DUPAN-2 as a Risk Factor of Early Recurrence After Curative Pancreatectomy for Patients With Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Several patients with pancreatic ductal adenocarcinoma (PDAC) experience postoperative early recurrence (ER). We evaluated PDAC patients to identify the risk factors for postoperative ER (≤6 months), including preoperative serum DUPAN-2 level. METHODS: We retrospectively evaluated 74 PDAC patients who underwent pancreatectomy with curative intent. Clinicopathological factors including age, sex, body mass index, postoperative complications, pathological factors, preoperative C-reactive protein/albumin ratio, neutrophil/lymphocyte ratio, modified Glasgow prognostic score, preoperative tumor markers (carcinoembryonic antigen, carbohydrate antigen 19-9, SPAN-1, and DUPAN-2), and history of adjuvant chemotherapy were investigated. Early recurrence risk factors were determined using multivariate logistic regression analysis. RESULTS: Recurrence and ER occurred in 52 (70.3%) and 23 (31.1%) patients, respectively. Univariate analysis revealed that postoperative complications, C-reactive protein/albumin ratio ≥0.02, neutrophil/lymphocyte ratio ≥3.01, carbohydrate antigen 19-9 ≥ 92.3 U/mL, SPAN-1 ≥ 69 U/mL, DUPAN-2 ≥ 200 U/mL, and absence of adjuvant chemotherapy were significant risk factors for ER. In multivariate analysis, DUPAN-2 ≥ 200 U/mL (P = 0.04) and absence of adjuvant chemotherapy (P = 0.02) were identified as independent risk factors for ER. CONCLUSIONS: A higher level of preoperative DUPAN-2 was an independent risk factor for ER. For patients with high DUPAN-2 level, neoadjuvant therapies might be required to avoid ER.

Liver metastases 2 years after resection of a very-low-risk duodenal gastrointestinal stromal tumor: a case report.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors, but are the most common mesenchymal tumors of the gastrointestinal tract. The risk classification of GISTs is based on the tumor size, mitotic index, tumor site, and presence of tumor rupture. Recurrence in the very-low-risk group is extremely rare. We herein report a case of liver metastases 2 years after resection of a very-low-risk duodenal GIST. CASE PRESENTATION: A 57-year-old woman presented to the hospital for evaluation of melena. Esophagogastroduodenoscopy showed bleeding from the exposed blood vessels at the top of a submucosal tumor approximately 20 mm in size located in the second (descending) part of the duodenum, and the bleeding was controlled with electrocoagulation. A GIST was suspected, and the patient underwent wedge resection of the duodenum. The resected specimen contained a 16- × 12-mm (< 20-mm) white submucosal tumor composed of spindle cells with a mitotic count of 4 per 50 high-power fields, and a histologically negative margin was achieved. Immunochemical analysis revealed positive tumor staining for c-kit protein and alpha-smooth muscle actin and negative staining for CD34, desmin, and S-100 protein. Therefore, the tumor was diagnosed as a very-low-risk duodenal GIST based on the Fletcher classification and modified Fletcher classification (Joensuu classification). The postoperative course was uneventful, and the patient was discharged on postoperative day 11. At the follow-up visit 2 years postoperatively, contrast-enhanced computed tomography revealed liver tumors in S8 and S6 measuring 26 × 24 and 10 × 10 mm, respectively. Both lesions showed peripheral dominant hyperenhancement with hypoenhancement inside, indicating tissue degeneration within the tumors. These imaging findings closely resembled those of the duodenal GIST. Hence, the patient was diagnosed with liver metastases of GIST 2 years postoperatively. She was subsequently started on treatment with 400 mg of imatinib. At the time of this writing (2 months after diagnosis), the patient was clinically well and asymptomatic and was continuing imatinib therapy. CONCLUSIONS: Recurrence of very-low-risk GISTs is extremely rare. Even a small GIST with low mitotic activity can never be considered completely benign, and long-term follow-up is necessary.

Maximum Diameter of the Gallbladder Determined Presurgically Using Computed Tomography as a Risk Factor for Difficult Emergency Laparoscopic Cholecystectomy in Patients With Mild to Moderate Acute Cholecystitis.

