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Introduction: The phase III REFLECT trial demonstrated that lenvatinib was superior to sorafenib in terms of progression-free survival (PFS), time to progression, and objective response rate (ORR) for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of preoperative lenvatinib therapy for patients with oncologically or technically unresectable HCC., Methods: In this multicenter single-arm phase II trial, patients with advanced HCC and factors suggestive of a poor prognosis (macroscopic vascular invasion, extrahepatic metastasis, or multinodular tumors) were enrolled. Patients with these factors, even with technically resectable HCC, were defined as oncologically unresectable because of the expected poor prognosis after surgery. After 8 weeks of lenvatinib therapy, the patients were assessed for resectability, and tumor resection was performed if the tumor was considered technically resectable. The primary endpoint was the surgical resection rate. The secondary endpoints were the macroscopic curative resection rate, overall survival (OS), ORR, PFS, and the change in the indocyanine green retention rate at 15 min as measured before and after lenvatinib therapy. The trial was registered with the Japan Registry of Clinical Trials (s031190057)., Results: Between July 2019 and January 2021, 49 patients (42 oncologically unresectable patients and 7 technically unresectable patients) from 11 centers were enrolled. The ORR was 37.5% based on mRECIST and 12.5% based on RECIST version 1.1. Thirty-three patients underwent surgery (surgical resection rate: 67.3%) without perioperative mortality. The surgical resection rate was 76.2% for oncologically unresectable patients and 14.3% for technically unresectable patients. The 1-year OS rate and median PFS were 75.9% and 7.2 months, respectively, with a median follow-up period of 9.3 months., Conclusions: The relatively high surgical resection rate seen in this study suggests the safety and feasibility of lenvatinib therapy followed by surgical resection for patients with oncologically or technically unresectable HCC., Competing Interests: E.H. reports honoraria from Eisai, Chugai Pharmaceutical, Bayer, Eli Lilly, and Takeda Pharmaceutical. J.S. reports honoraria from Eisai and Chugai Pharmaceutical. K.H. reports honoraria and grants from Eisai, Chugai Pharmaceutical, Bayer, Eli Lilly, and Takeda Pharmaceutical, and research funding from Chugai Pharmaceutical., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: The aim of this study was to evaluate the clinical impact of a combination of systemic sequential therapy and locoregional therapy on the long-term survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC)., Methods: Sixty-four consecutive patients with intrahepatic target nodules who had initially received systemic therapy (lenvatinib and atezolizumab plus bevacizumab) were reviewed. The clinical impact of the combined use of systemic sequential therapy and locoregional therapy was evaluated by determining overall survival (OS). The combined use of systemic sequential therapy with more than two agents and locoregional treatment was defined as multidisciplinary combination therapy (MCT), while only systemic sequential therapy and repeated locoregional-treatment was defined as a single treatment procedure (STP)., Results: R0 resection, MCT, and STP resulted in significantly better OS compared with no additional treatment (median OS, not reached vs. 18.2 months and 12.6 vs. 8.1 months, respectively; p = 0.002). Multivariate analysis confirmed that the use of R0 resection and MCT were associated with better OS (hazard ratio [HR]; 0.053, p = 0.006 and 0.189, p < 0.001, respectively) compared with that for STP (HR; 0.279, p = 0.003)., Conclusions: MCT is may effective in patients with BCLC stage C HCC and intrahepatic target nodules who have previously received systemic therapy-based treatment.

Background: Pancreatic head resection following proximal gastrectomy jeopardizes the blood flow of the remnant stomach owing to right gastroepiploic conduit sacrifice, thereby necessitating total gastrectomy. However, owing to its high invasiveness, concomitant remnant total gastrectomy with pancreatectomy should be avoided as much as possible. Herein, we describe our experience of total pancreatectomy with right gastroepiploic conduit preservation in a patient with a history of proximal gastrectomy and reconstruction by jejunum interposition., Case Presentation: A 78-year-old woman with a history of gastric cancer was followed up at our institute for multiple intraductal papillary mucinous neoplasm, and main pancreatic duct stricture in the pancreatic head was newly detected. The cystic lesion was extended to the pancreatic body. Proximal gastrectomy and reconstruction by jejunal interposition were previously performed, and the mesenteric stalk of the interposed jejunum was approached through the retrocolic route. We planned total pancreatectomy with right gastroepiploic conduit preservation. Following adhesiolysis, the interposed jejunum and its mesentery lying in front of the pancreas were isolated. The arterial arcade from the common hepatic artery to the right gastroepiploic artery was detached from the pancreas. Furthermore, the right gastroepiploic vein was isolated from the pancreas. The pancreatic body and tail were pulled up in front of the remnant stomach, and the splenic artery and vein were resected. The pancreatic body and tail were pulled out to the right side, and the pancreatic head was divided from the pancreatic nerve plexus to the portal vein. The jejunal limb for entero-biliary anastomosis was passed through the hole behind the superior mesenteric artery and vein, and gastrointestinal anastomosis using the antecolic route and Braun anastomosis were performed., Conclusions: To avoid remnant total gastrectomy, right gastroepiploic conduit preservation is an optional procedure for pancreatic head resection in patients who have undergone proximal gastrectomy with reconstruction by jejunal interposition., (© 2023. The Author(s).)

