Effect of surgical complications on outcomes of children with hepatoblastoma: a retrospective cohort study.

PURPOSE: This study aimed to investigate the incidence of severe surgical complications among children with hepatoblastoma, identify their risk factors, and evaluate the influence of surgical complications on long-term outcomes. METHODS: Children with hepatoblastoma who underwent liver resection at our hospital between September 1992 and January 2023 were included in this study. Clinical data were retrospectively reviewed, and patients were categorized into complication and non-complication groups based on the need for radiological or surgical interventions or massive intraoperative blood loss (> 80 mL/kg). RESULTS: Out of the 40 patients, 9 experienced severe complications (massive blood loss, n = 7; bile leakage, n = 3; and common bile duct stricture, n = 1). The participation of experienced liver surgeons was significantly greater in the non-complication group than in the complication group. The median duration from surgery to the start of postoperative chemotherapy was significantly shorter in the non-complication group than in the complication group. The overall 5-year survival rate was significantly higher in the non-complication group than in the complication group. CONCLUSION: Severe surgical complications were associated with a worse prognosis. An experienced liver surgeon should participate in technically demanding liver resections.

Feasibility and safety of laparoscopic tumor resection in children with abdominal neuroblastomas.

PURPOSE: This study aimed to evaluate the feasibility and safety of laparoscopic resection of abdominal neuroblastoma by comparing operative and long-term oncologic outcomes between open and laparoscopic surgeries. METHODS: This single-center retrospective study included patients who underwent laparoscopic tumor resection, between January 2000 and June 2021, with a maximum tumor diameter of ≤ 60 mm and without image-defined risk factors (IDRFs) at surgery. Data from 35 abdominal neuroblastoma resections were reviewed and compared between the laparotomy and laparoscopic groups. RESULTS: Nineteen patients underwent laparotomy and 16 had laparoscopic tumor resection. All laparoscopic surgeries achieved complete resection without conversion to open surgery. Median blood loss was significantly lower in the laparoscopic group (0.6 mL/kg) than in the laparotomy group (8.4 mL/kg) (P < 0.0001). There were two locoregional recurrences in the laparoscopic group and two metastatic recurrences in the laparotomy group. Five-year overall survival was 93.8% in both groups. CONCLUSION: Laparoscopic resection of abdominal neuroblastomas in children is a feasible and safe procedure for tumors ≤ 60 mm in diameter with no IDRFs at surgery, with long-term outcomes equivalent to laparotomy.

Analysis of factors associated with undescended testis in patients with congenital diaphragmatic hernia.

PURPOSE: This study aimed to investigate the incidence and clinical factors associated with undescended testes (UDT) in patients with congenital diaphragmatic hernia (CDH). METHODS: We retrospectively reviewed the incidence of UDT in male neonates admitted to our institution and underwent surgery for CDH between January 2006 and December 2022. Patients were divided into two groups based on the presence or absence of UDT, and risk factors for UDT were compared between the two groups. RESULTS: Among the 66 male neonates with CDH, 16 (24.2%) developed UDT. Patients with UDT had a significantly smaller gestational age (p = 0.026), lower birth weight (p = 0.042), and lower Apgar score at 1 min (p = 0.016) than those without UDT. They had a significantly higher incidence of large diaphragmatic defects (p = 0.005), received more patch closures (p = 0.020), had a longer mechanical ventilation period (p = 0.034), and longer hospital stay (p = 0.028). Multiple logistic regression analysis revealed that large diaphragmatic defect was an independent risk factor for UDT (adjusted odds ratio of 3.87). CONCLUSION: CDH and UDT are strongly correlated. In patients with CDH, the incidence of UDT was related not only to patients' prematurity but also to the large diaphragmatic defect. Large diaphragmatic defect is an independent risk factor for UDT in patients with CDH.

Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes.

