A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

PURPOSE: Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. PATIENTS AND METHODS: Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. RESULTS: Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. CONCLUSION: This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.

High-Titer Anti-ZSCAN1 Antibodies in a Toddler Clinically Diagnosed with Apparent Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome.

Severe obesity in young children prompts for a differential diagnosis that includes syndromic conditions. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) syndrome is a potentially fatal disorder characterized by rapid-onset obesity associated with hypoventilation, neural crest tumors, and endocrine and behavioral abnormalities. The etiology of ROHHAD syndrome remains to be established, but recent research has been focusing on autoimmunity. We report on a 2-year-old girl with rapid-onset obesity during the first year of life who progressed to hypoventilation and encephalitis in less than four months since the start of accelerated weight gain. The patient had a high titer of anti-ZSCAN1 antibodies (348; reference range < 40), and the increased values did not decline after acute phase treatment. Other encephalitis-related antibodies, such as the anti-NDMA antibody, were not detected. The rapid progression from obesity onset to central hypoventilation with encephalitis warns about the severe consequences of early-onset ROHHAD syndrome. These data indicate that serial measurements of anti-ZSCAN1 antibodies might be useful for the diagnosis and estimation of disease severity. Further research is needed to determine whether it can predict the clinical course of ROHHAD syndrome and whether there is any difference in antibody production between patients with and without tumors.

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

Introduction: Biliary 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 methods: Thirty 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 discussion: The 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. Conclusions: Non-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.

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

Introduction: Intractable 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. Methods: This 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. Results: Eleven 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. Conclusion: Sirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL.

Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects.

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

Scoring system for diagnosis and pretreatment risk assessment of neuroblastoma using urinary biomarker combinations.

The urinary catecholamine metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA), are used for the adjunctive diagnosis of neuroblastomas. We aimed to develop a scoring system for the diagnosis and pretreatment risk assessment of neuroblastoma, incorporating age and other urinary catecholamine metabolite combinations. Urine samples from 227 controls (227 samples) and 68 patients with neuroblastoma (228 samples) were evaluated. First, the catecholamine metabolites vanillactic acid (VLA) and 3-methoxytyramine sulfate (MTS) were identified as urinary marker candidates through comprehensive analysis using liquid chromatography-mass spectrometry. The concentrations of these marker candidates and conventional markers were then compared among controls, patients, and numerous risk groups to develop a scoring system. Participants were classified into four groups: control, low risk, intermediate risk, and high risk, and the proportional odds model was fitted using the L2-penalized maximum likelihood method, incorporating age on a monthly scale for adjustment. This scoring model using the novel urine catecholamine metabolite combinations, VLA and MTS, had greater area under the curve values than the model using HVA and VMA for diagnosis (0.978 vs. 0.964), pretreatment risk assessment (low and intermediate risk vs. high risk: 0.866 vs. 0.724; low risk vs. intermediate and high risk: 0.871 vs. 0.680), and prognostic factors (MYCN status: 0.741 vs. 0.369, histology: 0.932 vs. 0.747). The new system also had greater accuracy in detecting missing high-risk neuroblastomas, and in predicting the pretreatment risk at the time of screening. The new scoring system employing VLA and MTS has the potential to replace the conventional adjunctive diagnostic method using HVA and VMA.

Long-Term Outcomes of Infantile Sacrococcygeal Teratoma: Results from a Multi-Institutional Retrospective Observational Study in Japan.

BACKGROUND: Tumor recurrence, anorectal and urinary dysfunction, and lower limb dysfunction after surgery are observed in infantile sacrococcygeal teratoma (SCT). In this paper, a multi-institutional retrospective observational study was conducted to clarify the long-term functional prognosis in Japan. METHODS: This study was conducted using a paper-based questionnaire distributed to 192 facilities accredited by the Japanese Society of Pediatric Surgeons, covering patients who underwent radical surgery at less than 1 year old and who survived for at least 180 days after birth from 2000 to 2019. RESULTS: A total of 355 patients were included in this analysis. Altman type was I-II in 248 and type III-IV in 107, and the median maximum tumor diameter was 6.1 (range: 0.6-36.0) cm. There were 269 mature teratomas, 69 immature teratomas, and 10 malignant tumors. Total resection was performed in 325, subtotal or partial resection in 27, and surgical complications were noted in 54. The median postoperative follow-up was 6.6 (0.5-21.7) years. Eighty-three patients (23.4 %) had functional sequelae, including 62 (17.5 %) with anorectal dysfunction, 56 (13.0 %) with urinary dysfunction, and 15 (4.2 %) with lower limb motor dysfunction. Recurrence occurred in 42 (11.8 %) at a median age of 16.8 (1.7-145.1) months old. Risk factors for dysfunction included preterm delivery, a large tumor diameter, Altman type III-IV, incomplete resection, and surgical complications. Risk factors for recurrence included immature teratoma or malignancy, incomplete resection, and surgical complications. CONCLUSIONS: Postoperative dysfunction was not low at 23.4 %, and 11.8 % of the patients experienced recurrence occurring more than 10 years after surgery, suggesting the need for periodic imaging and tumor markers evaluations in patients with risk factors. It is necessary to establish treatment guidelines for best practice monitoring of the long-term quality of life. LEVEL OF EVIDENCE: Level II Retrospective Study.

