Reappraisal of anatomical liver resection for hepatoblastoma in children.

Background: The principle of hepatoblastoma (HB) treatment is complete resection. The removal of tumor-bearing section(s) or hemiliver is widely accepted. However, neither the standardized anterior approach for right hepatectomy nor parenchymal sparing anatomical liver resection has been described for HB. Methods: We retrospectively reviewed the clinical course of two pediatric HB patients who underwent extended right hepatectomy using the anterior approach with the liver hanging maneuver and one who underwent parenchymal sparing anatomical liver resection of S4 apical+S8 ventral/dorsal+S7. The critical aspects of surgical techniques are described in detail. Results: In all three patients, R0 resection was achieved without complications and are currently alive without recurrence after an average follow-up of 23 months. Intraoperative cardiac hemodynamics were stable, even in a trisomy 18 patient with cardiac disease. Conclusions: Our findings suggest that these innovative techniques established in adults are safe and feasible for HB in children. These techniques also allow optimal anatomical liver resection to accomplish curative surgery while maintaining the functional reserve of the remnant liver.

Potential involvement of IL-32 in cell-to-cell communication between macrophages and hepatoblastoma.

PURPOSE: This study investigated the expression of interleukin 32 (IL-32) in hepatoblastoma, the most common primary pediatric liver tumor, and its possible roles in tumorigenesis. METHODS: IL-32 expression was investigated in two hepatoblastoma cell lines (Hep G2 and HuH 6) in the steady state and after co-culture with macrophages by RNA-seq analysis and RT-qPCR, and after stimulation with chemotherapy. Cultured macrophages were stimulated by IL-32 isoforms followed by RT-qPCR and western blot analysis. IL-32 immunohistochemical staining (IHC) was performed using specimens from 21 hepatoblastoma patients. Clustering analysis was also performed using scRNA-seq data downloaded from Gene Expression Omnibus. RESULTS: The IL-32 gene is expressed by hepatoblastoma cell lines; expression is upregulated by paracrine cell-cell communication with macrophages, also by carboplatin and etoposide. IL-32 causes protumor activation of macrophages with upregulation of PD-L1, IDO-1, IL-6, and IL-10. In the patient pool, IHC was positive only in 48% of cases. However, in the downloaded dataset, IL-32 gene expression was negative. CONCLUSION: IL-32 was detected in hepatoblastoma cell lines, but not in all hepatoblastoma patients. We hypothesized that stimulation such as chemotherapy might induce expression of IL-32, which might be a critical mediator of chemoresistance in hepatoblastoma through inducing protumor activation in macrophages.

Hepatic venous outflow obstruction after adult living donor liver transplantation.

Hepatic venous outflow obstruction (HVOO) is a rare but critical vascular complication after adult living donor liver transplantation. We categorized HVOOs according to their morphology (anastomotic stenosis, kinking, and intrahepatic stenosis) and onset (early-onset < 3 mo vs. late-onset ≥ 3 mo). Overall, 16/324 (4.9%) patients developed HVOO between 2000 and 2020. Fifteen patients underwent interventional radiology. Of the 16 hepatic venous anastomoses within these 15 patients, 12 were anastomotic stenosis, 2 were kinking, and 2 were intrahepatic stenoses. All of the kinking and intrahepatic stenoses required stent placement, but most of the anastomotic stenoses (11/12, 92%) were successfully managed with balloon angioplasty, which avoided stent placement. Graft survival tended to be worse for patients with late-onset HVOO than early-onset HVOO (40% vs. 69.3% at 5 y, p = 0.162) despite successful interventional radiology. In conclusion, repeat balloon angioplasty can be considered for simple anastomotic stenosis, but stent placement is recommended for kinking or intrahepatic stenosis. Close follow-up is recommended in patients with late-onset HVOO even after successful treatment.

Recent advances in surgical strategies and liver transplantation for hepatoblastoma.

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although the development of treatment strategies with advances in chemotherapy has greatly improved the prognosis of HB, surgical resection and liver transplantation still play a vital role in the treatment of HB. In recent years, technological innovations have led to the development of new surgical approaches for HB. In this review, we describe the latest research on the surgical management of HB, including new imaging technologies, minimally invasive approaches, and the application of associating liver partition portal vein ligation for staged hepatectomy. We also discuss the current role of liver transplantation, use of ante-situm or ex-situ liver resection with auto-transplantation, and management of metastatic HB.

