Publications by authors named "Hiroomi Okuyama"

187 Publications

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

Asian J Endosc Surg 2022 Aug 13. Epub 2022 Aug 13.

Department of Pediatric Surgery, Graduate School of Medicine Osaka University, Osaka, Japan.

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.
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http://dx.doi.org/10.1111/ases.13111DOI Listing
August 2022

Suppression of xenogeneic innate immune response by a membrane-type human surfactant protein-A.

Exp Ther Med 2022 Sep 26;24(3):590. Epub 2022 Jul 26.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

Macrophage-mediated xenogeneic rejection is a major immunological obstacle. We recently reported that membrane-type surfactant protein-D (SP-D) on swine endothelial cells (SECs) suppressed macrophage-mediated rejection. Similar to SP-D, the carbohydrate recognition domain of surfactant protein-A (SP-A) can induce inhibitory signals in effector cells. The present study aimed to examine the suppressive effect of SP-A on macrophage-mediated xenogeneic rejection. Naive SECs and SPA-transfected SECs (SEC/SP-A) were co-cultured with THP-1 cells and cytotoxicity was evaluated. To investigate the effect of SP-A on phagocytosis, human macrophages were co-cultured with SEC or SEC/SP-A, and the extent of phagocytosis and production of reactive oxygen species were assessed via flow cytometry. The mRNA expression levels of inflammatory cytokines in macrophages were determined using reverse transcription-PCR. Additionally, the effects of THP-1-Lucia NF-κB cells on transcription factors were evaluated. The cytotoxicity and phagocytosis of SEC/SP-A were significantly decreased compared with those of naive SEC. Furthermore, the co-culture of human macrophages with SEC/SP-A decreased reactive oxygen species production, and the mRNA expression levels of TNFα were decreased in macrophages, whereas those of IL-10 were increased. In addition, NF-κB transcription was decreased in SEC/SP-A compared with that in SEC. In conclusion, the ectopic expression of human SP-A in porcine cells represents an attractive method for suppressing macrophage-mediated cytotoxicity.
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http://dx.doi.org/10.3892/etm.2022.11527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353545PMC
September 2022

Laparoscopic Percutaneous Extraperitoneal Closure for Hydrocele of the Canal of Nuck in Children.

J Laparoendosc Adv Surg Tech A 2022 Jul 29. Epub 2022 Jul 29.

Department of Pediatric Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.

Hydrocele of the canal of Nuck (HCN) is a rare cause of inguinal swelling in women. The optimal surgical procedure for HCN in children remains unclear. To assess the safety and efficacy of laparoscopic percutaneous extraperitoneal closure (LPEC) for HCN in a pediatric population, a retrospective study was conducted. In addition, to clarify the pathogenesis of HCN, we assessed the morphological findings of the internal inguinal ring (IIR). We retrospectively analyzed 10 consecutive female patients with HCN who underwent LPEC at our hospital between January 2010 and May 2020. Age, operative time, and complications were recorded. Concerning the findings of the IIR, we classified the morphological features as follows: Type 1 (flat), Type 2 (narrow patent processus vaginalis [PPV] with a peritoneal veil), and Type 3 (widely opening PPV). The median age of patients who underwent LPEC was 3 (1-12) years. Although 2 patients showed contralateral inguinal hernia (IH), there were no cases of ipsilateral IH. All patients showed ipsilateral PPV, and the morphological features of the IIR were mostly classified as Type 3 (70%). In total, 6 of 8 HCN cases without preoperatively diagnosed contralateral IH had contralateral PPV (75%), and all were closed by LPEC. All operations were accomplished laparoscopically, and the postoperative course was uncomplicated, with no recurrences observed during the study period. LPEC is a safe and simple surgical approach to repair the HCN in children with minimal complications.
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http://dx.doi.org/10.1089/lap.2021.0885DOI Listing
July 2022

Thoracoscopic segmentectomy for congenital pulmonary airway malformation arising in a lung with an accessory fissure: A case report.

Asian J Endosc Surg 2022 Jul 19. Epub 2022 Jul 19.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Congenital pulmonary airway malformation is a rare congenital lung lesion. This report documents the successful application of thoracoscopic segmentectomy in a 1-year-old boy prenatally diagnosed with congenital pulmonary airway malformation. Preoperative imaging studies revealed a microcystic lesion with a region of consolidation in the middle area of the right lung. Elective thoracoscopic resection was performed when the patient was aged 1 year and 4 months. Intraoperatively, the superior segment of the right lower lobe was partially separated from the normal lower lobe by a superior accessory fissure. A solid mass, fused with this segment, shared the visceral pleura. Thoracoscopic segmentectomy was successfully performed, and the patient had an uneventful postoperative course. Histological examination revealed congenital pulmonary airway malformation stocker type 2. Thoracoscopic segmentectomy is a viable surgical option that preserves the normal lung parenchyma in pediatric patients with congenital pulmonary airway malformation.
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http://dx.doi.org/10.1111/ases.13112DOI Listing
July 2022

Suppression of macrophage-mediated xenogeneic rejection by the ectopic expression of human CD177.

Transpl Immunol 2022 Oct 11;74:101663. Epub 2022 Jul 11.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan; Meiji University International Institute for Bio-Resource Research, Kanagawa, Japan.

