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Purpose: To investigate the timing of enucleation, treatment course, and outcome for retinoblastoma (RB) with optic nerve (ON) invasion on imaging., Study Design: Retrospective clinical study., Methods: Of the 160 patients with RB who presented to the National Center for Child Health and Development in Japan between 2005 and 2022, ON invasion on imaging at the initial presentation was seen in five patients. The clinical, computed tomography (CT), and magnetic resonance imaging (MRI) findings, and treatment courses were reviewed retrospectively., Results: MRI showed ON invasion in all five patients (three with unilateral RB, 2 with bilateral RB); in two patients CT detected no invasion. Enucleation was performed in four patients, three of whom underwent neoadjuvant therapy and one had a positive ON resection margin following the enucleation as initial treatment. One patient did not undergo enucleation due to cerebrospinal fluid dissemination. All enucleated patients underwent adjuvant chemotherapy. Four patients underwent radiotherapy. During follow-up (mean, 89.4 months), four patients survived and one died., Conclusion: MRI is recommended to evaluate ON invasion and determine the timing of enucleation for RB. The appropriate choice of neoadjuvant or adjuvant therapy would be helpful to avoid radiotherapy for RB with ON invasion on imaging., (© 2024. The Author(s).)

SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex, is the causative gene of rhabdoid tumors and epithelioid sarcomas. Here, we identify a paralog pair of CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers by using a dual siRNA screening method based on the "simultaneous inhibition of a paralog pair" concept. Treatment with CBP/p300 dual inhibitors suppresses growth of cell lines and tumor xenografts derived from SMARCB1-deficient cells but not from SMARCB1-proficient cells. SMARCB1-containing SWI/SNF complexes localize with H3K27me3 and its methyltransferase EZH2 at the promotor region of the KREMEN2 locus, resulting in transcriptional downregulation of KREMEN2. By contrast, SMARCB1 deficiency leads to localization of H3K27ac, and recruitment of its acetyltransferases CBP and p300, at the KREMEN2 locus, resulting in transcriptional upregulation of KREMEN2, which cooperates with the SMARCA1 chromatin remodeling complex. Simultaneous inhibition of CBP/p300 leads to transcriptional downregulation of KREMEN2, followed by apoptosis induction via monomerization of KREMEN1 due to a failure to interact with KREMEN2, which suppresses anti-apoptotic signaling pathways. Taken together, our findings indicate that simultaneous inhibitors of CBP/p300 could be promising therapeutic agents for SMARCB1-deficient cancers., (© 2024. The Author(s).)

Objective: Indirect revascularization is a common and effective treatment for pediatric moyamoya disease. However, in several cases postoperative angiogenesis is not sufficient. It is not fully understood which factors are involved in the development of postoperative collateral circulation. In this study, the authors aimed to elucidate the factors related to postoperative angiogenesis in indirect revascularization., Methods: Among the patients who underwent indirect revascularization for moyamoya disease from January 2015 to December 2022, those whose angiogenesis was evaluated using angiography were included. Age, onset symptoms, comorbidities, preoperative imaging findings, surgical details, perioperative complications, postoperative imaging findings, and modified Rankin Scale (mRS) score at the last outpatient visit were retrospectively examined., Results: Ninety cases (53 patients; 37 bilateral, 16 unilateral) were included. Sixty-eight cases (75.6%) were symptomatic. The mean age at surgery was 7.9 years, and the mean postoperative follow-up duration was 48.5 months. Frontotemporal encephalo-duro-arterio-synangiosis (EDAS) was performed in all cases, and simultaneous frontal encephalo-galeo-synangiosis (EGS) was performed in 34 cases. Postoperative angiography revealed insufficient angiogenesis in 14 of 90 cases (15.6%) after frontotemporal EDAS and in 8 of 34 cases (23.5%) after frontal EGS. A high degree of ivy sign depicted on preoperative MRI was found to be significantly correlated with good angiogenesis after both surgical procedures (p = 0.00030 for EDAS and p = 0.0039 for frontal EGS). In addition, an advanced preoperative Suzuki stage was significantly correlated with good postoperative angiogenesis after EDAS (p = 0.00040). Good angiogenesis was significantly correlated with postoperative improvement of the ivy sign in both procedures (p = 0.0005 in EDAS and p = 0.030 in frontal EGS) as well as correlated with a better mRS score at long-term follow-up after EDAS (p = 0.018)., Conclusions: Preoperative ivy sign and Suzuki classification are related to the degree of angiogenesis achieved after indirect revascularization for pediatric moyamoya disease.

