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Background/aim: No studies have investigated the advantage of laparoscopic hepatectomy (LH) compared with open hepatectomy (OH) from a nutritional perspective. This study aimed to compare the postoperative nutritional status between LH and OH., Patients and Methods: A total of 186 patients who underwent partial hepatic resection for liver tumors were analyzed retrospectively. We compared perioperative variables between LH and OH. The nutritional status was assessed using serum albumin (Alb) and rapid turnover protein concentrations. We investigated risk factors for postoperative malnutrition using univariate and multivariate analyses., Results: The LH group, compared with the OH group, had a significantly shorter operative time (239 vs. 344 min, p<0.03), less intraoperative blood loss (100 vs. 343 g, p<0.01), and a shorter length of postoperative stay (8 vs. 11 days, p<0.01). Postoperative serum Alb and prealbumin concentrations in the LH group were significantly higher than those in the OH group (3.4 vs. 3.2 g/dl, p<0.01; 15.0 vs. 12.0 mg/dl, p=0.02, respectively). The multivariate analysis showed that OH (p=0.02) and hepatocellular carcinoma (p<0.01) were significant and independent risk factors for postoperative malnutrition., Conclusion: LH may be superior to OH in terms of the postoperative nutritional status, intraoperative blood loss, and length of postoperative stay., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Owing to advances in the multidisciplinary treatment of hepatocellular carcinoma (HCC), a conceptualization and definition for borderline resectable (BR) HCC, which carries a high risk of recurrence, is warranted. In this study, we aimed to define BR-HCC using a prognosis-oriented approach., Study Design: The study included an original cohort of 221 patients and an independent validation cohort of 181 patients who had undergone primary hepatic resection for HCC. To define biological BR-HCC, we evaluated the risk factors for early recurrence beyond the Milan criteria within 1 year after hepatic resection using multivariable logistic regression models. Subsequently, we developed high-risk scores using the identified risk factors and defined BR-HCC. The utility of high-risk score was validated in the validation cohort., Results: In the original cohort (hepatitis B virus:hepatitis C virus = 20%:29%), recurrence beyond the Milan criteria within 1 year was observed in 28 patients (13%), with a 5-year survival rate of 25%. Multivariable analysis identified risk factors for recurrence beyond the Milan criteria within 1 year, including serum alpha-fetoprotein levels of 12 ng/mL or more (p = 0.02), tumor diameters less than 5 cm (p = 0.02), tumor number 3 or more (p = 0.001), and macrovascular invasion (p = 0.04). BR-HCC was defined as a tumor with 2 or more identified risk factors, and 42 patients (19%) were diagnosed with BR-HCC, with a 5-year survival rate of 51%. In the validation cohort, 45 (25%) patients had BR-HCC, with a 5-year survival rate of 42%., Conclusions: The prognosis-oriented definition of BR-HCC enabled us to identify patients who are susceptible to early unresectable recurrence and have poor survival after hepatic resection for HCC. For patients with BR-HCC, preoperative systemic therapy may be a viable option to improve postresection outcomes., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background/aim: With the aging of the population, there is a rising proportion of elderly patients undergoing liver resection. However, the safety and efficacy of laparoscopic liver resection (LLR) in the elderly have not yet been established. In this study, we compared the short-term results of LLR and open liver resection (OLR) in elderly patients using propensity score matched (PSM) analysis., Patients and Methods: The study comprised 237 elderly patients aged 65 years and older who had undergone liver resection between 2015 to 2021, excluding biliary and vascular reconstruction and simultaneous surgeries other than liver resection. We conducted PSM analysis for baseline characteristics (age, sex, BMI, ASA-PS, disease, procedure, tumor size, and number of tumors) to eliminate potential selection bias. We then compared short-term postoperative outcomes between LLR and OLR groups in patients selected by PSM analysis., Results: Applying PSM analysis, 90 cases each were selected for the LLR and OLR groups. The LLR group had a significantly lower complication rate (Clavien-Dindo: CD ≥II) (19% vs. 33%, p=0.03), especially bile leakage (CD ≥II) (0% vs. 6.7%, p=0.03) compared with those in the OLR group. In addition, a shorter operation time (244 min vs. 351 min, p<0.01), less blood loss (150 ml vs. 335 ml, p<0.01), and shorter hospital stay (8 days vs. 12 days, p<0.01) were observed in the LLR group. No operative or in-hospital deaths were observed in both groups., Conclusion: LLR can be safely performed in elderly patients and offers better short-term outcomes., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Laparoscopic hepatic resection is currently used for ruptured hepatocellular carcinoma (HCC); however, it is technically challenging. We developed and implemented surgical strategies for emergency laparoscopic partial liver resection in selected patients with peripheral lesions who were hemodynamically stable and without severe liver dysfunction., Patients and Methods: The surgical techniques used were as follows. First, the Pringle maneuver was performed to control hepatic blood inflow (step 1). Next, strong hemostatic agents were applied at the rupture point of the tumor (step 2). The hanging tape was positioned along the dorsal side of the resection line to control the partial blood inflow and outflow of the tumor, as well as to expose the surgical plane (step 3). The liver parenchyma was dissected along the hanging tape (step 4). We performed emergency laparoscopic partial liver resection in three patients who were in a pre-shock status., Results: The tumors were located in segments 6 (cases 1 and 2) and 2 (case 3). The tumor diameters were 90, 62, and 80 mm. The Preoperative Child-Pugh scores were B7, B9, and B8. The hemostatic products performed well and controlled bleeding from the ruptured HCC. The hanging tape facilitated the dissection of the liver parenchyma. The operative time and intraoperative blood loss were 135 min and 400 ml, 266 min and 200 ml, and 191 min and 495 ml for cases 1, 2, and 3 respectively. There were no in-hospital deaths., Conclusion: Emergency laparoscopic partial liver resection could be an option for patients with ruptured HCC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To study the effect of preoperative osteosarcopenia (OSP) on the prognosis of treatment (surgery or radiofrequency ablation (RFA)) in patients with Barcelona Cancer Liver Classification stage A hepatocellular carcinoma (BCLC A HCC)., Methods: This study enrolled 102 patients with BCLC A HCC who underwent surgical resection (n = 45) and RFA (n = 57); the patients were divided into two groups: OSP (n = 33) and non-OSP (n = 69). Overall survival (OS) and disease-free survival (DFS) curves for both the groups and treatment methods (surgery and RFA) were generated using the Kaplan-Meier method and compared using the log-rank test. Univariate analyses for OS and DFS were performed using log-rank test. Multivariate analyses were performed for factors that were significant at univariate analysis by Cox proportional hazard model., Results: Multivariate analysis showed that OSP (HR 2.44; 95 % CI 1.30-4.55; p < 0.01) and treatment (HR 0.57; 95 % CI 0.31-0.99; p = 0.05) were significant independent predictors of DFS; and treatment (HR, 0.30; 95 % CI 0.10-0.85; p = 0.03) was a significant independent predictor of OS in the non-OSP group, in which the OS rate was significantly lower in patients treated with RFA than in those treated by resection (p = 0.01)., Conclusions: OSP is a prognostic factor for BCLC A HCC treatment. Surgical approach was associated with a significantly better prognosis in patients without OSP compared to those who underwent RFA., Competing Interests: Declaration of competing interest The authors declare no Conflicts of Interest for this article., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Identifying the prognostic indicators that reflect the efficacy of preoperative chemotherapy is necessary. In this study, we investigated the prognostic indicators targeting the systemic inflammatory response for the administration of preoperative chemotherapy in patients with colorectal liver metastases., Methods: Data for 192 patients were retrospectively analyzed. The relationship between overall survival and clinicopathological variables, including biomarkers such as the prognostic nutritional index, was investigated in patients who underwent upfront surgery or preoperative chemotherapy., Results: In the upfront surgery group, extrahepatic lesion (p=0.01) and low prognostic nutritional index (p < 0.01) were significant prognostic indicators, whereas a decrease in the prognostic nutritional index (p=0.01) during preoperative chemotherapy were independent poor prognostic factors in the preoperative chemotherapy group. In particular, a decrease in the prognostic nutritional index was a significant prognostic marker in patients aged <75 years (p=0.04). In patients with a low prognostic nutritional index aged <75 years, preoperative chemotherapy significantly prolonged overall survival (p=0.02)., Conclusion: A decrease in the prognostic nutritional index during preoperative chemotherapy predicted overall survival of patients with colorectal liver metastases after hepatic resection, and preoperative chemotherapy may be effective for patients aged <75 years with a low prognostic nutritional index., Competing Interests: Declaration of competing interest Authors declare no Conflict of Interests for this article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: This study was performed to propose a strategy for repeat laparoscopic liver resection (RLLR) and investigate the preoperative predictive factors for RLLR difficulty., Methods: Data from 43 patients who underwent RLLR using various techniques at 2 participating hospitals from April 2020 to March 2022 were retrospectively reviewed. Surgical outcomes, short-term outcomes, and feasibility and safety of the proposed techniques were evaluated. The relationship between potential predictive factors for difficult RLLR and perioperative outcomes was evaluated. Difficulties associated with RLLR were analyzed separately in two surgical phases: the Pringle maneuver phase and the liver parenchymal transection phase., Results: The open conversion rate was 7%. The median surgical time and intraoperative blood loss were 235 min and 200 mL, respectively. The Pringle maneuver was successfully performed in 81% of patients using the laparoscopic Satinsky vascular clamp (LSVC). Clavien-Dindo class ≥III postoperative complications were observed in 12% of patients without mortality. An analysis of the risk factors for predicting difficult RLLR showed that a history of open liver resection was an independent risk factor for difficulty in the Pringle maneuver phase., Conclusion: We present a feasible and safe approach to address RLLR difficulty, especially difficulty with the Pringle maneuver using an LSVC, which is extremely useful in RLLR. The Pringle maneuver is more challenging in patients with a history of open liver resection., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The 5-5-500 rule has been proposed to increase the candidates of liver transplantation for patients with hepatocellular carcinoma with reasonable recurrence rates. However, the clinical significance of the 5-5-500 rule in patients who underwent hepatic resection for hepatocellular carcinoma has not been fully investigated., Patients and Methods: The study comprised 206 patients who had undergone primary hepatic resection for hepatocellular carcinoma between 2008 and 2018. We retrospectively investigated prognostic significance of the 5-5-500 rule and disease-free, as well as overall, survival and further prognostic stratification using inflammatory-based biomarkers., Results: 132 patients (64%) were classified within the 5-5-500 rule, while 74 patients (36%) were classified outside the 5-5-500 rule. Among the patients outside the 5-5-500 rule, 62 patients had tumors greater than 5 cm, and 23 patients showed serum AFP levels greater than 500 ng/ml. In the multivariate analysis, being female (p<0.01), HBs-Ag positive (p<0.01), having an ICG R15 ≥15% (p=0.03), and being outside the 5-5-500 rule (p=0.01) were independent and significant predictors of disease-free survival, while being HBs-Ag positive (p=0.04), having poor tumor differentiation (p=0.03), and residing outside the 5-5-500 rule (p=0.01) were independent and negative predictors of overall survival. Elevated CRP-to-albumin ratio was associated with poor overall survival in the patients outside the 5-5-500 rule, but not in patients within the 5-5-500 rule (p=0.17)., Conclusion: The 5-5-500 rule can be a prognostic factor in patients with hepatocellular carcinoma after hepatic resection. CRP-to-albumin ratio might be useful to stratify the outcomes in patients outside the 5-5-500 rule., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Frailty, represented by sarcopenia and osteopenia, has been associated with worse survival after hepatectomy in patients with hepatocellular carcinoma. Recently, the concept and term "osteosarcopenia" have been proposed, which has been associated with worse outcome in several malignancies., Methods: This study included 227 patients who underwent elective hepatic resection for hepatocellular carcinoma. Osteopenia was evaluated with computed tomographic measurement of pixel density in the midvertebral core of the 11th thoracic vertebra. The skeletal muscle index (SMI) was evaluated with psoas muscle areas at the third lumbar vertebra. Osteosarcopenia was defined as the concomitant occurrence of osteopenia and low SMI. We retrospectively investigated the relationship between osteosarcopenia and disease-free and overall survival., Results: Osteosarcopenia was identified in 27 (12%) of the patients. Multivariate analysis showed that osteosarcopenia (P < .001), C-reactive protein-to-albumin ratio ≥0.02 (P = .002), and stage ≥III (P ≤ .001) were independent predictors of disease-free survival, while osteosarcopenia (P < .001), Child-Pugh grade B (P = .002), C-reactive protein-to-albumin ratio ≥0.02 (P = .001), low SMI (P ≤ .001), and stage ≥III (P ≤ .001) were independent predictors of overall survival., Conclusion: Preoperative osteosarcopenia may be a prognostic factor in patients with hepatocellular carcinoma after hepatic resection. Our results suggests that the preoperative maintenance of skeletal muscle and bone density may potentially improve prognosis., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Preoperative systematic inflammatory response, represented by neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein-albumin ratio (CAR), has been associated with long-term outcomes in patients with hepatocellular carcinoma (HCC). However, the impact of sustained systematic inflammatory response after resection remains unclear., Methods: This study comprised 210 patients who had undergone primary hepatic resection for HCC between 2008 and 2018. Preoperative and postoperative NLR, LMR, and CAR were evaluated, and patients were then classified into three groups according to the status of each marker: persistently high inflammatory state (elevated group), preoperatively low inflammatory state (normal group), and preoperatively high but postoperatively low inflammatory state (normalized group). Multivariate Cox proportional hazard models were conducted to assess disease-free and overall survival, adjusting for potential confounders., Results: In multivariate analysis, sex (p = 0.002), hepatitis B surface antigen (HBsAg) positivity (p = 0.002), serum α-fetoprotein (AFP) level ≥ 20 ng/mL (p < 0.001), multiple tumors (p < 0.001), microvascular invasion (p = 0.003), type of resection (p = 0.007), and elevated CAR (hazard ratio [HR] 2.40, 95% confidence interval [CI] 1.55-3.73; p < 0.001) were independent and significant predictors of cancer recurrence, while sex (p = 0.05), HBsAg positivity (p = 0.03), serum AFP level ≥20 ng/mL (p = 0.009), multiple tumors (p = 0.03), microvascular invasion (p = 0.006), and elevated CAR (HR 2.10, 95% CI 1.13-3.91; p = 0.02) were independent predictors of overall survival., Conclusions: Sustained elevated CAR may be an independent and significant indicator of poor long-term outcomes in patients with HCC after hepatic resection, suggesting the interplay of the host's inflammatory state and tumor recurrence and progression in HCC., (© 2022. Society of Surgical Oncology.)

