Immunotherapy with immune checkpoint inhibitors has been shown to be beneficial for cancers originating from various organs. In May 2020, combination therapy with anti‐programmed death‐ligand 1 ...antibody atezolizumab and anti‐vascular endothelial growth factor (VEGF) antibody bevacizumab was approved as a novel first‐line systemic therapy for hepatocellular carcinoma (HCC). The number of patients with HCC not caused by hepatitis virus infection (non‐viral HCC), including non‐alcoholic steatohepatitis (NASH)‐related HCC, has been increasing in recent years. Recently, Pfister and colleagues reported that immune checkpoint inhibitors may exhibit limited efficacy against NASH‐related HCC, based on basic research and clinical data. This review will discuss the mechanism of impaired tumor immune surveillance in NASH and analyze the results of previously published clinical trials of immune checkpoint inhibitors to investigate whether patients with non‐viral HCC are less likely to benefit from immunotherapy with immune checkpoint inhibitors. Furthermore, we also discuss the possibility of enhancing the therapeutic effect of immune checkpoint inhibitors for NASH‐related HCC by combining anti‐VEGF agents.
To evaluate preoperative body composition, including skeletal muscle and visceral adipose tissue, and to clarify the impact on outcomes after hepatectomy for hepatocellular carcinoma (HCC).
Recent ...studies have indicated that sarcopenia is associated with morbidity and mortality in various pathologies, including cancer, and that obesity or visceral adiposity represents a significant risk factor for several cancers. However, the impact of sarcopenic obesity on outcomes after hepatectomy for HCC has not been fully investigated.
We retrospectively analyzed 465 patients who underwent primary hepatectomy for HCC between April 2005 and March 2015. Skeletal muscle mass and visceral adipose tissue were evaluated by preoperative computed tomography to define sarcopenia and obesity. Patients were classified into 1 of 4 body composition groups according to the presence or absence of sarcopenia and obesity.
Body composition was classified as nonsarcopenic nonobesity in 184 patients (39%), nonsarcopenic obesity in 219 (47%), sarcopenic nonobesity in 31 (7%), and sarcopenic obesity in 31 (7%). Compared with patients with nonsarcopenic nonobesity, patients with sarcopenic obesity displayed worse median survival (84.7 vs. 39.1 mo, P = 0.002) and worse median recurrence-free survival (21.4 vs. 8.4 mo, P = 0.003). Multivariate analysis identified sarcopenic obesity as a significant risk factor for death (hazard ratio HR = 2.504, P = 0.005) and HCC recurrence (HR = 2.031, P = 0.006) after hepatectomy for HCC.
Preoperative sarcopenic obesity was an independent risk factor for death and HCC recurrence after hepatectomy for HCC.
Purpose
To develop convolutional neural network (CNN) models for differentiating intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC) and predicting histopathological grade of ...HCC.
Materials and methods
Preoperative computed tomography and tumor marker information of 617 primary liver cancer patients were retrospectively collected to develop CNN models categorizing tumors into three categories: moderately differentiated HCC (mHCC), poorly differentiated HCC (pHCC), and ICC, where the histopathological diagnoses were considered as ground truths. The models processed manually cropped tumor with and without tumor marker information (two-input and one-input models, respectively). Overall accuracy was assessed using a held-out dataset (10%). Area under the curve, sensitivity, and specificity for differentiating ICC from HCCs (mHCC + pHCC), and pHCC from mHCC were also evaluated. We assessed two radiologists’ performance without tumor marker information as references (overall accuracy, sensitivity, and specificity). The two-input model was compared with the one-input model and radiologists using permutation tests.
Results
The overall accuracy was 0.61, 0.60, 0.55, 0.53 for the two-input model, one-input model, radiologist 1, and radiologist 2, respectively. For differentiating pHCC from mHCC, the two-input model showed significantly higher specificity than radiologist 1 (0.68 95% confidence interval: 0.50–0.83 vs 0.45 95% confidence interval: 0.27–0.63;
p
= 0.04).
Conclusion
Our CNN model with tumor marker information showed feasibility and potential for three-class classification within primary liver cancer.
Background Skeletal muscle depletion, referred to as sarcopenia, predicts mortality after major surgery. This study investigated the impact of preoperative skeletal muscle quantity and quality on ...outcomes in patients undergoing resection of extrahepatic biliary cancer. Methods We performed a retrospective analysis of 207 patients undergoing resection for biliary cancer between 2004 and 2013. The quantity and quality of skeletal muscle, indicated by the psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC), were measured on preoperative images of computed tomography. Overall survival (OS) and recurrence-free survival (RFS) rates were compared by PMI and IMAC, and prognostic factors after operation were assessed. Results The OS and RFS rates were less in patients with low PMI (low muscle quantity) than in those with normal PMI ( P < .001 and P < .001; 5-year OS, 15.7 vs 53.5%). The OS and RFS rates were also less in patients with high IMAC (low muscle quality) than in those with normal IMAC ( P < .001 and P < .001; 5-year OS, 23.8 vs 55.9%). Low PMI and high IMAC were independent factors predictive of poor OS (hazard ratio HR, 2.921 95% CI, 1.920–4.470; P < .001 and HR, 1.725 95% CI, 1.159–2.590; P = .007) and RFS (HR, 2.141 95% CI, 1.464–3.129, P < .001 and HR, 1.492 95% CI, 1.032–2.166, P = .034). Conclusion Preoperative sarcopenia, indicating a low quantity and quality of skeletal muscle, is related closely to mortality after resection of biliary cancer.
Background
Limited studies have reported the actual learning process of laparoscopic liver resection (LLR). This study aimed to chronologically evaluate our 15 years’ experience of LLR.
