Optimal transplant strategy of pediatric liver transplantation for fibropolycystic liver disease: Multicenter retrospective study in Japan.

AIM: To assess the preoperative disease characteristics and indications for living donor liver transplantation (LDLT), complications, patient survival, and prognosis after LDLT for fibropolycystic liver disease (FLD) in children. METHODS: We undertook a cross-sectional survey of patients who underwent LDLT for FLD between January 2002 and December 2020. RESULTS: A total of 35 patients (22 male and 13 female individuals) with FLD were included in this study, of whom 19 (54.3%) had isolated congenital hepatic fibrosis and 16 (45.6%) had Caroli syndrome. Refractory gastrointestinal bleeding was the most frequent symptom related to the indication for LDLT, being found in 48.6% of our patients, followed by uncontrollable cholangitis and ascites. The median age at the time of LDLT was 8.1 years old. Of the 27 patients presenting with renal involvement, 13 patients required kidney transplantation (KT). Overall, the renal function after LDLT decreased regardless of renal involvement; however, patients with renal involvement had a significantly lower estimated glomerular filtration rate than those without renal involvement throughout the course of this study (p < 0.01). The 5-year overall patient survival rate was 97.1%. Two patients died with a median follow-up of 8.9 years after LDLT; one died due to sepsis 2 weeks after simultaneous liver-kidney transplantation and the other committed suicide 10 years after LDLT. CONCLUSION: The prognosis of the pediatric patients who underwent LDLT for FLD was excellent. However, an individualized treatment approach based on the status of the renal function and liver disease is important, as a certain proportion of patients require KT.

Potential role of stem cells from human exfoliated deciduous teeth in inducing liver regeneration.

BACKGROUND AND AIM: Even with advancement of medical technologies, liver transplantation still faces several major challenges. Hence, other treatment modalities are urgently needed for patients with end-stage liver disease. Stem cells from human exfoliated deciduous teeth (SHED) was discovered to have highly proliferative and pluripotent properties; including differentiation into hepatocyte-like cells. This study aims to investigate the capability of intrasplenic transplanted SHED and SHED-Hep cells in inducing proliferation of stem cells and native hepatocytes in order to accelerate liver regeneration in liver fibrosis mice models. METHODS: Three carbon tetrachloride (CCl4)-injured male mice groups were used in this study. Two of those groups were transplanted with either SHED or SHED-Hep, while the other did not undergo transplantation. One age- and sex- matched healthy mice group was used as control. All specimens were immunohistochemically stained with anti-Ki-67 antibodies and anti-proliferating cell nuclear antigen (PCNA) antibodies before counter stained with hematoxylin-eosin. RESULTS: Anti-Ki-67 antibodies staining: at both 8 and 12 weeks, proliferating activity was predominantly seen on both SHED- and SHED-Hep-transplanted CCl4-injured mice groups, while control and non-transplanted CCl4-injured mice group showed little to no sign of proliferation activity. Anti-PCNA staining: at both 8 and 12 weeks, significant proliferating activity was detected by PCNA staining, mainly on stem cells population area on SHED- and SHED-Hep-treated group. CONCLUSIONS: In conclusion, this study has provided the evidence that transplantation of SHED or SHED-Hep on liver-injured mice induced proliferation of both transplanted stem cells and native liver cells in order to accelerate liver regeneration.

Current Status and Outcomes of Living Donor Liver Transplantation for Pediatric Acute Liver Failure: Results From a Multicenter Retrospective Study Over Two Decades.

BACKGROUND: Although the outcomes of living donor liver transplantation (LDLT) for pediatric acute liver failure (PALF) have improved, patient survival remains lower than in patients with chronic liver disease. We investigated whether the poor outcomes of LDLT for PALF persisted in the contemporary transplant era. METHODS: We analyzed 193 patients who underwent LDLT between December 2000 and December 2020. The outcomes of patients managed in 2000-2010 (era 1) and 2011-2020 (era 2) were compared. RESULTS: The median age at the time of LDLT was 1.2 years both eras. An unknown etiology was the major cause in both groups. Patients in era 1 were more likely to have surgical complications, including hepatic artery and biliary complications (p = 0.001 and p = 0.013, respectively). The era had no impact on the infection rate after LDLT (cytomegalovirus, Epstein-Barr virus, and sepsis). The mortality rates of patients and grafts in era one were significantly higher (p = 0.03 and p = 0.047, respectively). The 1- and 5-year survival rates were 76.4% and 70.9%, respectively, in era 1, while they were 88.3% and 81.9% in era 2 (p = 0.042). Rejection was the most common cause of graft loss in both groups. In the multivariate analysis, sepsis during the 30 days after LDLT was independently associated with graft loss (p = 0.002). CONCLUSIONS: The survival of patients with PALF has improved in the contemporary transplant era. The early detection and proper management of rejection in patients, while being cautious of sepsis, should be recommended to improve outcomes further.

