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RATIONALE: Epidermal growth factor receptor (EGFR) and its ligands play important roles in the regeneration of damaged epithelium and proliferation of various epithelial tumors. Although the EGFR-tyrosine kinase inhibitor gefitinib is effective against advanced non-small cell lung cancer with EGFR mutations, some patients treated with this agent develop severe acute interstitial pneumonia. Characteristics of patients who develop interstitial pneumonia include older age, smoking history, and preexisting interstitial pneumonia suggesting a connection between airway injury and alveolar dysfunction. OBJECTIVES: The purpose of this study was to investigate the effects of gefitinib on airway repair after injury. METHODS: C57BL/6J mice received intraperitoneally naphthalene at Day 0. Gefitinib (20, 90, or 200 mg/kg) was given daily at Days--1 to 13 after naphthalene administration. Bronchoalveolar lavage fluid and lung tissue were obtained at Days 7 and 14. Terminal bronchial epithelial cells from Days 7 and 14 were retrieved with laser capture microdissection, and gene expression analyzed using microarray. MEASUREMENTS AND MAIN RESULTS: Gefitinib treatment after naphthalene prolonged neutrophil sequestration and worsened acute lung injury. We found 17 genes with more than a threefold increase in bronchiolar epithelial cells from mice treated with 200 mg/kg of gefitinib after naphthalene at Day 14 compared with those treated with naphthalene alone. Up-regulated genes included S100A8, S100A6, and StefinA3. These genes are known to participate in neutrophil sequestration, acute inflammation, and airway remodeling. CONCLUSIONS: EGFR inhibition in repairing airway epithelial cells modulated significant expression of genes involved in the airway microenvironment, prolonged inflammation, and potentiated acute lung injury. [ABSTRACT FROM AUTHOR]

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., Competing Interests: MO received research funding from Nobelpharma Co. Ltd. in Tokyo. Sirolimus tablets were supplied by Nobelpharma Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ozeki, Endo, Yasue, Nozawa, Asada, Saito, Hashimoto, Fujimura, Yamada, Kuroda, Ueno, Watanabe, Nosaka, Miyasaka, Umezawa, Matsuoka, Maekawa, Hirakawa, Furukawa, Fumino, Tajiri, Takemoto, Souzaki, Kinoshita and Fujino.)

Background: Recently, reports of endoscopic approaches for neuroblastoma, ganglioneuroblastoma, and ganglioneuroma (peripheral neuroblastic tumor; PNTs) have been increasing. This study aimed to clarify the indications for endoscopic surgery for PNTs., Methods: Pediatric patients who underwent endoscopic surgery for PNTs at our institution were included in this study. Image-defined risk factors (IDRFs) were analyzed using preoperative computed tomography (CT)., Results: Twenty-four patients underwent endoscopic surgery for PNTs. The diagnoses included neuroblastoma (n = 11), ganglioneuroma (n = 10), and ganglioneuroblastoma (n = 3). Regarding the tumor site, there were 18 cases of adrenal tumors, five cases of mediastinal tumors, and one case of retroperitoneal tumors. Image-defined risk factors were positive in eight cases (contacted with a renal vessel, n = 6; compression of principal bronchi, n = 2). Complete resection was accomplished in 21 cases (14 of 16 IDRF-negative cases and seven of eight IDRF-positive cases). All patients survived without recurrence during the follow-up period., Conclusions: The CT findings of contact with renal vessels and compression of principal bronchi do not seem to be indicators of incomplete resection. An endoscopic approach to PNTs in pediatric patients is feasible with a good prognosis if patients are selected strictly., (© 2024 Japan Pediatric Society.)

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., (© 2023 Japan Pediatric Society.)

Purpose: This study aims to clarify the relationship between changes in skeletal muscle mass during treatment and prognosis of pediatric malignant solid tumors., Methods: Patients with pediatric malignant solid tumors who were treated at Kyushu University Hospital from 2007 to 2017 were divided into two groups: the progression-free survival (PFS) group and the relapse/death (R/D) group; the psoas major muscle volume (PMV) was then compared. We also measured the PMV and psoas muscle area (PMA) of pediatric patients with no complications who underwent surgery for acute appendicitis (control) and compared the values with those of patients with malignant tumors., Results: No significant differences were observed in the PMV and PMA between patients with appendicitis and those with malignant tumors. Significant differences were found in the rate of change in PMV between the PFS (1.424) and R/D groups (1.071) (P = 0.0024). When the cut-off value of the rate of change in the PMV was 1.20, patients whose rate of change in PMV was ≥ 1.20 had longer PFS (P = 0.0231) and overall survival (P = 0.0229) than those whose rate of change was < 1.20., Conclusion: Pediatric patients with malignant solid tumors and increased skeletal muscle mass during treatment have a good prognosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Some neuroblastoma (NB) cases are suitable for minimally invasive surgery (MIS), but indication and technical issue are unclear. We assessed the current status of MIS for abdominal NB after mass screening period in Japan., Methods: Preliminary questionnaires requesting the numbers of NB cases that underwent MIS from 2004 to 2016 were sent to 159 Japanese institutes of pediatric surgery. The secondary questionnaires were then sent to the institutions that reported MIS cases of NB in order to collect detailed data., Results: One hundred and thirty-four (84.2%) institutions responded to the preliminary questionnaires, and 83 (52.2%) reported managing operative cases. The total number of operative cases was 1496. MIS was performed for 175 (11.6%) cases, of which the completed forms of 140 patients were returned, including 100 abdominal NB cases. The male/female ratio was 51/49. Forty-seven cases underwent a laparoscopic biopsy, and 2 (4.3%) cases were converted to laparotomy due to bleeding. Sixty-five cases underwent MIS for radical resection, and 7 (10.8%) were converted to laparotomy. The reasons for open conversion were bleeding and severe adhesion. Regarding open conversion, there were no significant relationships between conversion and neo-adjuvant chemotherapy, biopsies, stage, size, or MYCN amplification. We found no relationship between resectability and vascular encasement in this study. There was relationship between the resected tumor size and the patients' height, which was expressed using the following formula: [Formula: see text] (x, patients height, y, tumor size; p = 0.004219, SE: 1.55566). Postoperative complications after radical resection were recognized in 7 (10.8%) cases., Conclusions: MIS was performed in limited cases of abdominal NB. A laparoscopic biopsy with careful attention to bleeding is feasible. The resected tumor size was shown to correlate with the patients' height. Tumor size within 6 cm of maximum diameter can be resected safely., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the JPLT3 study, a real-time central surgical reviewing (CSR) system was employed aimed at facilitating early referral of candidates for liver transplantation (LTx) to centers with pediatric LTx services. The expected consequence was surgery, including LTx, conducted at the appropriate time in all cases. This study aimed to review the effect of CSR on institutional surgical decisions in cases enrolled in the JPLT3 study. Real-time CSR was performed in cases in which complex surgeries were expected, using images obtained after two courses of preoperative chemotherapy. Using the cloud-based remote image viewing system, an expert panel consisting of pediatric and transplant surgeons reviewed the images and commented on the expected surgical strategy or the necessity of transferring the patient to a transplant unit. The results were summarized and reported to the treating institutions. A total of 41 reviews were conducted for 35 patients, and 16 cases were evaluated as possible candidates for LTx, with the treating institutions being advised to consult a transplant center. Most of the reviewed cases promptly underwent definitive liver surgeries, including LTx per protocol.