BACKGROUND: Early or emergency laparoscopic cholecystectomy (LC) was recommended in the 2018 Tokyo Guidelines for patients with mild to moderate acute cholecystitis (AC). Although surgical difficulty is frequently encountered during these surgeries, risk factors for predicting surgical difficulties have not been fully investigated, especially based on computed tomography (CT) findings. MATERIALS AND METHODS: We investigated 72 patients who underwent emergency LC with mild (n=45) to moderate (n=27) AC. Patients who previously underwent presurgical percutaneous or endoscopic biliary drainage were excluded from this study. Difficult LC was defined using any of the following surgical factors: surgical duration ≥180 minutes, blood loss ≥300 g, or a conversion to open cholecystectomy. Subsequently, several presurgical clinical factors were analyzed, including sex, age at surgery, experience of the surgeon, interval between symptom onset and surgery, body mass index, diabetes history, presurgical white blood cell count, and C-reactive protein level. Moreover, stones in the cystic duct or perigallblader fluid and the maximum thickness and diameter of the gallbladders were evaluated via presurgical CT. Finally, logistic regression analysis was performed to compare the relationship between surgical difficulty and each clinical factor. RESULTS: The average age at surgery of the included patients was 60.3 (range: 25 to 88 y), surgical duration was 112.2 (range: 29 to 296 min), and surgical blood loss was 55.2 (range: 0 to 530 g). Furthermore, 4 (5.6%) had to undergo open cholecystectomy, whereas postsurgical complications occurred in 5 (6.9%) patients. In addition, the mean postsurgical admission duration was 7 (range: 3 to 63 d). Thus, 12 patients experienced difficult LC, whereas 60 experienced nondifficult LC. Of the evaluated clinical factors, patients who experienced difficult LC showed higher presurgical C-reactive protein levels (10.78 vs. 6.76 mg/dL, P =0.01) and wider gallbladder diameters (48.4 vs. 41.8 mm, P <0.01) than those who experienced nondifficult LC. By univariate logistic regression analysis, results also showed that patients with a maximum gallbladder diameter had a higher risk of experiencing difficulty during emergency LC ( P =0.02). Moreover, the gallbladder diameter's cutoff value was 43 mm after the receiver operating characteristic curve analysis. CONCLUSIONS: In patients with mild to moderate AC, emergency LC can safely be performed. However, performing LC might be technically difficult in patients with AC after the identification of severe gallbladder swelling during presurgical CT.

Prognostic significance of intrahepatic lymphatic invasion in colorectal liver metastases.

BACKGROUND: Intrahepatic lymphatic invasion is an adverse prognostic factor after hepatectomy for colorectal liver metastases (CLMs). However, most patients in previous reports had liver resection before the era of FOLFOX/FIRI-based chemotherapy. METHODS: Forty-six patients who underwent hepatectomy for CLMs from 2004 to 2020 were evaluated. We histologically evaluated portal invasion, intrahepatic lymphatic invasion, and biliary invasion on hematoxylin-eosin slides. We also collected the following clinicopathologic factors: gender, age, timing, the number and maximum size of CLMs, preoperative tumor markers, neutrophil/lymphocyte ratio, location, and lymph node metastases of primary cancer, and chemotherapy after hepatectomy. A multivariate Cox proportional hazard model was used to define the relationship between overall (OS) or disease-free survival (DFS) and clinicopathologic factors. RESULTS: Histological invasions were portal invasion in 8 (17.4 %), intrahepatic lymphatic invasion in 6 (13.0 %), and biliary invasion in 5 (10.9 %). Chemotherapy for recurrence after hepatectomy (n = 29) was performed in 22 and 14 of those who received FOLFOX/FIRI-based chemotherapy. By multivariate analysis, the number of CLMs (p < 0. 01) and presence of intrahepatic lymphatic invasion (p = 0.02) were independent predictors of recurrence. The number of CLMs (p = 0.02) and prehepatectomy carcinoembryonic antigen level (p = 0.02), but not intrahepatic lymphatic invasion (p = 0.18), were independent predictors of survival using multivariate analysis. CONCLUSIONS: The presence of intrahepatic lymphatic invasion adversely affected patient's DFS, but not OS in patients with CLMs in the era of FOLFOX/FIRI chemotherapy. FOLFOX/FIRI-based chemotherapy might improve OS, even in patients with positive intrahepatic lymphatic invasion.