Background: Rectal neuroendocrine neoplasms can induce liver metastasis. However, few reports exist on the associated long-term recurrence rates. We report a case of liver metastasis identified 15 years after rectal neuroendocrine neoplasm resection., Case Presentation: A 50-year-old woman was on semi-annual follow-up after undergoing mastectomy for breast cancer (pT1N0M0) and low anterior resection for grade 1 rectal neuroendocrine neoplasm (pT1b, ly1, v1). Fifteen years postoperatively, a 7-mm hyperechoic mass was identified at liver segment 6. Magnetic resonance imaging revealed a slight growth of the mass. Positron emission tomography/computed tomography revealed radiotracer accumulation in the lesion. Laparoscopic hepatectomy was performed. The histopathological diagnosis was grade 2 neuroendocrine neoplasm. The pathological findings and clinical course indicated the tumor originated in the rectum., Conclusions: Our findings highlight the need to reassess the optimal postoperative follow-up period for patients with rectal neuroendocrine neoplasm., (© 2022. The Author(s).)

Background: Patients with esophageal cancer often feel depressed and are fearful of metastasis and death. Esophagectomy is an invasive procedure with a high incidence of complications. The objective of this study was to examine the association between psychological distress on each points of the treatment of esophageal cancer and stress coping strategy., Methods: In total, 102 of 152 consecutive patients who attended the outpatient clinic at Toranomon Hospital between April 2017 and April 2019 met the eligibility criteria for inclusion in this study. Questionnaires designed to identify psychological distress and stress coping strategies were longitudinally administered at 5 time points from the time of the first outpatient consultation to 3 months after esophagectomy., Results: Although 'fighting spirit' (OR 0.836, 95% CI 0.762-0.918; p < 0.001) and 'anxious preoccupation' (OR 1.482, 95% CI 1.256-1.748; p < 0.001) were strongly related to psychological distress before treatment, as time of treatment passes, 'helpless/hopeless' (OR 1.337, 95% CI 1.099-1.626; p = 0.004) was strongly related to psychological distress after esophagectomy. There were no relationships between psychological distress and individual patient characteristics, with the exception of 'history of surgery' and 'final staging'. The concordance index was 0.864 at time 1, 0.826 at time 2, 0.839 at time 3, 0.830 at time 4, and 0.840 at time 5., Conclusions: The relationship between psychological distress and the Coping strategies was stronger on each points of the treatment of esophageal cancer than that between psychological distress and individual patient characteristics. This study uses prospective basic clinical data and may provide the baseline information for risk stratification for psychological management and for future clinical studies in these patients., (© 2022. The Author(s).)

With recent advances in systemic therapy, an increasing number of patients with advanced hepatocellular carcinoma (HCC) are expected to benefit from surgery. However, given the complex background of the disease and frequent presence of underlying liver injury, treatment of advanced HCC is complex and the treatment principle applied to colorectal liver metastases, for which conversion surgery has been actively performed, is often not applicable to patients with HCC. To maximize the survival outcomes of patients with HCC, optimization of each step of treatment through a multidisciplinary approach is inevitable. As initial treatment, systematic removal of tumor-bearing portal territory is associated with improved survival in patients with solitary HCC, and radiofrequency ablation is also effective for small, oligo HCCs. Although the high incidence of recurrence even after curative-intent treatment is a major concern in HCC, aggressive treatment for recurrence is important, because a prolonged cancer-free interval is associated with improved overall survival. For patients with advanced disease, recently introduced molecular-targeted agents may be effective for successful conversion to surgery in initially unresectable cases, although the overall response rate of HCC to systemic therapies remains unsatisfactory as compared to that of colorectal liver metastases. This report revisits the theoretical bases for management of HCC and discusses current strategies for maximizing survival of patients with advanced HCC.