Background: We actively use novel endoscopic surgical approaches with complete curability and good cosmetic outcomes to facilitate the removal of resected tumors from the body via a small incision. Patients and Methods: This retrospective study reviewed the medical records of patients who underwent endoscopic surgery for treating solid tumors in the abdominal, thoracic, and urogenital regions between April 2013 and March 2020. Results: At our institution, minimally invasive surgery (MIS) is performed for malignant tumors with a maximum diameter of ≤5 cm and nonmalignant tumors without diameter restrictions, although both need to have no vascular encasement. In total, 135 pediatric solid tumor resections were performed at our institution during the aforementioned period, among whom 37 patients satisfied the MIS criteria. Among them, 28 patients underwent endoscopic surgeries, whereas 9 underwent open surgeries. The median surgical durations were 192 and 138 minutes in the MIS and open groups, respectively ( P  = .096). The median volume of blood loss was 1 and 8 mL in the MIS and open groups, respectively ( P  = .086). The median lengths of hospital stay were 8 and 7 days in the MIS and open groups, respectively ( P  = .178). One patient in each group had Clavien-Dindo grade ≥Ⅲ complications. However, there was no surgery-related death. All patients receiving MIS had satisfactory operative scarring, early recovery, and good cosmetic outcomes. Conclusion: MIS can be used for pediatric solid tumors, considering the patient's quality of life while allowing complete curability and providing endoscopic surgical advantages.

Background: Minimally invasive surgery (MIS) is appropriate for the treatment of some neuroblastomas (NBs); however, the indications and technical issues are unclear. This study aimed to clarify the current status of MIS for mediastinal NB in Japan., Methods: Preliminary questionnaires requesting the numbers of neuroblastoma cases in which MIS was performed from 2004 to 2016 were sent to 159 Japanese institutes of pediatric surgery. Secondary questionnaires were sent to institutions with MIS cases to collect detailed data., Results: One hundred thirty-four (84.2%) institutions returned the preliminary questionnaire and 83 institutions (52.2%) reported a total of 1496 operative cases. MIS was performed for 175 (11.6%) cases. Among the 175 cases, completed forms of 140 patients were returned and 40 (male, n = 28; female, n = 12) cases had mediastinal NB. Fourteen patients received thoracoscopic biopsy, none were converted to thoracotomy. Twenty-eight patients received MIS for radical resection, none were converted to thoracotomy. Perioperative complications (Horner's syndrome) were recognized after radical resection in one (2.5%) case., Conclusions: MIS was performed in a limited number of mediastinal NB cases. A thoracoscopic approach would be feasible for mediastinal NB., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

SMARCB1 is mutated in most rhabdoid tumors (RTs) developing in the kidney (RTK) and various other organs. Focal deletions found in patients with 22q11.2 deletion syndrome show breakpoints within clusters of segmental duplications (SDs), and those in some RTs show breakpoints in the 22q11-q12 region. SDs are known to cause focal deletion mediated by non-allelic homologous recombination. The present study identified SMARCB1 alterations in all 30 RTKs, using SNP array CGH, MLPA, and sequence analyses. Twenty-eight tumors had a total of 51 breakpoints forming focal 22q deletion and/or uniparental disomy (22qUPD), and the other two had compound mutation with no breakpoints in 22q. Twenty-four (47.1%) of the 51 breakpoints were within SDs, and occurred in 16 (53.3%) of the 30 tumors. The association of breakpoints with SDs was found not only in focal deletion, but also in 22qUPD, indicating that SDs mediate the first and second hits (focal deletion) and the second hit (22qUPD) of SMARCB1 alteration. Of the 51 breakpoints, 14 were recurrent, and 10 of the 14 were within SDs, suggesting the presence of hotspots in the 22q11.2 region. One recurrent breakpoint outside SDs resided in SMARCB1, suggesting inactivation of the gene by out-of-frame fusion. The association between SDs and focal deletion has been reported in two other types of cancer. RTKs may be the third example of SD-associated tumors. Thus, the present study indicated that RTKs exploit genomic instability in the 22q11.1-11.2 SDs region, and 22qUPD caused by mitotic recombination may also be mediated by SDs., (© 2021 Wiley Periodicals LLC.)

Aim: We evaluated a series of late-presenting congenital diaphragmatic hernia (Late-CDH) cases and assessed the reliability and risks of laparoscopic and thoracoscopic approaches for Late-CDH at a single institution. Materials and Methods: From 2005 to 2017, we experienced totally 11 patients with Late-CDH who received endoscopic repairs. We retrospectively surveyed the approach, defect size, operating time, and postoperative outcomes, including recurrence. Results: Eleven patients (Bochdalek, n  = 10; Morgagni, n  = 1) underwent a total of 14 endoscopic repairs (laparoscopy, n  = 10; thoracoscopy, n  = 4). The average defect size was ∼3.1 × 1.5 cm. In all 14 endoscopic repairs, patients received intracorporeal interrupted nonabsorbable stitches and extracorporeal knot tying were applied, without the use of an artificial patch. In the laparoscopic repairs, 7 patients received left-handed suturing when closing the diaphragmatic defect, because the reduced viscera lay directly below the posterior rim of the diaphragmatic defect, making it difficult to confirm the rim. In contrast, in the thoracoscopic repairs, the viscera were reduced over the diaphragmatic defect, so the surgeons could easily perform suturing. The average operating time was 172 minutes for laparoscopy and 194 minutes for thoracoscopy. No major intraoperative or postoperative complications occurred in association with either of the approaches. Among the 11 patients, 2 experienced a total of 3 recurrences (all after laparoscopic repairs). Conclusion: Although there were few differences between the laparoscopic and thoracoscopic approaches, because of the technical difficulty of the procedure and the possibility of recurrence with the laparoscopic approach, a thoracoscopic approach may be better for the repair of Late-CDH.

Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of NQO1 and ODC1 . Inhibition of NQO1 and ODC1 in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Emerging data have suggested that sirolimus may be a treatment option for complicated vascular anomalies (VAs). The present study aimed to investigate the immunologic effects of sirolimus treatment for 6 months in patients with VAs. Blood samples obtained from the patients enrolled in 2 multicenter studies to investigate the efficacy of sirolimus for VAs before and after sirolimus treatment for 6 months were used. Data for total white blood cell count, absolute lymphocyte count, serum immunoglobulins (Igs) levels (IgG, IgA, IgM), lymphocyte proliferation assays with mitogens including phytohemagglutinin and concanavalin A, and flow cytometric analysis of lymphocyte subsets were evaluated. A total of 18 patients with VAs receiving sirolimus treatment were included in the study. Comparisons of white blood cell, absolute lymphocyte count, IgG, IgA, IgM, and reaction rates of phytohemagglutinin and concanavalin A revealed no significant differences before and after treatment. No significant differences were observed in the absolute counts of lymphocyte subtypes before and after treatment, except for regulatory T-cell counts, which were significantly decreased after treatment. Severe infections were not observed during sirolimus treatment. The immunologic parameters assessed in the present study were hardly affected by sirolimus treatment for 6 months in patients with VAs.