Cellular xenogeneic rejection by the innate immune system is a major immunological obstruction that needs to be overcome for the successful clinical use of xenografts. Our focus has been on macrophage-mediated xenogeneic rejection, since suppressing macrophage function has considerable potential for practical applications in the area of xenotransplantation. We report herein on an investigation of the suppressive effect of human CD177 (hCD177) against macrophage-mediated xenogeneic rejection. Wild type swine aortic endothelial cell (SEC) and an SEC transfectant with hCD177 (SEC/hCD177) were co-cultured with macrophages, and the degree of cytotoxicity was evaluated by WST-8 assays, and phagocytosis was examined using Calcein-AM labeling methods. The expression of anti/pro-inflammatory cytokines was evaluated by RT-qPCR and the phosphorylation of SHP-1 on macrophages in co-culture was evaluated by Western blotting. The result of cytotoxicity assays indicated that hCD177 suppressed M1 macrophage-mediated xenogeneic rejection (vs. SEC, p < 0.0001). Similarly, the result of phagocytosis assays indicated that hCD177 suppressed it (vs. SEC, p < 0.05). In addition, hCD177 significantly suppressed the expression of IL-1β, a pro-inflammatory cytokine, in M1 macrophages (vs. SEC, p < 0.01). Luciferase assays using THP1-Lucia NF-kB also showed a significant difference in NF-kB activation (vs. SEC, p < 0.001). In addition, hCD177 was found to induce the phosphorylation of SHP-1 in M1 macrophages (vs. SEC, p < 0.05). These findings indicate that hCD177 suppresses M1 macrophage-mediated xenogeneic rejection, at least in part via in the phosphorylation of SHP-1.
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http://dx.doi.org/10.1016/j.trim.2022.101663DOI Listing
October 2022

Ileocecal valve-sparing surgery for duplication cysts in the terminal ileum: two case reports and literature review.

Surg Case Rep 2022 Jul 6;8(1):130. Epub 2022 Jul 6.

Department of Pediatric Surgery, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita-shi, Osaka, Japan.

Background: Duplication cysts close to the ileocecal valve are usually treated with ileocecal resection. However, loss of the ileocecal valve will lead to problems, especially in infants. Mucosectomy of the cyst would be a better alternative that preserves the ileocecal valve. We report two cases of duplication cyst in the terminal ileum successfully treated with mucosectomy.

Case Presentation: Case 1. A 3-month-old boy with bilious emesis and abdominal distention was referred to our hospital with a diagnosis of small bowel obstruction caused by an abdominal cyst. Computed tomography revealed a cystic mass compressing the terminal ileum and causing mechanical small bowel obstruction. His general condition deteriorated quickly; emergency laparotomy was performed. Although the small intestines were dilated and partially twisted, there was no necrosis. Following intestinal decompression, a cystic mass adjacent to the terminal ileum was confirmed on the mesenteric side. Cyst mucosectomy was performed to preserve the ileocecal valve.

Case 2: A 5-month-old boy with sudden onset of hematochezia was referred to our hospital with a diagnosis of intussusception. Following unsuccessful contrast enemas, emergency surgery was performed. A cystic mass adjacent to the terminal ileum was confirmed; there was no intussusception. Cyst mucosectomy was performed. Both patients had an uneventful postoperative course.

Conclusions: Cyst mucosectomy, which preserves the ileocecal valve, is safe and effective for treating duplication cysts in the terminal ileum.
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http://dx.doi.org/10.1186/s40792-022-01483-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259777PMC
July 2022

Long-Term Outcomes of Congenital Diaphragmatic Hernia: Report of a Multicenter Study in Japan.

Children (Basel) 2022 Jun 8;9(6). Epub 2022 Jun 8.

Department of Pediatric Surgery, Osaka Women's and Children's Hospital, Izumi 594-1101, Japan.

Background: Treatment modalities for neonates with congenital diaphragmatic hernia (CDH) have greatly improved in recent years, with a concomitant increase in survival. However, long-term outcomes restrict the identification of optimal care pathways for CDH survivors in adolescence and adulthood. Therefore, we evaluated the long-term outcomes within the Japanese CDH Study Group (JCDHSG).

Methods: Participants were born with CDH between 2006 and 2018 according to the JCDHSG. Participants were enrolled in the database at 1.5, 3, 6, and 12 years old. Follow-up items included long-term complications, operations for long-term complication, and home medical care.

Results: A total of 747 patients were included in this study, with 626 survivors (83.8%) and 121 non-survivors (16.2%). At 1.5, 3, 6, and 12 years old, 45.4%, 36.5%, 34.8%, and 43.6% developed complications, and 20.1%, 14.7%, 11.5%, and 5.1% of participants required home care, respectively. Recurrence, pneumonia, pneumothorax, gastroesophageal reflux disease, and intestinal obstruction decreased with age, and thoracic deformity increased with age.

Conclusions: As CDH survival rates improve, there is a need for continued research and fine-tuning of long-term care to optimize appropriate surveillance and long-term follow-up.
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http://dx.doi.org/10.3390/children9060856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9222080PMC
June 2022

Aspects of the Complement System in New Era of Xenotransplantation.

Front Immunol 2022 14;13:860165. Epub 2022 Apr 14.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

After producing triple (Gal, H-D and Sd)-KO pigs, hyperacute rejection appeared to no longer be a problem. However, the origin of xeno-rejection continues to be a controversial topic, including small amounts of antibodies and subsequent activation of the graft endothelium, the complement recognition system and the coagulation systems. The complement is activated via the classical pathway by non-Gal/H-D/Sda antigens and by ischemia-reperfusion injury (IRI), via the alternative pathway, especially on islets, and via the lectin pathway. The complement system therefore is still an important recognition and effector mechanism in xeno-rejection. All complement regulatory proteins (CRPs) regulate complement activation in different manners. Therefore, to effectively protect xenografts against xeno-rejection, it would appear reasonable to employ not only one but several CRPs including anti-complement drugs. The further assessment of antigens continues to be an important issue in the area of clinical xenotransplantation. The above conclusions suggest that the expression of sufficient levels of human CRPs on Triple-KO grafts is necessary. Moreover, multilateral inhibition on local complement activation in the graft, together with the control of signals between macrophages and lymphocytes is required.
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http://dx.doi.org/10.3389/fimmu.2022.860165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046582PMC
April 2022

The Innate Cellular Immune Response in Xenotransplantation.