"Honeycomb" appearance in large-duct type pancreatic ductal adenocarcinoma: Case report with radiologic-pathologic correlation.

Large-duct type pancreatic ductal adenocarcinoma (PDA) is a rare morphologic variant forming large duct elements. This case report, to our knowledge, is the first report of a large-duct type PDA with a "honeycomb" appearance resembling a serous cystic neoplasm (SCN) on CT and MRI. The patient is an 82-year-old woman who presented with upper abdominal pain. Dynamic contrast-enhanced CT revealed a multilocular cyst with honeycomb loculi, in which the cyst walls showed gradual enhancement. On T2-weighted MRI, the mass displayed inhomogeneous hyperintensity characterized by a honeycomb appearance with irregular and thick hypointense cyst walls. The patient underwent distal pancreatectomy; histopathological diagnosis was large-duct type PDA. Although the imaging features of large-duct type PDA may resemble those of SCN, this distinction between PDA and SCN is important because the treatment options are very different.

Modulation of Nqo1 activity intercepts anoikis resistance and reduces metastatic potential of hepatocellular carcinoma.

The processing of intracellular reactive oxygen species (ROS) by nuclear factor erythroid-derived 2-like 2 (Nrf2) and NADPH quinone oxidoreductase 1 (Nqo1) is important for tumor metastasis. However, the clinical and biological significance of Nrf2/Nqo1 expression in hepatocellular carcinoma (HCC) remains unclear. We aimed to clarify the clinical importance of Nrf2/Nqo1 expression in HCC and evaluate the association of Nrf2/Nqo1 expression with HCC metastasis. We also evaluated the impact of Nqo1 modulation on HCC metastatic potential. We used spheroids derived from HCC cell lines. In anchorage-independent culture, HCC cells showed increased ROS, leading to the upregulation of Nrf2/Nqo1. Futile stimulation of Nqo1 by ß-lapachone induces excessive oxidative stress and dramatically increased anoikis sensitivity, finally diminishing the spheroid formation ability, which was far stronger than depletion of Nqo1. We analyzed 117 cases of primary HCC who underwent curative resection. Overexpression of Nrf2/Nqo1 in primary HCC was associated with tumor size, high α-fetoprotein, and des-γ-carboxy-prothrombin levels. Overexpression of Nrf2/Nqo1 was also associated with multiple intrahepatic recurrences (P = .0073) and was an independent risk factor for poor prognosis (P = .0031). NADPH quinone oxidoreductase 1 plays an important role in anchorage-independent survival, which is essential for survival for circulation and distant metastasis of HCC cells. These results suggest that targeting Nqo1 activity could be a potential strategy for HCC adjuvant therapy.

Characterization of human pegivirus infection in liver transplantation recipients.

Approximately 2% of healthy persons are infected with human pegivirus (HPgV). HPgV is transmitted via vertical, sexual, and blood-borne routes. Recently, the association of HPgV infection with the risk of lymphoma was reported. Here, we examined the prevalence of chronic HPgV infection in liver transplantation (LT) recipients and patients with hepatectomy and the influence of HPgV infection after LT on clinical and perioperative factors. We enrolled 313 LT recipients and 187 patients with hepatectomy who received care at the Kyusyu University Hospital between May 1997 and September 2017. Of the 313 recipients and 187 patients enrolled in this study, 44 recipients (14.1%) and 2 patients (1.1%) had HPgV viremia, respectively. There was no significant association between HPgV infection and LT outcomes. Interestingly, one recipient was infected with HPgV during the peritransplant period, which was likely transmitted via blood transfusion because HPgV RNA was detected from the blood bag transfused to the recipient during LT. We reviewed the available literature on the prevalence HPgV infections in other organ-transplanted patients and whether they impacted clinical outcomes. They also had the higher prevalence of HPgV infection, while it appears to be of low or no consequences. In addition, HPgV infection induced the upregulation of interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells. LT recipients had higher HPgV viremia compared to patients with hepatectomy. Although HPgV infection was not associated with LT-related outcomes, it induced ISG expression in recipients.