Selective carbon-carbon (C-C) bond formation in chemical synthesis generally requires prefunctionalized building blocks. However, the requisite prefunctionalization steps undermine the overall efficiency of synthetic sequences that rely on such reactions, which is particularly problematic in large-scale applications, such as in the commercial production of pharmaceuticals. Herein, we describe a selective and catalytic method for synthesizing 1,3-enynes without prefunctionalized building blocks. In this transformation several classes of unactivated internal acceptor alkynes can be coupled with terminal donor alkynes to deliver 1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols, (homo)propargyl amine derivatives, and (homo)propargyl carboxamides. This method is facilitated by a tailored P,N-ligand that enables regioselective addition and suppresses secondary E/Z-isomerization of the product. The reaction is scalable and can operate effectively with as low as 0.5 mol % catalyst loading. The products are versatile intermediates that can participate in various downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II) catalytic cycle.

Can plain chest X-ray replace computed tomography for the follow-up of children who have undergone the Nuss procedure?

PURPOSE: To establish whether new indices on plain chest X-ray (CXR) can replace those on computed tomography (CT) for the follow-up of children who have undergone the Nuss procedure. METHODS: The subjects of this retrospective study were 45 children who underwent the Nuss procedure between 2000 and 2016. The Haller index (HI) was measured by preoperative CT. Preoperative and postoperative chest deformities were evaluated by two CXR measurements: the concave rate on the lateral view (CR; the depth of the concavity divided by the anterior-posterior diameter of the rib cage) and the tracheal bifurcation angle (TBA) on the anterior view. Data are expressed as the median with range. RESULTS: The median age and HI of the children, when they underwent the Nuss procedure, was 9.3 (3.8-17.3) years and 4.5 (3.2-10.1), respectively. The preoperative CR was correlated significantly with the HI. The postoperative CR was significantly lower than the preoperative CR [pre: 0.17 (0.08-0.37), post: 0.09 (0.01-0.18), p < 0.05], and the low value was sustained after bar removal. The TBA decreased significantly after the Nuss procedure from 74.2° (55-104) preoperatively to 65.0° (45-92) postoperatively (p < 0.05). CONCLUSIONS: These results suggest that CXR can replace CT for the follow-up of patients after the Nuss procedure, with lower radiation exposure.

Enantioselective Synthesis of Pyrroloindolines via Noncovalent Stabilization of Indole Radical Cations and Applications to the Synthesis of Alkaloid Natural Products.

While interest in the synthetic chemistry of radical cations continues to grow, controlling enantioselectivity in the reactions of these intermediates remains a challenge. Based on recent insights into the oxidation of tryptophan in enzymatic systems, we report a photocatalytic method for the generation of indole radical cations as hydrogen-bonded adducts with chiral phosphate anions. These noncovalent open-shell complexes can be intercepted by the stable nitroxyl radical TEMPO· to form alkoxyamine-substituted pyrroloindolines with high levels of enantioselectivity. Further elaboration of these optically enriched adducts can be achieved via a catalytic single-electron oxidation/mesolytic cleavage sequence to furnish transient carbocation intermediates that may be intercepted by a wide range of nucleophiles. Taken together, this two-step sequence provides a simple catalytic method to access a wide range of substituted pyrroloindolines in enantioenriched form via a standard experimental protocol from a common synthetic intermediate. The design, development, mechanistic study, and scope of this process are presented, as are applications of this method to the synthesis of several dimeric pyrroloindoline natural products.

Human CD31 on porcine cells suppress xenogeneic neutrophil-mediated cytotoxicity via the inhibition of NETosis.