Background: Cancer cachexia has been associated with unfavorable outcomes in several malignancies. The cachexia index (CXI), which consists of skeletal muscle, inflammation, and nutritional status, has been proposed as a novel biomarker of cachexia. Therefore, we here investigated prognostic value of the CXI in patients with hepatocellular carcinoma (HCC) after hepatic resection., Methods: The study comprised 213 patients who had undergone primary hepatic resection for HCC between 2008 and 2018. First, the skeletal muscle index (SMI) was calculated as the area of the psoas muscle at the third lumbar vertebra/(the height) 2 . The CXI was then calculated by the following formula: SMI x serum albumin level/neutrophil-to-lymphocyte ratio (NLR). We retrospectively investigated the relationship between the CXI and disease-free survival as well as overall survival., Results: In multivariate analyses, female (p < 0.01), hepatitis B surface antigen-positivity (p < 0.01), preoperative serum alpha-fetoprotein level ≥20 ng/mL (p = 0.01), preoperative serum protein induced by vitamin K absence or antagonist-II level ≥200 mAU/mL (p = 0.02), multiple tumors (p < 0.01), macrovascular invasion (p = 0.04), type of resection (p < 0.01), and low CXI (p = 0.03) were significant predictors of disease-free survival, while Child-Pugh grade B (p < 0.01), poor tumor differentiation (p = 0.05), multiple tumors (p = 0.01), macrovascular invasion (p = 0.04), NLR (p = 0.04), and low CXI (p < 0.01) were significant predictors of overall survival. In the subgroup analysis of advanced T stage, the CXI was associated with both disease-free (p < 0.01) and overall survival (p = 0.06)., Conclusions: The CXI can be a prognostic indicator in patients with HCC after hepatic resection, suggesting the importance of comprehensive biomarker which includes skeletal muscle, inflammation, and nutritional status., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background/aim: Although laparoscopic hepatectomy has been widely used in the management of liver tumors for its reduced invasiveness and magnified view, in the caudate lobe it remains challenging especially for patients with cirrhosis. Thus, this study aimed to evaluate patients undergoing laparoscopic hepatectomy for hepatic tumors in the caudate lobe and establish strategies for performing such procedure., Patients and Methods: Laparoscopic hepatectomy in the caudate lobe was performed in nine patients. We performed inflow control to reduce bleeding during hepatic transection and retraction of the left lateral section to the cranial side to obtain a sufficient surgical field using a Nathanson liver retractor. We approached tumors in the Spiegel lobe (SP) from caudal side for segment 1 (S1) partial hepatectomy and from caudal and left side for Spiegel lobectomy, the lower paracaval portion (PC) from caudal side for S1 partial hepatectomy, and the upper PC from caudal and bilateral side for total caudate lobectomy., Results: In 6 cases the tumors were in the SP and in 3 cases in the PC. The types of laparoscopic hepatectomy performed were total caudate lobectomy (n=1), Spiegel lobectomy (n=2), and partial hepatectomy of segment 1 (n=6). All the tumors were curatively resected, and no patient had complications. Operative time for tumors located in the PC was significantly longer than that for tumors located in the SP. Laparoscopic hepatectomy in the caudate lobe was safely performed for five patients with liver cirrhosis., Conclusion: Laparoscopic hepatectomy in the caudate lobe may become the standard surgical technique with hepatic inflow control, sufficient surgical field exposure, and appropriate approach., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Hepatectomy is currently recommended as the most reliable treatment for hepatocellular carcinoma. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial., Methods: Three-hundred thirty-nine patients who underwent hepatectomy were retrospectively analyzed using a propensity score matching analysis for the risk factors and outcomes for early recurrences within 6 months. The remnant liver volumes and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after surgery. The Student's t test and chi-square test, the likelihood-ratio test, Fisher's exact test, Mann-Whitney U test, or Wilcoxon signed-rank test were used in the statistical analyses., Results: Early recurrence developed in 41/312 patients (13.1%). Vascular invasion and non-curative resection were independent risk factors for the occurrence of early recurrence (P < 0.001 and < 0.001, respectively). Patients with early recurrence had a poorer prognosis than patients who developed later recurrences (P < 0.001). Patients who underwent surgery or other local treatments had better outcomes (P < 0.001). The changes in remnant liver volumes and laboratory data after postoperative month 2 were not significantly different between the two groups., Conclusion: Patients with early recurrence within 6 months had a poorer prognosis than patients who developed a later recurrence. However, patients who underwent repeat hepatectomy for recurrences had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Resection of huge hepatocellular carcinomas occupying the central portion of the liver is challenging. Exposure of an adequate liver transection plane using an anterior approach is likely to be difficult because of compression by the tumor. We herein propose a "triple liver hanging maneuver" technique for central bisectionectomy with caudate lobectomy for huge hepatocellular carcinomas stretching the hilar plate and the right and left hepatic veins. In this technique, the first tape is introduced for the transection plane along the right side of the umbilical portion to the anterior surface of the inferior vena cava. The second tape is introduced to lift the paracaval caudate Glissonean pedicles from the hilar plate. The third tape is introduced for the transection plane along the right hepatic vein to the anterior surface of the inferior vena cava. The triple liver hanging maneuver could be effective for huge tumors compressing major hepatic vessels., (© 2021. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Activation of diacylglycerol kinase alpha (DGKα) augments proliferation and suppresses apoptosis of cancer cells and induces T lymphocyte anergy. We investigated the dual effects of DGKα inhibition on tumorigenesis and anti-tumor immunity with the aim of establishing a novel therapeutic strategy for cancer. We examined the effects of a DGKα inhibitor (DGKAI) on liver cancer cell proliferation and cytokine production by immune cells in vitro and on tumorigenesis and host immunity in a hepatocellular carcinoma (HCC) mouse model. Oral DGKAI significantly suppressed tumor growth and prolonged survival in model mice. Tumor infiltration of T cells and dendritic cells was also enhanced in mice treated with DGKAI, and the production of cytokines and cytotoxic molecules by CD4 + and CD8 + T cells was increased. Depletion of CD8 + T cells reduced the effect of DGKAI. Furthermore, interferon-γ stimulation augmented the expression of programmed cell death-1 ligand (PD-L1) on cancer cells, and DGKAI plus an anti-PD-L1 antibody strongly suppressed the tumor growth. These results suggest that DGKα inhibition may be a promising new treatment strategy for HCC., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Liver fibrosis influences liver regeneration and surgical outcomes. The fibrosis-4 (FIB-4) index is strongly associated with liver fibrosis and cirrhosis. This study aimed to examine the prognostic significance of the combination of FIB-4 index and Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) (PIVKA-II-FIB-4 index score) in patients who underwent curative resection for hepatocellular carcinoma (HCC)., Methods: We included 284 patients who underwent elective hepatic resection for HCC between January 2000 and December 2018. We retrospectively investigated how FIB-4 index is related to disease-free survival and overall survival., Results: According to a receiver operating characteristic (ROC) analysis, the optimal cutoff value of the FIB-4 index was 3.44. In a multivariate analysis, high PIVKA-II and FIB-4 index values were independent predictors of both disease-free survival (P = 0.013 and P = 0.005, respectively) and overall survival (P = 0.048 and P < 0.001, respectively). We classified the PIVKA-II and FIB-4 index levels into two groups (high vs. low) and calculated a new score (PIVKA-II-FIB-4 index score; 0-2) by the sum of each measurement (high, 1; low, 0). The 5 year overall survival rates of patients with PIVKA-II-FIB-4 index scores of 0, 1, and 2 were 84.9, 74.4, and 47.1%, respectively (P < 0.001)., Conclusion: The combination of the preoperative PIVKA-II and FIB-4 index may be a prognostic factor of HCC after hepatic resection, suggesting that the combined score is useful in assessing the liver fibrosis status in cancer cases., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Nutritional status assessment is essential in cancer patients because a poor nutritional status has been associated with poor outcomes; however, the impact of rapid turnover proteins (RTPs), such as prealbumin, transferrin, and retinol-binding protein, on the outcomes of hepatocellular carcinoma (HCC) has not been well-investigated. We therefore examined the prognostic significance of RTPs in patients with HCC after curative resection., Methods: This study included 150 patients who underwent elective hepatic resection for HCC between January 2011 and December 2018. The prealbumin, transferrin, and retinol-binding protein levels were classified into two groups (high vs. low); the RTP score (0-3) was calculated as the sum of each RTP measurement (high = 0; low = 1). We retrospectively investigated the relationship between the RTP score and disease-free and overall survival., Results: Multivariate analysis showed that a high RTP score (P = 0.022), presence of sarcopenia (P = 0.001), and stage III or higher (P = 0.005) were independent predictors of disease-free survival, while a high RTP score (P < 0.001), presence of sarcopenia (P = 0.017), and stage III or higher (P = 0.012) were independent predictors of overall survival. In patients with high RTP scores, positive hepatitis B and C viral infection, high indocyanine green (ICG) at 15 min (ICG R15 ), Child-Pugh grade B, poorly differentiated carcinoma, and postoperative ascites were more common than in patients with low RTP scores., Conclusion: The preoperative RTP score may be a prognostic factor in patients with hepatocellular carcinoma after hepatic resection, suggesting an important role of RTP in the assessment of nutritional status in cancer patients., (© 2021. Society of Surgical Oncology.)