Objective The relationship between the prognosis and magnitude of a decrease in tumor blood flow according to estimated tumor differentiation remains unclear. This study investigated the relationship between reductions in the rate of mean computed tomography (CT) attenuation values and the clinical prognosis. Methods We evaluated 63 consecutive patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC). The oncological aggressiveness of the tumors was estimated using classification by dynamic CT enhancement patterns. The utility of changes in mean CT attenuation values of intra-hepatic targets during treatment to estimate the prognosis was investigated by calculating the progression-free survival (PFS) and post-progression survival (PPS). A multivariate analysis was used to identify potential confounders for the survival after progression during lenvatinib therapy. Results The rate of decrease in the mean CT attenuation value gradually increased according to the degree of deterioration in estimated tumor differentiation, and the rate of a decrease in attenuation ≥40% showed a tendency to increase (p=0.064). This trend was reflected by a better objective response in oncological aggressiveness heterogeneous enhancement patterns (Type-3 and Type-4) than a homogeneous enhancement pattern (Type-2) (83% vs. 56% of modified Response Evaluation Criteria in Solid Tumors). This resulted in a similar PFS between the groups (p=0.773), whereas the PPS was significantly worse when the rate of decrease in the attenuation value was ≥40% (p=0.012). A multivariate analysis confirmed that a rate of decease in attenuation value ≥40% was a poor prognostic factor for the PPS (hazard ratio, 2.993; 95% confidence interval, 1.196-7.490; p=0.019). Conclusion A rate of decrease in attenuation ≥40% may reflect a good response of a highly malignant tumor to lenvatinib. Therefore, this value may have utility as a surrogate marker for estimating the oncological aggressiveness of tumors and their associated prognosis.

Introduction and Importance: Indocyanine green (ICG) fluorescence angiography is being increasingly performed intraoperatively to detect restricted blood flow intraoperatively for the prevention of postoperative organ ischemia and anastomotic leakage. This is the first case report of simultaneous laparoscopic distal gastrectomy (LDG) and spleen-preserving distal pancreatectomy (LSPDP) involving ICG angiography use to avoid the remnant stomach ischemia., Case Presentation: A 55-year-old man was diagnosed with early cancer of the stomach body and intraductal papillary mucinous neoplasms of the pancreatic tail. We performed simultaneous LDG with D2 dissection and LSPDP to conserve the gastrosplenic ligament and preserve blood supply to the remnant stomach. Intraoperatively, blood flow to the remnant stomach was visualized using ICG fluorescence angiography, after which Roux-en-Y reconstruction was performed. There was no perioperative remnant stomach ischemia., Clinical Discussion: Despite the preserved splenic artery and vein, complete splenic infarction occurs after LSPDP possibly due to thrombus formation during surgical procedures. In this patient, we conserved the gastrosplenic ligament for the short gastric artery, which supplied blood to the remnant stomach; however, remnant stomach ischemia may occur. Therefore, we performed ICG fluorescence angiography during this operation to ensure that sufficient blood supply to the remnant stomach was maintained., Conclusion: Our experience demonstrates that ICG angiography may be useful for the prevention of remnant stomach ischemia., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: There has been no solid evidence regarding the actual efficacy of adhesion barriers in liver surgery., Methods: Difficulty grade of lysis of adhesion was evaluated in 122 patients who underwent repeat hepatectomy (ReHx) using the TORAD score. Technical difficulty of lysis of adhesion and incidence of complication were then compared between the group of patients who received a sheet-type adhesion barrier (Seprafilm®) in the previous hepatectomy (n = 70) and those who did not (n = 52) using the inverse probability weighting method., Results: Use of Seprafilm was significantly associated with lower grade of difficulty of lysis of adhesion according to the TORAD score (P < 0.001). Postoperative morbidity rate was lower and postoperative stay was shorter in the Seprafilm group in the propensity-score adjusted population (37% vs. 74%, P < 0.001 and 12 days vs. 14 days in median, P = 0.048). Multivariate analysis confirmed that use of Seprafilm was independent predictor for severity of adhesion (odds ratio [OR] 0.24, 95% CI, 0.09-0.65, P = 0.005) and decreased incidence of postoperative morbidity at ReHx (OR, 0.34; 95% CI, 0.14-0.84, P = 0.020)., Conclusions: Use of Seprafilm may be associated with decreased technical difficulty of lysis of adhesion and may correlate with lower risk of postoperative morbidity in patients undergoing ReHx., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Repeat hepatectomy has been recognized as an effective treatment for hepatic malignancies, and a sheet type adhesion barrier, Seprafilm® has increasingly been used during hepatectomy to ease future relaparotomy. However, there is not yet sufficient evidence to support the safety of use of Seprafilm in liver surgery., Methods: Data of 151 patients who had undergone open hepatectomy were retrospectively reviewed and the incidence of major abdominal morbidity was compared between patients in whom Seprafilm had and had not been used., Results: Seprafilm was used in 108 patients (Seprafilm group) and no adhesion barrier was used in 43 patients (comparison group). There was no significant difference in the rate of major abdominal morbidities between the two groups (Seprafilm vs. comparison: 10% vs. 16%, P = 0.403). Although the Seprafilm group showed a tendency toward increased incidence of bile leakage (7% vs. 2%), and placement of Seprafilm on the hepatoduodenal ligament or on the visceral surface of the liver seemed to be associated with an increased incidence of major morbidity, multivariate analysis showed no significant correlation between the use of Seprafilm and postoperative major abdominal morbidity., Conclusion: Use of Seprafilm may not increase the risk of major abdominal morbidity in liver surgery., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective A survival benefit was demonstrated for ramucirumab (RAM) in patients with unresectable hepatocellular carcinoma (uHCC) and α-fetoprotein (AFP) concentrations ≥400 ng/mL who had previously received sorafenib (SOR). However, it is unclear whether RAM has a similar efficacy in patients with uHCC that progresses after lenvatinib (LEN) treatment. This study aimed to evaluate the early anti-tumor response to RAM as a second-line treatment for advanced uHCC after LEN treatment. Methods We retrospectively assessed the efficacy and safety of RAM at 6 weeks after initiation. The therapeutic effects were evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients We evaluated 7 patients with uHCC who received RAM as a second- or third-line treatment after LEN failure. Results The disease control rate (DCR) was 28.6% (2 of 7 patients). After the initiation of RAM, a rapid disease progression resulted in 1 patient death after 19 days. The median progression-free survival (PFS) was 41 days. There were no grade 3 or 4 treatment-related adverse events. At 6 weeks, there was no deterioration in the modified albumin-bilirubin (mALBI) grade. In patients with an imaging response of stable disease (SD), the rate of AFP production decreased from the baseline. Conclusion RAM may have a therapeutic potential for the suppression of uHCC progression in patients previously treated with LEN, as well as for maintaining the liver function during treatment. Evaluating the AFP trends may therefore be useful for predicting RAM effectiveness.