BACKGROUND: Xenotransplantation is one of the promising strategies for overcoming the shortage of organs available for transplant. However, many immunological obstructions need to be overcome for practical use. Increasing evidence suggests that neutrophils contribute to xenogeneic cellular rejection. Neutrophils are regulated by activation and inhibitory signals to induce appropriate immune reactions and to avoid unnecessary immune reactivity. Therefore, we hypothesized that the development of neutrophil-targeted therapies may have the potential for increased graft survival in xenotransplantation. METHODS: A plasmid containing a cDNA insert encoding the human CD31 gene was transfected into swine endothelial cells (SEC). HL-60 cells were differentiated into neutrophil-like cells by culturing them in the presence of 1.3% dimethyl sulfoxide for 48 hours. The cytotoxicity of the differentiated HL-60 cells (dHL-60) and peripheral blood-derived neutrophils was evaluated by WST-8 assays. To investigate the mechanism responsible for hCD31-induced immunosuppression, citrullinated histone 3 (cit-H3) and phosphorylation of SHP-1 were detected by a cit-H3 enzyme-linked immunosorbent assay (ELISA) and Western blotting, respectively. RESULTS: A significant decrease in dHL-60 and neutrophil-mediated cytotoxicity in SEC/hCD31 compared with SEC was seen, as evidenced by a cytotoxicity assay. Furthermore, the suppression of NETosis and the induction of SHP-1 phosphorylation in neutrophils that had been co-cultured with SEC/CD31 were confirmed by cit-H3 ELISA and Western blotting with an anti-phosphorylated SHP-1. CONCLUSION: These data suggest that human CD31 suppresses neutrophil-mediated xenogenic cytotoxicity via the inhibition of NETosis. As CD31 is widely expressed in a variety of inflammatory cells, human CD31-induced suppression may cover the entire xenogeneic cellular rejection, thus making the generation of human CD31 transgenic pigs very attractive for use in xenografts.

Correction to: Human CD200 suppresses macrophage-mediated xenogeneic cytotoxicity and phagocytosis.

In the original publication, the fifth author name was erroneously published as "Patmika Jiaravuthiasan". The correct author name should read as, "Patmika Jiaravuthisan". The original article was corrected.

Human CD200 suppresses macrophage-mediated xenogeneic cytotoxicity and phagocytosis.

PURPOSE: Various strategies, such as the generation of alpha-1,3-galactosyltransferase knocked-out pigs and CD55 transgenic pigs, have been investigated to inhibit pig to human xenogeneic rejection. Our aim is to develop strategies to overcome the hurdle of not only hyper acute rejection, but also that of cellular xenogeneic rejection (CXR). Although macrophages have been well known to play a critical role in CXR, monocyte/macrophage-mediated xenogeneic rejection has not been well studied. In this study, we evaluated the effect of CD200 in xenogeneic rejection by macrophages. METHODS: Naïve swine endothelial cells (SEC) and SEC/CD200 were co-cultured with M0 macrophages and the cytotoxicity was measured by a WST-8 assay. The phagocytosis of SEC and SEC/CD200 by macrophages was analyzed by flow cytometry. RESULTS: While CD200 failed to suppress a significant amount of cytotoxicity against SEC by monocytes, M0 macrophage-mediated cytotoxicity was significantly suppressed by human CD200. The phagocytosis by M0 macrophages was also tested. The phagocytosis assay revealed that human CD200 suppresses M0 macrophage-mediated phagocytosis. CONCLUSIONS: Our findings indicate that human CD200 suppresses the xenogeneic rejection by CD200R+ macrophages and that the generation of hCD200 transgenic pigs for use in xenografts is very attractive for preventing the macrophage-mediated rejection.

Tridentate Directing Groups Stabilize 6-Membered Palladacycles in Catalytic Alkene Hydrofunctionalization.

Removable tridentate directing groups inspired by pincer ligands have been designed to stabilize otherwise kinetically and thermodynamically disfavored 6-membered alkyl palladacycle intermediates. This family of directing groups enables regioselective remote hydrocarbofunctionalization of several synthetically useful alkene-containing substrate classes, including 4-pentenoic acids, allylic alcohols, homoallyl amines, and bis-homoallylamines, under Pd(II) catalysis. In conjunction with previous findings, we demonstrate regiodivergent hydrofunctionalization of 3-butenoic acid derivatives to afford either Markovnikov or anti-Markovnikov addition products depending on directing group choice. Preliminary mechanistic and computational data are presented to support the proposed catalytic cycle.

Magnetic compression anastomosis for postoperative biliary atresia.