Background: Simultaneous dual hepatic vein embolization (DHVE) has been proposed for safe right-side massive hepatectomy, (Kobayashi et al. in Surgery 167:917-923, 2020, Heil J, Schadde E. in Langenbecks Arch Surg 2020, Narita et al. in Ann Surg 256:e7-8, 2012) and has demonstrated comparable results to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) (Chan et al. in Transl Gastroenterol Hepatol 5:37, 2020) in terms of liver hypertrophy. In this video, we describe our DHVE techniques to perform a safe right trisectionectomy., Methods: A 40-year-old man with unresectable intrahepatic cholangiocarcinoma with multiple intrahepatic metastases and vena cava invasion received 20 cycles of gemcitabine plus cisplatin, resulting in remarkable shrinkage of the tumor. Conversion surgery was planned to achieve no evidence of disease status. The future liver remnant (FLR) after right trisectionectomy was 363 ml (29.6% of the whole liver) and simultaneous DHVE was performed. The right portal vein embolization was performed via a transhepatic approach, while the right and middle hepatic veins were accessed via a transjugular approach and self-expandable mesh devices were deployed. Remarkable atrophy of the right lobe and hypertrophy of the left lobe was observed 2 weeks after the procedure. Volumetry showed the FLR increased to 485 ml (40.2% of the whole liver). Three weeks after DHVE, right trisectionectomy with combined resection of the vena cava was performed., Results: The operation time was 311 min, and the blood loss was 420 ml. Pathological examination revealed complete resection of liver tumors, and the volumetry on postoperative day 7 revealed an increased remnant liver volume of 874 ml. He was discharged on postoperative day 10 without any complications., Conclusion: Simultaneous DHVE could be an effective procedure to increase FLR with safety for massive hepatectomy., (© 2021. Society of Surgical Oncology.)