Background: Esophageal cancer patients often feel depressed and are fearful of metastasis and death. The objective of this study was to clarify the characteristics of patients with psychological distress at all 5 time points compared with patients with no psychological distress especially from standpoints of personal coping styles and QOL., Methods: In total, 102 of 152 consecutive patients who attended the outpatient clinic at Toranomon Hospital between April 2017 and April 2019 met eligibility criteria for inclusion in this study. Questionnaires designed to identify psychological distress (HADS-scores) and assess QOL (EORTC QLQ C-30/OES18) were administered at 5 time points from the time of the first outpatient consultation to 3 months after esophagectomy. The questionnaire of coping strategies (MAC-scales) was administered at only time 1 point., Results: Based on the trends of HADS-scores, we defined two groups: "persistent high-HAD scores" and "persistent low-HADS scores." There are strong relationships between psychological distress and coping strategy, and psychological distress and QOL. The possibility that there are relationships between stress coping strategies and some QOL status depending on some point of treatment., Conclusions: The psychological distress during the treatment course of esophageal cancer is significantly associated with the coping strategies and QOL influenced by esophagectomy. This study can provide baseline information for identifying patients in need of psychological management and paves the way for larger clinical studies in the future.

Competing Interests: The author has no conflicts of interest to declare.

Background: The aims of this study were to evaluate the efficacy of additional treatment, especially lenvatinib-transarterial chemoembolization (TACE) sequential therapy, for unresectable hepatocellular carcinoma (HCC)., Methods: Consecutive 56 patients who underwent lenvatinib treatment were reviewed. Oncological aggressiveness of tumor was estimated using a dynamic CT enhancement pattern classification, and clinical impact of subsequent treatment was investigated through analysis of progression-free survival (PFS), post-progression survival (PPS), and multivariate analysis of potential confounders for survival after progression during lenvatinib therapy., Results: Heterogeneous enhancement patterns ( Type-3 and -4 ), which are reportedly associated with higher oncological aggressiveness of HCC, were associated with better objective response to lenvatinib compared to homogeneous enhancement pattern ( Type-2 ) (86 and 85% vs. 53% in modified Response Evaluation Criteria in Solid Tumors), resulting in similar PFS ( p = 0.313). Because of significantly worse PPS, overall survival of Type-4 tumor was poor compared to Type-2 or -3 tumors ( p = 0.009). However, subgroup of patients who achieved subsequent treatment showed significantly better PPS, regardless of CT enhancement pattern. Multivariate analysis confirmed that use of lenvatinib-TACE sequential treatment after progression during lenvatinib therapy was associated with better PPS (hazard ratio [HR], 0.08; 95% CI, 0.01-0.71; p = 0.023), while Type-4 enhancement pattern was correlated with worse PPS (HR, 2.92; 95% CI, 1.06-8.05; p = 0.039)., Conclusion: Oncological aggressiveness of HCC estimated by CT enhancement pattern was predictive of PPS after progression during lenvatinib. Successful subsequent treatment with lenvatinib-TACE sequential therapy may offer survival benefit regardless of CT enhancement pattern of HCC., Competing Interests: Yusuke Kawamura, MD, PhD reports receiving a honoraria from Eisai. Masahiro Kobayashi, MD. reports receiving a honoraria from Eisai. Junichi Shindoh, MD, PhD reports receiving a honoraria from Eisai. Hiromitsu Kumada, MD, PhD reports receiving a honoraria from Eisai. The other authors declare no conflicts of interest., (Copyright © 2020 by S. Karger AG, Basel.)