Polyester fibers, comprising mostly poly(ethylene terephthalate) with high crystalline content, represent the most commonly produced plastic for ubiquitous textiles, and approximately 60 million tons are manufactured annually worldwide. Considering the social issues of mismanaged waste produced from used textile products, there is an urgent demand for sustainable waste polyester fiber recycling methods. We developed a low-temperature, rapid, and efficient depolymerization method for recycling polyester fibers. By utilizing methanolysis with dimethyl carbonate as a trapping agent for ethylene glycol, depolymerization of polyester fibers from textile products proceeded at 50 °C for 2 h, affording dimethyl terephthalate (DMT) in a >90% yield. This strategy allowed us to depolymerize even practical polyester textiles blended with other fibers to selectively isolate DMT in high yields. This method was also applicable for colored polyester textiles, and analytically pure DMT was isolated via depolymerization and decolorization processes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Achondroplasia is the most common form of dwarfism, caused by a mutation in fibroblast growth factor receptor 3 gene, leading to multiple pathological conditions. Herein, we present a case of an infant with achondroplasia associated with hydrocephalus and severe foramen magnum stenosis. Computed tomography (CT) venography showed prominent suboccipital emissary veins comprising major venous drainage routes and hypoplastic transverse sinuses, which increased the risk of foramen magnum decompression. The infant was initially treated with ventriculo-peritoneal (VP) shunt. After 8 months, CT venography showed regression of suboccipital emissary veins and more prominent transverse sinuses. Subsequently, foramen magnum decompression was safely performed without sacrificing major venous drainage routes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The purpose of this report is to investigate the association of atretic cephalocele (AC) with sinus pericranii (SP) in order to improve the management of AC., Methods: Pediatric patients with AC who underwent repair surgeries were retrospectively analyzed. Anomalies including SP were evaluated using computed tomography angiography and venography (CTA/V) as well as magnetic resonance imaging., Results: Fourteen patients were identified, comprising of 5 males and 9 females. The AC was located interparietally in 8 cases and occipitally in 6 cases. Seven cases (50%) were found to be associated with SP, all of which did not involve major intracranial venous circulation. Five out of 8 parietal ACs (63%) were accompanied by SP, while 2 out of 6 occipital ACs (33%) exhibited SP. All of the SP associated with AC only contributed to a small portion of the venous outflow, and the repair surgeries were successfully performed without excessive bleeding., Conclusion: More than half of the ACs were associated with SP, with a higher prevalence in the parietal region compared to the occipital region. For the appropriate management of AC, preoperative investigation of SP using CT venography is considered important., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Pineal region tumors (PRTs) are tumors arising from the pineal gland and the paraspinal structures. These tumors are rare and heterogeneous that account for 2.8-10.1% and 0.6-3.2% of tumors in children and in all ages, respectively. Almost all types and subtypes of CNS tumors may be diagnosed in this region. These tumors come from cells of the pineal gland (pinealocytes and neuroglial cells), ectopic primordial germ cells (PGC), and cells from adjacent structures. Hence, PRTs are consisted of pineal parenchyma tumors (PPTs), germ cell tumors (GCTs), neuroepithelial tumors (NETs), other miscellaneous types of tumors, cystic tumors (epidermoid, dermoid), and pineal cyst in addition. The symptoms of PRTs correlate to the increased intracranial cranial pressure due to obstructive hydrocephalus and dorsal midbrain compression. The diagnostic imaging studies are mainly MRI of brain (with and without gadolinium) along with a sagittal view of whole spine. Serum and/or CSF AFP/β-HCG helps to identify GCTs. The treatment of PRTs is consisted of the selection of surgical biopsy/resection, handling of hydrocephalus, neoadjuvant and/or adjuvant therapy according to age, tumor location, histopathological/molecular classification, grading of tumors, staging, and threshold value of markers (for GCTs) in addition., Methods: In this article, we review the following focus points: 1. Background of pineal region tumors. 2. Pineal GCTs and evolution of management. 3. Molecular study for GCTs and pineal parenchymal tumors. 4. Review of surgical approaches to the pineal region. 5. Contribution of endoscopy. 6. Adjuvant therapy (chemotherapy, radiotherapy, and combination). 7., Results: In all ages, the leading three types of PRTs in western countries were PPTs (22.7-34.8%), GCTs (27.3-34.4%), and NETs (17.2-28%). In children and young adults, the leading PRTs were invariably in the order of GCTs (40-80.5%), PPTs (7.6-21.6%), NETs (2.4-37.5%). Surgical biopsy/resection of PRTs is important for precision diagnosis and therapy. Safe resection with acceptable low mortality and morbidity was achieved after 1970s because of the advancement of surgical approaches, CSF shunt and valve system, microscopic and endoscopic surgery. Following histopathological diagnosis and classification of types and subtypes of PRTs, in PPTs, through molecular profiling, four molecular groups of pineoblastoma (PB) and their oncogenic driver were identified. Hence, molecular stratified precision therapy can be achieved., Conclusion: Modern endoscopic and microsurgical approaches help to achieve precise histopathological diagnosis and molecular classification of different types and subtypes of pineal region tumors for risk-stratified optimal, effective, and protective therapy. In the future, molecular analysis of biospecimen (CSF and blood) along with AI radiomics on tumor imaging integrating clinical and bioinformation may help for personalized and risk-stratified management of patients with pineal region tumors., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Surgical resection of pineal region tumors is challenging because of close proximity to the vein of Galen draining system and the quadrigeminal plate. Surgical resection usually is performed through the narrow corridor by piecemeal resection and en bloc resection is difficult in cases of large tumors. Moreover, in cases of hypervascular tumors, surgical resection through the narrow corridor could entail massive intraoperative bleeding. The effectiveness of neoadjuvant chemotherapy and second-look surgery for pineal region tumors for maximal safe resection was evaluated., Methods: Retrospective institutional review of pediatric patients with pineal region tumors who underwent second look surgery after neoadjuvant chemotherapy was performed., Results: Nine patients underwent surgical resection after neoadjuvant chemotherapy over the period of September 2017 to February 2022. The mean age was 7.7 years (ranged from 1.4 to 15.3 years). Three patients underwent partial resection via open craniotomy, and 6 underwent endoscopic biopsy as an initial surgery. The histopathological diagnoses were germ cell tumors in 5 patients (yolk sac tumors in 2, germinoma in 2, choriocarcinoma in 1), /rhabdoid tumor (AT/RT) in 2, medulloblastoma in 1, and high-grade glioneuronal tumor in 1. After several courses of chemotherapy, the second-look surgery was performed. The tumor volume was reduced in 8 patients (89%) after chemotherapy except for 1 case of growing teratoma syndrome. The tumor was extended laterally to the ambient cistern in 2 patients, and posteriorly to the tentorial surface of the cerebellum in 3 patients. The lesion was approached through occipital transtentorial approach in 8 patients and infratentorial supracerebellar approach in 1. Intraoperatively, the high vascularity of the tumor was not observed in all cases. Gross total resection (8 patients, 89%) or near total resection (1, 11%) was achieved in all cases. No complications were observed postoperatively in all cases. Eight patients subsequently underwent additional chemo-radiation therapy according to the initial diagnosis. All patients are alive with no evidence of recurrence with a mean follow-up of 33 months., Conclusions: Neoadjuvant chemotherapy and second-look surgery for pediatric pineal region tumors was considered to be effective in reducing the tumor volume and vascularity, which facilitates the safe maximal tumor resection., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The present study introduced the half-dose method (HDM), which halves the radiation dose for conventional head computed tomography (CT), for postoperative hydrocephalus and follow-up for craniosynostosis at a children's hospital. This study aimed to evaluate the contribution of selective head CT scanning optimization towards the overall reduction of radiation exposure., Materials and Methods: We retrospectively assessed 1227 and 1352 head CT examinations acquired before and after the introduction of the HDM, respectively, in children aged 0-15 years. The radiation exposure was evaluated using the CT dose index volume (CTDI-vol), dose-length product (DLP), rate of HDM introduction, and effect of reducing in-hospital radiation dose before and after the introduction of the HDM. For an objective evaluation of the image quality, head CT scans acquired with HDM and full-dose method (FDM) were randomly selected, and the image noise standard deviation (SD) was measured for each scan. In addition, some HDM images were randomly selected and independently reviewed by two radiologists., Results: The HDM was introduced in 27.9% of all head CTs. The mean CTDI-vol of all head CTs was 21.5 ± 6.9 mGy after the introduction, a 14.9% reduction. The mean DLP was 418.4 ± 152.9 mGy.cm after the introduction, a 17.2% reduction. Compared to the FDM images, the noise SD of the HDM ones worsened by almost 0.9; however, none of the images were difficult or impossible to evaluate., Conclusion: The HDM yielded diagnostically acceptable images. In addition, a change in protocol for only two diseases successfully reduced the patients' overall radiation exposure by approximately 15%. Introducing and optimizing the HDM for frequently performed target diseases will be useful in reducing the exposure dose for the hospital's patient population., (© 2023. The Author(s).)