Background: The superiority of outcomes associated with anatomical resection (AR) versus those associated with non-anatomical resection (NAR) remains controversial in patients with hepatocellular carcinoma (HCC). The aim of this study was to evaluate the significance of AR on therapeutic outcomes of patients with small HCCs (≤ 5 cm), using propensity score-matched (PSM) analysis., Methods: A total of 195 patients who had undergone elective hepatic resection for small HCCs (≤ 5 cm) were included in this study. We conducted PSM analysis for baseline characteristics (age, sex, hepatitis virus status, retention rate of indocyanine green at 15 min, and Child-Pugh grade), preoperative serum α-fetoprotein, and tumor characteristics (tumor size, tumor number, portal vein invasion, and surgical margin status) to eliminate potential selection bias. The prognostic significance of AR on the disease-free and overall survival was analyzed in patients selected by PSM analysis., Results: Applying PSM analysis, the patients were divided into PSM-AR (N = 66) and PSM-NAR (N = 66) groups. Disease-free survival was significantly better in the PSM-AR group than that of the PSM-NAR group (P = 0.018), while there was no significant difference in the overall survival between the PSM-AR and PSM-NAR groups (P = 0.292). The univariate HRs of the PSM-AR group were 0.55 (95% CI, 0.33-0.90) for disease-free survival and 0.61 (95% CI, 0.24-1.53) for overall survival, respectively. Remnant liver recurrence was significantly lower in the AR group (P = 0.014)., Conclusions: AR may improve the disease-free survival in HCC patients with tumors of ≤5 cm diameter., (© 2021. The Society for Surgery of the Alimentary Tract.)

A hepatic cone-unit represents an anatomical unit dominated by a smaller Glissonean pedicle. Anatomical resection of a tumor located in an intersegmental plane is challenging, but could be achieved effectively by performing multiple cone-unit resection. We performed double cone-unit laparoscopic resection of hepatocellular carcinoma located on the intersegmental plane between segments 6a, b. The liver parenchyma covering the posterior Glissonean pedicle was divided along Rouviere's sulcus, the Glissonean branches of segments 6a, b were isolated and ligated, and indocyanine green (ICG) negative counterstaining was performed. The hepatic parenchyma was dissected along the demarcation line to identify the right hepatic vein and the double cone-unit resection was then completed with a negative surgical margin. Thus, double cone-unit laparoscopic hepatectomy with ICG negative counterstaining may be a feasible option for tumors located in an intersegmental plane., (© 2021. Springer Nature Singapore Pte Ltd.)