We constructed a data set of EGFR-mutant non-small-cell lung carcinoma (NSCLC) patients, and compared the overall survival of first-generation (1G), and second-generation (2G) EGFR-tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR-mutated NSCLC patients who received EGFR-TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR-TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR-TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5-33.5] in the 1G group (gefitinib, 32.0 [28.1-35.8]; erlotinib, 27.5 [23.9-31.7]), and 38.6 [32.2-NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR-TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P < .0001; adjusted by matching, HR 0.725, P = .0418). Exploratory analysis showed that OS using the 2G EGFR-TKI was superior to that of the 1G EGFR-TKIs, suggesting the potential of sequential therapy of 2G EGFR-TKI followed by osimertinib. (HR 0.419, P = .0519) Real-world data analysis using 1354 data records, using propensity scoring, indicated that 2G EGFR-TKI had a trend of longer OS compared with 1G EGFR-TKIs., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Laparoscopic liver resection has become popular recent years. Laparoscopic left lateral sectionectomy (LLS) is now a standard operation with sufficient safety and feasibility. To improve the benefits of minimally invasive surgery, we invented and have been performing a reduced port LLS procedure using 3 ports since 2009., Materials and Methods: All patients who underwent LLS at Toranomon Hospital (Tokyo, Japan) were included, except for patients with a previous history of upper abdominal surgery or those who had undergone the simultaneous resection of another organ. An essential point of this procedure was the extracorporeal traction of the divided round ligament using a ligature. As a result, the operator was able to perform the parenchymal transection within a good operative field., Results: Twelve patients were enrolled in the study. All the patients had a Child-Pugh classification of Class A. The median indocyanine green retention rate at 15 min was 9.5%. Compared with previously reported results for conventional LLS, the median operation time (82.5 min), blood loss (0 mL) and rate of blood transfusion (0%) were lower for the 3-port LLS procedure. The rates of complications (9%) and a positive surgical margin (0%) were similar to those reported for the conventional approach., Conclusion: Three-port LLS appears to be a safe and feasible procedure., Competing Interests: None

Objective: The aim of this study was to evaluate the performance of pretreatment computed tomography (CT) enhancement of hepatocellular carcinoma (HCC) as a potential predictor of response to lenvatinib and its relevance to survival outcomes., Methods: We evaluated 51 consecutive patients who received lenvatinib treatment for unresectable HCC. On imaging analysis, pretreatment arterial/portal phase dynamic CT images were classified as follows: type 2, homogeneous enhancement pattern with increased arterial blood flow; type 3, heterogeneous enhancement pattern with a septum-like structure; and type 4, heterogeneous enhancement pattern with irregularly shaped ring structures. Treatment response was evaluated using modified Response Evaluation Criteria in Solid Tumors at 2-12 weeks after initiation of lenvatinib, and the correlations between the CT enhancement patterns and response to lenvatinib or survival outcomes were investigated., Results: Of the 51 patients, 38 (75%) experienced an objective response (OR). ORs were significantly more common in heterogeneously enhanced HCC (types 3 and 4) than in homogeneous HCC (type 2) (83 vs. 53%, respectively; p = 0.037). Multivariate analysis revealed that pretreatment heterogeneous enhancement pattern is an independent predictor for response to lenvatinib (odds ratio, 4.75; p = 0.042). Presence of OR was associated with longer progression-free survival (PFS) (hazard ratio, 0.36; p = 0.017), and patients with oncologically aggressive type 3 and 4 tumors showed similar PFS to those harboring type 2 tumors ( p = 0.455), reflecting that OR was more common in type 3 or 4 tumors compared with type 2 tumors. Although postprogression survival was extremely poor in patients with type 4 tumors ( p = 0.064), overall survival after introduction of lenvatinib was not statistically different among the three groups of patients ( p = 0.053)., Conclusion: The CT enhancement pattern of HCC may predict response to lenvatinib. OR seems to occur more frequently in HCC with oncologically aggressive features and may contribute to prolonged survival through a prolonged progression-free interval, even in an oncologically poor-risk group of patients., Competing Interests: Y. Kawamura, MD, PhD reports honoraria from Eisai. M. Kobayashi, MD reports honoraria from Eisai. J. Shindoh, MD, PhD reports honoraria from Eisai. H. Kumada, MD, PhD reports honoraria from Eisai. The other authors declare no conflicts of interest., (Copyright © 2020 by S. Karger AG, Basel.)