We report a case of successful magnetic compression anastomosis (MCA) for obstructed cyst-jejunostomy in a young woman who had undergone surgery for type 1 biliary atresia (BA) on day 78 of life. A 16-year-old girl was admitted with obstructive jaundice. Jaundice resolved with percutaneous trans-hepatic cholangiodrainage (PTCD) but contrast medium injected from the PTCD tube did not flow through the anastomosis. Magnets were placed on each side of the anastomosis, in the cyst and the jejunum, to compress the partition. On postoperative day (POD) 6, the anastomosis was recanalized and the PTCD tube placed trans-anastomotically until POD 245. The patient remained free from jaundice after removal of the PTCD tube. MCA can be a useful and less invasive procedure for treating biliary tract anastomotic obstruction in patients with BA.

Importance of nutrient balance in severe congenital diaphragmatic hernia: A retrospective case-control study.

BACKGROUND & AIMS: Growth retardation is a common morbidity in infants with severe congenital diaphragmatic hernia (CDH). This study aimed to investigate the appropriate amount of nutrition and nutrient balance in early infants with severe CDH. METHODS: This was a retrospective case-control study. Isolated CDH patients with more than half of the chest wall devoid of diaphragmatic tissue and treated between 2006 and 2022 were included. The patients were divided into positive (n = 16) or negative (n = 8) weight gain velocity groups in early infancy (from 1 to 3 months of age). Clinical variables and amount of nutrition were compared between the two groups. RESULTS: The earlier start of enteral nutrition (EN) and higher replacement rate of the naso-duodenal (ND) tube were observed more frequently in the positive group than in the negative group. Regarding daily intake by both EN and parenteral nutrition (PN), total caloric intake and caloric intake of proteins and lipids were significantly higher in the positive group than in the negative group at 1 month of age. At 2 months, total caloric intake and caloric intake of lipids were significantly higher in the positive group than in the negative group. At 3 months of age, only caloric intake of lipid was significantly higher in the positive group than in the negative group. CONCLUSIONS: The early replacement of the ND tube may contribute to the early start of EN, which may subsequently lead to appropriate nutrient supplementation including adequate lipid administration, resulting in early catch-up growth.

Factors reducing psychological satisfaction after the Nuss procedure in pediatric patients.

PURPOSE: We examined patient satisfaction with postoperative chest appearance after Nuss procedure and analyzed the factors for postoperative low satisfaction. METHODS: We retrospectively reviewed data of 133 patients who underwent the Nuss procedure from 2000 to 2016. Their medical records, X-rays, and computed tomography scans were evaluated. Haller index and concave rate were used as objective indices of the deformity. The questionnaires were used to evaluate satisfaction with the chest appearance by a linear scale including five markers (1: dissatisfaction, 5: satisfaction). The patients were divided into two groups: the low satisfaction (score = 1, 2) and the high satisfaction (score = 3-5). RESULTS: The median age during the Nuss procedure was 7.6 (interquartile range, 5.8-12.8) years. Out of 133, 65 patients replied, and the mean postoperative satisfaction score was 3.8 ± 0.2. Out of the 65 respondents, 16 patients (24.6%) were classified as low satisfaction group. Haller index and concave rate were significantly higher and the previous instances of chest operation history were more frequent in the low satisfaction group than in the high satisfaction group, although there was no significant intergroup difference in terms of the postoperative concave rate. CONCLUSIONS: Severe deformity and previous chest operation history were considered to be factors for low satisfaction.

Factors Associated With Adverse Outcomes Following Duodenal Atresia Surgery in Neonates: A Retrospective Study.

Objectives There is limited evidence on the infants' postoperative complications who have undergone surgical repair of duodenal atresia and stenosis. This study aimed to identify the factors associated with poor surgical outcomes after the initial repair. Methods We retrospectively reviewed the data of 82 patients who underwent surgery for duodenal atresia and stenosis between January 1994 and December 2013 at our institution. Gestational age, birth weight, fetal growth, and other associated anomalies were recorded. Multivariate regression analyses were used to identify the factors associated with surgical outcomes, including postoperative complications and time to full oral intake. Results The median gestational age was 37.6 weeks, with 30 (37%) preterm (<37 weeks) and 11 (13%) early preterm (<34 weeks) infants. The median birth weight was 2531 g, with 27 (33%) patients < 2000 g and 10 (12%) patients < 1500 g. Postoperative surgical complications were identified in 18 (22%) cases, of which 12 (15%) required additional operations. Multivariate regression analysis revealed that a combination of very low birth weight (<1500 g) and early preterm was significantly associated with both surgical and non-surgical postoperative complications (p = 0.0028 and 0.021, respectively) and a prolonged time to full oral intake postoperatively (p = 0.013). Conclusion Very low birth weight and early preterm were significantly associated with postoperative complications and a prolonged time to full oral intake.