Methods
All ...consecutive LLRs between 2006 to 2020 were retrospectively analyzed. The time period was divided into three groups; first (2006–2010), second (2011–2015), and third (2016–2020) period. The primary endpoint of this study was a composite of overall (Clavien–Dindo grade ≥ II) or major (grade ≥ IIIa) postoperative complications within 30 days. Using the IWATE criteria (four difficulty levels based on six indices), LLR was categorized as basic (< 7 points) and advanced (≥ 7 points) one. All analyses were performed based on the intention-to-treat principles.
Results
During the study period, a total of 382 LLRs were gradually performed (first period,
n
= 54; second period,
n
= 114, and third period,
n
= 214). Low incidences of overall and major complications were maintained (9.3, 10.5, and 7.0%,
p
= 0.514, and 1.9, 2.6, and 2.3%,
p
= 1.000). Meanwhile, pure LLRs (i.e., LLRs without hand-assisted or hybrid approach) and advanced LLRs were increasingly performed in 25 (46.3%), 71 (62.3%), and 205 (95.8%) patients (
p
< 0.001) and 3 (5.6%), 18 (15.8%), and 58 (27.1%) patients (
p
< 0.001), respectively.
Conclusions
This study suggests that stepwise approach from basic to advanced procedures and use of hand-assisted or hybrid approach during the early phases for starting LLR practice may allow for maintaining low morbidity in specialized center.
Background
Hepatopancreatoduodenectomy (HPD) is often indicated in the resection of cholangiocarcinoma but is associated with high mortality.
1
–
3
From a risk–benefit perspective, HPD can be ...justified only when curative resection is achievable.
4
–
6
Methods
A liver transection-first approach is a surgical technique in which liver transection precedes pancreatoduodenectomy (PD) and skeletonization of the hepatoduodenal ligament in HPD. This approach enables an early assessment of resectability and curability.
Results
A 64-year-old with jaundice had a tumor located mainly in the proximal bile duct, spreading from the confluence of hepatic ducts (dominant in the left hepatic duct) to the intrapancreatic bile duct. The right hepatic artery and portal vein existed in close proximity to the tumor. HPD (left hemi-hepatectomy and subtotal stomach-preserving PD) with vascular resection was performed. After liver transection along the Cantlie line, the right Glissonean pedicle was collectively secured inside the liver. The right hepatic artery, right portal vein, and right hepatic duct (RHD) were isolated, and the feasibility of vascular reconstruction was confirmed. After the RHD was divided and the negative margin was confirmed, we proceeded to perform PD. The portal vein was reconstructed between the right portal vein and the portal vein trunk. The right hepatic artery was anastomosed to the second jejunal artery of the jejunal loop with the right gastroepiploic artery as an interposition graft.
Conclusion
The liver transection-first technique in HPD facilitates early assessment of curability and resectability as well as a safe and secure manipulation and reconstruction of the hepatic artery and portal vein.
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•Hepatic myofibroblasts progressively accumulate in the livers of Mdr2−/− mice.•Myofibroblasts mostly originate from hepatic stellate cells or portal fibroblasts.•Meanwhile, ...fibrocytes minimally contribute to myofibroblasts in Mdr2−/− mice.•In addition to collagen production, myofibroblasts serve as a source of NADPH oxidase (NOX).•Therapeutic blocking of NOX1/4 ameliorates cholestatic fibrosis in Mdr2−/− mice.
Chronic liver injury often results in the activation of hepatic myofibroblasts and the development of liver fibrosis. Hepatic myofibroblasts may originate from 3 major sources: hepatic stellate cells (HSCs), portal fibroblasts (PFs), and fibrocytes, with varying contributions depending on the etiology of liver injury. Here, we assessed the composition of hepatic myofibroblasts in multidrug resistance gene 2 knockout (Mdr2−/−) mice, a genetic model that resembles primary sclerosing cholangitis in patients.
Mdr2−/− mice expressing a collagen-GFP reporter were analyzed at different ages. Hepatic non-parenchymal cells isolated from collagen-GFP Mdr2−/− mice were sorted based on collagen-GFP and vitamin A. An NADPH oxidase (NOX) 1/4 inhibitor was administrated to Mdr2−/− mice aged 12–16 weeks old to assess the therapeutic approach of targeting oxidative stress in cholestatic injury.
Thy1+ activated PFs accounted for 26%, 51%, and 54% of collagen-GFP+ myofibroblasts in Mdr2−/− mice at 4, 8, and 16 weeks of age, respectively. The remaining collagen-GFP+ myofibroblasts were composed of activated HSCs, suggesting that PFs and HSCs are both activated in Mdr2−/− mice. Bone-marrow-derived fibrocytes minimally contributed to liver fibrosis in Mdr2−/− mice. The development of cholestatic liver fibrosis in Mdr2−/− mice was associated with early recruitment of Gr1+ myeloid cells and upregulation of pro-inflammatory cytokines (4 weeks). Administration of a NOX inhibitor to 12-week-old Mdr2−/− mice suppressed the activation of myofibroblasts and attenuated the development of cholestatic fibrosis.
Activated PFs and activated HSCs contribute to cholestatic fibrosis in Mdr2−/− mice, and serve as targets for antifibrotic therapy.
Activated portal fibroblasts and hepatic stellate cells, but not fibrocytes, contributed to the production of the fibrous scar in livers of Mdr2−/− mice, and these cells can serve as targets for antifibrotic therapy in cholestatic injury. Therapeutic inhibition of the enzyme NADPH oxidase (NOX) in Mdr2−/− mice reversed cholestatic fibrosis, suggesting that targeting NOXs may be an effective strategy for the treatment of cholestatic fibrosis.
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