Purpose: This study aimed to evaluate the learning effects of continuous training with a disease-specific endoscopic surgical simulator for young pediatric surgeons. Materials and Methods: Participants trained with a laparoscopic fundoplication simulator for 1 hour every 10 days. At the start of each training session, we assessed the participant's surgical technique using the surgical skill evaluation system, which evaluates the following items: (1) task time, (2) right-left balance of suturing, (3) suture spacing between the three ligatures, (4) total path length traveled by forceps, (5) velocity of the forceps tips, (6) length of the wrap, (7) number of ligature failures, and (8) comparison of improvements according to assessment point. We examined the learning effects of this continuous training program. Results: Task time, right-left balance of suturing, and sum of the distance traveled by each forceps showed significant progressive improvements ( P  < .05). Suture spacing and average velocity of forceps tips did not change significantly with training ( P  = .5781, P  = .0781, respectively). However, the ratio of traveled distance between left and right forceps significantly improved ( P  < .05). There was a significant trend for the wrap length to approach the target value ( P  < .05). According to the linear mixed-effects model, the number of training sessions required for learning was not uniform and varied depending on the skill. Conclusion: This simulator training program can help pediatric surgeons to acquire surgical skills easily, economically, and safely. In the future, we need to evaluate how surgical skills acquired during this continuous training are reflected in clinical operations.

Background/objectives: Treatment is more intensive for stage III Wilms tumor (WT) than for stages I and II non-metastatic WTs. Various factors including tumor spillage, unresectability, and lymph node metastasis are responsible for stage III disease. The present study aimed to not identify clinical factors associated with the features of stage III WT to establish new treatment strategies., Design/methods: Of 166 patients with non-metastatic WT enrolled in the Japan Wilms Tumor Study (JWiTS)-2, 51 patients had stage III disease. The treatment protocol for JWiTS-2 was essentially the same as that in the National Wilms Tumor study (NWTS)-5. Local hospitals were surveyed to collect details of clinical findings related to stage III disease, and data regarding 45 (88%) patients were obtained., Results: Nine patients with massive tumors underwent preoperative chemotherapy. Biopsy was performed in 6. Reduction in the tumor size was achieved in 8 of the 9 cases. Nephrectomy was finally performed in all of them. Thirty-six patients underwent primary nephrectomy. The reason for the stage III disease was lymph node metastasis (n = 9, 25%), tumor spillage (n = 20, 56%), and tumor extension/incomplete resection (n = 17, 47%). Some patients had more than one of these factors. Most patients were treated with the DD-4A regimen, and 43 (95.6%) of the 45 patients received abdominal radiation therapy. Tumors recurred in three patients (local, 1; metastasis, 2), and two patients died. Overall and relapse-free survival rates were 95.2% and 90.8%, respectively., Conclusion: The prognosis of stage III WT was good. In the next stage, the doses of chemotherapy and radiotherapy should be reduced to avoid late effects. The high rate of tumor spillage after primary resection suggests that preoperative chemotherapy should be started instead of aggressive tumor resection in the large tumor cases with surgical risks.

Background: Sacrococcygeal teratoma (SCT) is the most common extragonadal germ cell tumor in neonates and infants. Although most cases of infantile SCT are benign tumors by nature, some develop into extremely large lesions, leading to massive bleeding, high-output heart failure, disseminated intravascular coagulation, and even fatal outcomes during the neonatal period. In addition, some patients may present with tumor recurrence, malignant transformation, long-term sequelae (including bladder and bowel dysfunction) and lower leg palsy during the long-term follow up. SCT, however, is very rare, and there are few opportunities to encounter this disease, therefore general physicians without expert credentials currently lack information relevant to clinical practice. For this reason, the research project committee has compiled guidelines concerning SCT., Methods: The purpose of these guidelines was to share information concerning the treatment and follow up of infantile SCT. The guidelines were developed using the methodologies in the Medical Information Network Distribution System. A comprehensive search of the English- and Japanese-language articles in PubMed and Ichu-Shi Web identified only case reports or case series, and the recommendations were developed through a process of informal consensus., Results: The clinical questions addressed the risk factors, the efficacy of cesarean section, the initial devascularization of tumor feeding vessels, interventional radiology, recommended clinical studies for follow up and possible long-term complications., Conclusions: These are the first guidelines for SCT to be established in Japan, and they may have huge clinical value and significance in terms of developing therapeutic strategies and follow up, potentially contributing to the improvement of the prognosis and quality of life of SCT patients., (© 2019 Japan Pediatric Society.)

Background: Technology for detecting liver tumors and identifying the bile ducts using indocyanine green (ICG) has recently been developed. However, the usefulness and limitations of ICG navigation surgery for hepatoblastoma (HB) have not been fully clarified. We herein report our experiences with surgical navigation using ICG for in HB patients., Methods: In 5 HB patients, 10 ICG navigation surgeries were performed using a 10-mm infrared fluorescence imaging scope after the injection of 0.5 mg/kg ICG intravenously. The surgical and clinical features were collected retrospectively., Results: Navigation surgery using ICG was performed for primary liver tumors in 4 cases, and the timing of ICG injection was 90.5 ± 33.7 h before the operation. All tumors exhibited intense fluorescence from the liver surface. ICG navigation for the primary liver tumor was useful for detecting the residual tumor at the stump and invasion to the diaphragm during surgery. Six lung surgeries using ICG navigation were performed. The timing of ICG injection was 21.8 ± 3.4 h before the operation. The size of the metastatic tumor was 7.4 ± 4.1 mm (1.2-15 mm). Of 11 metastatic tumors detected by computed tomography (CT), 10-including the smallest tumor (1.2 mm)-were able to be detected by ICG from the lung surface. The depth of the 10 ICG-positive tumors from the lung surface was 0.9 ± 1.9 mm (0-6 mm), and the depth of the single ICG-negative tumor was 12 mm. One lesion not detected by CT showed ICG false positivity., Conclusion: Navigation surgery using ICG for patients with HB was useful for identifying tumors and confirming complete resection. However, in ICG navigation surgery, we must be aware of the limitations with regard to the tumor size and the depth from the surface.

