The clinical impact of macrophage polarity after Kasai portoenterostomy in biliary atresia

IntroductionBiliary atresia (BA) is a cholestatic hepatopathy caused by fibrosing destruction of intrahepatic and extrahepatic bile ducts, and its etiology has not been clearly revealed. In BA, liver fibrosis progression is often observed even after Kasai portoenterostomy (KPE), and more than half of cases require liver transplantation in their lifetime in Japan. Macrophages play an important role in liver fibrosis progression and are classically divided into proinflammatory (M1) and fibrotic macrophages (M2), whose phenotypic transformation is called “macrophage polarity.” The polarity has been reported to reflect the tissue microenvironment. In this study, we examined the relationship between macrophage polarity and the post-KPE clinical course.Materials and methodsThirty BA patients who underwent KPE in our institution from 2000 to 2020 were recruited. Multiple immunostainings for CD68, CD163, CK19, and α-SMA were carried out on liver biopsy specimens obtained at KPE. ROC curves were calculated based on each clinical event, and the correlation with the clinical data was analyzed.Results and discussionThe M2 ratio, defined as the proportion of M2 macrophages (CD163-positive cells), was correlated inversely with the occurrence of postoperative cholangitis (AUC: 0.7602). The patients were classified into M2 high (n = 19) and non-high (n = 11) groups based on an M2 ratio value obtained from the Youden index ( = 0.918). As a result, pathological evaluations (Metavir score, αSMA area fraction, and CK19 area fraction) were not significantly different between these groups. In mild liver fibrosis cases (Metavir score = 0–2), the M2 non-high group had a significantly lower native liver survival rate than the high group (p = 0.02). Moreover, 4 out of 8 cases in the M2 non-high group underwent early liver transplantation within 2 years after KPE.ConclusionsNon-M2 macrophages, including M1 macrophages, may be correlated with postoperative cholangitis, and the M2 non-high group in mild liver fibrosis cases had a significantly lower native liver survival rate than the high group, requiring early liver transplantation in this study. Preventing advanced liver fibrosis is a key factor in improving native liver survival for BA patients, and liver macrophages may play important roles in liver homeostasis and the promotion of inflammation and fibrosis

Laparoscopic intraperitoneal onlay mesh for pediatric incisional hernia—a case report

Abstract Background The incidence of incisional hernia in pediatric patients is low in comparison with that reported in adults. In the pediatric population, primary closure has generally been favored. However, synthetic or biomedical mesh offers advantages in the repair of larger defects when primary closure is difficult. The use of laparoscopic intraperitoneal onlay mesh (IPOM) in the adult population has been well documented. In the pediatric population, a few laparoscopic approaches with direct suturing have been proposed; however, there are no reports of laparoscopic repair with the use of IPOM. Case presentation The patient was a 1-year-old girl with epigastric incisional hernia after an operation to correct a complete arteriovenous septal defect. The fascial defect (size 30 × 35 mm) was large; thus, direct suturing was considered to be associated with a high risk of thoracic deformation and recurrence. Laparoscopic IPOM was performed. The fascial defect was detected precisely through the laparoscopy, and non-absorbable mesh was placed through a 12-mm trocar. Minimal incisions were required for the trocars, and extensive dissection of the abdominal wall structure was not needed. This procedure allowed for the integrity and functional status of the abdominal wall to be maintained. Conclusion Laparoscopic IPOM is a minimally invasive and cosmetically acceptable method that can be applied to the treatment of large incisional hernias in children

Advanced surgical strategy for giant mediastinal germ cell tumor in children

Purpose: Giant mediastinal germ cell tumor (MGCT) requires a well-planned advanced surgical approach. We retrospectively reviewed our surgical strategy for giant MGCT. Methods: Five children (median age, 5 years) with giant MGCT were treated in our institute from 2012 to 2016. Results: The initial diagnosis was made by tumor markers and image inspection in all cases. Benign teratomas (2 girls) and malignancies (3 boys) were treated with upfront surgery and radical tumorectomy after neo-adjuvant chemotherapy, respectively. After detailed 3D-CT, radical tumor excision was performed supported by a skilled pediatric cardiovascular surgeon. The basic approach was as follows: under cardiopulmonary support (CPS) or with CPS on standby, via median sternotomy, the pericardium and phrenic nerve were resected en bloc with the tumor, followed by diaphragmatic plication. Open biopsy was performed via lateral thoracotomy in 1 patient who showed dense adhesion and fistula formation in the lung; lobectomy via hemi-clamshell incision was required. No deaths or severe sequelae occurred in this series. Conclusions: Resectability is the most important predictor of outcomes for MGCTs. Preoperative 3D-CT and CPS can enable complete resection and ensure surgical safety. Well-functioned surgical team is critical success factor in such advanced surgery

