectively. PHLF was defined per International Study Group of Liver Surgery (ISGLS) criteria and as PeakBil >7 mg/dl. Survival was analyzed using log-rank statistic and Cox regression; patient mortality within 90 days was excluded. RESULTS: Of 175 patients, 68 (39%) had PHLF according to ISGLS criteria, including 40 (23%) with ISGLS grade B/C, and 14 (8%) had PeakBil >7 mg/dl. Patients with PeakBil >7 mg/dl had significantly worse OS than patients without PHLF (median OS, 16 vs 58 months, p = 0.001). Patients with ISGLS defined PHLF (p = 0.251) and patients with ISGLS grade B/C PHLF (p = 0.220) did not have worse OS than patients without PHLF. CONCLUSION: Peak bilirubin >7 mg/dl impacts on long-term survival after hepatectomy for CRLM and is a better predictor of long-term survival than ISGLS-defined PHLF.

Conceptual framework of middle hepatic vein anatomy as a roadmap for safe right hepatectomy.

BACKGROUND: While the middle hepatic vein (MHV) guides parenchymal transection during right hepatectomy, its most proximal tributaries can be difficult to identify, and injury to its tributaries can be a source of major bleeding. METHOD: Following simulation modeling of right hepatectomy, reconstructed MHV data was pooled from 40 patients. MHV-tributaries and MHV-relationship to the portal pedicle were mapped out to facilitate their identification from the beginning of parenchymal transection. RESULTS: Hotspots for injury were identified: A median of 1 (1-3) tributaries draining segment 5 (V5) were within 45-90mm from the MHV termination, and 16mm above and 22mm caudal to the portal trunk. Simulation demonstrated a constant anatomic relationship between portal pedicle and the proximal MHV. A median of 2 (0-4) tributaries draining segment 8 (V8) were located 9-35mm from the MHV termination. This information was compiled into an "MHV-road-map" demonstrating 86% of the MHV tributaries at risk for significant bleeding are within 15mm of the MHV, while only thin tributaries are located in the outer area. CONCLUSIONS: The MHV-road-map led to a peripheral-to-central parenchymal transection approach to minimize the risk of MHV-injury thereby reducing bleeding during open and minimally invasive right hepatectomy.

Incidental versus non-incidental gallbladder cancer: index cholecystectomy before oncologic re-resection negatively impacts survival in T2b tumors.

BACKGROUND: Conflicting data exists whether non-oncologic index cholecystectomy (IC) leading to discovery of incidental gallbladder cancer (IGBC) negatively impacts survival. This study aimed to determine whether a subgroup of patients derives a disadvantage from IC. METHODS: Patients with IGBC and non-IGBC treated at an academic USA and Chilean center during 1999-2016 were compared. Patients with T1, T4 tumor or preoperative jaundice were excluded. T2 disease was classified into T2a (peritoneal-side tumor) and T2b (hepatic-side tumor). Disease-specific survival (DSS) and its predictors were analyzed. RESULTS: Of the 196 patients included, 151 (77%) had IGBC. One hundred thirty-six (90%) patients of whom 118 (87%) had IGBC had T2 disease. Three-year DSS rates were similar between IGBC and non-IGBC for all patients. However, for T2b patients, 3-year survival rate was worse for IGBC (31% vs 85%; p = 0.019). In multivariate analysis of T2 patients, predictors of poor DSS were hepatic-side tumor hazard ratio [HR], 2.9; 95% CI, 1.6-5.4; p = 0.001) and N1 status (HR, 2.4; 95% CI, 1.6-3.6; p < 0.001). CONCLUSIONS: Patients with T2b gallbladder cancer specifically benefit from a single operation. These patients should be identified preoperatively and referred to hepatobiliary center.

CAAT/enhancer binding protein-homologous protein deficiency attenuates liver ischemia/reperfusion injury in mice.

Ischemia/reperfusion injury (IRI) is one of the main causes of liver dysfunction after liver surgery. Involvement of endoplasmic reticulum (ER) stress in various diseases has been demonstrated, and CAAT/enhancer binding protein-homologous protein (CHOP) is a transcriptional regulator that is induced by ER stress. It is also a key regulator of ER stress-mediated apoptosis. The aim of this study was to investigate the role of CHOP in liver IRI. Wild type (WT) and CAAT/enhancer binding protein-homologous protein knockout (CHOP-/-) mice were subjected to 70% liver warm ischemia/reperfusion for 60 minutes. At different times after reperfusion, liver tissues and blood samples were collected for evaluation. Induction of ER stress including CHOP expression was ascertained. Liver damage was evaluated based on serum liver enzymes, liver histology, and neutrophil infiltration. Hepatocyte death including apoptosis was assessed. Liver warm IRI induced ER stress in both WT and CHOP-/- mice. In addition, CHOP expression was up-regulated in WT mice. At 6 hours after reperfusion, liver damage was attenuated in CHOP-/- mice. On the basis of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, apoptotic and necrotic cells were significantly reduced in CHOP-/- mice. CHOP deficiency also reduced the cleavage of caspase 3 and expression of the proapoptotic protein B cell lymphoma 2-associated X protein. Liver IRI induces CHOP expression, and CHOP deficiency attenuates liver IRI by inhibiting apoptosis. Elucidation of the function of CHOP in liver IRI may contribute to further investigation for a therapy against liver IRI associated with the ER stress pathway. Liver Transplantation 24 645-654 2018 AASLD.