Front Immunol 2022 28;13:858604. Epub 2022 Mar 28.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Xenotransplantation is very attractive strategy for addressing the shortage of donors. While hyper acute rejection (HAR) caused by natural antibodies and complement has been well defined, this is not the case for innate cellular xenogeneic rejection. An increasing body of evidence suggests that innate cellular immune responses contribute to xenogeneic rejection. Various molecular incompatibilities between receptors and their ligands across different species typically have an impact on graft outcome. NK cells are activated by direct interaction as well as by antigen dependent cellular cytotoxicity (ADCC) mechanisms. Macrophages are activated through various mechanisms in xenogeneic conditions. Macrophages recognize CD47 as a "marker of self" through binding to SIRPα. A number of studies have shown that incompatibility of porcine CD47 against human SIRPα contributes to the rejection of xenogeneic target cells by macrophages. Neutrophils are an early responder cell that infiltrates xenogeneic grafts. It has also been reported that neutrophil extracellular traps (NETs) activate macrophages as damage-associated pattern molecules (DAMPs). In this review, we summarize recent insights into innate cellular xenogeneic rejection.
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http://dx.doi.org/10.3389/fimmu.2022.858604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995651PMC
March 2022

A case of successful slide tracheoplasty for long-segment congenital tracheal stenosis in a neonate with a congenital diaphragmatic hernia and Fallot's tetralogy.

Surg Case Rep 2022 Apr 13;8(1):66. Epub 2022 Apr 13.

Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Congenital tracheal stenosis (CTS) is a rare and life-threatening airway disorder, which is often associated with cardiac malformations. Among them, neonatal symptomatic CTS with cardiac malformations has an extremely poor prognosis. In contrast to cardiac malformation, congenital diaphragmatic hernia (CDH) has rarely been associated with CTS. We report a neonatal case in which slide tracheoplasty and intracardiac repair were performed simultaneously for CTS and Fallot's tetralogy (TOF).

Case Presentation: An infant with left CDH and Fallot's tetralogy (TOF) was born by cesarean section at 38 weeks of gestation. At the time of resuscitation, a 2.5 mm (ID) endotracheal tube could only be inserted just below the vocal cords. After repairing the CDH at 3 days of age, planned extubation was performed at 7 days of age. However, the patient required re-intubation due to life-threatening episodes after 2 days of the extubation. Enhanced CT revealed a long segment CTS from the upper trachea to the right bronchus (length of stenosis: 40 mm, minimum inner diameter: 2 mm). At 24 days of age, veno-arterial extracorporeal membrane oxygenation (ECMO) was introduced due to severe respiratory failure. At 28 days of age, slide tracheoplasty and palliative right ventricular outflow tract reconstruction (RVOTR) was performed with cardiopulmonary bypass (CPB). After tracheoplasty, a 3.5 mm tracheal (ID) tube could be placed in the reconstructed trachea in a patient with CTS. ECMO was completed 7 days after the operation. On the 17th day after the operation, he was extubated successfully. He was discharged 5 months after birth with home oxygenation therapy.

Conclusions: We reported the successful simultaneous correction of slide tracheoplasty and palliative RVOTR for a neonate with CDH. ECMO was used for respiratory management before and after surgery.
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http://dx.doi.org/10.1186/s40792-022-01422-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008082PMC
April 2022

Clinical implications of serum autotoxin in regular follow up after pediatric living donor liver transplantation for biliary atresia.

J Pediatr Surg 2022 Jul 14;57(7):1215-1220. Epub 2022 Mar 14.

Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Background: Pediatric patients sometimes develop graft fibrosis after living donor liver transplant (LDLT). Autotaxin is a recently developed serum marker for hepatic fibrosis. We studied the relationship between serum autotaxin levels and histological findings in patients after LDLT for biliary atresia (BA).

Methods: Information on patients aged <19 years who received LDLT for BA and were followed for at least 1 year after LDLT was gathered. Autotaxin levels were compared with pathological fibrosis scores.

Results: The study included 52 patients, of whom 4 patients had no fibrosis (F0), 36 patients had F1 fibrosis, and 12 patients had F2. The median serum autotaxin level was 0.89 mg/L. In patients with portal vein (PV) complications such as stenosis or thrombosis (n = 7), the mean autotoxin level was 1.25 mg/L compared with 0.95 mg/L in patients without PV complications (p = 0.004). Among patients without PV complications, the mean autotaxin level was 0.90, 0.88, and 1.18 mg/L in F0, F1, and F2 fibrosis, respectively. The mean autotaxin was higher in F2 fibrosis than in F0 or F1 fibrosis (p<0.05). Autotoxin had a high area under the curve (0.86) with the cut-off level of 0.897 mg/L.

Conclusion: Serum autotaxin is a novel marker for liver fibrosis in patients after pediatric LDLT for BA.

Type Of Study: Study of Diagnostic Test.

Level Of Evidence: Level II.
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http://dx.doi.org/10.1016/j.jpedsurg.2022.02.041DOI Listing
July 2022

Tetracyclines Enhance Anti-tumor T-Cell Responses Induced by a Bispecific T-Cell Engager.

Biol Pharm Bull 2022 ;45(4):429-437

Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University.

Cancer immunotherapies are powerful therapeutic options for cancer patients. To enhance the therapeutic effects of cancer immunotherapies, we plan to develop novel immunostimulatory drugs for use in combination with cancer immunotherapy. In the present study, we focused on tetracyclines, the effects of which are controversial for immunotherapy. We examined the effects of tetracyclines on human T cells in the peripheral blood of healthy donors and the tumor tissues of non-small cell lung cancer (NSCLC) patients. By using bispecific T-cell engager technology to assess the cytotoxicity of peripheral T cells against tumor cells, we showed that tetracyclines (minocycline, tetracycline, doxycycline, meclocycline, chlortetracycline, and demeclocycline) enhanced T-cell cytotoxicity through granzyme B expression and CD4+ and CD8+ T-cell proliferation. In analyses of the peripheral blood mononuclear cells (PBMCs) and lung tumor-infiltrated cells of NSCLC patients, we found that demeclocycline enhanced T-cell cytotoxicity not only in PBMCs, but also in lung tumor tissues. These results support the further application of tetracyclines to combination cancer immunotherapy.
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http://dx.doi.org/10.1248/bpb.b21-00806DOI Listing
April 2022

Successful separation of male pygopagus with anal canal and urethral reconstruction: a case report.