M-CSFR expression in the embryonal component of hepatoblastoma and cell-to-cell interaction between macrophages and hepatoblastoma.

Tumor-associated macrophages (TAMs) have protumor functions in various cancers. However, their significance in hepatoblastoma, the most common liver tumor in children, remains unclear. The aim of this study was to explore the potential roles of TAMs in hepatoblastoma. Immunohistochemical analysis revealed that the density of CD204-positive TAMs was significantly higher in the embryonal component than in other histological subtypes of hepatoblastoma. An in vitro co-culture study with Huh6 cells and human monocyte-derived macrophages (HMDMs) showed that macrophage-colony-stimulating factor receptor (M-CSFR) was strongly up-regulated in the Huh6 cells that were directly co-cultured with HMDMs. The expressions of M-CSFR ligands (interleukin-34 and M-CSF) were also increased by co-culture with HMDMs. The proliferation of HepG2 cells (another hepatoblastoma cell line expressing M-CSFR) was inhibited by an M-CSFR inhibitor. M-CSFR was found to be highly expressed in the embryonal component and in recurrent lesions. The number of CD204-positive macrophages was also higher in the M-CSFR-positive areas than in the M-CSFR-negative areas. Thus, M-CSFR expression appeared to be induced by cell-cell contact with macrophages in hepatoblastoma cells, and M-CSFR inhibitor is potentially effective against M-CSFR-positive hepatoblastoma, especially recurrent cases.

IL-34 in hepatoblastoma cells potentially promote tumor progression via autocrine and paracrine mechanisms.

Hepatoblastoma is the most common pediatric liver tumor, but little research has been done on the role of macrophages in hepatoblastoma. The purpose of this study was to gain insight into potential roles for macrophages in hepatoblastoma. Paraffin-embedded specimens from 56 patients who underwent surgical resection were examined with immunohistochemical staining for the macrophage-specific markers, Iba1 and CD163. Significant differences were seen among histological subtypes. Significantly increased numbers of macrophages were detected in embryonal components compared to fetal components in the mixed epithelial type. In vitro studies using human monocyte-derived macrophages and two hepatoblastoma cell lines (HepG2 and Huh6) were performed. Conditioned medium from these cell lines induced increased CD163 expression in macrophages. Direct co-culture with macrophages induced tumor cell proliferation via induction of protumor cytokine secretion from macrophages. Direct co-culture with macrophages also induced interleukin (IL)-34 overexpression by Huh6 cells via Brd4 signaling. IL-34 overexpression promoted tumor cell proliferation and chemoresistance. High IL-34 and Brd4 expression was detected in embryonal components, which have potentially higher proliferation activity than fetal components. In conclusion, IL-34 expression in embryonal components may induce macrophage chemotaxis in a paracrine manner, and tumor cell proliferation and chemoresistance in an autocrine manner. IL-34 is a potential therapeutic target for hepatoblastoma.

Intellectual development of patients with biliary atresia who underwent living donor liver transplantation in infancy.

BACKGROUND: The impact of pediatric liver transplantation on intellectual development has yet to be determined. We investigated the intellectual outcomes of school-aged patients after living donor liver transplantation for biliary atresia in infancy. METHODS: The Wechsler Intelligence Scale for Children-fourth edition test was administered to 20 patients who survived [Formula: see text] 5 years after living donor liver transplantation. Borderline full scale intelligence quotient was defined as ≤ 85. Pre-, peri-, and postoperative data were compared between patients with > 85 and ≤ 85 to identify predictive factors of borderline performance. RESULTS: The one-sample t test demonstrated that the mean full scale intelligence quotient of patients after transplantation for biliary atresia was significantly lower than that of the general population (91.8 vs. 100.0, p = 0.026) and 7 (35%) were classified as intellectual borderline functioning. Multivariable logistic regression models were unable to identify any factors predictive of full scale intelligence quotients of ≤ 85. CONCLUSION: This is the first study to indicate that the mean full scale intelligence quotient among school-aged patients who underwent living donor liver transplantation for biliary atresia in infancy is significantly lower than that of the general population.

Portal Vein Complications After Adult Living Donor Liver Transplantation: Time of Onset and Deformity Patterns Affect Long-Term Outcomes.