It has been known that repeat laparoscopic hepatectomy (RLH) after open hepatectomy is technically challenging because of adhesions around the hilum. It is quite often that conventional tourniquet technique for the Pringle maneuver is difficult in RLH, and we introduced Laparoscopic Satinsky Vascular Clamp (LSVC) for inflow control in RLH. The Spiegel lobe is the anatomical landmark in LSVC technique. If a space behind the hepatoduodenal ligament and the Spiegel lobe was obtained, LSVC was applied laterally from the left side of the hepatoduodenal ligament, whereas LSVC was vertically applied for those with obstruction of a space behind the hepatoduodenal ligament. We performed 14 cases of RLH for those with histories of open hepatectomies by lateral (n = 6) and vertical (n = 8) LSVC technique with successful inflow control, confirmed by intraoperative Doppler ultrasound. Five patients underwent 2 or more previous histories of hepatectomies. The RLH included segmentectomy (n = 1), subsegmentectomy (n = 2) and partial hepatectomy (n = 11). The median time for the Pringle maneuver, operative time, and blood loss was 47 min, 237.5 min, and 160 mL. All the patients completed pure laparoscopic hepatectomy. In conclusion, LSVC technique is a safe and reliable technique for the Pringle maneuver in RLH., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The aim of this study is to investigate the relationship between preoperative serum transferrin level and long-term outcomes in patients with colorectal liver metastases after hepatic resection., Methods: We retrospectively investigated 72 patients who underwent hepatic resection for colorectal liver metastases and explored the relationship between serum transferrin level and long-term outcomes., Results: In multivariate analysis, H3 (odds ratio 3.43, 95% confidence interval 1.11-10.89 and P = 0.03) was an independent and significant predictor of the disease-free survival, and a transferrin level ≥ 190 mg/dl (odds ratio 0.20, 95% confidence interval 0.05-0.79 and P = 0.02) and the time to recurrence after hepatectomy <1 year (odds ratio 11.30, 95% confidence interval 2.63-48.59 and P < 0.01) were independent and significant predictors of the overall survival., Conclusions: The serum transferrin level is a useful predictor of poor overall survival in patients with colorectal liver metastases after hepatic reaction., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The aim of this retrospective study was to evaluate a revised classification system for predicting the difficulty of laparoscopic partial liver resection., Methods: Patients who had undergone initial laparoscopic partial liver resection for a solitary lesion from January 2012 to February 2021were classified into two groups according to the type of procedure performed, "scooping-out" versus "cutting." The participants were then further divided into "small" and "large" subgroups according to the tumor's depth and diameter. Finally, they were categorized into two groups, namely "standard" and "advanced." Operative outcomes were compared between the two groups and the proposed revised system for classifying difficulty of laparoscopic partial liver resection compared with the existing scoring system., Results: Of the 65 procedures assessed, 40 were categorized as standard and 25 as advanced. Tumor size (P < 0.001), operation time (P < 0.001), volume of intraoperative blood loss (P = 0.001), rate of the Pringle maneuver (P = 0.044), and resected liver weight (P < 0.001) were significantly greater in the advanced than in the standard group. Differences in operation time and intraoperative blood loss were not identified by the existing difficulty scoring system., Conclusion: The proposed revised classification is useful for predicting the difficulty of laparoscopic partial liver resection., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Laparoscopic liver resection (LLR) in obese patients has been reported to be particularly challenging owing to technical difficulties and various comorbidities., Methods: The safety and efficacy outcomes in 314 patients who underwent laparoscopic or open nonanatomical liver resection for colorectal liver metastases (CRLM) were analyzed retrospectively with respect to the patients' body mass index (BMI) and visceral fat area (VFA)., Results: Two hundred and four patients underwent LLR, and 110 patients underwent open liver resection (OLR). The rate of conversion from LLR to OLR was 4.4%, with no significant difference between the BMI and VFA groups ( P = .647 and .136, respectively). In addition, there were no significant differences in terms of operative time and estimated blood loss in LLR ( P = .226 and .368; .772 and .489, respectively). The incidence of Clavien-Dindo grade IIIa or higher complications was not significantly different between the BMI and VFA groups of LLR ( P = .877 and .726, respectively). In obese patients, the operative time and estimated blood loss were significantly shorter and lower, respectively, in LLR than in OLR ( P = .003 and < .001; < .001 and < .001, respectively). There was a significant difference in the incidence of postoperative complications, organ/space surgical site infections, and postoperative bile leakage between the LLR and OLR groups ( P = .017, < .001, and < .001, respectively)., Conclusion: LLR for obese patients with CRLM can be performed safely using various surgical devices with no major difference in outcomes compared to those in nonobese patients. Moreover, LLR has better safety outcomes than OLR in obese patients.

Background: Although indications of laparoscopic hepatectomy have been expanded, the laparoscopic approach after right hepatic lobectomy has a very high burden. The purpose of this study was to evaluate patients undergoing laparoscopic repeat hepatectomy for recurrent hepatic tumors after open right lobectomy., Patients and Methods: Five cases of laparoscopic repeat hepatectomy for recurrent hepatic tumors after open right lobectomy were included in the study., Results: All the tumors in segment 3 were intraoperatively detected and curatively resected by partial hepatectomy. The tumors in segment 2 could not be detected intraoperatively due to hypertrophic liver deformity and adhesion. They were curatively resected by anatomical subsegmental approach., Conclusion: For recurrent tumors located in segment 2 after right lobectomy, anatomical subsegmental approach should be preferred, not only from an oncological standpoint, but also for securing curative laparoscopic resection and overcoming anatomical difficulties., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Liver metastasis is a common problem after pancreatectomy for pancreatic cancer. In pancreatic cancer cells, nuclear factor-κB is activated constitutively. Nuclear factor-κB activates matrix metalloproteinase-2/9, which plays an important role in cancer metastasis. Because the serine protease inhibitor FUT-175 suppresses nuclear factor-κB, we hypothesized that perioperative treatment with FUT-175 for pancreatic cancer may help to prevent liver metastasis., Methods: We compared in vitro cell viability, cell invasiveness, nuclear factor-κB signaling, and the expression levels of matrix metalloproteinase signals between the control group (C group) and the FUT-175 group (F group) using the murine pancreatic cancer cells PAN02. In addition, we evaluated the in vivo effect of pretreatment with FUT-175 using an established model of liver metastasis in mice. Metastatic liver lesions were assessed with magnetic resonance imaging. Liver recurrence and overall survival were evaluated. Also, the antimetastatic effect of systemic administration of FUT-175 was examined., Results: FUT-175 did not suppress the cell viability of PAN02 cells at or after 24 hours of treatment (P > .05); however, cell invasion was suppressed in the F group compared with the C group (P < .05). The levels of nuclear factor-κB activation, membrane type-1 (MT-1) matrix metalloproteinase (MMP)/matrix metalloproteinase-14 (MMP-14), and matrix metalloproteinase-2/9 (MMP-2/9) were lower in the F group compared with the C group. In vivo, both disease-free and overall survivals were prolonged in the F group compared with the C group. Systemic administration was also effective in suppressing the number of metastases., Conclusion: Perioperative treatment with FUT-175 may help to prevent early liver metastasis after pancreatectomy for pancreatic cancer., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aim: We aimed to assess surgical outcome and long-term survival after elective hepatic resection for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in patients aged 80 years or older., Patients and Methods: This study included 100 patients aged 70 years or older, who underwent hepatic resection for HCC or CRLM between January 2000 and December 2012. Outcomes and clinicopathological data were compared between the elderly (aged 70-79 years; n=84) and extremely elderly groups (aged 80 years or older; n=16)., Results: Incidence of postoperative complications, in-hospital mortality, and postoperative OS in the extremely elderly group were comparable with those of the elderly group. In patients with HCC, the extremely elderly group was associated with shorter DFS (p=0.030) in univariate analysis, while multivariate analysis showed significant and independent factors of cancer recurrence., Conclusion: Hepatic resection for HCC and CRLM in patients aged 80 years and older may be safe and acceptable with appropriate selection. For HCC in patients aged 80 years and older, hepatic resection may be effective when negative surgical margins can be achieved., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Liver function in patients with hepatocellular carcinoma is generally graded according to the Child-Pugh system; however, some variables in the Child-Pugh grade are subjective. We developed a novel, objective score called the prothrombin time-international normalized ratio to albumin ratio. The aim of this study was to evaluate the prognostic value of this new score in patients with hepatocellular carcinoma after hepatic resection., Methods: The study comprised 199 patients who underwent elective hepatic resection for hepatocellular carcinoma between January 2003 and December 2014. We investigated retrospectively the relation between prothrombin time-international normalized ratio to albumin ratio, disease-free survival, and overall survival and compared the value of liver functional reserve between prothrombin time-international normalized ratio to albumin ratio and Child-Pugh grade., Results: The optimal cut-off level of the prothrombin time-international normalized ratio to albumin ratio was 0.288. In multivariate analysis, the independent and significant predictors of cancer recurrence consisted of hepatitis C virus infection (P = .043), preoperative retention rate of indocyanine green at 15 minutes ≥15% (P = .039), the presence of multiple tumors (P = .001) or microvascular invasion (P < .001), and prothrombin time-international normalized ratio to albumin ratio ≥0.288 (P = .022). The independent predictors of poor overall survival were microvascular invasion (P = .001) and prothrombin time-international normalized ratio to albumin ratio ≥0.288 (P = .001). In patients with a high prothrombin time-international normalized ratio to albumin ratio, pathologic liver cirrhosis (P < .001), postoperative ascites (P = .039), and postoperative liver failure (P = .040) were greater than for their counterparts., Conclusion: The prothrombin time-international normalized ratio to albumin ratio may reflect liver function and may be a novel indicator of poor long-term outcome in patients with hepatocellular carcinoma after hepatic resection., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The Barcelona Clinic Liver Cancer (BCLC) classification is the most widely used staging system for hepatocellular carcinoma (HCC), but its prognostic ability in patients after resection has not been yet validated. The aim of this study was to evaluate the BCLC classification among patients after resection., Methods: The subjects were 196 patients who underwent hepatic resection for HCC between April 2003 and December 2014 at Jikei University Hospital. All patients were classified into a tumor stage according to the BCLC classification. Overall survival rate was calculated according to stages defined by the BCLC classification., Results: Overall survival rates at 1, 3 and 5-year were 100%, 95.2% and 95.2% in BCLC 0, 96.7%, 90.0% and 78.4% in BCLC A solitary, 86.2%, 86.2% and 86.2% in BCLC A multiple, 100.0%, 78.8% and 78.8% in BCLC B and 86.5%, 63.3% and 57.6% in BCLC C, respectively. Postoperative complications and mortality rates in relation to BCLC stage were comparable., Conclusion: The BCLC treatment algorithm should consider the role of resection also for multiple early, intermediate and advanced stages., (© 2017 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