The Effectiveness of Deflux® Treatment for Vesicoureteral Reflux Following Pediatric Renal Transplantation: A Single-Institution Challenging Experience.

PURPOSE: To validate the effectiveness of Deflux® treatment for vesicoureteral reflux (VUR) following pediatric renal transplantation (RT), based on our single-institution experience. METHOD: A retrospective study was conducted using the medical records of pediatric patients who underwent Deflux® treatment for VUR after RT from April 2008 to March 2022. RESULTS: Sixty-eight pediatric patients underwent RT. VUR was subsequently detected in 22 (32 %) of these patients. Seven of the 22 patients (32 %) underwent Deflux® treatment to avoid renal dysfunction due to urinary infection (UTI). The median age at the time of RT was 4 years (range:2-12). All 7 patients had urinary UTIs before Deflux® treatment. The median estimated glomerular filtration rate (eGFR) before Deflux® treatment was 67 ml/min/1.73 m2 (range:42-138 ml/min/1.73 m2). After Deflux® treatment, VUR was downgraded in three cases (43 %). Four patients (57 %) experienced postoperative UTI, two of who underwent a second Deflux® treatment, one underwent submuscular tunnel reconstruction, and the other one experienced UTI without VUR after 1st Deflux® treatment but did not reoccur. All seven patients continued prophylactic medication after Deflux® treatment, without any history of recurrent UTIs during the observation period after treatment (median 37 months [range 7-86 months]). Furthermore, the eGFRs did not significantly decrease after Deflux® treatment (median eGFR 58 ml/min/1.73 m2 [range:33-99 ml/min/1.73 m2], p > 0.1). CONCLUSION: Deflux® treatment for VUR after RT is technically challenging because the new ureteral orifice is ventrally anastomosed at the bladder. We believe our results indicate the possibility of reducing the frequency of UTIs and contributing to preservation of the renal function after RT. TYPE OF STUDY: Retrospective Study. LEVEL OF EVIDENCE: Level III.

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

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

Minimal Residual Disease Detected by the 7NB-mRNAs ddPCR Assay Is Associated with Disease Progression in High-Risk Neuroblastoma Patients: A Prospective Multicenter Observational Study in Japan.

High-risk neuroblastoma (HR-NB) patients remain far from obtaining optimal outcomes, with more than 50% relapse/regrowth rate despite current intensive multimodal therapy. This originated from the activation/proliferation of chemoresistant minimal residual disease (MRD). MRD with a significant prognostic was reported by several quantitative PCR (qPCR) or droplet digital PCR (ddPCR) assays quantitating different sets of NB-associated mRNAs (NB-mRNAs). The 7NB-mRNAs ddPCR assay quantitating CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs was reported to outperform other qPCR assays by a retrospective in-house observational study. In the present study, the Japan Children's Cancer Group (JCCG) Neuroblastoma Committee conducted a prospective multicenter observational study aimed at evaluating a prognostic value of MRD in bone marrow (BM-MRD) and peripheral blood (PB-MRD) detected by 7NB-mRNAs ddPCR assay. Between August 2018 and August 2022, 7 HR-NB patients who registered for JCCG clinical trials (JN-H-11 and JN-H-15) were enrolled. A total of 19 BM and 19 PB samples were collected, and 4/15 BM and 4/15 PB samples were classified as progressive disease (PD)/non-PD samples. BM-MRD and PB-MRD estimated area under curve (AUC) of 0.767 and 0.800 with a significant accuracy (AUC > 0.7). The present study validated a prognostic value of BM-MRD obtained by a previous study (AUC 0.723) and revealed the significant accuracy of PB-MRD as well as BM-MRD.

Surgical outcome and prognosis of pediatric solid-pseudopapillary neoplasm.

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

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

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

Is neonatal uterine bleeding responsible for early-onset endometriosis?

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.

Development of anti-GD2 Antibody-producing Mesenchymal Stem Cells as Cellular Immunotherapy.