Purpose: Sarcopenia is a syndrome that is defined by the loss of skeletal muscle mass, quality, and strength. In adult patients with malignancies, the presence of sarcopenia is known to be correlated with a poor prognosis; however, there have been no reports on the influence of sarcopenia on malignant tumors in pediatric patients. In the present study, we investigated whether or not sarcopenia affects the prognosis of high-risk neuroblastoma., Materials and Methods: Thirteen patients with high-risk neuroblastoma who were treated according to the standard protocol at our hospital from 2007 to 2016 were divided into a progression-free survival group (n = 8) and a relapse/death group (n = 5). The rate of change in sarcopenia was calculated by comparing the psoas muscle area (PMA) of the L3-level lumbar spine on computed tomography before and after treatment with the standard protocol. The rate of change in the PMA, Kaup index, and serum albumin level were compared. Furthermore, we determined the cutoff rate of change in the PMA and compared the overall and progression-free survival., Results: The rates of change in the PMA were 1.24 and 0.84 in the progression-free survival and relapse/death groups, respectively (P = 0.0472). There were no significant differences in the rates of change in the Kaup index or the serum albumin level of the two groups. The patients whose rate of change in the PMA was >1.00 showed a prolonged overall (P = 0.0078) and progression-free survival (P = 0.006)., Conclusions: A decrease in the skeletal muscle mass was suggested to be a significant prognostic factor for high-risk neuroblastoma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The RNA-binding protein HuC/D displays a neuron-specific expression and is involved in neuronal differentiation and the maintenance of the nervous system. Here we investigated the diagnostic value of HuC/D in neuroblastomas. We evaluated 85 neuroblastic tumors: 81 neuroblastomas; 3 ganglioneuroblastomas, intermixed; 1 ganglioneuroma, maturing; and 101 other tumors consisting of 34 Ewing sarcomas, 14 nephroblastomas, 11 rhabdomyosarcomas, 15 pulmonary small cell carcinomas, 18 pancreatic neuroendocrine tumors, and 9 pheochromocytomas. Immunohistochemistry for HuC/D, PHOX2B, and tyrosine hydroxylase was performed. The immunoreactivity for HuC/D was semiquantified using the total score (TS; range, 0-8). HuC/D positivity was defined as a TS ≥6. The TS of the neuroblastic tumors (mean TS, 7.94) was significantly higher than those of the other small round cell tumors and neuroendocrine tumors (P < .001) except for the pheochromocytomas (mean TS, 6.89; P = .074). HuC/D was positive in all 85 neuroblastic tumors, 1 (2.9%) Ewing sarcoma, 1 (6.7%) pulmonary small cell carcinoma, and 8 (89%) pheochromocytomas. PHOX2B was positive in all of the neuroblastic tumors and pheochromocytomas. Tyrosine hydroxylase was positive in 80 (94%) neuroblastic tumors, 1 (9.1%) rhabdomyosarcoma, and all of the pheochromocytomas. Therefore, HuC/D serves as a highly sensitive diagnostic marker to distinguish neuroblastomas from other small round cell tumors. The combination of HuC/D and PHOX2B staining may be valuable for the diagnosis of neuroblastic tumors, especially in the assessment of small sections. HuC/D expression in tumors may be related to catecholamine production or a neural crest-derived cell origin., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Lymphatic anomalies (LAs) refer to a group of diseases involving systemic dysplasia of lymphatic vessels. These lesions are classified as cystic lymphatic malformation (macrocystic, microcystic or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs occur mainly in childhood, and present with various symptoms including chronic airway problems, recurrent infection, and organ disorders. Individuals with LAs often experience progressively worsening symptoms with a deteriorating quality of life. Although limited treatment options are available, their efficacy has not been validated in prospective clinical trials, and are usually based on case reports. Thus, there are no validated standards of care for these patients because of the lack of prospective clinical trials., Methods: This open-label, single-arm, multicenter, prospective study will assess the efficacy and safety of a mammalian target of the rapamycin inhibitor sirolimus in the treatment of intractable LAs. Participants will receive oral sirolimus once a day for 52 weeks. The dose is adjusted so that the nadir concentration remains within 5-15 ng/ml. The primary endpoint is the response rate of radiological volumetric change of the target lesion confirmed by central review at 52 weeks after treatment. The secondary endpoints are the response rates at 12 and 24 weeks, respiratory function, pleural effusion, ascites, blood coagulation parameters, bleeding, pain, quality of life, activities of daily living, adverse events, side effects, laboratory examinations, vital signs, and pharmacokinetic data., Results: This is among the first multicenter studies to evaluate sirolimus treatment for intractable LAs, and few studies to date have focused on the standard assessment of the efficacy for LAs treatment. Our protocol uses novel, uncomplicated methods for radiological assessment, with reference to the results of our previous retrospective survey and historical control data from the literature., Conclusions: We propose a multicenter study to investigate the efficacy and safety of sirolimus for intractable LAs (SILA study; trial registration UMIN000028905). Our results will provide pivotal data to support the approval of sirolimus for the treatment of intractable LAs.

Background: Thoracoscopic surgery for pediatric benign tumors is a common procedure. However, a large incision is needed to remove large tumors from the thoracic cavity. And, for intrapulmonary sequestration in lower lobe, it sometimes needs a large incision to ligate the aberrant vessels. A muscle-sparing axillar skin crease incision (MSASCI) has been introduced for thoracic open surgery, resulting in excellent aesthetic outcomes compared with a standard incision. We herein report the utility of this MSASCI technique in thoracoscopic surgery to remove large tumors from the thoracic cavity and to ligate the aberrant vessels in intrapulmonary sequestration in lower lobe., Materials and Methods: From 2014 April to 2016 March, we performed the MSASCI technique in thoracoscopic surgeries for 5 children., Result: Five cases were diagnosed as mediastinal masses (mature teratoma for 1 case, ganglioneuroblastoma for 2 cases, and extrapulmonary sequestration and intrapulmonary sequestration for 1 case each). The age at surgery was 32.0 ± 25.0 months (range 5-58 months). The size of the mediastinal mass was 9 × 5 × 5 cm, 4 × 3 × 3 cm, 5 × 5 × 2.5 cm, and 3 × 2.5 × 2 cm. For 4 other cases, except for the intrapulmonary sequestration case, the mass was resected under thoracoscopic surgery using only three or four 5-mm trocars and the mass was removed from the thoracic cavity using the MSASCI technique. For the intrapulmonary sequestration case, the aberrant vessels were resected under thoracoscopic surgery using only two 5-mm and one 12-mm trocars and the left lower lobectomy was performed using the MSASCI technique. All lesions were resected completely. No cases had surgical complications, none showed recurrence, and all cases demonstrated good cosmetic outcomes., Conclusions: Performing thoracoscopic surgery using a MSASCI technique is associated with good cosmetic outcome.

The mechanism underlying the spontaneous regression of neuroblastoma is unclear. Although it was hypothesized that this regression occurs via an immunological mechanism, there is no clinical evidence, and no animal models have been developed to investigate the involvement of immune systems, especially natural antibodies, against neuroblastoma. We performed an immunological analysis of homo- and heterozygous TH-MYCN transgenic mice as a model of aggressive neuroblastoma. Mice with no or small (<5 mm) tumors showed higher antibody titers in plasma than mice with large (>5 mm) tumors. A significant negative correlation was observed between the tumor diameter and the titer of antitumor antibody. This antibody had complement-dependent cytotoxicity but not antibody-dependent cellular cytotoxicity against neuroblastoma cells. Moreover, B-cell depletion had no effect on the tumor incidence in vivo. We revealed that TH-MYCN transgenic mice have a natural antibody against neuroblastoma that correlate with tumor size. However, this antibody does not correlate with the spontaneous regression of neuroblastoma. Thus, the function of the natural antibody is limited., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The occupational exposure to hazardous drugs(HD)has already been investigated; however, the actual exposure of the attendant family members of patients with childhood cancer has remained unknown. Here, we analyzed cyclophosphamide (CPM)exposure in attendant family members and the environment after the administration of CPM to patients with pediatric cancer. CPM of 320(8.39-1,510)ng from infant-families and 0(0-58.4)ng from adolescent-families were detected(p= 0.01). The exposure of infant-families was significantly greater than those of adolescent-families. In addition, CPM were detected in the hot water after bathing the infant, underwear, and sheets. We elucidated that the exposures take place through body fluid and excretions of the children. In the field of childhood cancer, HD exposure measures should be taken according to the age of the child to minimize health damage to medical personnel, family members, and other children who share the room. Nurses are recommended to educate the patients and their family members about preventing exposure to HD in pediatric medical centers.