Surg Case Rep 2022 Mar 16;8(1):43. Epub 2022 Mar 16.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.

Background: Pygopagus is a type of conjoined twin binding at the buttocks. Some cases of pygopagus involve the fusion of the gastrointestinal tract, urinary tract, and spinal cord. Few cases of male pygopagus have been reported; however, the prognosis after separation is unclear. Herein, we report a case of male pygopagus in which successful separation was performed with the reconstruction of the anal canal.

Case Presentation: Twins with male pygopagus were born at 35 weeks by cesarean section. They shared a common anus, penis, and scrotum with four testes. The infants had normal defecation and urination after birth. The separation surgery was scheduled when they were 5 months. Two distinct anesthesia teams and four surgical teams (neurosurgery, pediatric urology, plastic surgery, and pediatric surgery) were involved in the multidisciplinary approach. After separating the spinal cord, we found that the anal canal and sphincter muscle complex were fused near the anal aperture, and we separated them. The fused penis and testis were separated and reconstructed using the same incisional line as the other separation, and the reconstructions of the anal canals with the sphincter muscle complex were completed. Both patients had an uneventful postoperative course. At 2 years of age, they could walk and defecate independently. In addition, they voided spontaneously without urinary incontinence at the time of 3 years and 11 months.

Conclusions: Separation of the spinal cord with anal canal and urethral reconstruction is important for male pygopagus patients as it allows them to preserve their independent function.
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http://dx.doi.org/10.1186/s40792-022-01398-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924340PMC
March 2022

Efficacy of a 365 nm Ultraviolet A1 light Emitting Diode (UVA1-LED) in in vitro Extracorporeal Photopheresis.

Photochem Photobiol 2022 Mar 3. Epub 2022 Mar 3.

Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan.

Extracorporeal photochemotherapy (ECP) is one of the more effective cell therapies for graft-versus-host disease (GvHD). ECP is a widely recommended therapeutic approach for the treatment of chronic GvHD, particularly steroid-refractory GVHD. In recent years, the use of a light emitting diode (LED) in the clinic has attracted considerable interest. In this study, we examined the issue of whether an ultraviolet A1-light emitting diode (UVA1-LED) can be used as a light source in ECP. To compare the efficacy of ECP with conventional UVA lamp and a UVA1-LED, we established an in vitro ECP model. Treatment efficacy was evaluated by measuring the % apoptosis and the inhibition of T-cell proliferation. To investigate the effect of ECP on the innate immune reaction, THP-1 cells with a luciferase reporter gene driven by a NF-kB response element (THP-1 luc NF-kB) were treated with ECP. The LED-ECP induced apoptosis and inhibition of T-cell proliferation as efficiently as a conventional ECP. However, LED-ECP induced less innate immunity in THP-1. Since LED devices are more compact compared with conventional UVA irradiation devices, the use of a UVA1-LED in the treatment of ECP may be a better alternative to conventional ECP therapy.
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http://dx.doi.org/10.1111/php.13613DOI Listing
March 2022

Effect of a C5a receptor antagonist on macrophage function in an intestinal transplant rat model.

Transpl Immunol 2022 06 25;72:101559. Epub 2022 Feb 25.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Background: C5a promotes alloreactivity via the C5a receptor 1 (C5aR1) on immune cells, but this has not been confirmed in the case of small intestine transplantation immunity. In the present study, we examined the effect of C5aR1 antagonist (PMX53) on macrophage function in small intestinal transplantation.

Methods: The model was created by heterotopic intestinal transplantation using donor Dark Agouti and recipient Lewis rats. PMX53 was administered starting on the day of operation until postoperative day 7. The graft survivals were compared, and HE staining of grafts, lymphocyte mixed reaction test (MLR, mixed culture of T cells from lymph nodes and spleen cells from donors), and changes in macrophage and T cell accumulation in grafts on day 6 after transplantation were evaluated. In addition, the effect of PMX53 on macrophage differentiation and activation was assessed using macrophages derived from bone marrow (BMDM).

Results: Graft survival was significantly prolonged in the therapeutic group compared to the untreated group. Histological evaluation showed that PMX53 inhibited the shortening of the graft villus, and the stimulation index of MLR was significantly lower in the therapeutic group compared to the untreated group. In the therapeutic group, the accumulation of macrophages in intestinal graft and monocyte in blood were reduced, compared with the untreated group. PMX53 decreased the differentiation in BMDM and the mRNA expression of IL-1β and TNF-α in activated BMDM.

Conclusion: Inhibition of C5a/C5aR1 signaling appears to regulate macrophage differentiation and suppress rejection in small intestine transplantation immunity.
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http://dx.doi.org/10.1016/j.trim.2022.101559DOI Listing
June 2022

Inhibition of cIAP1 in the effective suppression of chemotherapy‑resistant hepatoblastoma.

Oncol Rep 2022 Apr 25;47(4). Epub 2022 Feb 25.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.