Successful endoscopic approach for peripheral neuroblastic tumors in children.

BACKGROUND: Recently, reports of endoscopic approaches for neuroblastoma, ganglioneuroblastoma, and ganglioneuroma (peripheral neuroblastic tumor; PNTs) have been increasing. This study aimed to clarify the indications for endoscopic surgery for PNTs. METHODS: Pediatric patients who underwent endoscopic surgery for PNTs at our institution were included in this study. Image-defined risk factors (IDRFs) were analyzed using preoperative computed tomography (CT). RESULTS: Twenty-four patients underwent endoscopic surgery for PNTs. The diagnoses included neuroblastoma (n = 11), ganglioneuroma (n = 10), and ganglioneuroblastoma (n = 3). Regarding the tumor site, there were 18 cases of adrenal tumors, five cases of mediastinal tumors, and one case of retroperitoneal tumors. Image-defined risk factors were positive in eight cases (contacted with a renal vessel, n = 6; compression of principal bronchi, n = 2). Complete resection was accomplished in 21 cases (14 of 16 IDRF-negative cases and seven of eight IDRF-positive cases). All patients survived without recurrence during the follow-up period. CONCLUSIONS: The CT findings of contact with renal vessels and compression of principal bronchi do not seem to be indicators of incomplete resection. An endoscopic approach to PNTs in pediatric patients is feasible with a good prognosis if patients are selected strictly.

Factors predicting the need for liver transplantation in biliary atresia patients after 18 years of age.

PURPOSE: We aimed to identify factors predicting the need for future liver transplantation (LT) at 18 years of age in patients with biliary atresia (BA). METHODS: BA patients with native liver survival at > 18 years of age were retrospectively reviewed. The clinical characteristics, outcomes, hepatobiliary function, and liver fibrosis markers of native liver survivors (NLS group) were compared with patients who subsequently underwent LT (LT group). RESULTS: The study population included 48 patients (NLS, n = 34; LT, n = 14). The male-to-female ratio, age at Kasai procedure, and type of BA in the two groups did not differ to a statistically significant extent. There was no significant difference in the MELD scores between the groups at 18 years of age. The aspartate aminotransferase-to-platelet ratio index (APRI), albumin-bilirubin (ALBI), and BA liver fibrosis (BALF) scores at 18 years of age were significantly higher in the LT group. The AUCs for APRI, ALBI, and BALF were 0.91, 0.79, and 0.85, respectively. CONCLUSION: Adult BA patients have limited options for LT owing to the lack of donor candidates and the low prevalence of deceased donors. The elucidation of prognostic factors for LT in adulthood is important. APRI was the most useful marker in this study.

A retrospective study investigating the risk of graft loss in living donor liver transplant cases where size mismatching is predicted from graft-to-recipient weight ratio.

BACKGROUND/PURPOSE: Living donor liver transplantation (LDLT) is vital for pediatric end-stage liver disease due to organ shortages. The graft-to-recipient weight ratio (GRWR) preoperatively measured predicts the outcomes of LDLT. We typically target between 0.8 and 3.0-4.0%, but the ideal GRWR remains controversial. We compared the outcomes of LDLT according to the GRWR to examine whether the criteria could be expanded while ensuring safety. METHODS: We retrospectively reviewed 99 patients who underwent LDLT in our department by dividing them into three groups according to their GRWR: Group S, with GRWR values lower than the normal range (GRWR < 0.8%); Group M, with GRWR values in the normal range (GRWR ≥ 0.8 to < 3.5%); and Group L, with GRWR values above the normal range (GRWR ≥ 3.5%). RESULTS: In Groups S and L, 46.2 and 44.4% of patients underwent splenectomy and delayed abdominal wall closure, respectively. After these intraoperative adjustments, there were no significant differences between the groups in 5-year patient survival, 5-year graft survival, or the occurrence of post-transplantation thrombosis. CONCLUSION: When the GRWR is beyond the normal threshold, the risk of complications associated with graft size might be reduced by adjustments to provide appropriate portal blood flow and by delayed abdominal wall closure.