This study investigated whether parameters derived from hand motions of expert and novice surgeons accurately and objectively reflect laparoscopic surgical skill levels using an artificial intelligence system consisting of a three-layer chaos neural network. Sixty-seven surgeons (23 experts and 44 novices) performed a laparoscopic skill assessment task while their hand motions were recorded using a magnetic tracking sensor. Eight parameters evaluated as measures of skill in a previous study were used as inputs to the neural network. Optimization of the neural network was achieved after seven trials with a training dataset of 38 surgeons, with a correct judgment ratio of 0.99. The neural network that prospectively worked with the remaining 29 surgeons had a correct judgment rate of 79% for distinguishing between expert and novice surgeons. In conclusion, our artificial intelligence system distinguished between expert and novice surgeons among surgeons with unknown skill levels.

We report 2 infantile cases of pulmonary tumor carrying a chimeric A2M-ALK gene. A2M-ALK is a newly identified anaplastic lymphoma kinase (ALK)-related chimeric gene from a tumor diagnosed as fetal lung interstitial tumor (FLIT). FLIT is a recently recognized infantile pulmonary lesion defined as a mass-like lesion that morphologically resembles the fetal lung. Grossly, FLIT characteristically appears as a well-circumscribed spongy mass, whereas the tumors in these patients were solid and firm. Histologically, the tumors showed intrapulmonary lesions composed of densely proliferating polygonal or spindle-shaped mesenchymal cells with diffuse and dense infiltrations of inflammatory cells forming microcystic or micropapillary structures lined by thyroid transcription factor 1-positive pneumocytes, favoring inflammatory myofibroblastic tumor rather than FLIT. The proliferating cells were immunoreactive for ALK, and A2M-ALK was identified in both tumors with reverse-transcription polymerase chain reaction. The dense infiltration of inflammatory cells, immunoreactivity for ALK, and identification of an ALK-related chimeric gene suggested a diagnosis of inflammatory myofibroblastic tumor. Histologically, most reported FLITs show sparse inflammatory infiltrates and a relatively low density of interstitial cells in the septa, although prominent infiltration of inflammatory cells and high cellularity of interstitial cells are seen in some FLITs. The present cases suggest that ALK rearrangements, including the chimeric A2M-ALK gene, may be present in these infantile pulmonary lesions, especially those with inflammatory cell infiltration. We propose that these infantile pulmonary lesions containing a chimeric A2M-ALK gene be categorized as a specific type of inflammatory myofibroblastic tumor that develops exclusively in neonates and infants., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: We developed and validated a specific laparoscopic fundoplication simulator for use with the objective endoscopic surgical skills evaluation system. The aim of this study was to verify the quality of skills of surgeons., Materials and Methods: We developed a 1-year-old infant body model based on computed tomography data and reproduced pneumoperitoneum model based on the clinical situation. The examinees were divided into three groups: fifteen pediatric surgery experts (PSE), twenty-four pediatric surgery trainees (PSN), and ten general surgeons (GS). They each had to perform three sutures ligatures for construction of Nissen wrap. Evaluate points are time for task, the symmetry of the placement of the sutures, and the uniformity of the interval of suture ligatures in making wrap. And the total path length and velocity of forceps were measured to assess bi-hand coordination., Results: PSE were significantly superior to PSN regarding total time spent (p < 0.01) and total path length (p < 0.01). GS used both forceps faster than the other groups, and PSN used the right forceps faster than the left forceps (p < 0.05). PSE were shorter with regard to the total path length than GS (p < 0.01). PSE showed most excellent results in the symmetry of the wrap among three groups., Conclusion: Our new model was used useful to validate the characteristics between GS and pediatric surgeon. Both PSE and GS have excellent bi-hand coordination and can manipulate both forceps equally and had superior skills compared to PSN. In addition, PSE performed most compact and accurate skills in the conflicted operative space.

Purpose: We developed and evaluated a visual compensation system that allows surgeons to visualize obscured regions in real time, such that the surgical instrument appears virtually transparent., Methods: The system consists of two endoscopes: a main endoscope to observe the surgical environment, and a supporting endoscope to render the region hidden from view by surgical instruments. The view captured by the supporting endoscope is transformed to simulate the view from the main endoscope, segmented to the shape of the hidden regions, and superimposed to the main endoscope image so that the surgical instruments look transparent. A prototype device was benchmarked for processing time and superimposition rendering error. Then, it was evaluated in a training environment with 22 participants performing a backhand needle driving task with needle exit point error as the criterion. Lastly, we conducted an in vivo study., Results: In the benchmark, the mean processing time was 62.4 ms, which was lower than the processing time accepted in remote surgeries. The mean superimposition error of the superimposed image was 1.4 mm. In the training environment, needle exit point error with the system decreased significantly for experts compared with the condition without the system. This change was not significant for novices. In the in vivo study, our prototype enabled visualization of needle exit points during anastomosis., Conclusion: The benchmark suggests that the implemented system had an acceptable performance, and evaluation in the training environment demonstrated improved surgical task outcomes in expert surgeons. We will conduct a more comprehensive in vivo study in the future.

In neuroblastoma (NB), one of the most common paediatric solid tumours, activation of anaplastic lymphoma kinase (ALK) is often associated with poor outcomes. Although genetic studies have identified copy number alteration and nonsynonymous mutations of ALK, the regulatory mechanism of ALK signalling at protein levels is largely elusive. Neuronal leucine-rich repeat 1 (NLRR1) is a type 1 transmembrane protein that is highly expressed in unfavourable NB and potentially influences receptor tyrosine kinase signalling. Here, we showed that NLRR1 and ALK exhibited a mutually exclusive expression pattern in primary NB tissues by immunohistochemistry. Moreover, dorsal root ganglia of Nlrr1+/+ and Nlrr1-/- mice displayed the opposite expression patterns of Nlrr1 and Alk. Of interest, NLRR1 physically interacted with ALK in vitro through its extracellular region. Notably, the NLRR1 ectodomain impaired ALK phosphorylation and proliferation of ALK-mutated NB cells. A newly identified cleavage of the NLRR1 ectodomain also supported NLRR1-mediated ALK signal regulation in trans. Thus, we conclude that NLRR1 appears to be an extracellular negative regulator of ALK signalling in NB and neuronal development. Our findings may be beneficial to comprehend NB heterogeneity and to develop a novel therapy against unfavourable NB.

Purpose: We verified the appropriate port location for laparoscopic hepaticojejunostomy using a comprehensive laparoscopic training simulator., Methods: We developed a hepaticojejunostomy model, consist of common hepatic duct and intestine and participants required to place two sutures precisely using two different port locations (A: standard port location, B: modified port location). The order of tasks was randomly determined using the permuted block method (Group I: Task A → Task B, Group II: Task B → Task A). The time for task completion and total number of errors were recorded. In addition, we evaluated the spatial paths and velocity of both forceps. Statistical analyses were performed using a statistical software program., Results: The time for the task, the total error score, and the spatial paths and velocity of both forceps were not significantly different between groups I and II. Furthermore, the port location and order of tasks (group I or group II) did not significantly affect the results. In contrast, there were significant differences in the performance between experts and novices, who were classified as such based on the total number of experienced endoscopic surgeries., Conclusion: Preoperative port simulation in advanced surgery using our artificial simulator is feasible and may facilitate minimally invasive surgery for children.

