Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma.

Although gemcitabine (GEM) is widely used in chemotherapy for pancreatic ductal adenocarcinoma (PDA), drug resistance restricts its clinical effectiveness. To examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM and CoCl2-induced chemical hypoxia. One resistant cell line possessed reduced energy production and decreased mitochondrial reactive oxygen species levels, while the other resistant cell line possessed increased stemness. In both cell lines, ethidium bromide-stained mitochondrial DNA levels decreased, suggesting mitochondrial DNA damage. Inhibition of hypoxia-inducible factor-1α in both cell lines did not restore the GEM sensitivity. In contrast, treatment of both cell types with lauric acid (LAA), a medium-chain fatty acid, restored GEM sensitivity. These results suggest that decreased energy production, decreased mitochondrial reactive oxygen species levels, and increased stemness associated with mitochondrial damage caused by GEM lead to GEM resistance, and that hypoxia may promote this process. Furthermore, forced activation of oxidative phosphorylation by LAA could be a tool to overcome GEM resistance. Clinical verification of the effectiveness of LAA in GEM resistance is necessary in the future.

Importance of triple tumor markers as biomarkers in patients with pancreatic ductal adenocarcinoma.

Aim: There is an urgent need to establish biomarkers for the treatment of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the usefulness of the combined assessment of carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and duke pancreatic monoclonal antigen type 2 (DUPAN-2) in PDAC. Methods: We retrospectively investigated the impact of three tumor markers on overall survival (OS) and recurrence-free survival (RFS). Patients were classified into two groups: upfront surgery (US) and neoadjuvant chemoradiation (NACRT) groups. Results: In total, 310 patients were evaluated. In the US group, patients who had all three elevated markers showed a significantly worse prognosis than the others (median: 16.4 months, P = .005). In the NACRT group, patients who had elevated CA 19-9 and CEA levels after NACRT had significantly worse prognosis than the others (median: 26.2 months, P < .001). The elevated DUPAN-2 levels before NACRT were associated with significantly worse prognosis than normal levels (median: 44.0 vs 59.2 months, P = .030). Patients who had elevated DUPAN-2 levels before NACRT with elevated CA 19-9 and CEA levels after NACRT showed extremely poor RFS (median: 5.9 months). Multivariate analysis revealed that a modified triple-positive tumor marker indicating elevated DUPAN-2 levels before NACRT and elevated CA19-9 and CEA levels after NACRT was an independent prognostic factor of OS (hazard ratio: 2.49, P = .007) and RFS (hazard ration: 2.47, P = .007). Conclusions: The combined evaluation of three tumor markers may provide useful information for the treatment of patients with PDAC.

Liver metastases of a neuroendocrine tumor arising from a tailgut cyst treated with interventional locoregional therapies: a case report and review of the literature on recurrent cases.

A tailgut cyst is a rare, developmental cyst occurring in the presacral space. Although primarily benign, malignant transformation is a possible complication. Herein, we report a case of liver metastases after resection of a neuroendocrine tumor (NET) arising from a tailgut cyst. A 53-year-old woman underwent surgery for a presacral cystic lesion with nodules in the cyst wall. The tumor was diagnosed as a Grade 2 NET arising from a tailgut cyst. Thirty-eight months after surgery, multiple liver metastases were identified. The liver metastases were controlled with transcatheter arterial embolization and ablation therapy. The patient has survived for 51 months after the recurrence. Several NETs derived from tailgut cysts have been previously reported. According to our literature review, the proportion of Grade 2 tumors in NETs derived from tailgut cysts was 38.5%, and four of the 5 cases of Grade 2 NETs (80%) relapsed, while all eight cases of Grade 1 NETs did not relapse. Grade 2 NET may be a high-risk group for recurrence in NETs arising from tailgut cysts. The percentage of Grade 2 NETs in tailgut cysts was higher than that of rectal NETs, but lower than that of midgut NETs. To the best of our knowledge, this is the first case of liver metastases of a neuroendocrine tumor arising from a tailgut cyst that was treated with interventional locoregional therapies, and the first report to describe about the degree of malignancy of neuroendocrine tumors originating from tailgut cysts in terms of the percentage of Grade 2 NETs.