A 6 1-year-old man with unresectable multiple hepatic metastases after resection of sigmoid colon carcinoma was treated with irinotecan and infused 5-fluorouracil (5-FU) plus Leucovorin (FOLFIRI). Since the levels of tumor markers increased, the 5-FU dose was increased from 2,700 to 3,000 mg/m2 using a Jackson-type pump and an extended infusion time of 53 hours. The blood level of 5-FU was 507 ng/mL 16 hours after starting the infusion. The pump was then changed to a bottle-type pump with the same dose of 3,000 mg/m2. At 16 hours, the 5-FU level was 964.5 ng/mL. The areas under the concentration vs. time curve (AUC mg・h/L)were 21 and 44 mg・h/L for the Jackson- and bottle-type pumps, respectively. Owing to the development of Grade 3 stomatitis and hand-foot syndrome, 5-FU was reduced to 2,700 mg/m2 with a bottle-type pump. The AUC decreased to 27 mg・h/L, but the liver metastases were reduced and the adverse effects subsided to Grade 1. This case shows that individual dose adjustment of 5-FU to the appropriate AUC based on pharmacokinetic monitoring of the blood 5-FU level can improve the response, reduce adverse effects, and have a clinical benefit.

Background & Aims: The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated., Methods: We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines., Results: In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p=0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence (p=0.008). We confirmed that ULBP1 was expressed in the well- and mod-HCC cell lines, but not in the poor-HCC cell line KYN-2. However, inhibition of proteasome activity resulted in significant up-regulation of ULBP1 expression in KYN-2. Moreover, we found that 20S proteasome expression was more abundant in KYN-2 than that in the well- and mod-HCC cell lines., Conclusions: ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

In the present retrospective study, we tested the hypothesis that neoadjuvant chemotherapy (NAC) as a treatment for patients with colorectal carcinoma liver metastases (CRLM) may reduce intrahepatic micrometastases. The incidence and distribution of intrahepatic micrometastases were determined in specimens resected from 63 patients who underwent hepatectomy for CRLM (21 treated with NAC and 42 without). In addition, the therapeutic efficacy of NAC was evaluated histologically. Intrahepatic micrometastases were defined as microscopic lesions spatially separated from the gross tumor. The distance from these lesions to the border of the hepatic tumor was measured on histological specimens and the density of intrahepatic micrometastases (number of lesions/mm(2)) was determined in regions close to (<1 cm) the gross hepatic tumor. Of the 21 patients treated with NAC, 13 were identified as having a partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines; thus, the overall response rate was 62%. Histologic evaluation of the therapeutic efficacy of NAC was significantly associated with tumor response to NAC according to the RECIST guidelines (p=0.048). In all, 260 intrahepatic micrometastases were detected in 39 patients (62%). Intrahepatic micrometastases were less frequently detected in NAC-treated patients than in untreated patients (5/21 [24%] vs. 34/42 [81%], respectively; p<0.001). There were no significant differences in the distance and density of intrahepatic micrometastases between the two groups (p=0.313 and p=0.526, respectively). In conclusion, NAC reduces the incidence of intrahepatic micrometastases in patients with CRLM, but NAC has no significant effect on their distribution when intrahepatic micrometastases are present.

Background/aims: Liver-intestine cadherin (LI-cadherin) is a member of the cadherin superfamily and aberrant expression of LI-cadherin is associated with intestinal metaplasia. The aim of this study was to identify factors associated with LI-cadherin expression in biliary intraepithelial lesions of intrahepatic cholangiocarcinoma (ICC)., Methodology: We evaluated the immunoreactivity of LI-cadherin, MUC2, CDX2, MUC5AC and HGM, according to the grade of biliary intraepithelial lesion in 16 resected specimens of ICC without hepatolithiasis., Results: A total of 168 biliary intraepithelial lesions were classified into four grades: reactive change (42 lesions), biliary intraepithelial neoplasia (BilIN)-1 (10 lesions), BilIN-2 (40 lesions) and BilIN-3 (76 lesions). Biliary intraepithelial lesions were classified into three mucin phenotypes: null (46 lesions), gastric (97 lesions) and gastrointestinal phenotype (25 lesions). LI-cadherin expression was found in 45 (27%) of 168 biliary intraepithelial lesions. BilIN-2/3 (p<0.001), gastrointestinal phenotype (p=0.006) and CDX2 expression (p=0.002) were significantly associated with LI-cadherin expression. Logistic regression analysis revealed that BilIN-2/3 (p=0.002) was the only independently significant factor associated with LI-cadherin expression., Conclusions: The grade of BilIN independently correlates with LI-cadherin expression in biliary intraepithelial lesions of ICC without hepatolithiasis, whereas the mucin phenotype or CDX2 expression does not.

Background/aims: Ribonucleotide reductase M1 (RRM1) is a key molecule for gemcitabine resistance. This study evaluated the immunohistochemical expression of RRM1 in resected specimens of intrahepatic cholangiocarcinoma (ICC) and investigated the efficacy of gemcitabine-based neoadjuvant chemotherapy in relation to RRM1 expression in tumors., Methodology: A retrospective analysis was conducted on 34 consecutive Japanese patients who underwent resection of ICC. Of the 34 patients, 2 were treated with neoadjuvant chemotherapy consisting of gemcitabine 800mg/m2 every 2 weeks to address extrahepatic tumor extension. Expression of RRM1 in tumor specimens was assessed using immunohistochemistry and was classified as either positive or negative., Results: RRM1-positive expression was detected in 19/34 (56%) tumor specimens. Two patients were treated with gemcitabine-based neoadjuvant chemotherapy; one had a tumor specimen showing RRM1-positive expression and showed a 14% tumor reduction rate (stable disease); another patient had a tumor showing RRM1-negative expression and showed a 68% tumor reduction rate (partial response). Surgical procedures planned before administration of neoadjuvant chemotherapy were performed in both patients., Conclusions: Neoadjuvant chemotherapy with gemcitabine for locally advanced ICC was well tolerated and did not impair planned surgical resections. Tumor expression of RRM1 may determine the efficacy of gemcitabine-based chemotherapy for patients with ICC.