Cellular inhibitor of apoptosis protein‑1 (cIAP1) is a key regulator of programmed cell death and is known to be associated with chemotherapeutic resistance. The present study aimed to investigate the antitumor efficacy of birinapant, a novel selective inhibitor of cIAP1, against cisplatin (CDDP)‑resistant hepatoblastoma (HB) cells. Western blot analysis was used to investigate the antitumor effect of birinapant on cIAP1 expression in Huh6 cells at the protein level. A WST‑8 assay was performed to evaluate the tumor growth inhibitory effect of birinapant on the human HB cell lines, Huh6 and HepG2. Huh6 cells were exposed to CDDP and/or birinapant in order to confirm tumor growth inhibition. The antitumor efficacy of birinapant plus CDDP combination therapy was significantly higher than that of CDDP monotherapy in a dose‑dependent manner (P=0.035). The study also investigated the antitumor efficacy of birinapant plus CDDP combination therapy in an established xenograft model of SCID mice. Compared with CDDP monotherapy, birinapant combined with CDDP showed better inhibition of tumor growth (P=0.121). It was observed that the mRNA expression of cIAP1 in tumors was significantly enriched in the CDDP monotherapy group compared with that in the untreated group. Furthermore, immunohistochemical staining was performed to compare cIAP1 expression in pre‑ and post‑chemotherapy specimens in patients with HB, and a significant increase was observed in the post‑chemotherapy specimens (P<0.001). CDDP‑resistant Huh6 (Huh6‑CDDP) cells were also established following repeated exposure to CDDP. Birinapant was substantially more effective against the Huh6‑CDDP cells than against the Huh6 wild‑type cells. Taken together, these findings suggest that repeated exposure to CDDP enhances cIAP1 expression in HB cells and that birinapant is a promising therapeutic drug for CDDP‑resistant HB.
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http://dx.doi.org/10.3892/or.2022.8290DOI Listing
April 2022

Etiologies and treatments of chronic intestinal failure-short bowel syndrome (SBS) in Japanese adults: a real-world observational study.

Surg Today 2022 Feb 23. Epub 2022 Feb 23.

Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.

Purpose: Short bowel syndrome (SBS) with intestinal failure (SBS-IF) requires long-term parenteral nutrition (PN). This study investigated the real-world etiologies of SBS, treatment patterns, and PN-related outcomes among adult patients with SBS-IF in Japan.

Methods: This retrospective, observational cohort study was based on data from April, 2008 to January, 2020 from one of the largest hospital-based claim databases in Japan. Analyzed patients were aged ≥ 16 years, had received continuous PN for ≥ 6 months, and had SBS or undergone SBS-related surgery with a diagnosis of a causative disease. The primary endpoint was PN weaning.

Results: We analyzed data for 393 patients. The most frequent causes of SBS-IF were ileus (31.8%), Crohn's disease (20.1%), and mesenteric ischemia (16.0%). Of 144/393 (36.6%) patients who were weaned off their PN, 48 (33.3%) were subsequently restarted on PN. Of 276/393 (70.2%) patients whose PN was initiated in hospital, 156 (56.5%) transitioned to home management. The mean duration of initial PN was 450.4 and 675.5 days for patients who were able or unable to be weaned off PN, respectively. Sepsis (67.4%), catheter-related bloodstream infections (49.1%), and liver disorders (45.0%) were the most reported PN-related complications.

Conclusions: Most patients with SBS-IF in Japan could not be weaned off PN and suffered life-threatening complications.
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http://dx.doi.org/10.1007/s00595-022-02469-9DOI Listing
February 2022

Early Use of Everolimus as a Third Immunosuppressive Agent for Intestinal Transplantation: A Report of 2 Cases.

Transplant Proc 2022 Mar 11;54(2):472-475. Epub 2022 Feb 11.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Background: In patients with intestinal transplantation (ITx), renal function is easily impaired because of long-term parenteral nutrition and side effects of tacrolimus. Everolimus was used in patients with renal insufficiency in our study.

Methods: We administered everolimus as a third immunosuppressive agent in addition to tacrolimus and steroids for renal sparing in patients who received ITx. We assessed everolimus levels, complications, and renal function.

Results: Two patients received everolimus after ITx. Patient 1 was a 13-year-old boy who underwent ITx for an allied disorder of Hirschsprung's disease. After induction therapy with rabbit antithymocyte globulin, maintenance therapy consisted of tacrolimus and steroids. Everolimus was introduced 3 months after ITx for renal sparing. Seven months later, the patient required partial intestinal graft resection owing to bowel obstruction. Everolimus was suspended for only 2 weeks. Four years after ITx, the trough level of tacrolimus was maintained at 3 to 5 ng/mL. The trough level of everolimus was maintained at 3 to 5 ng/mL. Patient 2 was a 32-year-old man who underwent deceased ITx for short gut syndrome. Induction and maintenance immunosuppression was the same as for patient 1. Everolimus was introduced 1 month after surgery. Two years after ITx, trough levels of tacrolimus and everolimus were the same as in patient 1. No rejection was observed in either patient, and renal function was well maintained. We observed no side effects caused by everolimus.

Conclusions: Everolimus could be used safely and effectively after ITx. Early use of everolimus after ITx did not affect wound healing.
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http://dx.doi.org/10.1016/j.transproceed.2022.01.010DOI Listing
March 2022

Long-Term Outcome of Portal Vein Stenting After Pediatric Living Donor Liver Transplantation.

Transplant Proc 2022 Mar 9;54(2):454-456. Epub 2022 Feb 9.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Portal vein (PV) stenosis is sometimes seen in pediatric living donor liver transplantation (LDLT). PV stents have been attempted in adults with persistent stenosis. However, long-term usefulness of PV stenting is unknown because stents do not expand with growth. We investigated the effect and long-term outcome of PV stenting for stenosis after pediatric LDLT.

Methods: We included patients aged <18 years who underwent LDLT from 1998 to 2020 and who underwent PV stenting for stenosis. We assessed age at procedure, stent complications, and long-term outcomes.

Results: Five patients underwent PV stent placement. The median age at LDLT was 10 years (range, 0.8-18.1 years). The median interval between LDLT and stent placement was 25 months. The median age at stent placement was 16 years (range, 3-20 years). The median body weight was 38 kg (range, 13-63 kg). The median stent diameter was 8 mm. The median observation period after stent placement was 8 years. On average, body weight increased 1.6 times. One complication associated with stent placement was PV thrombosis, which resulted in stent failure, but we observed no portal hypertension. In the other 4 patients, the stent has remained functioning, and there was no clinical evidence of portal hypertension.

Conclusions: PV stents are effective for intractable PV stenosis in children. PV stents were successfully placed in children as young as 3 years old and weighing 13 kg. Our data suggests that a stent placed in young children does not cause portal hypertension as patients grow.
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http://dx.doi.org/10.1016/j.transproceed.2022.01.008DOI Listing
March 2022

Successful Surgical Resection and Chemotherapy for Unresectable Hepatoblastoma With Pulmonary Metastases and for Lung Recurrence After Liver Transplantation: A Case Report.