The repertoire of tumor-infiltrating T cells is an emerging method for characterizing effective antitumor T-cell responses. Oligoclonal expansion of the tumor T-cell repertoire has been evaluated; however, their association with antitumor effects is unclear. We demonstrate here that the polyclonal fraction of the tumor-reactive T-cell repertoire, consisting of relatively minor clones, increased in tumor-bearing mice treated with monoclonal anti-programmed death-ligand 1 (PD-L1) or anti-CD4, which correlated with antitumor effects. Meanwhile, the size of the oligoclonal fraction consisting of major clones remained unchanged. Moreover, the polyclonal fraction was enriched in progenitor exhausted T cells, which are essential for a durable antitumor response, and was more dependent on CCR7+ migratory dendritic cells, which are responsible for priming tumor-reactive T cells in the tumor-draining lymph nodes. These results suggest that the expansion of diverse tumor-reactive clones ("clonal spreading") represents characteristics of antitumor T-cell responses induced by anti-CD4 and anti-PD-L1 treatment., (©2023 American Association for Cancer Research.)

Objective: Untethering surgery for a tight filum terminale is a common treatment with considerable efficacy and safety. On the other hand, retethering has been reported to occur. One of the major mechanisms of retethering is adherence of the cut end of the sectioned filum to the midline dorsal dural surface. To prevent retethering, the authors sectioned a filum terminale at the rostral level to the dural incision to keep the distance between the cut end of the sectioned filum and the dural incision and investigated whether this procedure decreased the occurrence of retethering., Methods: Among the patients who underwent untethering surgery for a tight filum terminale between 2012 and 2016, patients followed up more than 5 years were included in the study. Symptoms, comorbid malformations, preoperative imaging, surgical details, perioperative complications, and long-term outcomes were reviewed retrospectively., Results: Retrospective data for a total of 342 cases were included. The median age at surgery was 11 months (range 3-156 months). Preoperative MRI revealed 254 patients (74.3%) had a low-set conus. There were 142 patients (41.5%) with filar lipoma and 42 patients (12.3%) with terminal cyst. Syringomyelia was found in 29 patients (8.5%). In total, 246 patients (71.9%) were symptomatic and 96 patients (28.1%) were asymptomatic. There were no perioperative complications that required surgical intervention or prolonged hospitalization. The mean postoperative follow-up was 88 months (range 60-127 months). There were 4 patients (1.2%) with retethering who presented with bladder and bowel dysfunction. The mean time from initial untethering to retethering was 54 months (range 36-80 months). All 4 patients underwent untethering surgery, and preoperative symptoms resolved in 3 patients., Conclusions: The retethering rate after untethering surgery for a tight filum terminale in our series was lower than those in previously reported studies. Sectioning the filum terminale at the rostral level to the dural incision was considered an effective way to prevent retethering.