Purpose: This study aimed to identify detailed differences in laparoscopic surgical processes between expert and novice surgeons in a training environment and demonstrate that surgical process modeling can be used for such detailed analysis., Methods: Eleven expert surgeons each of whom had performed [Formula: see text] laparoscopic procedures were compared with 10 young surgeons each of whom had performed [Formula: see text] laparoscopic procedures, and five medical students. Each examinee performed a specific skill assessment task. During tasks, instrument motion was monitored using a video capture system. From the video, the corresponding workflow was recorded by labeling the surgeons' activities according to a predefined terminology. Activities represented manual work steps performed during the task, described by a combination of a verb (representing the action), a tool, and the involved structure. The results were described as the number of occurrences (times), average duration (seconds), total duration (seconds), minimal duration (seconds), maximal duration (seconds), and occupancy percentage (%)., Results: The terminology for describing the processes of this task included 10 actions, six tools, four structures, and three events for each hand. There were 63 combinations of different possible activities; significant differences in 12 activities were observed between the expert and novice groups (young surgeons and medical students). The expert group performed the task with fewer occurrences and shorter duration than did the novice group in the left hand., Conclusions: We identified differences in surgical process between experts and novices in laparoscopic surgical simulation. Our proposed method would be useful for education and training in laparoscopic surgery.

Purpose: This study evaluated the stability and risk of single-incision laparoscopic percutaneous extraperitoneal closure (SILPEC) for pediatric inguinal hernia performed by inexperienced pediatric surgeons versus conventional LPEC procedure., Methods: Between 2011 and 2012, a randomized prospective study was performed comparing SILPEC (n = 37, 16 uni- and 21 bilateral patent processus vaginalis [PPV]) to LPEC (n = 72, 39 uni- and 33 bilateral PPV). The procedures were performed in girls with inguinal hernia by inexperienced pediatric surgeons with the assistance of an expert pediatric surgeon. In SILPEC, a laparoscope was placed through a transumbilical incision. A 2-mm trocar for the grasper was inserted through the same incision and introduced into the extraperitoneal cavity. The tip of the trocar was inserted in the abdominal cavity distant from the umbilical incision by the expert surgeon to avoid any complications caused by the in-line view. Using a special needle, the hernial sac was closed extraperitoneally by the inexperienced surgeon. A statistical survey of the mean age at operation, mean operative time, intra- and postoperative complications, and recurrence in the SILPEC and LPEC groups was performed., Results: There were no significant differences in the mean age or operative time. There were fewer total number of postoperative complications in the SILPEC group compared with the LPEC group (P = .0707). No intraoperative complications or recurrence occurred., Conclusions: Considering the risks and need to improve endoscopic surgical skills with useful instruments specialized for SILPEC, inexperienced surgeons can successfully perform SILPEC safely under expert pediatric surgeons.

Background: Three-dimensional (3D) printed models based on computed tomography (CT) images facilitate the visualization of complex structures and are useful for understanding the surgical anatomy preoperatively. We developed a preoperative surgical simulation method using a 3D printed model based on CT images obtained prior to laparoscopic adrenalectomy for adrenal neuroblastomas (NBs)., Materials and Methods: The multi-detector CT images were transferred to a 3D workstation, and 3D volume data were obtained by reconstructing the sections. A model was made with a 3D printer using acrylic ultraviolet curable resin. The adrenal tumor, kidney, renal vein and artery, inferior vena cava, aorta, and outer body were fabricated. The pneumoperitoneum, insertion of trocars, and laparoscopic view were all attainable in this model. We used this model for three cases with adrenal NB., Results: We used this model to discuss the port layout before the operation and to simulate the laparoscopic view and range of forceps movement. All three cases with NB were completely resected without any surgical complications., Conclusions: The surgical simulation using 3D printed models based on preoperative CT images for adrenal NB was very useful for understanding the patient's surgical anatomy and for planning the surgical procedures, especially for determining the optimal port layout., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Japanese Neuroblastoma Study Group (JNBSG) has been employing image-defined risk factors (IDRFs) since 2010. However, the report from INRG in 2011 supplemented description stating that isolated contact is considered to be IDRF-positive only in renal vessels. The aim of this study was to evaluate the validity of IDRFs by comparing the previous (PG) and new guidelines (NG)., Methods: IDRFs of patients with localized neuroblastoma treated at two centers in Western Japan from 2002 to 2013 were retrospectively reviewed by radiologists., Results: 47 neuroblastomas (abdomen 38, pelvis 2, mediastinum 7) were evaluated. For abdominal neuroblastomas, IDRFs were present in 15/38 (39.5%) using PG and in 31/38 (81.6%) using NG. Moreover, the IDRF-positive rate increased from 26.7% (4/15) to 80.0% (12/15) in 15 cases diagnosed during mass screening. Of the IDRF-positive cases, complete primary resection was achieved in 2/15 (13.3%) using PG and 17/31 patients (54.8%) using NG. There were two major surgical renal complications in the IDRF-positive cases based on the use of either guidelines, and the specificity decreased from 64% to 19%., Conclusions: According to NG, the IDRF-positive rate increased, and the resection rate decreased. NG may overestimate surgical risks, leading to unnecessary chemotherapy and a prolonged hospital stay., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Pediatric surgeons require highly advanced skills when performing endoscopic surgery; however, their experience is often limited in comparison to general surgeons. The aim of this study was to evaluate the effectiveness of endoscopic surgery training for less-experienced pediatric surgeons and then compare their skills before and after training., Methods: Young pediatric surgeons (n = 7) who participated in this study underwent a 2-day endoscopic skill training program, consisting of lectures, box training and live tissue training. The trainees performed the Nissen construction tasks before and after training using our objective evaluation system. A statistical analysis was conducted using the two-tailed paired Student's t tests., Results: The time for task was 984 ± 220 s before training and 645 ± 92.8 s after training (p < 0.05). The total path length of both forceps was 37855 ± 10586 mm before training and 22582 ± 3045 mm after training (p < 0.05). The average velocity of both forceps was 26.1 ± 3.68 mm/s before training and 22.9 ± 2.47 mm/sec after training (p < 0.1). The right and left balance of suturing was improved after training (p < 0.05)., Conclusion: Pediatric surgery trainees improved their surgical skills after receiving short-term training. We demonstrated the effectiveness of our training program, which utilized a new laparoscopic fundoplication simulator.