Delayed Presentation and Referral Time from General Practitioners Contribute to Increased Complicated Appendicitis during the Initial COVID-19 Pandemic Period in Japan.

Objectives: This study aims to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the situation of acute appendicitis (AA) with respect to patients' and general practitioners' behaviors in a general community hospital in Japan. Methods: The surgical outcomes and periods from symptom onset to medical presentation besides practitioners' referral time for consecutive AA patients were compared between the control (January 2016 to March 2020) and COVID-19 periods (April 2020 to April 2021). Results: Eighty-three patients who underwent emergency surgery for AA were reviewed. Complicated appendicitis significantly increased in the COVID-19 period (63.6% vs. 31.2%, P = 0.023). In the COVID-19 period, the time from symptom onset to the medical presentation (2.2 vs. 0.9 days, P < 0.001) was significantly longer than in the control period. Among the patients who first presented to a general practitioner, the referral time from the practitioner to our hospital was significantly longer in the COVID-19 period (1.6 vs. 0.7 days, P = 0.017). Furthermore, among patients with a fever of higher than 38°C at medical presentation, the time from symptom onset to medical presentation was significantly longer in the COVID-19 period (3.0 vs. 0.7 days, P = 0.015). There was no difference in severe postoperative complications. Conclusions: Hesitation to seek surgical treatment for AA was seen in both the patients and practitioners in the COVID-19 period. The delay in surgical treatment presumably led to the increase in severe AA. In a pandemic era, timely care for emergent conditions is a crucial challenge.

Short Telomere Lesions with Dysplastic Metaplasia Histology May Represent Precancerous Lesions of Helicobacter pylori-Positive Gastric Mucosa.

Gastric cancers are strongly associated with Helicobacter pylori infection, with intestinal metaplasia characterizing the background mucosa in most cases. However, only a subset of intestinal metaplasia cases proceed to carcinogenesis, and the characteristics of high-risk intestinal metaplasia that link it with gastric cancer are still unclear. We examined telomere reduction in five gastrectomy specimens using fluorescence in situ hybridization, and identified areas with localized telomere loss (outside of cancerous lesions), which were designated as short telomere lesions (STLs). Histological analyses indicated that STLs were characteristic of intestinal metaplasia accompanied by nuclear enlargement but lacking structural atypia, which we termed dysplastic metaplasia (DM). A review of gastric biopsy specimens from 587 H. pylori-positive patients revealed 32 cases of DM, 13 of which were classified as high-grade based on the degree of nuclear enlargement. All high-grade DM cases exhibited a telomere volume reduced to less than 60% of that of lymphocytes, increased stemness, and telomerase reverse transcriptase (TERT) expression. Two patients (15%) exhibited low levels of p53 nuclear retention. After a 10-year follow-up, 7 (54%) of the high-grade DM cases had progressed to gastric cancer. These results suggest that DM is characterized by telomere shortening, TERT expression, and stem cell proliferation, and high-grade DM is a high-grade intestinal metaplasia that likely represents a precancerous lesion of gastric cancer. High-grade DM is expected to effectively prevent progression to gastric cancer in H. pylori-positive patients.

Colonic gallstone ileus treated by a transanal ileus tube followed by spontaneous gallstone dislodgement: A case report.

A 71-year-old obese woman was referred to our hospital with lower left abdominal pain. Computed tomography showed a 46 mm elliptic calcification lodged in the sigmoid-descending colon junction (SDJ), which had been detected 5 years prior but was not within the gall bladder at presentation. Therefore, we diagnosed colonic gallstone ileus with obstructive colitis caused by a gallstone. Colonoscopy revealed a smooth gallstone impacted at the sigmoid-descending colon junction, which was not fixed and could be pushed proximally with the endoscope. Dislodgement of the stone was unsuccessful with both a large polypectomy snare and a retrieval basket. Considering the high risk of surgery, we chose a non-surgical treatment strategy for obstructive colitis. Accordingly, a transanal ileus tube was placed to drain the proximal portion of the gallstone. The drainage of the colon by the ileus tube was satisfactory; the proximal colon was decompressed, ameliorating the obstructive colitis. Five days after tube placement, a colonoscopy revealed spontaneous passage of the gallstone into the rectum where it was finally removed. Cholecystocolonic fistula formation was confirmed by magnetic resonance imaging. We decided to surgically close the cholecystocolonic fistula to prevent future retrograde biliary infections. The surgery used a surgical stapler and was successful, with an uneventful postoperative course. Since radical surgical treatment of colonic gallstones and cholecystoenteric fistulas has a risk of postoperative morbidity and mortality, this case illustrates the importance of thoroughly considering nonsurgical interventions and surgeries for the safe treatment of colonic gallstone ileus.