小児外科医による小児がんに対するトランスレーショナルリサーチ

In the multidisciplinary therapy for childhood cancer, surgeons mainly play a role of surgical resection as a local therapy. When the surgeons gain a better understanding of total management of cancer therapy and tumor biology, they could conduct the advanced tailor-made therapy including QOL-based surgery, and organ-preserving surgery. Therefore, the translational research for childhood cancer conducted by surgeons is meaningful and could lead the development of the surgical treatment. In this manuscript, we introduced our history of translational researches for neuroblastoma, the most common extracranial solid tumor in children. Briefly, weʼve been doing research on 1) MEK inhibitor which inhibit MAPK pathway, as a novel molecurar-targeted therapy for MAPK-activated neuroblastoma, 2) the Drug Delivery System using tumor-homing ability of mesenchymal stem cells in a transgenic TH-MYCN mouse model of neuroblastoma, 3) the impact of local tumor resection on metastatic lesions in newly established MYCN transgenic allograft mouse model. Through these research, we are aiming to develop novel multi-modality therapy for high-risk neuroblastoma from the perspective of pediatric surgeons. It is of importance that young pediatric surgeons make these basic research by themselves and understand the current standard of care for pediatric tumors and the biology of tumors as well as surgical technique to achieve the optimal surgery in the treatment of pediatric tumors

Is neonatal uterine bleeding responsible for early-onset endometriosis?

Abstract Background It has been hypothesized that the origin of early-onset endometriosis could be from endometrial mesenchymal stem cells (eMSCs) in neonatal uterine blood (NUB). There is no information on the possible mechanistic basis linking an association between NUB/neonatal endometrium and development of early-onset endometriosis. In this study we performed a series of experiments to clarify the mechanistic link between NUB and/or neonatal endometrium and development of early-onset endometriosis. Methods We retrospectively collected postmortem neonatal endometria (n = 15) and prospectively collected NUB (n = 18) of female babies for the analysis of different biological markers including eMSCs. Immunohistochemical analysis of neonatal endometria was performed to examine the expression patterns of ovarian steroid receptors (ER/PGR), decidualization (prolactin, IGFBP1), pre-decidualization (Glycodelin A, α-SMA), proliferation (Ki-67 index), vascularity (CD31 + cells), immunocompetent CD68+, CD45+, CD56 + cells and some putative markers of eMSCs. Cell transfer method and immunocytochemistry were used to investigate the eMSCs and/or endometrial cells in NUB. Results Immunohistochemical analysis of postmortem neonatal endometria revealed variable staining response to ER/PGR, decidual markers, and substantial proliferative and angiogenic activity. A moderate to strong immunoexpression of Glycodelin-A was found in both neonatal and adult endometria. The tissue infiltration of CD56+, CD45 + and CD68 + immunocompetent cells was significantly low in neonatal endometria than that in adult endometria (p = 0.0003, p < 0.0001, p = 0.034, respectively). No eMSCs or even endometrial cells were detected in NUB. However, a variable expression of some phenotypes of eMSCs (CD90/CD105) was found in neonatal endometria. Conclusions Based on our serial experiments we did not find any supporting evidence for the role of NUB in early-onset endometriosis. Neonatal endometria showed variable expression of ovarian steroid receptors, decidualization, and a substantial amount of proliferative and angiogenic activity. As an alternative mechanism, a significantly less tissue accumulation of immunocompetent cells in neonatal endometria may explain the survival of ER + and PGR + cells should they make entry into the pelvis and consequent development of early endometriosis with the onset of ovarian function. Future study with large sample size and application of modified technological tools is warranted to test the NUB hypothesis and to clarify their biological or clinical significance. Trial registration not applicable

Data_Sheet_1_Sirolimus treatment for intractable lymphatic anomalies: an open-label, single-arm, multicenter, prospective trial.PDF

IntroductionIntractable lymphatic anomalies (LAs) include cystic lymphatic malformation (LM; macrocystic, microcystic, or mixed), generalized lymphatic anomaly, and Gorham–Stout disease. LAs can present with severe symptoms and poor prognosis. Thus, prospective studies for treatments are warranted. We conducted a prospective clinical trial of sirolimus for intractable LAs.MethodsThis was an open-label, single-arm, multicenter, prospective trial involving five institutions in Japan. All patients with LAs received oral sirolimus once daily, and the dose was adjusted to ensure that the trough concentration remained within 5–15 ng/mL. We prospectively assessed the drug response (response rate for radiological volumetric change in target lesion), performance state, change in respiratory function, visceral impairment (pleural effusion, ascites, bleeding, pain), laboratory examination data, quality of life (QOL), and safety at 12, 24, and 52 weeks of administration.ResultsEleven patients with LAs (9 generalized lymphatic anomaly, 1 cystic LM, 1 Gorham–Stout disease) were treated with sirolimus, of whom 6 (54.5%; 95% confidence interval: 23.4–83.3%) demonstrated a partial response on radiological examination at 52 weeks of administration. No patients achieved a complete response. At 12 and 24 weeks of administration, 8 patients (72.7%) already showed a partial response. However, patients with stable disease showed minor or no reduction after 12 weeks. Adverse events, such as stomatitis, acneiform dermatitis, diarrhea, and fever, were common with sirolimus. Sirolimus was safe and tolerable.ConclusionSirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL.</p