Background: The present study investigated outcomes following surgical resection of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease (NAFLD)., Methods: Patients (n = 225) undergoing resection for HCC were divided into three groups: hepatitis C viral group (n = 147), hepatitis B viral group (n = 61), and NAFLD group (n = 17). Clinicopathological characteristics and surgical outcomes were analyzed retrospectively., Results: Patients in the NAFLD group were older (P < 0.001), with a higher body mass index (P < 0.001) and larger tumors (P = 0.002) than patients who were positive for hepatitis viral markers. Eight patients in the NAFLD group were found to have nonalcoholic steatohepatitis (NASH) histologically. Postoperative morbidity and 30-day mortality rates were significantly higher in the NAFLD group (59% and 12%, respectively) than in the hepatitis C viral (31% and 0.7%, respectively) and hepatitis B viral (28% and 3.3%; P = 0.043 and P = 0.016, respectively) groups. All deaths in the NAFLD group were in patients with NASH-related cirrhosis who had undergone right hemihepatectomy. Survival after resection was comparable among the three groups (P = 0.391), but patients with NAFLD showed better disease-free survival on univariate (P = 0.048) and multivariate (P = 0.020) analyses., Conclusions: Surgical resection may provide a survival benefit for patients with NAFLD-related HCC. Patients with NASH-related cirrhosis undergoing major hepatic resection should be treated carefully.

Background/aims: This study aimed to evaluate the usefulness of immunohistochemical combinations for discrimination between intraepithelial ductal spread of colorectal carcinoma liver metastasis (CRLM) and that of intrahepatic cholangiocarcinoma (ICC)., Methodology: A retrospective analysis of resected specimens from 151 patients with CRLM and 28 patients with ICC was conducted. Intraepithelial ductal spread along the bile ducts was judged positive when tumor cells spreading along the intact basement membranes of intrahepatic bile ducts. We evaluated immunoreactivity of cytokeratin (CK) 7, CK20, CDX2, MUC2, MUC5AC and human gastric mucin (HGM)., Results: Of the 151 patients with CRLM, 21 had intrahepatic bile duct involvement verified histologically. Intraepithelial ductal spread was detected in 17 of 21 (81%) patients with CRLM with bile duct involvement, whereas it was detected in 22 of 28 (79%) patients with ICC. CK20-positive/ CK7-negative immunophenotype demonstrated a high accuracy of 95% for evaluation of intraepithelial ductal spread from CRLM. CK7-positive/ CK20-negative immunophenotype demonstrated the highest accuracy of 85% for evaluation of intraepithelial ductal spread from ICC., Conclusion: Intraepithelial ductal spread is a common feature of CRLM with bile duct involvement. Immunohistochemical combination of CK7 and CK20 is useful for discrimination between intraepithelial ductal spread of CRLM and that of ICC.

Aim: The aim of this study was to evaluate the clinical usefulness of measuring the Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) for prognostic predictor in patients with hepatocellular carcinoma (HCC)., Methods: A total of 477 HCC patients who underwent percutaneous ablative therapy or hepatectomy were enrolled. Overall survival and recurrence-free survival were respectively evaluated retrospectively and prospectively. Multivariate analyses of clinical prognostic factors were performed by Cox's stepwise proportional hazard model., Results: AFP-L3 status was a statistically significant independent prognostic factor of long-term survival (P = 0.013) and recurrence-free survival (P = 0.006) in patients who underwent percutaneous ablative therapy. In contrast, AFP-L3 did not affect prognosis in patients who underwent hepatectomy., Conclusions: AFP-L3 had different impacts on prognosis in patients with HCC who underwent percutaneous ablative therapy and hepatectomy. Our results suggest that AFP-L3 positivity (>or=15%) might be a promising indicator for choosing therapeutic modalities in HCC patients.

Background/aims: The current study sought to clarify whether intracapsular venous invasion and extratumoral venous invasion confer different prognostic significance in patients undergoing hepatectomy for hepatocellular carcinoma., Methodology: A retrospective study of 275 consecutive patients who underwent hepatectomy for hepatocellular carcinoma was conducted. Extratumoral venous invasion was defined as gross or microscopic involvement of vessels within the peritumoral liver tissue, whereas intracapsular venous invasion was defined as microscopic involvement of vessels within the fibrous tumor capsule. The median follow-up time was 64 months., Results: Vascular invasion was found in 104 (38%) of the 275 patients. Intracapsular venous invasion was present in 16 patients and extratumoral venous invasion observed in 88 patients. Overall cumulative survival rates were 64% at 5 years and 45% at 10 years. Vascular invasion was a strong prognostic factor by univariate (p = 0.0001) and multivariate (p = 0.006) analyses. Survival after hepatectomy was significantly worse in patients with extratumoral venous invasion (cumulative 10-year survival rate of 28%) than in patients with intracapsular venous invasion (cumulative 10-year survival rate of 70%; p = 0.0082)., Conclusions: Extratumoral venous invasion adversely influences survival after hepatectomy for hepatocellular carcinoma compared to intracapsular venous invasion.

We hypothesized that expression of multidrug resistance-associated protein 2 (MRP2), a major cisplatin transporter, may determine the efficacy of cisplatin as a treatment for patients with hepatocellular carcinoma (HCC). A prospective analysis was conducted of 49 consecutive patients who underwent resection for HCC (16 patients treated with cisplatin-based neoadjuvant chemotherapy and 33 patients treated without neoadjuvant chemotherapy). Expression of MRP2 in resected specimens was assessed by immunohistochemical and Western blot analyses. The extent of tumor necrosis was assessed histologically in the greatest dimension of the tumor specimen from each patient. The median percentage of tumor necrosis was 81% (range: 0-100%) and complete tumor necrosis was found in 3 patients. Overexpression of MRP2 was detected in 24/46 (52%) tumor specimens. In 16 patients treated with cisplatin, tumor size and dose of cisplatin did not correlate with tumor necrosis of the resected specimens (P=0.706 and P=0.555, respectively). Of 13 tumor specimens containing vivid tumor from 16 patients treated with cisplatin, 8 had overexpression of MRP2. Tumor specimens with overexpression of MRP2 showed a lower percentage of tumor necrosis than those with non-overexpression (median percentage of tumor necrosis, 19% vs. 99%, P=0.003). In conclusion, overexpression of MRP2 correlates with a lower percentage of tumor necrosis in patients treated with cisplatin-based neoadjuvant chemotherapy for HCC, whereas either tumor size or dose of cisplatin does not. Expression of MRP2 determines the efficacy of cisplatin-based chemotherapy in patients with HCC.

Background and Aim: Histological criteria for intracapsular venous invasion (IVI) that would allow its discrimination between portal and hepatic venous invasion in hepatocellular carcinoma (HCC) have not been established., Methods: We evaluated IVI immunohistochemically to discriminate between portal and hepatic venous invasion in 89 resected specimens from patients with HCC. IVI was defined as the microscopic involvement of the vessels within the fibrous capsule of HCC. The hepatic venous system was subdivided into the central vein and the sublobular/hepatic vein. Immunohistochemical analysis with the D2-40 monoclonal antibody revealed lymphatic vessels., Results: In non-neoplastic liver tissues, the portal veins (n = 4355) were accompanied by lymphatic vessels (99.7%), bile ductules (100%) and arteries (96%), whereas the central veins (n = 3932) and sublobular/hepatic veins (n = 662) were rarely accompanied by lymphatic vessels (0% and 17%, respectively) and bile ductules (12% and 33%, respectively). In total, 29 IVI foci were detected; three foci were clearly visible within vessels that contained a distinct layer of connective tissue fibers, signifying sublobular/hepatic venous invasion. As the remaining 26 foci were accompanied by lymphatic vessels (26/26 [100%]), bile ductules (21/26 [81%]) and arteries (10/26 [38%]), these foci were considered to reflect intracapsular portal venous invasion rather than venous invasion of the central vein. Intracapsular portal venous invasion was significantly associated with extratumoral portal venous invasion (P < 0.001)., Conclusions: D2-40 immunoreactivity for the histological evaluation of IVI in HCC allows discrimination between portal and hepatic venous invasion for cases in which portal venous invasion predominates.