Background: Longstanding overt ventriculomegaly in adults (LOVA) is a new form of progressive hydrocephalus characterized by onset in early childhood and gradual progression into adulthood. Patients with LOVA are usually asymptomatic in childhood. The diagnosis of LOVA in adolescence has not been reported., Case Report: A patient with macrocephaly and mild ventriculomegaly from infancy developed headache exacerbation and cognitive dysfunction at the age of 11 years. Brain magnetic resonance imaging showed mild tri-ventriculomegaly with no radiological aggravation compared to imaging at the age of 8 years. No papilledema was observed. Drainage of 15 ml of spinal fluid via a lumbar puncture relieved the headache and cognitive dysfunction. Based on repeated improvements in cognitive function and headaches after spinal fluid drainage, we diagnosed the patient with LOVA with symptom onset in early adolescence. A ventriculoperitoneal shunt was placed, and the headaches disappeared completely. The full-scale intellectual quotient, verbal comprehension, and working memory improved significantly., Conclusions: LOVA may manifest as early as adolescence. The clinical presentation, age, clinical, radiological features, and management vary, and a spinal tap exam is useful for diagnosing LOVA, even in children. The spinal tap exam may be indicated in children with longstanding ventriculomegaly and deteriorating neurological symptoms to diagnose this "treatable intellectual disability.", (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

Posterior fossa tumors tend to entail obstructive hydrocephalus, and urges initiating prompt treatment. Prevalent pathologies include medulloblastoma, ependymoma, pilocytic astrocytoma, and atypical teratoid/rhabdoid tumor(AT/RT). In most cases, maximal safe resection is related to better prognosis. In some cases of ependymoma and AT/RT with high vascularity, second-look surgery with neoadjuvant chemotherapy is effective. The treatment strategy should be tailored according to each tumor.

Purely prepontine arachnoid cysts not extending into the suprasellar region in neonates are rare. Herein, we report a purely prepontine arachnoid cyst in a neonate which caused central apnea and was successfully treated with microscopic cyst fenestration and C1 laminectomy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10 -9 , odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10 -4 , Spearman's ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites., (© 2022. The Author(s).)

In the field of drug repurposing, the use of statins for treating dyslipidemia is considered promising in ovarian cancer treatment based on epidemiological studies and basic research findings. Biomarkers should be established to identify patients who will respond to statin treatment to achieve clinical application. In the present study, we demonstrated that statins have a multifaceted mode of action in ovarian cancer and involve pathways other than protein prenylation. To identify biomarkers that predict the response to statins, we subjected ovarian cancer cells to microarray analysis and calculated Pearson's correlation coefficients between gene expression and cell survival after statin treatment. The results showed that VDAC1 and LDLRAP1 were positively and negatively correlated with the response to statins, respectively. Histoculture drug response assays revealed that statins were effective in clinical samples. We also confirmed the synergistic effects of statins with paclitaxel and panobinostat and determined that statins are hematologically safe to administer to statin-treated mice. Future clinical trials based on the expression of the biomarkers identified in this study for repurposing statins for ovarian cancer treatment are warranted.

The expansion of intratumoral stem-like/progenitor exhausted CD8 + T (Tstem/Tpex) cells provides a potential approach to improve the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, here we demonstrate a strategy to facilitate Tstem/Tpex cell expansion by combining an alarmin high-mobility group nucleosome binding domain 1 (HMGN1) peptide with programmed death-ligand 1 (PD-L1) blockade. The antitumor effects of HMGN1, anti-PD-L1, and their combined treatment were monitored in the B16F10, LLC, Colon26, or EO771 tumor-bearing mice. The comprehensive immunologic analyses, such as high-dimensional flow cytometry, transcriptome analysis, and single-cell RNA-sequencing (scRNA-seq), were used to investigate the cellular and molecular mechanisms of antitumor immune responses after treatments. We identified the immunostimulatory domain (EPKRR SARLS AKPPA KVEAK PKK) on HMGN1 and synthesized this domain as a therapeutic peptide (minP1). Combined treatment with minP1 and PD-L1 blockade induced durable tumor regression in tumor-bearing mice. minP1 increased the number of intratumoral mature DCs enriched in immunoregulatory molecules (mregDC) and enhanced their MHC class I antigen-presenting program. minP1 also synergized with PD-L1 blockade in augmenting intratumoral Tstem/Tpex cell number. Analysis of our scRNA-seq dataset by CellPhonDB suggested potential interactions between mregDCs and Tstem/Tpex cells in tumors. Our results indicate that HMGN1 peptide (minP1) serves as an immunoadjuvant to promote effective anti-PD-L1 immunotherapy with increased Tstem/Tpex cells in tumors., (©2021 American Association for Cancer Research.)