A lmod1a mutation causes megacystis microcolon intestinal hypoperistalsis in a CRISPR/Cas9-modified zebrafish model.

PURPOSE: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is defined as a congenital visceral myopathy with genetic mutations. However, the etiology and pathophysiology are not fully understood. We aimed to generate a gene leiomodin-1a (lmod1a) modification technique to establish a zebrafish model of MMIHS. METHODS: We targeted lmod1a in zebrafish using CRISPR/Cas9. After confirming the genotype, we measured the expression levels of the target gene and protein associated with MMIHS. A gut transit assay and spatiotemporal mapping were conducted to analyze the intestinal function. RESULTS: Genetic confirmation showed a 5-base-pair deletion in exon 1 of lmod1a, which caused a premature stop codon. We observed significant mRNA downregulation of lmod1a, myh11, myod1, and acta2 and the protein expression of Lmod1 and Acta2 in the mutant group. A functional analysis of the lmod1a mutant zebrafish showed that its intestinal peristalsis was fewer, slower, and shorter in comparison to the wild type. CONCLUSION: This study showed that targeted deletion of lmod1a in zebrafish resulted in depletion of MMIHS-related genes and proteins, resulting in intestinal hypoperistalsis. This model may have the potential to be utilized in future therapeutic approaches, such as drug discovery screening and gene repair therapy for MMIHS.

Qualitative inductive analysis of the lives of women with persistent cloaca based on their narratives.

PURPOSE: The study aimed to explore and describe the lives of patients with persistent cloaca (PC) from childhood to adulthood. METHODS: Semistructured interviews were conducted with nine adult patients with PC. Their experiences and thoughts regarding this disease were analyzed qualitatively and inductively. RESULTS: After classifying the experiences and thoughts of patients with PC, 13 categories were extracted. The following five themes emerged from these categories. (1) Difficulties with excretion and vaginal management because of the disease. (2) The degree of understanding of those around them and society has a huge effect on their way of life. (3) The inferiority of a woman who is not a "normal woman." (4) A "never-ending disease" in which problems continue even after the transition period. (5) Differences in the central point of the narrative depending on the age group. CONCLUSIONS: In this study, qualitative and inductive analyses of data from semistructured interviews with patients with PC revealed their experiences and thoughts. The results will provide a guide for young patients and the medical professionals who treat them. Accordingly, monitoring their lives until adulthood is necessary.

Efficacy and Safety of Teduglutide in Infants and Children With Short Bowel Syndrome Dependent on Parenteral Support.

OBJECTIVES: Our objective was to evaluate the short- and long-term safety and efficacy of teduglutide treatment in infants and children with short bowel syndrome with intestinal failure (SBS-IF). METHODS: Two open-label phase 3 studies and 1 extension study investigated the short- and long-term safety and efficacy of teduglutide (0.05 mg/kg/day) in infants and children with SBS-IF: NCT03571516, 24-week study of infants who were randomized to receive teduglutide or standard of care (SoC); NCT02980666, 24-week study of infants and children who all received teduglutide; and NCT03268811, 24-week extension study of patients who completed NCT02980666 (patients could receive up to 48 weeks of total treatment). RESULTS: Twelve infants and 8 children enrolled in the core studies, and 2 infants and 7 children in the extension study. After 24 weeks of treatment, parenteral support (PS) requirements reduced by ≥20% from baseline for 4 infants (57.1%) and 4 children (66.7%) receiving teduglutide and for 2 infants receiving SoC (50.0%). One infant (50.0%) and 4 children (80.0%) receiving teduglutide maintained the ≥20% reduction in PS at 48 weeks of treatment. Two children receiving teduglutide achieved enteral autonomy, after 12 weeks and 28 weeks of treatment, respectively. All adverse events (AEs) were in line with known impacts of SBS-IF and adverse reactions to teduglutide. Only one serious AE (abdominal pain) was considered related to teduglutide. CONCLUSIONS: Short- and long-term treatment with teduglutide resulted in clinically meaningful reductions in PS requirements for infants and children with SBS-IF. Teduglutide was well tolerated, and efficacy improved with longer-term treatment.