Transplant Proc 2022 Mar 21;54(2):556-559. Epub 2022 Jan 21.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Background: Liver transplantation (LTx) is indicated for unresectable hepatoblastoma (HB) without distal metastasis. However, to our knowledge, there is no consensus on the management of unresectable HB with pulmonary metastases, or on the treatment of recurrent HB. We report a successful case of metastatic HB treated with repeated lung resection, chemotherapy, and LTx. This study strictly complied with the Helsinki Congress and the Istanbul Declaration regarding donor source.

Case Report: Our case was a 1-year-old boy who developed pre-treatment extent of disease (PRETEXT) Ⅲ HB with multiple pulmonary metastases. The liver tumor was unresectable because it involved all hepatic veins. After 3 cycles of chemotherapy (cisplatin/carboplatin plus doxorubicin), the remaining 2 pulmonary metastases were resected and living donor liver transplantation (LDLT) was performed. Five months after LDLT, a tumor recurrence was detected in the right lung. Repeat lung resection was performed followed by 1 cycle of chemotherapy (carboplatin plus doxorubicin). There has been no recurrence for 18 months since the last lung resection.

Discussion: Previous reports revealed that 14 patients, including the present case, underwent LTx after resection of metastatic HB pulmonary lesions. Of these patients, the 2-year survival rate after LTx was 91%. Recurrence was reported in 5 patients, 2 of whom were successfully treated with repeated resection of the metastatic lesions. LTx after resection of lung recurrence may be a potential treatment for unresectable HB with pulmonary metastases.
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http://dx.doi.org/10.1016/j.transproceed.2021.12.037DOI Listing
March 2022

Impact of Monosegment Graft Use for Infants in Pediatric Living Donor Liver Transplantation.

Transplant Proc 2022 Mar 21;54(2):391-394. Epub 2022 Jan 21.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Left lateral segment grafts are generally used for very young pediatric patients undergoing living donor liver transplantation (LDLT). Recently, graft reduction techniques were developed for LDLT. Monosegment grafting has been used in newborns. The aim of this study was to determine the usefulness of monosegment grafting for infants.

Methods: Recipients <2 years of age who underwent LDLT with a monosegment graft between 2010 and 2020 were gathered. Parents comprised all LDLT donors. A segment 2 monosegment graft was resected as a graft from the donor. Standard liver volume (SLV) was estimated using Urata's equation. Graft type, graft weight (GW), and native liver weight were assessed.

Results: Eight patients were included in the study. Original diseases consisted of biliary atresia (n = 6) and fulminant hepatitis (n = 2). Final graft type included monosegment (n = 5) and reduced monosegment (n = 3). Median final GW/body weight after reduction was 3% (range, 2%-3.4%). Median native liver weight/SLV was 134% except in patients with fulminant hepatitis. Median pre-reduction graft volume (GV)/estimated GV was 113% (range, 60%-208%). Median pre-reduction GV/SLV of monosegment grafts that required reduction (n = 3) was 109% (range, 106%-121%). Median final reduced graft GV/SLV was 80% (range, 74%-91%). Complications due to large-for-size grafts were not observed. One case of bile leakage due to graft reduction occurred as a complication. Grafts were functioning well with the exception of one graft loss due to antibody-mediated rejection.

Conclusion: Estimated GV in infants varies widely. Monosegment grafting can be useful for infants as well as newborns.
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http://dx.doi.org/10.1016/j.transproceed.2021.12.034DOI Listing
March 2022

A Retransplant Case for Hepatopulmonary Syndrome Without Liver Cirrhosis or Portosystemic Shunt After Living-Donor Liver Transplantation: A Case Report.

Transplant Proc 2022 Mar 21;54(2):552-555. Epub 2022 Jan 21.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Hepatopulmonary syndrome (HPS) is a disease of gas exchange caused by intrapulmonary shunting secondary to liver disease-associated intrapulmonary vascular dilation. HPS is characterized by the triad of cirrhosis, chronic liver disease, or portosystemic shunting (PSS); arterial hypoxemia; and intrapulmonary arteriovenous shunting in the absence of a primary cardiopulmonary anomaly. We encountered a rare case of HPS without liver disease or PSS. The patient was an 8-year-old girl who underwent living donor liver transplantation (LDLT) shortly after developing fulminant hepatitis at 11 months of her age. Eight years after LDLT, hypoxemia and shortness of breath developed. The shunt ratio on Tc-macroaggregated albumin (MAA) lung perfusion scintigraphy (Tc-MAA lung scan) was 32%. The patient had no cardiopulmonary disease, so we diagnosed her illness as HPS. We did not find cirrhosis, chronic liver disease, or PSS as a cause of HPS. We thought the graft was the cause of HPS. A second transplantation was planned. One year after the diagnosis of HPS, the shunt ratio on Tc-MAA lung scan worsened to 42%, digital clubbing appeared, and hypoxemia was worsening. Thus, we performed a second LDLT. After LDLT the shunt ratio on Tc-MAA lung scan normalized (6%) and cyanosis resolved. We determined that the graft was the cause of HPS; the typical causes of HPS were not clearly revealed in the histologic examination of the second liver explant. Acute rejection occurred twice after LDLT, so we speculated that HPS occurred because the graft became stressed over the long term.
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http://dx.doi.org/10.1016/j.transproceed.2021.12.022DOI Listing
March 2022

Long-Term Outcome After Tacrolimus-Related Neurotoxicity in Pediatric Living Donor Liver Transplantation.

Transplant Proc 2022 Mar 21;54(2):468-471. Epub 2022 Jan 21.

Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Tacrolimus-related neurotoxicity is a serious complication. Posterior reversible encephalopathy syndrome, which is severe neurotoxicity after pediatric living donor liver transplantation (LDLT), is a medication-induced complication related to calcineurin inhibitors. The purpose of this study was to evaluate the long-term outcome of tacrolimus-related neurotoxicity after pediatric LDLT.