Purpose: Recent reports regarding endoscopic third ventriculostomy (ETV) for pediatric hydrocephalus revealed that ETV could avoid cerebrospinal fluid (CSF) shunting in certain types of hydrocephalus. However, the effectiveness of ETV for "pure" communicating hydrocephalus that has no obstruction through CSF pathway is still unknown. In this study, we report clinical outcome of ETV and CSF shunting for communicating hydrocephalus and discuss the efficacy of ETV for pure communicating hydrocephalus., Methods: Children less than 15 years old who underwent ETV or CSF shunting for communicating hydrocephalus were retrospectively reviewed. The absence of obstruction through CSF circulation was confirmed by CT cisternography or cine-contrast image in MRI., Results: Sixty-three patients (45 CSF shunting and 18 ETV) were included. The mean follow-up period was 6.1 years. The success rate was 60% in CSF shunting and 67% in ETV at the last visit (p = 0.867). Normal development was observed in 24 patients (53%) in CSF shunting and 12 patients (67%) in ETV (p = 0.334). There was a significant difference in the mean time to failure (CSF shunting: 51.1 months, ETV 3.6 months, p = 0.004). The factor that affected success rate in ETV was the age at surgery (success 21.6 months, failure 4.4 months, p = 0.024) and ETV success score (success 66.7, failure 50.0, p = 0.047)., Conclusion: Clinical outcomes of ETV were not inferior to those of CSF shunting in patients with communicating hydrocephalus. Further studies is required to elucidate to establish the consensus of ETV as a treatment option for communicating hydrocephalus., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Despite numerous studies, the etiology of spinal extradural arachnoid cyst (SEDAC), a lesion associated with neurological symptoms, remains unknown. In this genomic twin study, we investigated the genetic etiology of SEDACs., Methods: The subjects were identical twins who developed notably similar SEDACs at the same vertebral level. Accordingly, we performed whole-exome sequencing analyses of genomic material from the twins and their parents using a next-generation sequencer. Additionally, we determined their detailed family history and analyzed the family pedigree., Results: The pedigree analysis suggested the potential presence of SEDACs in certain family members, indicating a genetic disease. Sequenced data were analyzed and filtered using a purpose-built algorithm, leading to the identification of 155 novel single-nucleotide polymorphisms (SNPs), of which 118 encoded missense or nonsense variants. A functional analysis of the proteins encoded by these SNP alleles revealed strong enrichment for the fibronectin type III (FN3) protein domain (q = 0.00576). Specifically, the data indicated that a missense variant affecting the FN3 protein domain of fibronectin 1 (FN1, p.P969S) can be the causal mutation underlying the SEDACs., Conclusion: The data suggest that deleterious mutations in fibronectin-related genes may cause SEDACs. In particular, it was suspected that a variant of FN1 may be the cause of the SEDACs in the twin cases studied herein. Detailed studies with a larger number of cases are needed.

Antibody-mediated transient depletion of CD4 + cells enhances the expansion of tumor-reactive CD8 + T cells and exhibits robust antitumor effects in preclinical and clinical studies. To investigate the clonal T-cell responses following transient CD4 + cell depletion in patients with cancer, we conducted a temporal analysis of the T-cell receptor (TCR) repertoire in the first-in-human clinical trial of IT1208, a defucosylated humanized monoclonal anti-CD4. Transient depletion of CD4 + cells promoted replacement of T-cell clones among CD4 + and CD8 + T cells in the blood. This replacement of the TCR repertoire was associated with the extent of CD4 + T-cell depletion and an increase in CD8 + T-cell count in the blood. Next, we focused on T-cell clones overlapping between the blood and tumor in order to track tumor-associated T-cell clones in the blood. The total frequency of blood-tumor overlapping clones tended to increase in patients receiving a depleting dose of anti-CD4, which was accompanied by the replacement of overlapping clones. The greater expansion of CD8 + overlapping clones was commonly observed in the patients who achieved tumor shrinkage. These results suggested that the clonal replacement of the TCR repertoire induced by transient CD4 + cell depletion was accompanied by the expansion of tumor-reactive T-cell clones that mediated antitumor responses. Our findings propose beneficial remodeling of the TCR repertoire following transient CD4 + cell depletion and provide novel insight into the antitumor effects of monoclonal anti-CD4 treatment in patients with cancer. See related Spotlight on p. 601 ., (©2021 American Association for Cancer Research.)

Pediatric gliomas include various types of glioma broadly categorized as low- or hi-grade based on histopathological features. Clinically significant types include cerebellar astrocytomas, optic pathway / hypothalamic pilocytic astrocytomas, and brainstem gliomas. Neurosurgical roles vary for different kinds of pediatric gliomas. Since these representative tumors remain rare, the patients should be directed toward facilities with experienced neurosurgeons. Radiotherapy and chemotherapy are very important as either adjuvant or primary treatment modalities. Recent advancements in molecular biology have revealed unique genetic aberrations in different types of pediatric gliomas. The RAS/MAPK pathway anomalies, including BRAF-KIAA1549 fusion and BRAF V600E mutation, are present in most low-grade gliomas. BRAF/MEK-inhibitors have yielded promising clinical study results. Diffuse midline gliomas, including diffuse intrinsic pontine gliomas, often harbor H3 mutations such as H3K27M. Agents that target these molecular aberrations are unavailable. Because gliomas in infants are sub-categorized by their genetic abnormalities, novel agents targeting ALK , ROS1 , or NTRK fusions are promising treatments.

The chemical structure of a branch point of star-shaped polymers has been considered to have a small influence on the physical properties of the entire polymer. Contrary to this general notion, here we show that a 3-arm star polymer, composed of three poly(δ-valerolactone) arms extended from one side of a triptycene branch point, exhibits a remarkably high complex viscosity, compared to the analogous star-shaped polymers with a branch point of a triptycene isomer or triphenylethane.

We reported a 7-month-old female with intraorbital Ewing's sarcoma. Infantile Ewing's sarcoma is rare and its prognosis is poor. Ewing's sarcoma of orbital origin is even rare. There has been only 1 case of infantile intraorbital Ewing's sarcoma reported, and only 5 infantile primary orbital ESFTs (Ewing's sarcoma family of tumors) have been reported. Among these 5 cases, 2 infants who did not receive multimodal therapy died, whereas 3 who received multimodal therapy demonstrated long-term survival. The present case was also treated with multimodal therapy consisting of surgery, chemotherapy, and proton beam radiotherapy. There is no recurrence at 15 months follow-up. No specific treatment strategies have been established yet, and accumulation of cases is necessary. Ewing's sarcoma should be included in the differential diagnosis of infantile intraorbital tumors.