Portal vein complications (PVCs) after adult living donor liver transplantation (LDLT) are potentially lethal. We categorized PVCs by the time of onset (early versus late, <1 month versus ≥1 month, respectively) and deformity patterns (portal vein stenosis [PVS], portal vein thrombosis [PVT], and portal vein occlusion [PVO]) to establish optimal treatment strategies. Overall, 35/322 (10.9%) recipients developed PVCs between 2000 and 2019. Pretransplant PVT (odds ratio [OR], 15.20; 95% confidence interval [CI], 3.70-62.40; P < 0.001) was the only independent risk factor for PVS. In contrast, male sex (OR, 5.57; 95% CI, 1.71-18.20; P = 0.004), pretransplant PVT (OR, 4.79; 95% CI, 1.64-14.00; P = 0.004), and splenectomy (OR, 3.24; 95% CI, 1.23-8.57; P = 0.018) were independent risk factors for PVT. PVS was successfully treated with interventional radiology regardless of its time of onset. On the other hand, late PVT and PVO had significantly lower treatment success rates (2/15, 13%) compared with those that occurred in the early period (10/11, 91%) despite aggressive intervention (P < 0.001). Deformity patterns had a significant impact on the 5-year cumulative incidence of graft loss as a result of PVC (PVO + Yerdel grades 2-4 PVT group [n = 16], 41% versus PVS + Yerdel grade 1 PVT group [n = 19], 0%; P = 0.02). In conclusion, late grades 2 to 4 PVT and PVO are refractory to treatment and associated with poor prognoses, whereas PVS has a good prognosis regardless of time of onset. A tailored approach according to the time of onset and deformity patterns of PVC is essential.

Asymptomatic hepatic artery dissection early after living-donor liver transplantation with simultaneous splenectomy: two case reports.

BACKGROUND: Hepatic artery dissection after liver transplantation is an uncommon morbidity. The onset mechanism and management for this disorder remain unclear. The present report describes the cases of two patients with hepatic artery dissection after living-donor liver transplantation (LDLT) with simultaneous splenectomy and provides new insight into the onset mechanism of this disorder. CASE PRESENTATION: CASE 1: A 51-year-old man with liver cirrhosis caused by hepatitis B virus underwent LDLT with a right lobe graft and splenectomy simultaneously. The recipient's right hepatic artery had partial dissection at the anastomosis site; therefore, his left hepatic artery was anastomosed. Contrast-enhanced computed tomography (CT) on postoperative day (POD) 27 showed dissection from his celiac artery to his left hepatic artery with bleeding in the false lumen. There was a risk of rupture of the false lumen; therefore, emergency interventional radiology and coil embolization of the false lumen were performed. The patient was doing well at 6 months after LDLT. CASE 2: A 58-year-old woman with liver cirrhosis caused by primary biliary cholangitis underwent LDLT with a left lobe graft and splenectomy simultaneously. Her hepatic artery had a dissection that extended from her left hepatic artery to the proper hepatic artery. The gastroduodenal artery was anastomosed. Contrast-enhanced CT on POD 8 revealed dissection from the celiac artery to the common hepatic artery as well as a pseudoaneurysm at the celiac artery. We managed the patient with conservative treatment and performed daily follow-ups with Doppler ultrasonography examination and serial contrast-enhanced CT. At the time of writing this report, the patient was doing well at 34 months after LDLT. CONCLUSIONS: Patients who have an intimal dissection at the anastomosis site and/or simultaneous splenectomy are at a higher risk of hepatic artery dissection. Most patients with asymptomatic hepatic artery dissections can be treated conservatively. Blood flow in the intrahepatic artery should be checked frequently using Doppler ultrasonography or contrast-enhanced CT soon after diagnosis.

The duodenal tube test is more specific than hepatobiliary scintigraphy for identifying bile excretion in the differential diagnosis of biliary atresia.