Gemcitabine Resistance in Pancreatic Ductal Carcinoma Cell Lines Stems from Reprogramming of Energy Metabolism.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis because it is often detected at an advanced stage, and drug resistance interferes with treatment. However, the mechanism underlying drug resistance in PDAC remains unclear. Here, we investigated metabolic changes between a parental PDAC cell line and a gemcitabine (GEM)-resistant PDAC cell line. We established a GEM-resistant cell line, MIA-G, from MIA-PaCa-2 parental (MIA-P) cells using continuous therapeutic-dose GEM treatment. MIA-G cells were also more resistant to 5-fluorouracil in comparison to MIA-P cells. Metabolic flux analysis showed a higher oxygen consumption rate (OCR) in MIA-G cells than in MIA-P cells. Notably, OCR was suppressed by GEM treatment only in MIA-G cells. GEM treatment increased mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS) in MIA-P cells, but not in MIA-G cells. Glutamine uptake and peroxidase levels were elevated in MIA-G cells. The antioxidants N-acetyl-L-cysteine and vitamin C increased the sensitivity to GEM in both cell lines. In MIA-G cells, the expression of the mitochondrial transcription factor A also decreased. Furthermore, rotenone reduced the sensitivity of MIA-P cells to GEM. These findings suggest that the suppression of oxidative phosphorylation contributes to GEM resistance by reducing ROS production. Our study provides a new approach for reducing GEM resistance in PDAC.

Proposal of a Novel Index of Abdominal Compliance and the Association With Postoperative Pain After Laparoscopic Inguinal Hernia Repair.

BACKGROUND: In laparoscopic surgery, low pneumoperitoneum pressure is reported to reduce pain, which suggests that easing abdominal expansion is crucial for less postoperative pain. However, although abdominal compliance (AC) is associated with the degree of abdominal expansion, the role of AC in pain by pneumoperitoneum is unknown. In this study, we devised a novel index as a surrogate of AC to evaluate the association between AC and postoperative pain in laparoscopic inguinal hernia repair. MATERIALS AND METHODS: We reviewed 83 patients who underwent elective transabdominal preperitoneal repair from 2019 to 2021 at Heisei Memorial Hospital. Insufflation pressure was set to low pressure (8 mm Hg). The abdominal compliance index [ACI; insufflated intra-abdominal volume (L)/body surface area (m2)] was utilized to evaluate the association between AC and postoperative pain. RESULTS: ACI was evaluated in 30 patients. Median ACI was 1.53 (1.00 to 2.48) L/m2. Although there was no difference in the average body constitution, the high ACI group (n=15) had significantly higher intra-abdominal volume at 8 mm Hg pressure, compared with the low ACI group (n=15) (3.1 vs. 2.1 L, P<0.0001). The high ACI group had significantly higher pain than the low ACI group on the day of surgery (2.0 vs. 1.0, P=0.006) and the day after (0.8 vs. 0.3, P=0.007). In addition, 46.7% of the patients in the high ACI group experienced pneumoperitoneum-associated pain, whereas patients in the low ACI group experienced incision pain only. Additional analgesics were administered in 53.3% of the high ACI group, compared with 33.3% in the low ACI group. CONCLUSIONS: AC was suggested to be a vital factor of postoperative pain after laparoscopic inguinal hernia repair. Patients with high AC may be susceptible to higher pain by pneumoperitoneum, even in low-pressure settings.

Does direct invasion of peripancreatic lymph nodes impact survival in patients with pancreatic ductal adenocarcinoma? A retrospective dual-center study.