RAS Mutation is Associated with Unsalvageable Recurrence Following Hepatectomy for Colorectal Cancer Liver Metastases.

BACKGROUND: RAS mutation status predicts survival after hepatectomy for colorectal liver metastases (CRLM) and survival after repeat hepatectomy for intrahepatic recurrence. This study was aimed at determining the impact of RAS mutation on amenability of recurrence to local therapy and on post-recurrence survival following hepatectomy. METHODS: CRLM patients with recurrence at any location after curative intent hepatectomy during the period 2006-2015 were retrospectively analyzed. Factors associated with recurrence not amenable to local therapy and with post-recurrence survival were evaluated. RESULTS: Of 566 patients with recurrence, 309 (54.6%) underwent chemotherapy only, 189 (33.4%) underwent surgical resection, 47 (8.3%) underwent ablation, and 21 (3.7%) underwent radiation therapy. Median post-recurrence survival was significantly longer in patients with local therapy than in those with chemotherapy only (65.1 vs. 26.5 months, p < 0.0001). RAS mutation (p = 0.01), presence of extrahepatic metastases (p = 0.0006), and positive surgical margin at prior hepatectomy (p = 0.01) were associated with recurrence not amenable to local therapy. RAS mutation [hazard ratio (HR) 1.49, p = 0.0012], disease-free interval < 12 months (HR 1.76, p < 0.0001), recurrence at multiple organs (HR 1.71, p < 0.0001), and recurrence not amenable to local therapy (HR 4.11, p < 0.0001) were independent risk factors for shorter post-recurrence survival. RAS mutation was associated with poor post-recurrence survival in both patients who received local therapy and those who received chemotherapy only. CONCLUSIONS: RAS mutation predicts recurrence not amenable to any local therapy and shorter post-recurrence survival after hepatectomy for CRLM.

Long-Term Survival According to Histology and Radiologic Response to Preoperative Chemotherapy in 126 Patients Undergoing Resection of Non-GIST Sarcoma Liver Metastases.

BACKGROUND: Non-gastrointestinal stromal tumor sarcomas (NGSs) have heterogeneous histology, and this heterogeneity may lead to uncertainty regarding the prognosis of patients with liver metastases from NGS (NGSLM) and decision regarding their surgical management. Furthermore, the role of preoperative chemotherapy in treatment of NGSLM remains poorly defined. We investigated long-term survival and its correlation to response to preoperative chemotherapy in patients with NGSLM. PATIENTS AND METHOD: Patients who underwent liver resection for NGSLM during 1998-2015 were identified. Clinical, histopathologic, and survival data were analyzed. Multivariate analysis was performed using a Cox proportional hazards model. RESULTS: 126 patients [62 (49%) with leiomyosarcoma] were included. Five-year overall survival (OS) and recurrence-free survival (RFS) rates were 49.3 and 14.9%, respectively. Survival did not differ by histologic subtype, primary tumor location, or use of preoperative or postoperative chemotherapy. NGSLM ≥ 10 cm and extrahepatic metastases at NGSLM diagnosis were the only independent risk factors for OS. In the 83 (66%) patients with metachronous NSGLM, disease-free interval > 6 months was associated with improved OS and RFS. Among the 65 patients (52%) who received preoperative chemotherapy, radiologic response according to Choi criteria specifically was associated with improved OS (p = 0.04), but radiologic response according to RECIST 1.1 criteria was not. CONCLUSIONS: Resection of NGSLM led to a 5-year OS rate of 49%, independent of histologic subtype and primary tumor location. Choi criteria (which take into account tumor density) are superior to RECIST 1.1 in assessing radiologic response and should be used to assess response to preoperative chemotherapy.

Operative and short-term oncologic outcomes of laparoscopic versus open liver resection for colorectal liver metastases located in the posterosuperior liver: a propensity score matching analysis.