Purpose: Endoscopic surgery is performed under a horizontal view in comparison to the vertical view that is associated with open surgery. We developed an endoscopic pseudo-viewpoint alternation system with out any scope action. We investigate the effect of this novel system on forceps manipulation among expert pediatric surgeons., Methods: Six expert pediatric surgeons performed a Nissen wrap in a fundoplication simulator either with or without this system. The constructed Nissen wrap was evaluated. The total path length and the average velocity of the forceps were also analyzed., Results: The times required either with or without this system were 587.5 ± 122.7 and 634.0 ± 212.4 s (p = 0.45), respectively. The total path lengths of right and left forceps either with or without this system were 12,309 ± 2495.5 and 15,726 ± 5649.6 mm (p = 0.07), 10,091 ± 2439.2 and 12,575 ± 5511.1 mm (p = 0.11), respectively. The average velocity of the right and left forceps with or without this system were 26.9 ± 5.29 and 31.6 ± 1.62 mm/s (p = 0.04), 21.6 ± 2.48 and 25.5 ± 6.48 mm/s (p = 0.15), respectively. There was no significance in the suture balance and suture interval., Conclusion: The endoscopic pseudo-viewpoint alternation system thus made it possible for expert pediatric surgeons to carry out slow and economical forceps manipulation. These effects make it possible for surgeons to perform safe and precise surgery, thus leading to a shortening of operation time.

Purpose: We developed a system to objectively verify the endoscopic surgical skills of pediatric surgeons., Materials and Methods: We developed a thoracoscopic model of congenital diaphragmatic hernia mimicking a newborn's size. The examinees were divided into Experts (n = 10) and Trainees (n = 19), and each group performed two tasks (Task 1, reduction of a herniated intestine from the thoracic space to the abdomen; Task 2, perform three suture ligatures of a diaphragm defect using intracorporeal knot-tying). The end points were the time required to complete Task 1, time score calculated using the residual time from the time limit for Task 2, number of complete full-thickness sutures, maximum air-pressure tolerance, degree of diaphragm deformation, and the residual defect areas after suturing. We also evaluated the total path length and velocity of the forceps tips using a three-dimensional position measurement instrument., Results: The Experts had significantly superior results for the time for Task 1, time score, number of complete full-thickness sutures, maximum air-pressure tolerance, and degree of diaphragm deformation in Task 2 (all P < .05). We found that the total path length and average velocities for the left forceps were inferior to those of the right forceps in both tasks in the Trainees (both P < .05, respectively), whereas the Expert group showed no significant laterality in these tasks., Conclusions: Our model could validate the quality of endoscopic surgical skills and could differentiate between Expert and Trainee pediatric surgeons. The Experts could use their forceps equally well to perform tasks even in a small working space.

Background/aim: Neuroblastoma (NB) is the most common and lethal extracranial solid tumor in children. The present study aimed to verify that the heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a rational target in NB therapy., Material and Methods: We examined expression of EGFR ligands in four NB cell lines using 2-dimensional culture (DC) and 3DC conditions. To assess the anti-tumor effect of cross-reacting material 197 (CRM197), which is a specific inhibitor of HB-EGF, on NB cells, we also performed terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay to detect apoptotic cells., Results: HB-EGF was predominantly expressed in two out of four NB cell lines under 2DC and 3DC conditions. CRM197 significantly induced apoptosis of NB cells with high HB-EGF expression., Conclusion: HB-EGF plays an important role in neuroblastoma tumorigenesis and CRM197 showed an effective antitumor effect in neuroblastoma cells., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Here we studied 60 RMSs using whole-exome/-transcriptome sequencing, copy number (CN) and DNA methylome analyses to unravel the genetic/epigenetic basis of RMS. On the basis of methylation patterns, RMS is clustered into four distinct subtypes, which exhibits remarkable correlation with mutation/CN profiles, histological phenotypes and clinical behaviours. A1 and A2 subtypes, especially A1, largely correspond to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes are characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite the better prognosis of embryonal RMS, patients in the E2 are likely to have a poor prognosis. Our results highlight the close relationships of the methylation status and gene mutations with the biological behaviour in RMS.

The patient is a 3-year-old female diagnosed with PRETEXT IV hepatoblastoma (HB). Although the tumor was decreased after the neoadjuvant chemotherapy, HB still located at the porta hepatis. The patient underwent extended left lobectomy successfully after surgical simulation using three-dimensional (3D) printing liver model based on preoperative CT.

Background: Bariatric surgical procedures are becoming a standard treatment for morbid obesity in many western countries and in some Asian countries., Aim: The aim of the current study was to evaluate the efficacy and safety of the initial 30 cases of bariatric surgical procedures performed for morbid obesity at a single institution in Japan., Materials and Methods: From March 2012 until September 2014, 30 bariatric surgical procedures were performed for morbid obesity at a single medical center (Kyushu University Hospital) in Japan., Results: All of the operations procedures were planned laparoscopic procedures, and none required conversion to laparotomy. There were no perioperative or postoperative mortalities. Postoperative complications occurred in 3 patients: 1 patient developed an intra-abdominal abscess, 1 patient experienced temporary food intolerance, and 1 patient developed small bowel obstruction. The excessive body weight reduction rates after surgery at 1 month, 3 months, 6 months, and 1 year post-surgery were 26.1%, 39.2%, 41.7%, and 51.2%, respectively. The mean body mass index (BMI) at the same time points were 38.3%, 36.4%, 35.5%, and 31.4%, respectively. Eighteen patients had type II diabetes mellitus (T2DM). The mean preoperative fasting blood glucose levels were 169 ± 37 mg/dL. Following surgery, the blood glucose levels at 3, 6 and 12 months were 113 ± 12, 115 ± 22, and 110 ± 19, mg/dL, respectively. The preoperative HbA1c percentage was 7.9 ± 0.5. Following surgery, the HbA1c percentages at 3, 6, and 12 months were 6.9 ± 0.5, 6.2 ± 0.9, and 5.9 ± 0.6, respectively., Conclusions: Bariatric surgical procedures are effective and safe for the treatment of morbid obesity. Our results indicate that the mechanism of improvement of diabetes and related diseases following bariatric surgical procedures is not simply as a result of calorie restriction and weight reduction.