BACKGROUND: Pancreatic ductal adenocarcinoma can directly invade the peripancreatic lymph nodes; however, the significance of direct lymph node invasion is controversial, and it is currently classified as lymph node metastasis. This study aimed to identify the impact of direct invasion of peripancreatic lymph nodes on survival in patients with pancreatic ductal adenocarcinoma. METHODS: A total of 411 patients with resectable/borderline resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection at two high-volume centers from 2006 to 2016 were evaluated retrospectively. RESULTS: Sixty (14.6%) patients had direct invasion of the peripancreatic lymph nodes without isolated lymph node metastasis (N-direct group), 189 (46.0%) had isolated lymph node metastasis (N-met group), and 162 (39.4%) had neither direct invasion nor isolated metastasis (N0 group). There was no significant difference in median overall survival between the N-direct group (35.0 months) and the N0 group (45.6 month) (p = 0.409), but survival was significantly longer in the N-direct compared with the N-met group (25.0 months) (p = 0.003). Similarly, median disease-free survival was similar in the N-direct (21.0 months) and N0 groups (22.7 months) (p = 0.151), but was significantly longer in the N-direct compared with the N-met group (14.0 months) (p < 0.001). Multivariate analysis identified resectability, adjuvant chemotherapy, and isolated lymph node metastasis as independent predictors of overall survival. However, direct lymph node invasion was not a predictor of survival. CONCLUSION: Direct invasion of the peripancreatic lymph nodes had no effect on survival in patients undergoing pancreatic resection for pancreatic ductal adenocarcinoma, and should therefore not be classified as lymph node metastasis.

Is Neoadjuvant Treatment Justified in Clinical T1 Pancreatic Ductal Adenocarcinoma?

Introduction: Studies on neoadjuvant treatment have been actively conducted in patients with resectable pancreatic cancer. However, neoadjuvant treatment effectiveness, especially in clinical T1 stage patients, still needs to be determined. We comparatively evaluated the oncologic benefit of preoperative neoadjuvant treatment in clinical T1 stage pancreatic cancer. Methods: Data from two centers were included in the comparative analysis, with overall and recurrence-free survival as primary outcomes, between January 2010 and December 2017. Results: In total, 45 patients were retrospectively reviewed in this study. Two patients in the neoadjuvant group were excluded because of distant metastasis during neoadjuvant treatment. Finally, 43 patients underwent a pancreatectomy for clinical T1 pancreatic cancer, of whom, 35 and 8 patients underwent upfront surgery and neoadjuvant treatment, respectively. Overall survival was similar in the two study groups (5-year overall survival rate: neoadjuvant group, 75%; upfront surgery group, 43.9%, p = 0.066). Conclusions: In our study on patients with clinical T1 stage pancreatic cancer, no significant differences were reported in the oncological outcome in the neoadjuvant therapy group. Large-scale prospective studies are needed to determine the survival benefits of neoadjuvant treatment for early-stage pancreatic cancer.

Clinical relevance of CD70 expression in resected pancreatic cancer: Prognostic value and therapeutic potential.

BACKGROUND: Aberrant expression of CD70 in several malignancies is potentially associated with poor patient prognosis and could serve as a therapeutic target. However, the clinical relevance of CD70 expression in pancreatic cancer has not been thoroughly explored. METHODS: We evaluated CD70 expression in 166 surgical specimens obtained from human patients with pancreatic cancer. We analyzed the function of CD70 in proliferation and migration using pancreatic cancer cell lines with silenced CD70 expression. RESULTS: CD70 expression was positively stained in 42 patients (25%). In the whole cohort, high CD70 expression was not associated with overall survival (OS: 33.1 vs. 40.8 months, P = 0.256), although it was significantly associated with inferior OS in a population of patients that completed adjuvant chemotherapy (OS: 45.4 vs. 63.8 months, P = 0.027). Moreover, the incidence of hematogenous metastasis was significantly higher in patients with high CD70 expression than in those with low CD70 expression (P = 0.020). This finding was also statistically significant in multivariate analyses (P = 0.001). In vitro experiments demonstrated that CD70 expression contributed to cancer cell proliferation independently of gemcitabine treatment as well as cell migration. Furthermore, real-time polymerase chain reaction analysis of frozen surgical tissues showed a correlation between the expression of CD70 and mesenchymal markers. CONCLUSIONS: CD70 expression in pancreatic cancer might be involved in hematogenous metastasis. Furthermore, our results imply that CD70 overexpression can serve as a novel prognostic factor and a potential therapeutic target in patients who have completed adjuvant chemotherapy.