A study of the mechanisms responsible for the action of new immunosuppressants and their effects on rat small intestinal transplantation.

In a series of studies, using an identical rat intestinal transplantation model, we evaluated the effects of several drugs. FK-506 caused a significant attenuation in the proliferation of allogeneic CD4+ T cells and IFN-γ secreting effector functions. FYT720 resulted in a marked reduction in the numbers of lymphocytes, associated with a reduction of T cell recruitment, in grafts. An anti-MAdCAM antibody was next reported to significantly down-regulate CD4+ T cell infiltration in intestinal grafts by blocking the adhesion molecule, and could be useful as an induction therapy. Concerning TAK-779, this CCR5 and CXCR3 antagonist diminished the number of graft-infiltrating cells by suppressing the expression of their receptors in the graft. As a result, it reduced the total number of recipient T cells involved in graft rejection. As the next step, we focused on the participation of monocytes/ macrophages in this field. PQA-18 has been the focus of a novel immunosuppressant that attenuates not only the production of various cytokines, such as IL-2 & TNF-α, on T cells, but the differentiation of macrophages by inhibiting PAK2 as well. In this report, we summarize our previous studies not only regarding the above drugs, but on an anti-complement drug and a JAK inhibitor as well.

Mechanistic Studies of Pd(II)-Catalyzed E/Z Isomerization of Unactivated Alkenes: Evidence for a Monometallic Nucleopalladation Pathway.

Pd(II)-catalyzed E/Z isomerization of alkenes is a common process-yet its mechanism remains largely uncharacterized, particularly with non-conjugated alkenes. In this work, the mechanism of Pd(II)-catalyzed E/Z isomerization of unactivated olefins containing an aminoquinoline-based amide directing group is probed using in situ kinetic analysis, spectroscopic studies, kinetic modeling, and DFT calculations. The directing group allows for stabilization and monitoring of previously undetectable intermediates. Collectively, the data are consistent with isomerization occurring through a monometallic nucleopalladation mechanism.

Human CD200 Suppresses the HL-60 Mediated Xenocytotoxicity.

BACKGROUND: Neutrophils play an important role in xenogeneic rejection and represent a major obstacle in clinical application of xenografts. CD200 and its receptor CD200R are both type-1 membrane glycoproteins, which are members of the immunoglobulin superfamily (IgSF) and the ligation of CD200 with CD200R induces inhibitory NPXY signaling. The expression of CD200R appears in myeloid cells such as macrophages and granulocytes. Thus, we hypothesized that human CD200 expression on porcine cells might suppress the xenogeneic neutrophil-mediated cytotoxicity against porcine cells. METHODS: To prove our hypothesis, the suppressive effect of human CD200 in neutrophil-like human cell line 60 (HL-60)-mediated xenogeneic cytotoxicity against swine endothelial cells (SECs) was examined. Cytotoxicity was assessed with water-soluble tetrazolium salt 8 (WST-8) assay. RESULTS: HL-60 cells differentiated into CD66b+ CD200R+ neutrophil-like cells in the presence of dimethyl sulfoxide (DMSO). HL-60-mediated cytotoxicity against SECs was significantly suppressed by human CD200 on SECs. CONCLUSIONS: The findings in this study indicate that human CD200 may suppress neutrophil-mediated xenogeneic rejection.

The novel immunosuppressant prenylated quinolinecarboxylic acid-18 (PQA-18) suppresses macrophage differentiation and cytotoxicity in xenotransplantation.