Introduction: For prognostication of hepatocellular carcinoma (HCC), the optimal size cutoff value and the significance of microvascular invasion (mvi) remain inconclusive., Objective: This study sought to revisit the inconclusive components of current American Joint Committee on Cancer (AJCC) staging system and to develop a new practical prognostication model for patients with HCC based on 2 large cohorts., Method: In 1,175 patients who underwent resection for HCC (training cohort), prognostic significance of mvi, and optimal size cutoff value were revisited and a new staging model was established. Then, its performance was validated using 5,249 patients derived from a population-based database (validation cohort)., Results: The optimal size cutoff value was 2 cm in multiple HCC, similar to that for solitary HCC. Multivariate analyses confirmed that mvi, a size >2 cm, and multiple lesions were independent predictors with similar weights for disease-specific survival. Based on these results, earlier stages of HCC were reclassified according to the number of the following factors: multiple tumors, >2 cm in diameter, and presence of mvi. Also, given the similar prognosis of Stages IIIB and IVA according to the AJCC 8th edition, these groups were reclassified into the same stage. This new staging model had a better performance than the AJCC 8th edition in both training cohort (c-statistics, 0.648 vs. 0.629) and the validation cohort (c-statistics, 0.646 vs. 0.645) regardless of the presence of cirrhosis., Conclusions: Inclusion of a size cutoff value of 2 cm and mvi could reclassify the current version of the AJCC staging system and offer an alternative prognostication model using a single size-cutoff value of HCC., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by S. Karger AG, Basel.)

Background: Hepatocellular carcinoma (HCC) de-differentiation is thought to correlate with size, therefore well-differentiated HCC ≥3 cm are considered rare and not fully understood., Methods: Patients who underwent hepatectomy for HCC between 1998-2016 were retrospectively analyzed. Patient's characteristics and recurrence-free (RFS) and overall (OS) survival were compared between those with atypical- (well-differentiated-HCC ≥3 cm) and typical-HCC (moderate-to-poorly-differentiated HCC ≥3 cm)., Results: Of 176 patients included in this study, 37 (21%) had atypical-HCC. Patients with atypical-HCC were less likely to be Asian ethnicity (3% vs. 17%, p = 0.062), have lower rate of viral infection (14% vs. 43%, p = 0.003), cirrhosis (8% vs. 27%, p = 0.015). The tumors were less likely to demonstrate vascular invasion (30% vs. 59%, p = 0.002), and were associated with a lower alpha-fetoprotein level (3.5 ng/ml vs. 33.2 ng/ml, p < 0.001). Patients with atypical-HCC had a longer RFS (5-y RFS: 58.3% vs. 35.7%, p = 0.016) and OS (5-y OS: 79.1% vs 53.3%, p = 0.029) as compared to those with typical-HCC following univariate analysis, however this did not appear following multivariate analysis., Conclusion: Patients with atypical-HCC have different characteristic in terms of epidemiology, etiology, cirrhosis and vascular invasion as compared to typical-HCC. The etiology of atypical-HCC may be non-alcoholic fatty liver disease-related and/or malignant transformation of hepatocellular adenoma., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Multidisciplinary treatment for colorectal liver metastases (CLMs) often includes major hepatectomy for preoperative chemotherapy-related hepatic injury, although the safety limit for resection extent is unclear. We investigated this parameter using the estimated indocyanine green clearance rate (ICG-K) of liver remnants, focusing on postoperative subclinical hepatic insufficiency (PHI)., Methods: Altogether, 225 patients who underwent resection of CLMs were studied. The predictive power of estimated ICG-K of liver remnant (ICG-Krem) for subclinical PHI (peak bilirubin ≥3 mg/dL or refractory ascites) was compared with those of other potential predictors. The suggested safety limit of ICG-Krem ≥0.05 was also assessed., Results: Receiver-operating curve analysis revealed that ICG-Krem [area under the curve (AUC) 0.752, cutoff 0.102] was the best predictor of subclinical PHI (AUC range for others was 0.632-0.668). Makuuchi's criteria corresponded to ICG-Krem 0.10. Subclinical PHI incidence was significantly elevated at ICG-Krem <0.10 (26% vs 8%, p = 0.002), while potentially fatal PHI (peak bilirubin >7 mg/dL) was not observed until down to ICG-Krem of 0.05., Conclusions: ICG-Krem sensitively predicts subclinical PHI. Liver failure-related death could be avoided so long as ICG-Krem remains at ≥0.05. However, patients with ICG-Krem 0.05-0.10 are at high risk of subclinical PHI and require intensive care postoperatively., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: This study aimed to identify the utility of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) as a predictor of the response of hepatocellular carcinoma (HCC) to lenvatinib., Methods: We evaluated 28 consecutive patients with HCC diagnosed by dynamic CT or magnetic resonance imaging combined with 18 F-FDG-PET/CT. The tumor-to-normal liver standardized uptake value ratio (TLR) of the target tumor was measured before treatment using 18 F-FDG-PET/CT, with a TLR ≥2 classified as a high potential for malignant HCC. The treatment response was evaluated 2 weeks after the initiation of lenvatinib using modified Response Evaluation Criteria in Solid Tumors., Results: Of the 28 patients, 12 (43%) presented with a TLR ≥2. Evaluation of the treatment response at 2 weeks in these 12 patients revealed that 2 (17%) exhibited a complete response, 8 (67%) a partial response, 2 (17%) stable disease, and none with progressive disease. Therefore, 10 of the 12 patients (83%) experienced an objective response to lenvatinib. On the other hand, 7 of the 16 patients with a TLR <2 (44%) experienced an objective response. Thus, the objective response rate was higher in patients with a TLR ≥2 than in those with a TLR <2. Multivariate logistic regression analysis revealed that a TLR ≥2 (odds ratio 10.53; p = 0.028) is a useful predictor of an early objective response at 2 weeks., Conclusion: Patients with unresectable HCC showed a good early treatment response to lenvatinib. High TLR (≥2) may be a useful predictor of an extremely rapid treatment response., Competing Interests: Yusuke Kawamura, Masahiro Kobayashi, Junichi Shindoh, and Hiromitsu Kumada report honoraria from Eisai. The other authors declare no conflicts of interest., (Copyright © 2019 by S. Karger AG, Basel.)