A gene expression signature for predicting response to neoadjuvant chemoradiotherapy in pancreatic ductal adenocarcinoma.

In patients with pancreatic ductal adenocarcinoma (PDAC), optimal treatment selection, including multimodality regimens such as neoadjuvant chemoradiotherapy (NACRT), can be clinically transformative. Unfortunately, currently no predictive biomarkers are available that can guide the use of NACRT in PDAC patients. Accordingly, herein we developed a novel gene signature that can preoperatively predict NACRT-sensitivity in PDAC patients. Herein, we evaluated the performance of a 10-gene panel in 749 PDAC cases, which included two public datasets (The Cancer Genome Atlas and International Cancer Genome Consortium; n = 276), and three clinical specimen cohorts (n = 417), and a pre-NACRT endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy cohort (n = 56). The potential predictive performance of this signature was evaluated and compared to CA-19-9 levels and key clinicopathological factors. We first evaluated the prognostic potential of a 10-gene panel which significantly predicted overall survival in both public datasets (P < .01, P < .01), and two in-house patient cohorts (P < .01, P = .04). In the pre-NACRT EUS-FNA cohort, we established a radio-sensitivity gene panel (RSGP) which yielded highly robust (area under the curve [AUC] = 0.91; 95% CI: 0.81-0.97) for predicting response to gemcitabine-based NACRT. Multivariate logistic regression analysis revealed that RSGP was an independent predictor for response to NACRT (OR = 2.70; 95% CI: 1.25-5.85), and this response-prediction was even more robust when CA-19-9 levels were included into the model. In conclusion, we have validated and developed a novel gene signature that is highly robust in predicting response to NACRT, even in preoperative settings, highlighting its clinical significance for optimizing and personalizing treatment strategies in PDAC patients.

Impact of Antithrombotic Agents on Postpancreatectomy Hemorrhage: Results from a Retrospective Multicenter Study.

BACKGROUND: This retrospective multicenter study aimed to evaluate the risk of postpancreatectomy hemorrhage (PPH) in patients receiving antithrombotic agents (ATAs). PPH is the most severe complication after pancreatectomy. However, there is little known about the strength of the association between ATA use, PPH, and other clinical outcomes. STUDY DESIGN: Between 2007 and 2016, 1,297 patients underwent pancreatectomy at 2 surgical centers. ATA use included aspirin, clopidogrel, ticlopidine, warfarin, direct oral anticoagulants, and intravenous unfractionated heparin. The ATA group was composed of 144 patients who were taking ATAs before surgery. RESULTS: A total of 35 patients developed PPH. The patients in the ATA group showed higher frequency (8.3% vs 2.0%, p < 0.001) of PPH compared with the control group (n = 1,153). In multivariate analysis, ATA use was an independent adverse risk factor for PPH (odds ratio [OR] 3.58, 95% CI 1.29-9.91, p = 0.014). Stratification by preoperative ATA therapy revealed a significant risk of PPH Grade C in patients receiving combined AT therapy. The median onset of late hemorrhage (>24 hours post-surgery) in the ATA group was later than in the control group (17.5 vs 8.5 days, p = 0.032), and the incidence tended to be higher in patients who restarted ATAs postoperatively. CONCLUSIONS: History of ATA use is a significant risk factor for PPH, and postoperative resumption of ATAs appears to be associated with an increased risk of PPH. Patients receiving combined antithrombotic therapy may be at particularly high risk for PPH.

New insight into the association between bile infection and clinically relevant pancreatic fistula in patients undergoing pancreatoduodenectomy.