Surgical outcome and prognosis of pediatric solid-pseudopapillary neoplasm.

BACKGROUND: The aim of this study was to clarify the characteristics and outcomes of pediatric patients with solid pseudopapillary neoplasms (SPNs) who underwent pancreatectomy. METHODS: Pediatric patients with SPNs who underwent pancreatectomy at our institution between 1995 and 2020 were included in the study. RESULTS: During the period under review, 12 patients underwent pancreatectomy for SPNs (median age: 10 years; range: 6-15 years). The surgical procedures included pancreatoduodenectomy (n = 2; 16.6%), distal pancreatectomy (n = 3; 25%), and enucleation (n = 7; 58.3%). The most common postoperative complication was postoperative pancreatic fistula (n = 6; 50%). Patients who underwent enucleation tended to have higher postoperative complication rates compared with those who underwent other procedures. All patients were alive without recurrence at the end of the study period. CONCLUSIONS: SPN is associated with a good prognosis, regardless of the surgical procedure. If surgeons select enucleation for pediatric SPNs, they should bear in mind that it is associated with a higher complication rate.

Cutting-edge regenerative therapy for Hirschsprung disease and its allied disorders.

Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy. Notably, HSCR involving the small intestine, isolated hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction, and megacystis-microcolon-intestinal hypoperistalsis syndrome carry a poor prognosis. Ultimately, small-bowel transplantation (SBTx) is necessary for refractory cases, but it is highly invasive and outcomes are less than optimal, despite advances in surgical techniques and management. Thus, regenerative therapy has come to light as a potential form of treatment involving regeneration of the enteric nervous system, mesenchyme, and smooth muscle in affected areas. We review the cutting-edge regenerative therapeutic approaches for managing HSCR and AD-HSCR, including the use of enteric nervous system progenitor cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells as cell sources, the recipient intestine's microenvironment, and transplantation methods. Perspectives on the future of these treatments are also discussed.

Present state of intestinal transplantation in Japan.

INTRODUCTION: Intestinal transplantation (ITx) is the ultimate treatment for intestinal failure (IF). In Japan, most cases of IF are a result of pediatric disease, including secondary or congenital intestinal disease or allied disorders of Hirschsprung's disease. Here, we report the results of the Japanese ITx registry. METHODS: A web-based survey form was completed. We investigated the number, age, sex, indication, surgical procedure, immunosuppressants, postoperative course, and the effects of transplantation in patients who underwent cadaveric or living-donor ITx. RESULTS: By the end of 2022, 42 cases of ITx have been performed in 38 patients in Japan. The donor sources included cadavers (29 cases) and living donors (13 cases). The surgical method was isolated ITx (N = 40) and combined liver and ITx (n = 2). Survival rates were 92%, 73%, and 59% at 1 year, 5 years, and 10 years, respectively. Ninety percent of patients completely discontinued parenteral nutrition. Approximately 80% of the patients had a performance status of 1 or less, indicating that the QOL of patients after ITx was extremely good. CONCLUSION: The results of ITx are acceptable to treat IF patients and the QOL after transplantation is also good.

The advantages of duct-to-duct biliary reconstruction in pediatric living donor liver transplantation.

BACKGROUND/PURPOSE: Whether Roux-en-Y hepatic jejunectomy (HJ) or duct-to-duct biliary reconstruction (DD) is more useful in pediatric living donor liver transplantation has not yet been fully investigated. Therefore, to assess the feasibility and safety of DD, we compared the surgical outcomes of DD to HJ. METHODS: We divided 45 patients, excluding those with biliary atresia, into the DD group (n = 20) and the HJ group (n = 25), according to the type of biliary reconstruction they received. RESULTS: The 5-year survival rates (DD vs. HJ = 79.7% vs. 83.6%, p = 0.70) and the incidence of biliary complications, including bile leakage and stricture (DD vs. HJ = 1 [5.0%] vs. 1 [4.0%], p = 0.87) were not significantly different between the groups. However, intestinal complications, including bowel perforation or ileus, were significantly common in the HJ group (9/25 [36.0%]) than in the DD group (1/20 [5.0%]; p = 0.01). The three patients in the HJ group with intestinal perforation all suffered perforation at the anastomosed site in the Roux-en-Y procedure. The subgroup analysis showed the non-inferiority of DD to HJ for biliary or intestinal complications in patients weighting < 10 kg. CONCLUSION: With a proper selection of cases, DD should be a safe method for biliary reconstruction in pediatric recipients with little risk of biliary complications equivalent to HJ and a reduced risk of intestinal complications.