Methods: Pediatric patients who underwent LDLT between 2007 and 2020 at our institution and developed neurologic symptoms with tacrolimus were included in the study. Tacrolimus-related encephalopathy was defined as encephalopathy that resolved after tacrolimus was discontinued. All patients received tacrolimus and a steroid for immunosuppression starting just after LDLT.

Results: During the study period, 128 patients underwent LDLT. All patients received tacrolimus and a steroid. Six patients (5%) developed tacrolimus-related encephalopathy. The median age at transplant was 1.6 years. The original diseases were biliary atresia (n = 5) and progressive familial intrahepatic cholangiopathy type 2 (n = 1). Patients developed encephalopathy at a median of 9 days after LDLT. All patients recovered with conversion to cyclosporine. Posterior reversible encephalopathy syndrome was confirmed by magnetic resonance imaging in 3 patients. The mean tacrolimus level at encephalopathy was 11 ng/dL (range, 5.6-14.6 ng/dL). White blood cell count elevation was observed in all patients. One patient died of pancreatitis. Surviving patients (n = 5) were followed for a median of 9 years. All patients resumed tacrolimus a median of 8 months from onset. No neurologic complications were observed after resuming tacrolimus.

Conclusion: We observed tacrolimus-induced encephalopathy in 5% of patients after pediatric LDLT. Patients can resume tacrolimus safely without further neurologic symptoms.
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http://dx.doi.org/10.1016/j.transproceed.2021.12.036DOI Listing
March 2022

Prenatally diagnosed accessory scrotum: A case report and review of the literature on prenatal features.

Radiol Case Rep 2022 Mar 12;17(3):881-885. Epub 2022 Jan 12.

Department of Pediatric Surgery, Graduate School of Medicine, Osaka University.

Accessory scrotum (AS) is rarely diagnosed antenatally, and its prenatal features remain unknown. Here, we report a case of a prenatally diagnosed accessory scrotum with perineal lipoma. A 33-year-old woman was referred to our hospital at 35 weeks of gestation to evaluate a mass in the fetal perineal region. Prenatal ultrasonography showed a 2.0 × 2.0 cm sized, echogenic, and circular mass located posterior to the left scrotum in a male fetus. Magnetic resonance imaging (MRI) showed a mass containing adipose tissue. A 6.5 cm elastic mass (AS and protruding lipoma) was observed in the perineal region, and surgical excision was performed at 8 months of age. Histological examination confirmed the diagnosis of AS with perineal lipoma, and there was no recurrence at follow-up. The typical prenatal presentation of AS was a circular perineal mass located posterior to the normal scrotum and was associated with perineal lipoma. The prenatal detection of AS was feasible with careful observation via ultrasonography, and prenatal MRI was useful in characterizing perineal tumors and evaluating associated anomalies.
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http://dx.doi.org/10.1016/j.radcr.2021.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760351PMC
March 2022

Study of the CRISPR/Cas3 System for Xenotransplantation.

Transplant Proc 2022 Mar 11;54(2):522-524. Epub 2022 Jan 11.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

The CRISPR/Cas3 system, classified in class I system, was recently focused as a new technology. For application of this system to porcine cells, the plasmids of bpNLS-Cascade, BPNLS-hCas3, and pBS-U6icrRNA were prepared. Initially, 2 crRNAs were established in the exon 9 of pig Gal-T (GGTA1) as #45 and #86. Next, hCas3 + #45 + #86 (group 1, control), Cascade + hCas3 + #45 (group 2), Cascade + hCas3 + #86 (group 3), and Cascade + hCas3 + #45 + #86 (group 4) were set and transfected into pig fibroblasts. Transfected cells were analyzed for bulk expression of α1,3Gal epitope by fluorescence-activated cell sorting (FACS), using a GSI-B4 lectin 2 days after the transfection. As the results, changes of expression are observed in order of G4>G2>G3, indicating the effect of the Cas3 system. Therefore, the nested polymerase chain reaction (PCR) for target region of GGTA1 was performed. Next, the PCR products from each group were checked in blotting, and the products were placed into the cloning sit of TOPO vector and transformed into Escherichia coli. Sixteen colonies of each group were checked by PCR, and clones containing PCR product with slightly varying length were evaluated. The direct sequence of these PCR changes were demonstrated as 294 to 754 bp deletions. In conclusion, we confirmed the effect of the CRISPR/Cas3 system on pig cell, especially in xenotransplantation.
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http://dx.doi.org/10.1016/j.transproceed.2021.09.070DOI Listing
March 2022

Clinical outcomes of surgical management for rare types of progressive familial intrahepatic cholestasis: a case series.

Surg Case Rep 2022 Jan 13;8(1):10. Epub 2022 Jan 13.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of genetic autosomal recessive diseases that cause severe cholestasis, which progresses to cirrhosis and liver failure, in infancy or early childhood. We herein report the clinical outcomes of surgical management in patients with four types of PFIC.

Case Presentation: Six patients diagnosed with PFIC who underwent surgical treatment between 1998 and 2020 at our institution were retrospectively assessed. Living-donor liver transplantation (LDLT) was performed in 5 patients with PFIC. The median age at LDLT was 4.8 (range: 1.9-11.4) years. One patient each with familial intrahepatic cholestasis 1 (FIC1) deficiency and bile salt export pump (BSEP) deficiency died after LDLT, and the four remaining patients, one each with deficiency of FIC1, BSEP, multidrug resistance protein 3 (MDR3), and tight junction protein 2 (TJP2), survived. One FIC1 deficiency recipient underwent LDLT secondary to deterioration of liver function, following infectious enteritis. Although he underwent LDLT accompanied by total external biliary diversion, the patient died because of PFIC-related complications. The other patient with FIC1 deficiency had intractable pruritus and underwent partial internal biliary diversion (PIBD) at 9.8 years of age, pruritus largely resolved after PIBD. One BSEP deficiency recipient, who had severe graft damage, experienced recurrence of cholestasis due to the development of antibodies against BSEP after LDLT, and eventually died due to graft failure. The other patient with BSEP deficiency recovered well after LDLT and there was no evidence of posttransplant recurrence of cholestasis. In contrast, recipients with MDR3 or TJP2 deficiency showed good courses and outcomes after LDLT.