Background: Recent advances in liver surgery have dramatically improved the safety of hepatectomy for hepatocellular carcinoma (HCC). The aim of this study was to compare outcomes for patients fulfilling an extended criteria vs. those fulfilling the conventional criteria based on the bilirubin and indocyanine green (ICG) clearance (Makuuchi's criteria)., Methods: The short term outcomes of patients undergoing hepatectomy for HCC and who fulfilled the expanded criteria (ICG clearance of future remnant liver [ICG-Krem] ≥ 0.05 estimated using 3-D volumetry) were retrospectively reviewed and were compared between those fulfilling the conventional criteria. Postoperative hepatic insufficiency (PHI) was defined as peak total bilirubin >7 mg/dL., Results: A total of 323 patients undergoing resection of whom 269 (83%) met conventional criteria (In-M) and 54 (17%) extended criteria (Ex-M). The overall morbidity rates were not significantly different. The incidence of PHI was 0.37% in In-M and 3.7% in Ex-M (P = 0.074), with no liver-related deaths. When the ICG-Krem ≥ 0.05 criterion was included, major hepatectomy was performed in 24 patients (41%) in Ex-M with no significant increase in major morbidity (13%), PHI(3.3%), or liver-related death (0%) compared with minor hepatectomy (n = 30) in Ex-M(10%, 4% and 0%, respectively)., Conclusions: Objective criteria using ICG clearance rate and 3-D volumetry may offer opportunities for safe surgical resection in selected patients exceeding the conventional criteria., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Prediction of nodal involvement in colorectal cancer is an important aspect of preoperative workup to determine the necessity of preoperative treatment and the adequate extent of lymphadenectomy during surgery. This study aimed to investigate newer multidetector-row computed tomography (MDCT) findings for better predicting lymph node (LN) metastasis in colorectal cancer., Methods: Seventy patients were enrolled in this study; all underwent MDCT prior to surgery and upfront curative resection for colorectal cancer. LNs with a short-axis diameter (SAD) ≥ 4 mm were identified on MDCT images, and the following measures were recorded by two radiologists independently: two-dimensional (2D) SAD, 2D long-axis diameter (LAD), 2D ratio of SAD to LAD, 2D CT attenuation value, three-dimensional (3D) SAD, 3D LAD, 3D SAD to LAD ratio, 3D CT attenuation value, LN volume, and presence of extranodal neoplastic spread (ENS), as defined by indistinct nodal margin, irregular capsular enhancement, or infiltration into adjacent structures., Results: Forty-six patients presented 173 LNs with a SAD ≥ 4 mm, while 24 patients exhibited pathologically confirmed LN metastases. Receiver operating characteristic analysis revealed that 2D LAD was the most sensitive measure for LN metastases with an area under the curve of 0.752 (cut-off value, 7.05 mm). When combined with CT findings indicating ENS, 2D LAD (> or ≤ 7 mm) showed enhanced predictive power for LN metastases (area under the curve, 0.846; p < 0.001)., Conclusions: LAD in axial MDCT imaging is the most sensitive measure for predicting colorectal LN metastases, especially when MDCT findings of ENS are observed.