Pilot study to determine the safety and feasibility of deceased donor liver natural killer cell infusion to liver transplant recipients with hepatocellular carcinoma.

Liver transplantation (LT) is a viable treatment option for cirrhosis patients with hepatocellular carcinoma (HCC). However, recurrence is the rate-limiting factor of long-term survival. To prevent this, we conducted the phase I study of the adoptive transfer of deceased donor liver-derived natural killer (NK) cells. Liver NK cells were extracted from donor liver graft perfusate and were stimulated in vitro with IL-2. The patient received an intravenous infusion of NK cells 3-5 days after LT. Eighteen LT recipients were treated. There were no severe cell infusion-related adverse events or acute rejection episodes. One patient withdrew from the study because the pathological observation revealed sarcoma instead of HCC. All patients who received this immunotherapy completed the follow-up for at least 2 years without evidence of HCC recurrence (median follow-up, 96 months [range, 17-121 months]). Considering that 9 (52.9%) of the 17 patients pathologically exceeded the Milan criteria, liver NK cell infusion is likely to be useful for preventing HCC recurrence after LT. This is the first-in-human immunotherapy study using deceased donor liver-derived NK cells to prevent HCC recurrence after LT. This treatment was well tolerated and resulted in no HCC recurrence after LT.Clinical trial registration www.clinicaltrials.gov ; NCT01147380; registration date: June 17, 2010.

Serum matrix metalloproteinase-7 in biliary atresia: A Japanese multicenter study.

BACKGROUND: Biliary atresia (BA) is among the commonest indications for liver transplantation (LT) in children. We examined whether serum matrix metalloproteinase-7 (MMP-7) is useful for diagnosis of BA in Japanese infants, and whether serum MMP-7 concentrations before and after Kasai portoenterostomy (KP) predicted LT within a year. METHODS: Subjects under 6 months old at eight pediatric centers in Japan were enrolled retrospectively, including patients with cholestasis and normal controls (NC) without liver disease. Patients with cholestasis were divided into groups representing BA versus cholestasis from other causes (non-BA). Serum samples were collected from patients with BA at diagnosis and 1 and 4 weeks after KP, as well as from non-BA and NC. RESULTS: Serum MMP-7 concentrations were significantly higher in BA at diagnosis (median, 89.1 ng/ml) than in non-BA (11.0; p < 0.001) or NC (10.3; p < 0.001). Receiver operating characteristic (ROC) analysis of MMP-7 for BA versus non-BA yielded an area under the ROC curve of 0.99 (95% confidence interval, 0.96-1.00). An optimal cut-off value of 18.6 ng/ml for serum MMP-7 in diagnosing BA demonstrated sensitivity and specificity of 100% and 90%, respectively. Serum MMP-7 before and 1 week and 4 weeks after KP did not differ significantly between BA requiring only KP and BA requiring LT after KP. CONCLUSION: Serum MMP-7 is a useful marker for diagnosis of BA in Japanese infants, but it could not predict LT within a year.

Characteristics of intussusception in the period of arbitrary Rotavirus vaccination.

BACKGROUND: In November 2011, rotavirus (RV) vaccine was launched in Japan as a voluntary vaccination to prevent RV-associated gastroenterocolitis. We examined the characteristics of intussusception following RV vaccination in our two centers. METHODS: We investigated intussusception patients <16 years old from January 2006 to September 2020. Patients were categorized according to the period (before [Group A] or after the introduction of arbitrary RV vaccination [Group B]). The patient characteristics and treatment of intussusception were retrospectively investigated. RESULTS: During the study period, 560 patients (group A, n = 233; group B, n = 327) were identified. The distribution of patients who were 0-6 months old was not significantly different between the groups (group A, n = 12, 5.2%; group B, n = 18, 5.5%). Among these 18 patients in Group B, 7 were vaccinated against RV, and 10 were not. One patient was excluded due to incomplete data. On comparing patients with and without RV vaccination, the mean age at the onset of intussusception was 3.3 ± 0.4 versus 4.0 ± 0.3 months (P = 0.19), the mean interval from the onset to treatment was 7.5 ± 2.4 versus 16.0 ± 2.2 h (P = 0.03), the time of the contrast enema for treatment was 9.1 ± 3.3 versus 7.7 ± 2.8 min (P = 0.76), and the final pressure of the contrast enema was 92.5 ± 4.4 versus 92.2 ± 4.4 cmH2 O (P = 0.97). CONCLUSIONS: Arbitrary RV vaccination did not influence the age distribution of intussusception, and the interval from the onset to treatment was significantly shorter in the patients with RV vaccination than in those without it. Recognizing the presence of intussusception following RV vaccination enables accurate treatment.