The Role of DNA Repair Glycosylase OGG1 in Intrahepatic Cholangiocarcinoma.

BACKGROUND/AIM: The effects of oxidative stress on various carcinomas were reported in previous studies, but those in intrahepatic cholangiocarcinoma (ICC) have not been fully elucidated. The purpose of this study was, thus, to reveal the effects of oxidative DNA damage and repair enzymes on ICC. MATERIALS AND METHODS: The levels of 8-hydroxydeoxyguanosine (8-OHdG) and 8-OHdG DNA glycosylase (OGG1) were immunohistochemically evaluated in specimens resected from 63 patients with ICC. RESULTS: Low OGG1 expression was related to tumour depth T4 (p=0.04), venous invasion (p=0.0005), lymphatic vessel invasion (p=0.03), and perineural invasion (p=0.03). Compared to the high-OGG1-expression group, patients with low OGG1 expression had a significantly poorer prognosis (overall survival: p=0.04, recurrence-free survival: p=0.02). Unlike for OGG1, the expression levels of 8-OHdG showed no association with prognosis. CONCLUSION: Oxidative DNA damage and DNA repair enzymes may be closely related to ICC progression.

Long-term Outcomes and Risk Factors After Adult Living Donor Liver Transplantation.

BACKGROUND: Although risk factors for the long-term mortality of liver transplantation are well described, there is a lack of detailed study regarding these factors for adult living donor liver transplantation (LDLT). METHODS: We retrospectively analyzed 528 adult LDLT recipients in our hospital. The risk factors were analyzed for overall deaths more than 5 years post-LDLT. RESULTS: Over the 20-year follow-up, 137 patients died. Patient survival at 1, 3, 5, and 10 years post-LDLT was 87.8%, 81.8%, 79.4%, and 72.8%, respectively. The independent risk factors for more than 5 years post-LDLT overall death were hepatocellular carcinoma recurrence (hazard ratio [HR], 38.9; P < 0.001), lymphoid de novo malignancy (HR, 47.2; P = 0.001), primary sclerosing cholangitis as primary diagnosis (HR, 11.5; P < 0.001), chronic rejection (HR, 6.93; P = 0.006), acute rejection (HR, 2.96; P = 0.017), and bile duct stenosis (HR, 2.30; P = 0.045). CONCLUSIONS: Not only malignancies and rejection but also bile duct stenosis and primary sclerosing cholangitis had significant impacts on late period post-LDLT mortality.

Prognostic Significance of Preoperative Controlling Nutritional Status (CONUT) Score in Patients Undergoing Hepatic Resection for Hepatocellular Carcinoma.

BACKGROUND: The Controlling Nutritional Status (CONUT) score is an objective tool widely used to assess nutritional status in patients with inflammatory disease, chronic heart failure, and chronic liver disease. The relationship between CONUT score and prognosis in patients who have undergone hepatic resection, however, has not been evaluated. METHODS: Data were retrospectively collected for 357 consecutive patients with hepatocellular carcinoma (HCC) who had undergone hepatic resection with curative intent between January 2004 and December 2015. The patients were assigned to two groups, those with preoperative CONUT scores ≤3 (low CONUT score) and >3 (high CONUT score), and their clinicopathological characteristics, surgical outcomes, and long-term survival were compared. RESULTS: Of the 357 patients, 69 (19.3%) had high (>3) and 288 (80.7%) had low (≤3) preoperative CONUT scores. High CONUT score was significantly associated with HCV infection, low serum albumin and cholesterol concentrations, low lymphocyte count, shorter prothrombin time, Child-Pugh B and liver damage B scores, and blood transfusion. Multivariate analysis identified six factors prognostic of poor overall survival (older age, liver damage B score, high CONUT score, poor tumor differentiation, the presence of intrahepatic metastases, and blood transfusion) and five factors prognostic of reduced recurrence-free survival (older age, higher ICGR15, larger tumor size, presence of intrahepatic metastasis, and blood transfusion). CONCLUSIONS: In patients with HCC, preoperative CONUT scores are predictive of poorer overall survival, even after adjustments for other known predictors.