BACKGROUND/AIM: Using the tyrosine hydroxylase (TH)-MYCN mouse neuroblastoma (NB) model, we have previously reported the accumulation of mouse mesenchymal stem cells (mMSCs) on tumors in vivo and the antitumor effect of mMSCs transfected with a small molecule (IFN-ß) expression gene. In this study, we have developed novel MSCs secreting anti-disialoganglioside GD2 antibody (anti-GD2-MSCs) and evaluated their antitumor effects in vitro. MATERIALS AND METHODS: We generated an anti-GD2 antibody construct (14.G2a-Fcx2-GFP) incorporating FLAG-tagged single-chain fragment variable against GD2 fused to a linker sequence, a fragment of the constant portion of human IgG1, and GFP protein. The construct was lentivirally transduced into mMSCs and the transduction efficiency was assessed by GFP expression. The secretion of FLAG-tagged anti-GD2 antibody was detected by Western blotting using anti-FLAG antibody. Antibody binding capacity was confirmed by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) was evaluated using human NB cells and human natural killer (NK) cells to assess whether the antitumor activity was enhanced in the presence of the produced antibodies. RESULTS: The transduction efficiency of anti-GD2-MSCs was more than 90%. anti-GD2-MSCs secreted antibodies extracellularly and these antibodies had high affinity to GD2-expressing human NB cells. ADCC assays showed that the addition of antibodies secreted from anti-GD2-MSCs significantly increased the cytotoxic activity of NK cells against NB cells. CONCLUSION: Newly developed anti-GD2-MSCs produced functional antibodies that have affinity to the GD2 antigen on NB cells and can induce ADCC-mediated cytotoxicity. Anti-GD2-MSCs based cellular immunotherapy has the potential to be a novel therapeutic option for intractable NB.

The Factors Associated with the Selection of Early Excision Surgery for Congenital Biliary Dilatation with a Prenatal Diagnosis.

PURPOSE: The aim of this study was to clarify the appropriate management after birth for congenital biliary dilatation (CBD, choledochal cyst) patients with a prenatal diagnosis. METHOD: Thirteen patients with a prenatal diagnosis of CBD who underwent liver biopsy during excision surgery were divided into two groups and retrospectively analyzed: group A, with liver fibrosis above F1 and group B, without liver fibrosis. RESULTS: Excision surgery was performed earlier in group A (F1-F2), at a median of 106 days old (p = 0.04). There were significant differences between the two groups in the presence symptoms and sludge, the cyst size, and the level of serum bilirubin and gamma glutamyl transpeptidase (GGT) before excision surgery (p < 0.05). Especially, in group A, prolonged serum GGT elevation and larger cysts were consistently observed from birth. The cut-off values of predictions for the presence of liver fibrosis in serum GGT and cyst size were 319 U/l and 45 mm. No significant differences were observed in the postoperative liver function or complications during the follow-up period. CONCLUSION: In patients with prenatally diagnosed CBD, the postnatal serial changes of serum GGT values and cyst size, in addition to symptoms, could help to prevent progressive liver fibrosis. LEVEL OF EVIDENCE: Ⅲ. TYPE OF STUDY: Treatment Study.

The Volume of Intestinal Decompression can Predict the Necessity of Surgical Intervention for Adhesive Small Bowel Obstruction.

BACKGROUND: There is no standard timing for switching to surgical management for children with adhesive small bowel obstruction (ASBO) who initially receive conservative treatment. We hypothesized that an increased gastrointestinal drainage volume may indicate the need for surgical intervention. METHODS: The study population included 150 episodes in the patients less than 20 years of age who received treatment for ASBO in our department from January 2008 to August 2019. Patients were divided into two groups: the successful conservative treatment group (CT) and the eventual surgical treatment group (ST). Following the analysis of all episodes (Study 1), we limited our analysis to only first ASBO episodes (Study 2). We retrospectively reviewed their medical records. RESULTS: There were statistically significant differences in the volume on the 2nd day in both Study 1 (9.1 ml/kg vs. 18.7 ml/kg; p < 0.01) and study 2 (8.1 ml/kg vs. 19.7 ml/kg; p < 0.01). The cut-off value was the same for both Study 1 and Study 2 (11.7 ml/kg). CONCLUSIONS: The gastrointestinal drainage volume on the 2nd day in ST was significantly larger than that in CT. Accordingly, we considered that the drainage volume may predict eventual surgical intervention for children with ASBO who initially receive conservative treatment. LEVEL OF EVIDENCE: Level IV.

Necrotizing enterocolitis associated with food protein-induced enterocolitis syndrome: A case report.