Background: While the middle hepatic vein (MHV) guides parenchymal transection during right hepatectomy, its most proximal tributaries can be difficult to identify, and injury to its tributaries can be a source of major bleeding., Method: Following simulation modeling of right hepatectomy, reconstructed MHV data was pooled from 40 patients. MHV-tributaries and MHV-relationship to the portal pedicle were mapped out to facilitate their identification from the beginning of parenchymal transection., Results: Hotspots for injury were identified: A median of 1 (1-3) tributaries draining segment 5 (V5) were within 45-90mm from the MHV termination, and 16mm above and 22mm caudal to the portal trunk. Simulation demonstrated a constant anatomic relationship between portal pedicle and the proximal MHV. A median of 2 (0-4) tributaries draining segment 8 (V8) were located 9-35mm from the MHV termination. This information was compiled into an "MHV-road-map" demonstrating 86% of the MHV tributaries at risk for significant bleeding are within 15mm of the MHV, while only thin tributaries are located in the outer area., Conclusions: The MHV-road-map led to a peripheral-to-central parenchymal transection approach to minimize the risk of MHV-injury thereby reducing bleeding during open and minimally invasive right hepatectomy., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Regorafenib is a multi-kinase inhibitor, which was shown to be effective for patients with metastatic colorectal cancer refractory to standard therapies. However, its patterns of response has not yet been fully understood., Methods: Clinical records of 10 patients who received regorafenib for evaluable colorectal liver metastases were reviewed. Response to chemotherapy was evaluated with the RECIST and morphologic response criteria, and its clinical relevance was analyzed., Results: All patients received multiple lines of fluorouracil-based chemotherapy before regorafenib. The median follow-up duration after introduction of regorafenib was 4.9 months (range, 2 to 12.5 months). Median number of chemotherapy cycles was 2 (range, 1 to 15). In size-based response evaluation, 4 patients presented SD and 6 patients showed PD according to the RECIST. In non-size-based response evaluation, 3 patients were classified as optimal morphologic response and 7 patients were categorized as suboptimal morphologic response. Patients who presented optimal morphologic response showed significantly longer progression-free survival compared with those presented suboptimal response (median, 4.9 months vs. 0.7 months; P = 0.028), while size-based response evaluation could not well stratify patient prognosis., Conclusion: Non-size-based CT morphologic response could be a potential alternative response marker for patients treated with regorafenib.

Background: Pseudoprogression refers to a specific pattern of response sometimes observed in malignant melanoma patients receiving treatment with immune-checkpoint inhibitors. Although cases with pseudoprogression documented once have been reported previously, there have been no case reports yet of pseudoprogression events documented twice during treatment., Case Presentation: A 55-year-old man underwent surgery for locally advanced esophageal malignant melanoma and received postoperative adjuvant interferon therapy. However, he presented with multiple liver and bone metastases at 6 months after the surgery, and was initiated on treatment with nivolumab 2 mg/kg every 3 weeks as the first-line treatment for recurrent disease. Follow-up computed tomography revealed that the liver metastases initially increased transiently in size, but eventually regressed. However, while the liver metastases continued to shrink, a new peritoneal nodule emerged, that also subsequently shrinked during the course of treatment with nivolumab. With only grade 1 pruritus, the patient continues to be on nivolumab treatment at 15 months after the induction therapy, with no progression observed after the second episode of pseudoprogression in the liver and peritoneal nodule., Conclusions: We present the case of a patient with metastatic malignant melanoma who showed the unique response pattern of serial pseudoprogression during treatment with nivolumab. This case serves to highlight the fact that development of a new lesion may not always signify failure of disease control during treatment with nivolumab.

Background: For proximal gastric cancer invading the greater curvature, concomitant splenectomy is frequently performed to secure the clearance of lymph node metastases. However, prognostic impact of prophylactic splenectomy remains unclear. The aim of this study was to clarify the oncological significance of prophylactic splenectomy for advanced proximal gastric cancer invading the greater curvature., Methods: Retrospective review of 108 patients who underwent total or subtotal gastrectomy for advanced proximal gastric cancer involving the greater curvature was performed. Short-term and long-term outcomes were compared between the patients who underwent splenectomy (n = 63) and those who did not (n = 45)., Results: Patients who underwent splenectomy showed higher amount of blood loss (538 vs. 450 mL, p = 0.016) and morbidity rate (30.2 vs. 13.3, p = 0.041) compared with those who did not undergo splenectomy. In particular, pancreas-related complications were frequently observed among patients who received splenectomy (17.4 vs. 0%, p = 0.003). However, no significant improvement of long-term outcomes were confirmed in the cases with splenectomy (5-year recurrence-free rate, 60.2 vs. 67.3%; p = 0.609 and 5-year overall survival rates, 63.7 vs. 73.6%; p = 0.769). On the other hand, splenectomy was correlated with marginally better survival in patients with Borrmann type 1 or 2 gastric cancer (p = 0.072)., Conclusions: For advanced proximal gastric cancer involving the greater curvature, prophylactic splenectomy may have no significant prognostic impact despite the increased morbidity rate after surgery. Such surgical procedure should be avoided as long as lymph node involvement is not evident.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy. Although surgical resection has been a cornerstone in the management of ICC, the efficacies of several non-surgical management strategies have been actively investigated and somewhat preferable outcomes have been reported for ablation therapies in selected cases. Nevertheless, because of the rarity of these tumors and the small number of studies, the clinical significance and actual role of ablation therapies in a multidisciplinary approach for ICC remain unclear. In this article, the reported outcomes of ablation therapies for ICC will be summarized and their potential indications will be discussed., Competing Interests: Conflicts of Interest: The author has no conflicts of interest to declare.