Background: Although terminal syringomyelia suggests a tethered spinal cord, a consensus has still not been established for surgical indications, when there are no associated abnormalities or only minor associated abnormalities. We analyzed surgical outcomes of sectioning a filum terminale in patients with terminal syringomyelia to elucidate the significance of untethering surgery., Methods: Fifty-seven pediatric patients with terminal syringomyelia who underwent untethering via sectioning the filum terminale between 2007 and 2018 were retrospectively analyzed. Postoperative outcomes of symptoms and MRI findings were evaluated., Results: Of 57 patients, 40 had other associated abnormalities (25 with filar lipoma and 29 with low conus medullaris) that could be responsible for tethered cord. Nineteen patients had symptoms. The mean age at the time of surgery was 18 months (3-96 months). The mean follow-up period was 3.3 years (1-9 years). Preoperative symptoms improved in 9 patients (47%) after surgery. At 1 year after the surgery, the size of syringomyelia decreased in 19 (33%), increased in 4 (8%), and did not change in 34 (69%) patients. Of 28 patients who were followed up for more than 3 years, the size decreased in 17 (61%), increased in 1 (4%), and did not change in 10 (35%)., Conclusion: When untethering was performed by sectioning a filum terminale, the size of terminal syringomyelia decreased in more than half of patients in the long term. Sectioning the filum terminale demonstrated the possibility of radiological and clinical improvement in patients with terminal syringomyelia.

Objective: The basal encephalocele (BEC) is the rarest form of encephalocele, with an incidence of about 1/35,000 live births. The incidence of its subtype, sphenoidal BEC, is even lower at about 1/700,000 live births. The aim of this study was to propose the optimal surgical approach to repairing BEC, with special attention to the reconstruction of the skull base bone defect., Methods: Fourteen consecutive pediatric patients with BEC who underwent surgical repair between March 2004 and March 2020 (10 boys and 4 girls, age 25 days to 7 years, median age 4 months) were enrolled. The follow-up period of the surviving patients ranged from 53 to192 months (mean 119.8 months). The patient demographics, BEC subtypes, preoperative clinical condition, radiographic findings, surgical procedures, and postoperative course were retrospectively analyzed., Results: There were 4, 8, and 2 cases of sphenoidal BEC, sphenoethmoidal BEC, and ethmoidal BEC, respectively. The size of the bone defect was small in 3 patients, medium in 7, and large in 4 patients. All the patients with sphenoethmoidal and ethmoidal BEC showed associated congenital anomalies other than cleft palate. In total, 25 operations were performed. Two patients underwent multiple operations, whereas the remaining 9 patients received only 1 operation. The transoral transpalatal approach was the initial procedure used in all 14 patients. The transfrontobasal approach was applied as an additional procedure in 2 patients and as part of a 1-stage combined operation in 2 patients. Autograft bone alone was used for skull base reconstruction in 17 early operations. A titanium mesh/plate was used in the remaining 8 operations without any perioperative complications. All BECs were successfully repaired. Three patients died during the clinical course due to causes unrelated to their surgery. All but one of the surviving patients started growth hormone replacement therapy before school age., Conclusions: Based on the authors' limited experience, the key to successful BEC repair involves circumferential dissection of the BEC and a firm reconstruction of the skull base bone defect with a titanium plate/mesh. The transoral transpalatal approach is a promising, reliable procedure that may be used in the initial operation. When a cleft palate is absent, transnasal endoscopic repair is recommended. The transfrontobasal approach should be reserved for cases with a huge BEC and other anomalies. Long-term prognosis is apparently favorable in survivors.

Background: A prolonged interval between onset of symptoms and diagnosis of childhood brain tumor is associated with worse neurological outcomes. The objectives of this study are to determine factors contributing to diagnostic delay and to find an interventional focus for further reduction in the interval between symptom onset and diagnosis in Japan., Methods: We retrospectively analyzed 154 patients younger than 18 years with newly diagnosed brain tumors who visited our institution from January 2002 to March 2013., Results: The median age at diagnosis was 6.2 years and the median total diagnostic interval (TDI) was 30 days. Patients with low-grade tumors and cerebral midline tumor location had significantly long TDI. Durations between the first medical consultation and diagnosis (diagnostic interval, DI) were exceedingly longer for patients with visual, hearing, or smelling abnormalities as the first symptom (median, 303 days). TDI and DI of patients who visited ophthalmologists or otolaryngologist for the first medical consultation were significantly longer. Among these patients, longer DI was associated with worse visual outcome., Conclusion: Raising awareness of brain tumor diagnosis among ophthalmologists and otolaryngologists may reduce diagnostic delay and may improve the neurological impairment of children with brain tumors in Japan., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We report the unusual case of a 7-month-old girl presenting with congenital cervical dermal sinus tract in which the intradural tract was not detected on preoperative imaging and was identified intraoperatively. Considering possible devastating sequelae of infection, excision of dermal sinus tract might be justified even in the case with radiologically undetected intradural tract.