Innate immunity plays a major role in xenograft rejection. However, the majority of immunosuppressants focus on inhibiting acquired immunity and not innate immunity. Therefore, a novel immunosuppressant suitable for use in conjunction with xenografts continues to be needed. It has been reported that prenylated quinolinecarboxylic acid-18 (PQA-18), a p21-activated kinase 2 (PAK2) inhibitor, exerts an immunosuppressive function on T cells. Hence, the possibility exists that PQA-18 might be used in conjunction with xenografts, which prompted us to investigate the efficacy of PQA-18 on macrophages compared with Tofacitinib, a janus kinase (JAK) inhibitor. Initial experiments confirmed that PQA-18 is non-toxic to swine endothelial cells (SECs) and human monocytes. Both PQA-18 and Tofacitinib suppressed macrophage-mediated cytotoxicity in both the differentiation and effector phases. Both PQA-18 and tofacitinib suppressed the expression of HLA-ABC by macrophages. However, contrary to Tofacitinib, PQA-18 also significantly suppressed the expression of CD11b, HLA-DR and CD40 on macrophages. PQA-18 significantly suppressed CCR7 expression on day 3 and on day 6, but Tofacitinib-induced suppression only on day 6. In a mixed lymphocyte reaction (MLR) assay, PQA-18 was found to suppress Interleukin-2 (IL-2)-stimulated T cell proliferation to a lesser extent than Tofacitinib. However, PQA-18 suppressed xenogeneic-induced T cell proliferation more strongly than Tofacitinib on day 3 and the suppression was similar on day 7. In conclusion, PQA-18 has the potential to function as an immunosuppressant for xenotransplantation.

Palladium(ii)-catalyzed γ-selective hydroarylation of alkenyl carbonyl compounds with arylboronic acids.

A catalytic γ-selective syn-hydroarylation of alkenyl carbonyl compounds using arylboronic acids has been developed using a substrate directivity approach with a palladium(ii) catalyst. This method tolerates a wide range of functionalized (hetero)arylboronic acids and a variety of substitution patterns on the alkene. Preliminary mechanistic studies suggest that transmetalation is rate-limiting.

A membrane-type surfactant protein D (SP-D) suppresses macrophage-mediated cytotoxicity in swine endothelial cells.

OBJECTIVE: Surfactant protein D (SP-D), which is secreted mainly in the lung, is an oligometric C type lectin that promotes phagocytosis by binding to carbohydrates on microbial surfaces. SP-D can also bind SIRPα, leading to a decrease in cytokine production by monocytes/macrophages. In the present study, we examined the possibility that SP-D suppresses macrophage-mediated xenogeneic cytotoxicity, by creating a membrane-type SP-D. METHODS: The cDNA for the carbohydrate recognition domain (CRD) of human SP-D was switched to that of a membrane-type protein, collectin placenta 1 (CL-P1), with a Flag-tag. The cDNA of CD47 was prepared as a control. The suppressive function of the membrane-type protein of the hybrid molecule, CL-SP-D, to monocytes/macrophages was then studied and the results compared with that for CD47. RESULTS: The expression of Flag-tagged CL-SP-D on the transfected SECs and the SIRPα on monocyte-like cells, THP-1 cells, was confirmed by FACS using anti-Flag Ab and anti-CD172a, respectively. The molecular size of the hybrid protein was next assessed by western blot. While significant cytotoxicity against SEC was induced in differentiated THP-1 cells, CL-SP-D significantly reduced THP-1-mediated cytotoxicity. In addition, phosphorylated SHP-1 was clearly detected in SEC/CL-SP-D in western blots. Moreover, IL-10 production was upregulated and IL-1ß production was suppressed in the case of THP-1 and SEC/CL-SP-D, compared with naïve SEC. Next, the cytotoxicity caused by the in vitro generated macrophage was assessed under the same conditions as were used for THP-1. CL-SP-D also showed the significant down-regulation on the macrophage. In addition, changes in IL-10 production by the macrophage confirmed the results. CONCLUSIONS: These findings indicate that the membrane-type SP-D serve as an effective therapeutic strategy for inhibiting macrophage-mediated xenograft rejection in xenotransplantation.