This study aimed to clarify the mode of hepatic spread from gallbladder carcinoma and to elucidate its prognostic value. A retrospective analysis was conducted of 42 consecutive patients who underwent resection for gallbladder carcinoma with hepatic involvement verified histologically. The mode of hepatic spread was classified into 3 patterns: direct invasion through the gallbladder bed, portal tract invasion, and hepatic metastatic nodules. Intrahepatic lymphatic invasion was declared when either single tumor cells or cell clusters were clearly visible within vessels that showed immunoreactivity to the D2-40 monoclonal antibody. Seven, 24, and 11 patients had direct invasion alone, portal tract invasion with (22 patients) or without (2 patients) direct invasion, and hepatic metastatic nodules, respectively. Of the 24 patients with portal tract invasion, 14 had intrahepatic lymphatic invasion, 8 had neither intrahepatic lymphatic nor venous invasion, and 2 had both intrahepatic lymphatic and venous invasion. To date, 4 patients with direct invasion alone and 4 patients with portal tract invasion survived more than 5 years after resection, whereas all the patients with hepatic metastatic nodules died within 11 months after resection, irrespective of the type of hepatectomy. The mode of hepatic spread (P<0.001) was a strong independent prognostic factor. Direct liver invasion and portal tract invasion, which features intrahepatic lymphatic invasion, are the main modes of hepatic spread from resectable gallbladder carcinoma. The mode of hepatic spread independently predicts long-term survival after resection for patients with gallbladder carcinoma. Hepatic metastatic nodules indicate a dismal outcome after resection.

Information concerning the pulmonary toxicity of oxaliplatin with infusional 5-fluorouracil plus leucovorin (FOLFOX) is very limited. We herein report the case of a patient with FOLFOX-induced interstitial pneumonia. An 82-year-old man with unresectable colon cancer liver metastases was referred to our department for chemotherapy with the FOLFOX protocol. After the administration of ten cycles, he visited our outpatient clinic with a 2-week history of coughing and shortness of breath; he was afebrile. A chest radiograph showed reticular shadows with ground-glass opacities mainly involving the middle and lower zones of the right lung. Computed tomography depicted ground-glass opacities with superimposed reticulation in the right lung. A diagnosis of FOLFOX-induced interstitial pneumonia was made based on the clinical course and imaging findings. The symptoms disappeared within 3 days after the cessation of the FOLFOX regimen and the initiation of high-dose corticosteroid treatment. Two months after the initiation of the corticosteroid treatment, complete remission of the radiological abnormalities was confirmed; thereafter, interstitial pneumonia did not recur despite the reintroduction of 5-fluorouracil/leucovorin alone, suggesting that 5-fluorouracil/leucovorin alone was not responsible for the development of the interstitial pneumonia. Thus, oxaliplatin, alone or in combination with 5-fluorouracil/leucovorin, may have caused the interstitial pneumonia in this patient. Once interstitial pneumonia has occurred, cessation of the regimen is mandatory, and high-dose corticosteroid treatment is commonly given to rescue patients from this potentially lethal complication.

Purpose: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a member of the carcinoembryonic antigen family of immunoglobulin-like adhesion molecules. The aim of this study was to test the hypothesis that loss of CEACAM1 expression in hepatoblastoma cells may promote hematogeneous metastasis and function as an adverse prognostic factor., Methods: Immunohistochemical expression of CEACAM1 in surgically resected specimens from 19 patients with hepatoblastoma was examined retrospectively. The CEACAM1 expression in the epithelial area of the tumor was classified into 2 categories as follows: diffuse expression, characterized by positive staining throughout the tumor specimen, or loss of expression, in which there were distinct areas of negative staining within the tumor specimen., Results: Of the 19 patients, 12 were classified as having tumors with diffuse expression, and 7 had loss-of-expression tumors. Survival after treatment was significantly worse in patients with tumors with loss of CEACAM1 expression (cumulative 5-year survival rate, 29%) than in patients with diffuse CEACAM1 expression (cumulative 5-year survival rate, 92%; P = .0062). Loss of CEACAM1 expression was a significant risk factor for metachronous pulmonary metastases (P = .0105)., Conclusions: Loss of CEACAM1 expression may reflect a high metastatic potential and thus indicate a poor prognosis for patients with hepatoblastoma.

The aim of this study was to determine to what extent hypermethylation of the p16(INK4A) (p16) gene promoter is increased in nontumorous liver tissues compared with in normal liver, using two quantitative methylation-specific polymerase chain reaction (MS-PCR) methods and a bisulfite sequencing method. Methylation of the p16 gene was detected more frequently in nontumorous liver than in normal liver using the TaqMan PCR method. Methylation indices also were significantly higher in nontumorous than in normal liver. However, the bisulfite sequencing method did not detect significantly more methylation of the p16 gene in nontumorous than normal liver, nor was there a significant difference in the level of p16 mRNA. There may be a greater proportion of cells which contain methylated p16 in nontumorous than in normal liver. However, the difference was so small that the functional relevance to hepatocarcinogenesis remains elusive.

Serum levels of 5-fluorouracil(5-FU)were measured in a patient receiving pharmacokinetic modulation chemotherapy( PMC), with 5-FU, as well as a combination of oxaliplatin and infusional 5-FU plus leucovorin(FOLFOX). A 77- year-old man presented with unresectable multiple hepatic metastases after abdominoperineal resection of rectal / carcinoma, and was successfully treated by PMC. The patient initially received infusional 5-FU at 750 mg/m(2) once a week, and showed a partial response. Serum 5-FU levels were higher at night, and the peak concentration of 5-FU was / 398 ng/mL. After 13 months of PMC, second-line chemotherapy with FOLFOX was initiated because new liver metastases had appeared. After 4 cycles of FOLFOX4, progression was observed, and the concentration profile of 5-FU / was measured. The area under the concentration vs. time curve(AUC ngxh/mL)was smaller with FOLFOX4 than with PMC, so the FOLFOX6 regimen was tried instead. The AUC increased and disease progression was suppressed. This case shows that individual adjustment of the dose and regimen based on pharmacokinetic monitoring can increase the clinical benefit of fluorouracil.

Background/aims: This retrospective study aimed to define the role of hepatic lymph node dissection in the surgical management of patients with resectable colorectal carcinoma liver metastases., Methodology: Fourteen of the 130 consecutive patients who had hepatectomy for colorectal carcinoma liver metastases underwent concomitant hepatic lymph node dissection for nodal disease suspected during the operation. A total of 125 hepatic lymph nodes (median, 8 per patient) were examined histologically for metastases. The therapeutic value index of hepatic lymph node dissection was estimated by multiplying the incidence of hepatic lymph node metastasis by the 5-year survival rate of patients with hepatic lymph node metastasis. The median follow-up time was 98 months., Results: Mortality occurred within 30 days after resection in 1 patient. Hepatic lymph node metastases were detected in 7 patients, of whom 2 with no residual tumor survived for 10 years. The incidence and 5-year survival rate for patients with hepatic lymph node metastases were 50% and 29%, respectively. The therapeutic value index of hepatic lymph node dissection was 14.5., Conclusions: Hepatic lymph node dissection provides a survival benefit for some patients with hepatic nodal disease of resectable colorectal carcinoma liver metastases, provided that a potentially curative (R0) resection is feasible.