After untethering surgery of a tethered spinal cord of a tight filum terminale, patients are usually kept in the horizontal decubitus position to prevent cerebrospinal fluid (CSF) leakage. However, the optimal period for keeping these patients in this position has not been established yet. Surgical results in two groups of pediatric patients with a tight filum terminale were retrospectively analyzed. Group A was maintained in the horizontal decubitus position for 72 h and group B was managed without being kept in this position postoperatively. A total of 313 patients underwent sectioning of a tight filum terminale. Of these patients, 144 were maintained horizontally for 72 h postoperatively (group A) and 169 were managed without this position (group B). Among the patients who were maintained horizontally for 72 h, one (0.7%) developed pseudomeningocele. No patients experienced CSF leakage in this group. Among the patients who were not horizontal, one (0.6%) developed CSF leakage and one (0.6%) developed pseudomeningocele. Maintaining patients without restriction of their position does not appear to change the rate of postoperative CSF leakage or pseudomeningocele. This suggests that maintaining patients horizontally after transection of a tight filum terminale is not necessary for preventing CSF leakage.

Purpose: Atypical teratoid rhabdoid tumor (AT/RT) is a rare, clinically highly malignant tumor. The extent of the surgical resection may affect survival. However, it is often difficult to perform gross total resection (GTR) at an initial surgery because of the large tumor size and high vascularity. Neoadjuvant chemotherapy may reduce not only the size but also the vascularity. We report our experience, review the literature, and analyze its effectiveness., Methods: A retrospective chart review of patients who underwent neoadjuvant chemotherapy and second-look surgery was performed. Demographic data, treatment courses, changes in tumor after the chemotherapy, extent of resection and estimated blood loss (EBL) during the second-look surgery, and outcome of each children were evaluated., Results: There are 4 cases. The average age at diagnosis was 13.3 months (2-30 months). Two to 4 courses of neoadjuvant chemotherapy were performed. MRI after the chemotherapy showed reduction of tumor volume, and tumor vascularity at the second-look surgery decreased in all cases. GTR was achieved in 3 cases, and NTR in 1 case. The mean EBL/estimated blood volume (EBL/EBV) was 21.3% (1.5-39%). The mean follow-up period was 23 months (2-48 months). At the last follow-up, 2 patients were alive without recurrence of the tumor (the follow-up periods were 48 and 16 months)., Conclusions: Neoadjuvant chemotherapy for AT/RTs might reduce both tumor size and vascularity, which enabled the maximal tumor resection. It may contribute to improve the prognosis of AT/RT through facilitating the tumor resection.

The SWI/SNF chromatin remodeling complex is composed of approximately 15 subunits, and approximately 20% of all cancers carry mutations in the genes encoding these subunits. Most of the genetic alterations in these genes are loss-of-function mutations. The identification of vulnerability based on synthetic lethality in cancers with SWI/SNF chromatin remodeling complex deficiency contributes to precision medicine. The SWI/SNF chromatin remodeling complex is involved in transcription, DNA repair, DNA replication, and chromosomal segregation. Cancers with deficiency in the SWI/SNF chromatin remodeling complex show increased vulnerability derived from the loss of these functions. Synthetic lethal targets have been identified based on vulnerabilities in the functions of the SWI/SNF chromatin remodeling complex. In this review article, we propose a precision medicine strategy using chemotherapeutic methods, such as molecular targeted therapy and immunotherapy, based on harnessing synthetic lethality in cancers with deficiency in the SWI/SNF chromatin remodeling complex., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, increases the intracellular levels of glutathione (GSH) by upregulating solute carrier family 7 member 11 (SLC7A11). Diffuse-type gastric cancer is an aggressive tumor that is frequently associated with ARID1A deficiency. Here, we investigated the efficacy of GSH inhibition for the treatment of diffuse-type gastric cancer with ARID1A deficiency using ARID1A-proficient or -deficient patient-derived cells (PDCs). ARID1A-deficient PDCs were selectively sensitive to the GSH inhibitor APR-246, the GCLC inhibitor buthionine sulfoximine, and the SLC7A11 inhibitor erastin. Expression of SLC7A11, which is required for incorporation of cystine, and the basal level of GSH were lower in ARID1A-deficient than in ARID1A-proficient PDCs. Treatment with APR-246 decreased intracellular GSH levels, leading to the excessive production of reactive oxygen species (ROS), and these phenotypes are suppressed by supply of cystine and GSH compensators. Taken together, vulnerability of ARID1A-deficient gastric cancer cells to GSH inhibition is caused by decreased GSH synthesis due to diminished SLC7A11 expression. The present results suggest that GSH inhibition is a promising strategy for the treatment of diffuse-type gastric cancers with ARID1A deficiency., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Ovarian clear cell carcinoma (OCCC) is often resistant to conventional, standard chemotherapy using cytotoxic drugs. OCCC harbors a unique genomic feature of frequent (approximately 50%) ARID1A deficiency. The present study was performed to investigate standard chemotherapeutic options suitable for ARID1A-deficient OCCC patients., Methods: Drugs with selective toxicity to ARID1A-deficient OCCC cells were identified among six cytotoxic drugs used in standard chemotherapy for OCCC by employing multiple ARID1A-knockout cell lines and an OCCC cell line panel. Anti-tumor effects of drug treatment were assessed using a xenograft model. To obtain proof of concept in patients, seven OCCC patients who received single-agent therapy with gemcitabine were identified in a retrospective cohort of 149 OCCC patients. Patient samples and cases were analyzed for association between therapeutic response and ARID1A deficiency., Results: ARID1A-knockout and ARID1A-deficient OCCC cells had selective sensitivity to gemcitabine. IC50 values for gemcitabine of ARID1A-deficient cells were significantly lower than those of ARID1A-proficient cells (p = 0.0001). Growth of OCCC xenografts with ARID1A deficiency was inhibited by administration of gemcitabine, and gemcitabine treatment effectively induced apoptosis in ARID1A-deficient OCCC cells. Three ARID1A-deficient OCCC patients had significantly longer progression-free survival after gemcitabine treatment than four ARID1A-proficient OCCC patients (p = 0.02). An ARID1A-deficient case that was resistant to multiple cytotoxic drugs, including paclitaxel plus carboplatin in the adjuvant and etoposide plus irinotecan in the first-line treatment, exhibited a dramatic response to gemcitabine in the second-line treatment., Conclusion: ARID1A-deficient OCCC patients could benefit from gemcitabine treatment in clinical settings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this paper is to provide novel insight into the rare pediatric meningiomas., Methods: We retrospectively analyzed pediatric surgical cases of meningioma during 2002 to 2017 in our institution. The preoperative, intraoperative, and the postoperative status were collected to find any unique features that has not reported in the past., Results: Nine surgeries out of 5 patients were identified. The mean age was 7 years old (range 1-14 years old). Four patients were females. The mean tumor diameter was 52 mm (range 23-81 mm). The tumor locations were optic nerve sheath, Sylvian fissure, parasagittal, trigone of the lateral ventricle, and cerebellopontine angle. The Sylvian fissure meningioma without dural attachment (MWODA) was found in a 15-month-old female. A relapsed parasagittal meningioma showed regression in histological grade and residual tumor demonstrated spontaneous regression. In the initial surgeries, Simpson grade 1 resection was achieved in 2 cases. The pathological diagnoses were 1 meningothelial, 1 metaplastic, 2 atypical, and 1 clear cell meningiomas. The mean postoperative follow-up period was 71 months. Three patients experienced recurrence of the tumor. At the latest follow-up, all patients were free of radiological tumor recurrence or regrowth with a mean follow-up of 4 years (range 1-6.9 years). All patients were in the modified Rankin scale of 0-1., Conclusions: MWODA is not considered to be rare in pediatric meningioma and should be included in the differential diagnosis. We presented a histologically regressed relapsed meningioma, which spontaneously regressed after subtotal resection. In the case of recurrent meningioma, surgical resection and adjuvant radiation therapy could be effective for long-term control of the tumor.