PURPOSE: Confirmation of bile excretion into the gastrointestinal tract is important to exclude biliary atresia (BA). We compared the duodenal tube test (DTT) with hepatobiliary scintigraphy (HS) for their efficiency in detecting bile secretion. METHODS: The subjects of this retrospective study were 47 infants who underwent both DTT and HS to diagnose or exclude BA between January 2000 and March 2018. RESULTS: BA was diagnosed in 32 of the 47 patients, and 7 of the remaining 15 non-BA patients underwent intraoperative cholangiography. Among the various DTT parameters, the total bile acid in duodenal fluid (DF-TBA)/serum (S) gamma-glutamyl transferase (γGTP) ratio was found to be the most specific for BA, with sensitivity and specificity of 98.0-100%, respectively. One BA patient in whom cut off values were not met was a premature infant. The sensitivity and specificity of HS were 100-56.3%, respectively. The diagnostic accuracy of the DF-TBA/S-γGTP parameter was higher than that of HS (98.6% vs. 85.1%, respectively). CONCLUSIONS: The DTT could be more a specific method than HS to detect bile excretion. Thus, the DTT should be incorporated into the multidisciplinary diagnostic approach for the differential diagnosis of BA to prevent unnecessary intraoperative cholangiography in patients who do not have BA.

Hypogenesis of right hepatic lobe in a laparoscopic cholecystectomy for acute gallstone cholecystitis: A case report.

Hypogenesis or agenesis of right hepatic lobe is a rare abnormality and is generally associated with gallbladder and biliary tract abnormalities. Cases of biliary injury following cholecystectomy have been reported in patients with agenesis of right hepatic lobe because the anatomical anomalies complicate the surgical approach. We report a case of laparoscopic cholecystectomy in a patient with hypogenesis of right hepatic lobe. A 92-year-old male patient was admitted to our hospital with fever and right lower abdominal pain with suspected acute appendicitis. Abdominal computed tomography revealed gallstones with acute cholecystitis and hypogenesis of right hepatic lobe. He underwent laparoscopic cholecystectomy with the left semilateral decubitus position. The patient's postoperative course was uneventful. In conclusions, some patients with liver lobe hypoplasia do not present with the typical symptoms of acute cholecystitis due to dislocation of the gallbladder. The left semilateral decubitus position with modified placement of port sites is useful for laparoscopic cholecystectomy in patients with hypogenesis of right hepatic lobe.

Living donor liver transplantation for a patient with a history of total gastrectomy.

Adhesions due to previous upper abdominal surgery may complicate later liver transplantation. Here we report successful living donor liver transplantation (LDLT) in a patient with a history of total gastrectomy. A 32-year-old Japanese woman developed end-stage liver failure due to alcoholic cirrhosis. She had undergone total gastrectomy, pancreato-splenectomy, and partial colectomy due to rupture of a pancreatic cyst. LDLT was performed using a right lobe graft from her sister. To minimize blood loss and injury to the jejunum, adhesions between the left lobe and nearby organs were dissected without blood flow in or out of the liver. The right liver graft was implanted uneventfully. She was extubated on postoperative day (POD) 1, but then developed septic shock due to aspiration pneumonia on POD 2. She was reintubated and antibiotics and antifungal agents were administered. Administration of tacrolimus was changed to an intravenous route on POD 3. Her condition improved and she was re-extubated on POD 9. On POD 14, tacrolimus was administered orally. She was discharged from our hospital on POD 30 without any other events and is doing well 6 months after LDLT. We believe that careful planning, such as mobilizing the left lobe with the blood flow blocked just before liver explantation, elevating the head of the bed during tube-feeding, and calculating the area under the curve after drug administration will enable liver transplantation for patients with a history of total gastrectomy.

Antibody-mediated rejection after ABO-incompatible pediatric living donor liver transplantation for propionic acidemia: A case report.

We herein present the case of a four-yr-old boy with PA who developed AMR after ABO-incompatible LDLT despite undergoing B cell desensitization using rituximab. Although the CD19+ lymphocyte count decreased to 0.1% nine days after the administration of rituximab, he developed a high fever which was accompanied by arthralgia due to a streptococcal infection 13 days after rituximab prophylaxis. After the clearance of the infection, he underwent ABO-incompatible LDLT 36 days after the administration of rituximab. The CD19+ lymphocyte count just prior to LDLT was 1.2%. He developed AMR five days after LDLT, and the antidonor-type IgM and IgG antibody titers increased to 1:1024 and 1:1024, respectively. He was treated by plasma exchange, IVIG, steroid pulse therapy, and rituximab re-administration; however, his liver dysfunction continued. Despite intensive treatment, he died due to complicated abdominal hernia, acute renal failure, and ARDS. This case suggests that a streptococcal infection may induce the activation of innate immune responses; thus, additional desensitization therapy should be considered prior to ABO-incompatible LDLT if B cell reactivation is suspected.