Liver transplantation for cryptogenic liver failure caused by diffuse hepatic angiosarcoma: case report.

BACKGROUND: Primary hepatic angiosarcoma is a non-epithelial malignancy derived from sinusoidal endothelial cells, accounting for approximately 1.8% of primary hepatic malignancies. Diagnosis of primary hepatic angiosarcoma is complicated by difficulties in the qualitative radiological assessment of these tumors. Prognosis is very poor due to local recurrence and distant metastasis after liver resection or liver transplantation (LT). CASE PRESENTATION: This case report describes two patients with primary hepatic angiosarcoma who were diagnosed by histopathological examination of the explanted liver after LT. One patient had undergone living donor LT, and the other had undergone deceased donor LT. Neither showed evidence of malignancy on the pre-operative imaging tests. CONCLUSIONS: Hepatic angiosarcoma has a very high relapse rate after LT. Pre-transplant liver biopsy may be necessary to distinguish diffuse hepatic angiosarcoma from tumors of other origin in patients with cryptogenic liver failure.

Prognostic significance of combined albumin-bilirubin and tumor-node-metastasis staging system in patients who underwent hepatic resection for hepatocellular carcinoma.

BACKGROUND: In recent years, the establishment of new staging systems for hepatocellular carcinoma (HCC) has been reported worldwide. The system combining albumin-bilirubin (ALBI) with tumor-node-metastasis stage, developed by the Liver Cancer Study Group of Japan, was called the ALBI-T score. METHODS: Patient data were retrospectively collected for 357 consecutive patients who had undergone hepatic resection for HCC with curative intent between January 2004 and December 2015. The overall survival and recurrence-free survival were compared by the Kaplan-Meier method, using different staging systems: the Japan integrated staging (JIS), modified JIS, and ALBI-T. RESULTS: Multivariate analysis identified five poor prognostic factors (higher age, poor differentiation, the presence of microvascular invasion, the presence of intrahepatic metastasis, and blood transfusion) that influenced overall survival, and four poor prognostic factors (the presence of intrahepatic metastasis, serum α-fetoprotein level, blood transfusion, and each staging system (JIS, modified JIS, and ALBI-T score)) that influenced recurrence-free survival. Patients for each these three staging system had a significantly worse prognosis regarding recurrence-free survival, but not with overall survival. The modified JIS score showed the lowest Akaike information criteria statistic value, indicating it had the best ability to predict overall survival compared with the other staging systems. CONCLUSIONS: This retrospective analysis showed that, in post-hepatectomy patients with HCC, the ALBI-T score is predictive of worse recurrence-free survival, even when adjustments are made for other known predictors. However, modified JIS is better than ALBI-T in predicting overall survival.

The learning curves in living donor hemiliver graft procurement using small upper midline incision.

The learning curve for performing living donor hemiliver procurement (LDHP) via small upper midline incision (UMI) has not been determined. Living donors (n=101) who underwent LDHP via UMI were included to investigate the learning curve using cumulative sum analysis. The cumulative sum analysis showed that nine cases for right lobe (case #23) and 19 cases for left lobe (case #32 in the whole series) are needed for stable and acceptable surgical outcomes in LDHP via UMI. The established phase (n=69, since case #33) had a significantly shorter operative time, a smaller incision size, and less blood loss than the previous learning phase (n=32, serial case number up to the last 19th left lobe case). Multivariate analysis showed that the learning phase, high body mass index ≥25 kg/m2 , and left lobe graft procurement are the factors associated with surgical events including operative blood loss ≥400 mL, operative time ≥300 minutes, or surgical complications ≥Clavien-Dindo grade II. There is an obvious learning curve in performing LDHP via UMI, and 32 cases including both 19 cases for left lobe and nine cases for right lobe are needed for having stable and acceptable surgical outcomes.

Left lobe living donor liver transplantation in adults: What is the safety limit?