Effects of changes in skeletal muscle mass on the prognosis of pediatric malignant solid tumors.

PURPOSE: This study aims to clarify the relationship between changes in skeletal muscle mass during treatment and prognosis of pediatric malignant solid tumors. METHODS: Patients with pediatric malignant solid tumors who were treated at Kyushu University Hospital from 2007 to 2017 were divided into two groups: the progression-free survival (PFS) group and the relapse/death (R/D) group; the psoas major muscle volume (PMV) was then compared. We also measured the PMV and psoas muscle area (PMA) of pediatric patients with no complications who underwent surgery for acute appendicitis (control) and compared the values with those of patients with malignant tumors. RESULTS: No significant differences were observed in the PMV and PMA between patients with appendicitis and those with malignant tumors. Significant differences were found in the rate of change in PMV between the PFS (1.424) and R/D groups (1.071) (P = 0.0024). When the cut-off value of the rate of change in the PMV was 1.20, patients whose rate of change in PMV was ≥ 1.20 had longer PFS (P = 0.0231) and overall survival (P = 0.0229) than those whose rate of change was < 1.20. CONCLUSION: Pediatric patients with malignant solid tumors and increased skeletal muscle mass during treatment have a good prognosis.

"A salvage technique using a fibrous sheath to avoid the loss of the central veins in cases of pediatric intestinal failure".

PURPOSE: The number of accessible central veins (CVs) affects the prognosis of patients with intestinal failure (IF). The loss of residual CVs should be avoided. We, therefore, evaluated the efficacy of a new CV catheter-exchange technique using a subcutaneous fibrous sheath (FS) in pediatric IF patients. METHODS: We retrospectively collected the CV catheter (CVC) data of pediatric IF patients managed from January 2009 to December 2019. The data were divided into two groups; Groups 1 (CVCs placed with the FS method) and Group 2 (CVCs placed by the primary or another insertion). The main outcome was the CVC indwelling time. RESULTS: Eighty-five CVCs were analyzed. The FS method was attempted in 47 cases and succeeded in 40 (85%). No significant difference was observed between the groups regarding characteristics. A log-rank test revealed an equivalent CVC indwelling time between the two groups (Group 1: 268 [126-588] days vs. Group 2: 229 [126-387] days, p = 0.256). CONCLUSIONS: The FS method is highly recommended for pediatric IF patients, as its attempt showed a high success rate with an indwelling time equivalent to primary insertion. The FS method leads to the prolonged use of a single CV and thereby contributes to improving the outcomes of pediatric IF patients.

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.

Survival outcomes of very low birth weight infants with trisomy 18.

Trisomy 18 (T18) is one of the most commonly diagnosed aneuploidies leading to poor survival outcome. However, little is known about the dual risk of T18 and very low birth weight (VLBW, weighing <1500 g at birth). We aimed to investigate the survival and clinical features of VLBW infants with T18. In this observational cohort study, infants with T18 admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2019 were eligible. Among 30 infants with T18 who were enrolled as study participants, 11 (37%) were born with VLBW. VLBW infants had lower gestational age (34.4 vs. 39.4 weeks, p < 0.01) and a higher incidence of esophageal atresia (64% vs. 11%, p < 0.01) than non-VLBW infants. The proportions of patients who underwent any surgery (55% vs. 5%, p < 0.01) and positive pressure ventilation (82% vs. 32%, p = 0.02) were higher in VLBW than non-VLBW infants. One-year overall survival rate (45% vs. 26%, p = 0.32 by log-rank test) did not differ between the two groups. In conclusion, being born at VLBW may not be fatal for infants with T18 undergoing active interventions.