Conclusions: Although LDLT was considered an effective treatment for PFIC, the clinical courses and outcomes after LDLT were still inadequate in patients with FIC1 and BSEP deficiency. LDLT accompanied by total biliary diversion may not be as effective for patients with FIC1 deficiency.
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http://dx.doi.org/10.1186/s40792-022-01365-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758805PMC
January 2022

Effect of Japanese Kampo medicine, eppikajutsuto, in patients with lymphatic malformation: A retrospective observational study.

Medicine (Baltimore) 2021 Dec;100(51):e28420

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Abstract: Lymphatic malformations (LMs) are congenital malformations of the lymphatic system that cause considerable cosmetic and functional complications. In this study, we present 8 children with LM who were treated with the Kampo medicine eppikajutsuto (EKJT).Between 2001 and 2020, 8 children (male: 4, female: 4) with LMs who underwent magnetic resonance imaging (MRI) evaluation both before and after treatment or observation were selected for investigating the effect of EKJT. Two patients were observed without any treatment for 24 and 60 months. EKJT was evaluated based on percentage reduction, defined as the percentage of total lesions that decreased in size, confirmed by radiological examination after initiating treatment with EKJT or determined by observation alone. Volumetric analysis of LMs on MRI was performed using the Digital Imaging and Communications in Medicine viewer.Six patients were treated with EKJT. The mean observational period was 13.2 months (range: 6-24 months). The mean reduction in LM volume on MRI was 73.0% in treated patients and -66.3% in observed patients. Two of the 6 lesions exhibited complete reduction, 2 exhibited marked (>90%) reduction, 1 exhibited moderate reduction, and 1 exhibited a small response. The treatment was well-tolerated, with no severe adverse events.This preliminary study demonstrated the beneficial effects of EKJT. Prospective evaluations of this promising therapeutic modality are warranted based on the results of this study.
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http://dx.doi.org/10.1097/MD.0000000000028420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8701444PMC
December 2021

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

Transpl Immunol 2022 02 14;70:101497. Epub 2021 Nov 14.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Japan.

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.
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http://dx.doi.org/10.1016/j.trim.2021.101497DOI Listing
February 2022

The Regulation of Neutrophil Extracellular Trap-induced Tissue Damage by Human CD177.

Transplant Direct 2021 Aug 23;7(8):e734. Epub 2021 Jul 23.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Background: Neutrophil-induced tissue damage contributes to the rejection in xenotransplantation. Therefore, suppressing neutrophil function could be effective in suppressing xenogeneic rejection. In a previous study, we demonstrated that the ectopic expression of human cluster of differentiation 31 (CD31) on porcine endothelial cells (PEC) significantly suppressed neutrophil-mediated cytotoxicity through the homophilic binding of CD31. Cluster of differentiation 177 (CD177) was recently reported to be a high-affinity heterophilic binding partner for CD31 on endothelial cells. Thus, we hypothesized that human CD177 on PEC might induce a stronger suppression in neutrophil-mediated cytotoxicity compared with CD31. In this study, the inhibitory function of human CD177 on PEC in neutrophil-mediated cytotoxicity was investigated.

Methods: PEC were transfected with a cloning plasmid containing cDNA inserts that encoded for hCD177 and hCD31 genes. Neutrophil-induced cytotoxicity was evaluated by flow cytometry after coculturing with PEC or PEC/CD177 in the presence of phorbol 12-myristate 13-acetate. To elucidate the mechanisms responsible for hCD177-induced suppression, the phosphorylation of src homology region 2 domain containing phosphatase 1 was measured by immunoblot analysis.

Results: Human CD177 on PEC induced a significant reduction in neutrophil-induced cytotoxicity. In addition, CD177 on PEC induced a significant increase in the phosphorylation of src homology region 2 domain-containing phosphatase 1 in neutrophils and suppressed NETosis.

Conclusions: These findings suggest that human CD177 suppresses neutrophil-mediated cytotoxicity through the inhibition of NETosis.
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http://dx.doi.org/10.1097/TXD.0000000000001175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439991PMC
August 2021

Elevation of microRNA-214 is associated with progression of liver fibrosis in patients with biliary atresia.

Pediatr Surg Int 2022 Jan 21;38(1):115-122. Epub 2021 Sep 21.

Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: MicroRNAs (miRNAs) play an important role in regulating fibrogenesis in the liver. The current study examined the ability of microRNA-214 (miR-214) level in liver and serum samples obtained from patients with BA to predict progressive liver fibrosis in patients with biliary atresia (BA).

Methods: We examined miR-214 level in relation to conventional markers of liver fibrosis, with liver and serum samples from BA patients. Fifty-two patients with BA who underwent Kasai portoenterostomy and four control patients underwent liver biopsy. In 28 patients with BA, blood samples were collected to analyze circulating serum miR-214.

Results: MiR-214 levels in liver tissue were significantly upregulated in patients with BA who had severe liver fibrosis (F3-4) compared to those with none to mild fibrosis (F0-2), whereas suppressors-of-fused homolog (Sufu) mRNA levels were significantly suppressed in F3-4. Serum miR-214 levels were significantly higher in patients with F3-4 compared with F0-2. Area under the curve analysis showed that the serum miR-214 cut-off level for predicting F3-4 was 0.805 (p = 0.0046).

Conclusion: Hepatic overexpression of miR-214 is associated with progression of liver fibrosis in patients with BA, and the circulating miR-214 level may serve as a non-invasive predictor of liver fibrosis.
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http://dx.doi.org/10.1007/s00383-021-05009-7DOI Listing
January 2022
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