Purpose: Glypican 3 (GPC3) is one of the cell surface heparan sulfate proteoglycans that binds to the cell membrane, and it is known as an oncofetal protein in adult malignant tumors. Clinical trials using a GPC3 peptide vaccine have already been started in Japan as a new immunotherapy for hepatocellular carcinoma in adult patients. To investigate the possibility of GPC3 immunotherapy for pediatric malignant tumors, we assessed the expression of GPC3 in pediatric malignant tumors., Methods: Immunohistochemically, the GPC3 expression was examined in 159 pediatric solid tumors, including 35 cases of neuroblastoma, 30 cases of Wilms tumor, 10 cases of hepatoblastoma, 25 cases of germ cell tumors, 56 cases of rhabdomyosarcoma, and 3 cases of other tumors. In addition, to clarify the physiological expression during the fetal to neoinfantile period, autopsy specimens of subjects without any neoplastic diseases were assessed in 9 fetal cases and 21 neoinfantile cases. The serum levels of GPC3 were also analyzed using specimens obtained from 53 subjects by the sandwich enzyme-linked immunosorbent assay method., Results: Histologically, a high rate of GPC3 expression was noted in 10 (90.9%) of the 11 subjects with yolk sac tumors and 6 (60.0%) of the 10 subjects with hepatoblastoma. In addition, 9 (30.0%) of the 30 subjects with Wilms tumors and 14 (25.0%) of the 56 subjects with rhabdomyosarcoma were positive for the expression of GPC3. Concerning autopsy specimens, most of the 23 subjects younger than 7 months showed positive findings in the liver (94.7%) and kidney (81.8%). Two subjects (100%) with yolk sac tumors and six (75.0%) of the eight subjects with hepatoblastoma serologically demonstrated a high rate of positive expression. Concerning the distribution of the serum GPC3 level according to age, 8 (80.0%) of the 10 subjects younger than 1 year showed a positive finding, while only 16 (37.3%) of the 43 subjects older than 1 year showed a positive finding., Conclusion: Most cases of hepatoblastoma and yolk sac tumor, and some cases of other tumors were found to express GPC3 either histologically or serologically. On the other hand, GPC3 was physiologically expressed during the fetal and neoinfantile period under 1 year of age. Although, more preliminary data and experience are required, patients older than 1 year that show a positive finding for GPC3 are considered to be appropriate candidates to receive the new immunotherapy using GPC3 peptide vaccination., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The purpose of this study was to develop a new objective assessment system for the suture ligature method employed in the laparoscopic intestinal anastomosis model. Suturing skills were evaluated objectively using this system., Methods: This study compared 17 expert surgeons, each of whom had performed >500 laparoscopic procedures, with 36 novice surgeons, each of whom had performed <15 laparoscopic procedures. Each examinee performed a specific skill assessment task using an artificial model that mimics living tissue, which is linked with the Suture Simulator Instruction Evaluation Unit. The model used internal air pressure measurements and image processing to evaluate suturing skills. Five criteria were used to evaluate the skills of participants., Results: The volumes of air pressure leak in the expert and novice groups were 21.13 ± 6.68 and 8.51 ± 8.60 kPa, respectively. The numbers of full-thickness sutures in the expert and novice groups were 2.94 ± 0.24 pairs and 2.47 ± 0.77 pairs, respectively. Suture tensions in the expert and novice groups were 60.99 ± 11.81 and 80.90 ± 16.63 %, respectively. The areas of wound-opening in the expert and novice groups were 1.76 ± 2.17 and 11.06 ± 15.37 mm(2), respectively. The performance times in the expert and novice groups were 349 ± 120 and 750 ± 269 s, respectively. Significant differences between the expert and novice groups for each criterion were observed. The acceptable range of values for each criterion except for the number of full-thickness sutures was statistically defined by the performance of the expert group., Conclusions: Our system is useful for the quantitative assessment of suturing skill in laparoscopic surgery. We believe that this system is a useful tool for training and assessment of laparoscopic surgeons.

Background: The number of operations performed by a surgeon may be an indicator of surgical skill. The hand motions made by a surgeon also reflect skill and level of expertise. We hypothesized that the hand motions of expert and novice surgeons differ significantly, regardless of whether they are familiar with specific tasks during an operation., Methods: This study compared 11 expert surgeons, each of whom had performed >100 laparoscopic procedures, and 27 young surgeons, each of whom had performed <15 laparoscopic procedures. Each examinee performed a specific skill assessment task, in which instrument motion was monitored using magnetic tracking system. We analyzed the paths of the centers of gravity of the tips of the needle holders and the relative paths of the tips using two mathematical methods of detrended fluctuation analysis and unstable periodic orbit analysis., Results: Detrended fluctuation analysis showed that the exponent in the function describing the initial scaling exponent (α1) differed significantly for experts and novices, being close to 1.0 and 1.5, respectively (P < 0.01). This indicated that the expert group had a greater long-range coherence with an intrinsic sequence and smooth continuity among a series of motions. Likewise, unstable periodic orbit analysis showed that the second period of unstable orbit was significantly longer for experts in comparison with novices (P < 0.01). This demonstrates mathematically that the hands of experts are more stable when performing laparoscopic procedures., Conclusions: Objective evaluation of hand motion during a simulated laparoscopic procedure showed a significant difference between experts and novices., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: 2q37 deletion syndrome is a rare congenital disorder that is characterized by facial dysmorphism, obesity, vascular and skeletal malformations, and a variable degree of intellectual disability. To date, common but variable phenotypes, such as skeletal or digit malformations and obesity, have been associated with the deleted size or affected genes at chromosome 2q37. However, it remains elusive whether 2q37 deletion per se or other genetic factors, such as copy number variations (CNVs), may confer the risk for the tumorigenic condition., Case Presentation: We report a two-year-old Japanese boy with 2q37 deletion syndrome who exhibited the typical facial appearance, coarctation of the aorta, and a global developmental delay, while lacking the symptoms of brachydactyly and obesity. He developed a sex cord-stromal tumor of the right testis at three months of age. The array comparative genome hybridization analysis identified an 8.2-Mb deletion at 2q37.1 (chr2:234,275,216-242,674,807) and it further revealed two additional CNVs: duplications at 1p36.33-p36.32 (chr1:834,101-2,567,832) and 20p12.3 (chr20:5,425,762-5,593,096). The quantitative PCRs confirmed the heterozygous deletion of HDAC4 at 2q37.3 and duplications of DVL1 at 1q36 and GPCPD1 at 20p12.3., Conclusion: This study describes the unique phenotypes in a boy with 2q37 deletion and additional CNVs at 1p36.33-p36.32 and 20p12.3. The data provide evidence that the phenotypic variations and unusual complications of 2q37 deletion syndrome are not simply explained by the deleted size or genes located at 2q37, but that external CNVs may account at least in part for their variant phenotypes. Accumulating the CNV data for chromosomal disorders will be beneficial for understanding the genetic effects of concurrent CNVs on the syndromic phenotypes and rare complications.

Background: Aberrant methylation at imprinted differentially methylated regions (DMRs) in human 11p15.5 has been reported in many tumors including hepatoblastoma. However, the methylation status of imprinted DMRs in imprinted loci scattered through the human genome has not been analyzed yet in any tumors., Methods: The methylation statuses of 33 imprinted DMRs were analyzed in 12 hepatoblastomas and adjacent normal liver tissue by MALDI-TOF MS and pyrosequencing. Uniparental disomy (UPD) and copy number abnormalities were investigated with DNA polymorphisms., Results: Among 33 DMRs analyzed, 18 showed aberrant methylation in at least 1 tumor. There was large deviation in the incidence of aberrant methylation among the DMRs. KvDMR1 and IGF2-DMR0 were the most frequently hypomethylated DMRs. INPP5Fv2-DMR and RB1-DMR were hypermethylated with high frequencies. Hypomethylation was observed at certain DMRs not only in tumors but also in a small number of adjacent histologically normal liver tissue, whereas hypermethylation was observed only in tumor samples. The methylation levels of long interspersed nuclear element-1 (LINE-1) did not show large differences between tumor tissue and normal liver controls. Chromosomal abnormalities were also found in some tumors. 11p15.5 and 20q13.3 loci showed the frequent occurrence of both genetic and epigenetic alterations., Conclusions: Our analyses revealed tumor-specific aberrant hypermethylation at some imprinted DMRs in 12 hepatoblastomas with additional suggestion for the possibility of hypomethylation prior to tumor development. Some loci showed both genetic and epigenetic alterations with high frequencies. These findings will aid in understanding the development of hepatoblastoma.