BACKGROUND: Laparoscopic resection (LLR) of colorectal liver metastases (CRLM) located in the posterosuperior liver (segments 4a, 7, and 8) is challenging but has become more practical recently due to progress in operative techniques. We aimed to compare tumor-specific, perioperative, and short-term oncological outcomes after LLR and open liver resection (OLR) for CRLM. METHODS: Patients who underwent curative resection of CRLM with at least 1 tumor in the posterosuperior liver during 2012-2015 were analyzed. Tumor-specific factors associated with the adoption of LLR were analyzed by logistic regression model. One-to-one propensity score matching was used to match baseline characteristics between patients with LLR and OLR. RESULTS: The original cohort included 30 patients with LLR and 239 with OLR. Median follow-up time was 23.8 months. Logistic regression analysis showed that multiple, diameter ≥30 mm, deep location, and closeness to major vessels were associated with OLR. None of the 24 patients with none or one of these factors were converted from LLR to OLR. After matching, 29 patients with LLR and 29 with OLR were analyzed. The 2 groups had similar preoperative factors. The LLR and OLR groups did not differ with respect to operative time, intraoperative bleeding, incidence of blood transfusion, surgical margin positivity, incidence of postoperative complications, and unplanned readmission within 45 days. Median length of postoperative hospital stay was significantly shorter for LLR versus OLR (4 days [1-12] vs. 5 days [4-18]; p = 0.0003). Median recurrence-free survival was similar for patients who underwent LLR versus OLR (10.6 months for LLR vs. 13.4 months for OLR; p = 0.87). CONCLUSIONS: Compared to OLR, LLR of posterosuperior CRLM is associated with significantly shorter postoperative hospital stay but otherwise similar perioperative and short-term oncological outcomes. Tumor-specific factors associated with safe and routine LLR approach despite challenging location are superficial, solitary, and small (<30 mm) CRLM not associated with major vessels.

Tips and tricks of splenic vessel preservation during laparoscopic distal pancreatectomy.

BACKGROUND: While a laparoscopic approach can minimize postoperative morbidity in splenic vessel preserving (SVP) distal pancreatectomy (DP), this procedure can be technically challenging. A systematic approach to SVP minimizes the chances of vascular injury and maximizes the chances of successful splenic preservation. This video demonstrates a laparoscopic DP with SVP, highlighting technical tips and tricks that optimize the chances for SVP. PATIENT: The patient is a 14-year-old male with an incidentally discovered pancreatic tail mass. CT imaging demonstrates a 4.5 cm well-circumscribed tumor with the typical solid and cystic components of a solid pseudopapillary tumor (SPPT). Since SPPT is a rare pancreatic tumor associated with excellent prognosis following surgery, upfront minimally invasive DP with SPV was considered the optimal approach in this young patient. Following successful surgery, the postoperative course was uneventful. Pathology confirmed the diagnosis of a pT3N0. SPPT with negative margins. TECHNIQUE: Here we demonstrate a systematic approach to maximize the changes of SVP in DP. This approach, as demonstrated in the video, includes optimal patient and port positioning, dissection to optimize exposure of the distal splenic vessels, techniques to minimize vascular trauma especially splenic venous trauma, as well as supplemental measures to ensure postoperative patency of splenic vessels following completion of the case. CONCLUSIONS: This systematic approach may maximize the changes of successful SVP, while avoiding postoperative complications such as splenic infarct, left-sided portal hypertension or overwhelming post-splenectomy sepsis.

Pathological diaphragmatic invasion by colorectal liver metastases is associated with RAS mutation, peritoneal recurrence and worse survival.

BACKGROUND: Risk factors for pathological diaphragmatic invasion from colorectal liver metastases (CRLM) and differences in recurrence patterns and survival between patients with true pathological diaphragmatic invasion versus inflammatory adhesions only remain poorly understood. This study aimed at identifying risk factors for and survival impact of pathological diaphragmatic invasion in patients with CRLM. METHODS: Patients with CRLM who underwent hepatectomy with or without diaphragmatic resection from 1998 to 2015 were retrospectively analyzed. Recurrence-free survival (RFS), overall survival (OS), and recurrence patterns were examined according to the presence or absence of pathological invasion. RESULTS: Of 1860 patients, 70 underwent hepatectomy with diaphragmatic resection and 1799 had hepatectomy only. Among the patients with gross diaphragmatic involvement, 15 (21%) had pathological invasion, and 55 (79%) had inflammatory adhesion only. Multiple tumors (p = 0.019) and RAS mutation (p = 0.047) were significantly associated with pathological invasion. Pathological invasion was associated with a higher incidence of peritoneal recurrence (33% vs. 11%, p = 0.041), worse median RFS (6 months vs. 11 months, p = 0.21) and OS (26 months vs. 51 months, p = 0.046) compared to inflammatory adhesion. CONCLUSION: Multiple tumors and RAS mutant were predictors for pathological diaphragmatic invasion, which was associated with a higher incidence of peritoneal recurrence and worse OS.