Small-for-size syndrome (SFSS) is the most significant cause of graft loss after living donor liver transplantation (LDLT), especially after left lobe (LL) LDLT in adults. The safety limit of applying LL-LDLT in adults without severe SFSS with a high rate of lethality needs to be determined. A total of 207 LL-LDLTs in adults since September 2005 were evaluated to analyze the risk factors for severe SFSS, defined as a serum total bilirubin concentration of ≥20.0 mg/dL after LDLT. Although there were no significant differences in cumulative graft survival after LDLT between medium grafts (graft volume [GV] to standard liver volume [SLV] ratio ≥ 40.0%), small grafts (35.0% ≤ GV/SLV < 40.0%), and extra small grafts (GV/SLV < 35.0%), patients with severe SFSS showed a significantly lower 5-year graft survival rate than those without (42.9% versus 94.3%, respectively; P < 0.001). Multivariate analysis for severe SFSS after LL-LDLT showed that donor age of ≥48 years (P = 0.01), Model for End-Stage Liver Disease (MELD) score of ≥ 19 (P < 0.01), and end portal venous pressure of ≥19 mm Hg (P = 0.04) were the significant and independent factors for severe SFSS after LL-LDLT. Within such high-risk subgroups of patients with a donor age of ≥48 years or MELD score of ≥ 19 before LDLT, operative blood loss volume of ≥8.0 L was a risk factor for severe SFSS. LL-LDLT in adults could be indicated and provide acceptable outcomes for the combinations of donors aged < 48 years and recipients with a MELD score of <19. Smaller grafts might yield acceptable outcomes in appropriately selected donor-recipient combinations. Liver Transplantation 22 1666-1675 2016 AASLD.

Sarcopenia is a poor prognostic factor following hepatic resection in patients aged 70 years and older with hepatocellular carcinoma.

AIM: The present study investigated the effect of sarcopenia on short- and long-term surgical outcomes and identified potential prognostic factors for hepatocellular carcinoma (HCC) following hepatectomy among patients 70 years of age and older. METHODS: Patient data were retrospectively collected for 296 consecutive patients who underwent hepatectomy for HCC with curative intent. Patients were assigned to two groups according to age (younger than 70 years, and 70 years and older), and the presence of sarcopenia. The clinicopathological, surgical outcome, and long-term survival data were analyzed. RESULTS: Sarcopenia was present in 112 of 296 (37.8%) patients with HCC, and 35% of patients aged 70 years and older. Elderly patients had significantly lower serum albumin levels, prognostic nutrition index, percentage of liver cirrhosis, and histological intrahepatic metastasis compared with patients younger than 70 years. Overall survival and disease-free survival rates in patients with sarcopenia correlated with significantly poor prognosis in the group aged 70 years and older. Multivariate analysis revealed that sarcopenia was predictive of an unfavorable prognosis. CONCLUSION: This retrospective analysis revealed that sarcopenia was predictive of worse overall survival and recurrence-free survival after hepatectomy in patients 70 years of age and older with HCC.

Novel Surgical Skill Evaluation with Reference to Two-handed Coordination.

INTRODUCTION: We evaluated the differences in instrument manipulation skills between expert laparoscopic surgeons and novices. METHODS: Six expert surgeons who had performed more than 500 laparoscopic surgeries and one skilled instructor at Kyushu University Training Center for Minimally Invasive Surgery, and 20 medical students who had experienced no laparoscopic surgery were enrolled. A new skill assessment task was designed using zippers on an unstable, mobile platform in a box trainer. The examinees were asked to close the zippers, while trying to avoid moving the platform. The path lengths of the tips of the instruments and of the platform were measured, and the performance time was also recorded. Surgical skill score was calculated from the correlation between the path lengths of the instruments and that of the platform, in addition to the performance time. RESULTS: The path lengths of the tips of both instruments and of the platform were significantly shorter in the experts than in the novices (all p < 0.05). The performance time was also significantly shorter for experts than novices (p < 0.05). The surgical skill score was significantly higher for experts than novices (p < 0.01). CONCLUSION: The differences in the instrument manipulation skills between expert laparoscopic surgeons and novices could therefore be evaluated using our surgical skill scoring system.