INTRODUCTION: Food protein-induced enterocolitis syndrome (FPIES) is a T-cell-mediated allergy that can occur in newborns and infants who are introduced to milk protein. Some of the serious complications of FPIES include necrotizing enterocolitis (NEC), massive bloody stools, and disseminated intravascular coagulation. Here we report a case of NEC caused by FPIES. PRESENTATION OF CASE: A 28-day-old girl born at full term suddenly developed marked abdominal distention and shock a few hours after being fed highly regulated milk protein. Emergency laparotomy was performed, and extensive small-intestinal necrosis was found. The histological examination showed chronic inflammation with typical ghost crypts, hemorrhage, and extensive pneumatosis intestinalis, a presentation consistent with NEC. DISCUSSION: In this case, the fragile intestinal mucosa associated with FPIES was stimulated by milk protein, leading to NEC. The greatest diagnostic difficulty is the lack of a definitive method for distinguishing between NEC and FPIES. The allergen-specific lymphocyte stimulation test with lactotransferrin was positive, indicating that the primary condition was FPIES. However, no eosinophilic infiltrate was found in the histological examination, but there was chronic inflammation with typical ghost crypts, hemorrhage, and extensive pneumatosis intestinalis. Consequently, the final histological diagnosis in our case was NEC rather than FPIES. CONCLUSION: FPIES has a variable clinical course, and severe FPIES may become exacerbated even after ingestion of highly regulated milk protein. Taking appropriate actions after correct diagnosis can prevent progression to surgical emergency and secondary NEC.

Successful management of pyriform sinus cyst and fistula using endoscopic electrocauterization.

Objectives: Pyriform sinus cyst (PSC) and pyriform sinus fistula (PSF) is a rare congenital malformation that arises from the third or fourth branchial structure. In our study, we describe the safety and the utility of endoscopic electrocauterization against PSC/PSF. Methods: We retrospectively reviewed the records of patients who underwent endoscopic electrocauterization for PSC/PSF at our hospital. The internal opening of the fistula was identified under general anesthesia using a flexible endoscope (XQ-260 or H-290; Olympus, Tokyo, Japan), and the DualKnifeJ (KD-655L; Olympus) was used to ablate the internal opening. Results: We experienced three PSF and three PSC patients. The postoperative course was uneventful in all cases. The patients declared no pain in the neck, and there were no cases showing recurrent nerve paralysis. Five in six cases (83%), the closure of fistula was archived in the first cauterization. One case (16.6%) required repeated cauterization. No recurrence was found during the follow-up period ( median: 1 year) in any cases. Conclusions: Owing to its rarity in neonates, the diagnosis and treatment of PSC remains complicated and not clearly described. Complete removal of the fistula and the cyst with or without affected thyroid tissue was previously the most commonly used treatment. From our experience, we believe that endoscopic electrocauterization can be the first choice not only for PSF but also for neonatal PSC. In conclusion, endoscopic electrocauterization is feasible even for neonatal PSC. Further investigations including multicenter analyses are needed.

Development of minimally invasive cancer immunotherapy using anti-disialoganglioside GD2 antibody-producing mesenchymal stem cells for a neuroblastoma mouse model.

PURPOSE: Mouse IgG anti-disialoganglioside GD2 antibody-secreting mouse mesenchymal stem cells (anti-GD2-MSCs) were developed, and their anti-tumor effects were validated in an in vivo neuroblastoma mouse model. METHODS: Anti-GD2 antibody constructs were generated, incorporating FLAG-tagged single-chain fragment variables against GD2 fused to a linker sequence, and a fragment of a stationary portion was changed from human IgG to mouse IgG and GFP protein. The construct was lentivirally introduced into mouse MSCs. A syngeneic mouse model was established through the subcutaneous transplantation of a tumor tissue fragment from a TH-MYCN transgenic mouse, and the homing effects of anti-GD2-MSCs were validated by In vivo imaging system imaging. The syngeneic model was divided into three groups according to topical injection materials: anti-GD2-MSCs with IL-2, IL-2, and PBS. The tumors were removed, and natural killer (NK) cells were counted. RESULTS: Anti-GD2-MSCs showed homing effects in syngeneic models. The growth rate of subcutaneous tumors was significantly suppressed by anti-GD2-MSCs with IL-2 (p < 0.05). Subcutaneous tumor immunostaining showed an increased NK cell infiltration in the same group (p < 0.01). CONCLUSION: Anti-GD2-MSCs using mouse IgG showed a homing effect and significant tumor growth suppression in syngeneic models. Anti-GD2-MSC-based cellular immunotherapy could be a novel therapeutic strategy for intractable neuroblastoma.