BACKGROUND: The association between bacterial infection and clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD) has not been fully elucidated. METHODS: Microbiological data for intraoperative bile culture (BC) and drain culture on postoperative day 4 (DC) were collected. The study population was classified into the following three groups: P1 (positive BC and DC), P2 (positive BC and negative DC), and N (negative BC). A total of 209 patients (P1: 38, P2: 72, and N: 99) who underwent PD between May 2013 and May 2018 met the inclusion criteria of the study. RESULTS: The rate of CR-POPF was significantly higher in the P1 group (34.2%) than in the P2 (12.5%; P = .007) and N groups (14.1%; P = .008). Between P1 and P2 groups, a significant difference was observed in the proportion of Enterococcus faecalis grown in BC (42.1% vs 4.2%; P < .001). Multivariable logistic regression analysis showed that the presence of E faecalis in bile was independently associated with CR-POPF. CONCLUSIONS: The detection of both bile and postoperative abdominal fluid infections can be more accurate in predicting CR-POPF. Furthermore, the presence of E faecalis in bile may serve as a novel surrogate marker for CR-POPF.

Significance of the inflammation-based prognostic score in recurrent pancreatic cancer.

BACKGROUND: Although the prognosis of recurrent pancreatic cancer (RPC) is improving with the appearance of new anticancer drugs, prognostic indicators for RPC are still poorly understood. The aim of this study was to evaluate significance of the inflammation-based prognostic score, including modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and Prognostic Nutritional Index (PNI), in patients with RPC. METHODS: This study reviewed 263 patients of pancreatic ductal adenocarcinoma at our institution between 2006 and 2015. A receiver operating characteristics curve analysis was performed to determine the cut-off values. The prognostic significance of the inflammation-based prognostic scores were evaluated by a multivariate analysis. RESULTS: 172 patients (65.4%) who had recurrence was included in this study. The optimal PNI for predicting 1-year survival after recurrence was 40 with higher area under receiver operating characteristics curve value (0.704) in comparison with other inflammation-based prognostic scores. A univariate and multivariate analysis revealed that liver metastasis (P < 0.001) and PNI < 40 (P < 0.001) were independently associated with the survival time after recurrence. When each of the two predictors was counted as one point and the points were calculated for all cases, a good stratified survival curve was obtained, showing the shorter survival in the higher points: median survival times of 2, 1, and 0 points were 4.3, 11.1, and 21.2 months, respectively (P < 0.001). CONCLUSIONS: Inflammation-based prognostic scores, especially PNI is useful clinical biomarker for predicting the survival time after recurrence in patients with pancreatic adenocarcinoma.

Retrocaval liver lifting maneuver and modifications of total hepatic vascular exclusion for liver tumor resection.

AIM: To evaluate the efficacy of technical modifications of total hepatic vascular exclusion (THVE) for hepatectomy involving inferior vena cava (IVC). METHODS: Of 301 patients who underwent hepatectomy during the immediate previous 5-year period, 8 (2.7%) required THVE or modified methods of IVC cross-clamping for resection of liver tumors with massive involvement of the IVC. Seven of the patients had diagnosis of colorectal liver metastases and 1 had diagnosis of hepatocellular carcinoma. All tumors involved the IVC, and THVE was unavoidable for combined resection of the IVC in all 8 of the patients. Technical modifications of THVE were applied to minimize the extent and duration of vascular occlusion, thereby reducing the risk of damage. RESULTS: Broad dissection of the space behind the IVC coupled with lifting up of the liver from the retrocaval space was effective for controlling bleeding around the IVC before and during THVE. The procedures facilitate modification of the positioning of the cranial IVC cross-clamp. Switching the cranial IVC cross-clamp from supra- to retrohepatic IVC or to the confluence of hepatic vein decreased duration of the THVE while restoring hepatic blood flow or systemic circulation via the IVC. Oblique cranial IVC cross-clamping avoided ischemia of the remnant hemi-liver. With these technical modifications, the mean duration of THVE was 13.4 ± 8.4 min, which was extremely shorter than that previously reported in the literature. Recovery of liver function was smooth and uneventful for all 8 patients. There was no case of mortality, re-operation, or severe complication (i.e., Clavien-Dindo grade of III or more). CONCLUSION: The retrocaval liver lifting maneuver and modifications of cranial cross-clamping were useful for minimizing duration of THVE.