Minimally invasive management of the entire treatment sequence in patients with stage IV colorectal cancer: a propensity-score weighting analysis.

BACKGROUND: In patients with stage IV colorectal cancer (CRC), minimally invasive surgery (MIS) may offer optimal oncologic outcome with low morbidity. However, the relative benefit of MIS compared to open surgery in patients requiring multistage resections has not been evaluated. METHODS: Patients who underwent totally minimally invasive (TMI) or totally open (TO) resections of CRC primary and liver metastases (CLM) in 2009-2016 were analyzed. Inverse probability of weighted adjustment by propensity score was performed before analyzing risk factors for complications and survival. RESULTS: The study included 43 TMI and 121 TO patients. Before and after adjustment, TMI patients had significantly less cumulated postoperative complications (41% vs. 59%, p = 0.001), blood loss (median 100 vs. 200 ml, p = 0.001) and shorter length of hospital stay (median 4.5 vs. 6.0 days, p < 0.001). Multivariate analysis identified TO approach vs. MIS (OR = 2.4, p < 0.001), major liver resection (OR = 4.4, p < 0.001), and multiple CLM (OR = 2.3, p = 0.001) as independent risk factors for complications. 5-year overall survival was comparable (81% vs 68%, p = 0.59). CONCLUSION: In patients with CRC undergoing multistage surgical treatment, MIS resection contributes to optimal perioperative outcomes without compromise in oncologic outcomes.

Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3.

Nardilysin (NRDC) is a metalloendopeptidase of the M16 family. We previously showed that NRDC activates inflammatory cytokine signaling, including interleukin-6-signal transducer and activator of transcription 3 (STAT3) signaling. NRDC has been implicated in the promotion of breast, gastric and esophageal cancer, as well as the development of liver fibrosis. In this study, we investigated the role of NRDC in the promotion of hepatocellular carcinoma (HCC), both clinically and experimentally. We found that NRDC expression was upregulated threefold in HCC tissue compared to the adjacent non-tumor liver tissue, which was confirmed by immunohistochemistry and western blotting. We also found that high serum NRDC was associated with large tumor size (>3 cm, P = 0.016) and poor prognosis after hepatectomy (median survival time 32.0 vs 73.9 months, P = 0.003) in patients with hepatitis C (n = 120). Diethylnitrosamine-induced hepatocarcinogenesis was suppressed in heterozygous NRDC-deficient mice compared to their wild-type littermates. Gene silencing of NRDC with miRNA diminished the growth of Huh-7 and Hep3B spheroids in vitro. Notably, phosphorylation of STAT3 was decreased in NRDC-depleted Huh-7 spheroids compared to control spheroids. The effect of a STAT3 inhibitor (S3I-201) on the growth of Huh-7 spheroids was reduced in NRDC-depleted cells relative to controls. Our results show that NRDC is a promising prognostic marker for HCC in patients with hepatitis C, and that NRDC promotes tumor growth through activation of STAT3.

Total Laparoscopic Management for Stage IV Colorectal Cancer Requiring Multivisceral Resection.

BACKGROUND: Surgical resection of all sites of disease, in combination with effective systemic chemotherapy, offers the only potential chance for cure for patients with stage IV colorectal cancer (CRC). Coordinated multistage resection using a minimally invasive approach may provide optimal oncologic outcome while potentially offering the benefit of decreased morbidity. PATIENT: A 66-year-old women presented with transverse colon cancer and synchronous metastasis (CRLM) in segment IV involving the middle hepatic vein and main left portal pedicle, as well as the left adrenal gland. Due to favorable response to neoadjuvant chemotherapy (FOLFOX/bevacizumab), the patient was considered for resection but developed some obstructive symptoms from the primary tumor, necessitating re-coordination of treatment sequencing from the 'liver-first' approach. METHODS: The first procedure combined laparoscopic subtotal colectomy (extracorporeal anastomosis) with left adrenalectomy. After restaging, CRLM was removed separately 2 months later via laparoscopic left hepatectomy extending beyond the middle hepatic vein. Successful completion of the two procedures depended on optimal patient/port positioning for the combined colon/adrenal surgery and the second-stage liver resection. Postoperative lengths of stay were 4 and 3 days, respectively, and were without complication. Adjuvant FOLFOX was initiated 21 days following liver surgery, and the patient has been disease-free for 36 months. CONCLUSION: This case illustrates the feasibility of the total laparoscopic approach to multivisceral resection for synchronous stage IV CRC in the context of a preplanned, staged multidisciplinary strategy. This approach may offer optimal cancer management, including early return to systemic therapy, shortened time intervals between stages, and minimal postoperative morbidity.1 - 3.