We present a 3-year-old girl with decreased visual acuity of the left eye. Radiological studies revealed a mass lesion at the roof of the left optic canal with bony erosion, which compressed the left optic nerve. Gross total resection of the mass and decompression of the optic canal were performed. Histopathological study was consistent with nodular fasciitis. This is the first report of nodular fasciitis at the roof of the optic canal in a young child. Nodular fasciitis compressing the optic nerve should be included in differential diagnoses of optic neuropathy in young children.

Purpose: The best management of pediatric unruptured brain arteriovenous malformations (ubAVM) should be further elucidated., Methods: Pediatric patients who presented to our facility with ubAVM and were treated nonconservatively were retrospectively analyzed regarding demographics, presenting symptoms, AVM characteristics, treatment modality, and outcome., Results: Thirteen patients were included. There were 9 male and 4 female patients with an average age (± SD) of 7.8 ± 4.6 years. The most common presenting symptom was seizure. The mean Spetzler Martin (SM) grade was 3.2. Seven patients were treated by surgical excision, 8 by embolization, 6 by radiosurgery, and during the mean follow-up period of 8.9 years (2.6-14.4 years), there were no hemorrhage. Complete ubAVM obliteration was achieved in all 7 patients (100%) who underwent surgical excision. AVM was obliterated in 5 out of 9 patients whose SM grade was 3 or 4. Modified Rankin scale was good (mRS 0-2) in all 13 patients., Conclusions: Since the lifetime hemorrhage rate of pediatric ubAVM is high, it may be better to proceed with nonconservative treatment, especially when surgical excision is amenable. Nonconservative treatment could be an appropriate treatment with acceptable neurological outcome even in those with moderate to high-grade AVMs in selected cases.

Background: Transient CD4 + T cell depletion led to the proliferation of tumor-specific CD8 + T cells in the draining lymph node and increased infiltration of PD-1 + CD8 + T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice. This is a first-in-human study of IT1208, a defucosylated humanized anti-CD4 monoclonal antibody, engineered to exert potent antibody-dependent cellular cytotoxicity., Methods: Patients with advanced solid tumors were treated with intravenous IT1208 at doses of 0.1 or 1.0 mg/kg. The first patient in each cohort received a single administration, and the other patients received two administrations of IT1208 on days 1 and 8., Results: Eleven patients were enrolled in the 0.1 mg/kg (n = 4) and 1.0 mg/kg cohorts (n = 7). Grade 1 or 2 infusion-related reactions was observed in all patients. Decreased CD4 + T cells in peripheral blood due to IT1208 were observed in all patients and especially in those receiving two administrations of 1.0 mg/kg. CD8 + T cells increased on day 29 compared with baseline in most patients, resulting in remarkably decreased CD4/8 ratios. One microsatellite-stable colon cancer patient achieved durable partial response showing increased infiltration of both CD4 + and CD8 + T cells into tumors after IT1208 administration. Moreover, transcriptomic profiling of the liver metastasis of the patient revealed upregulation of the expression of interferon-stimulated genes, T cell activation-related genes, and antigen presentation-related genes after IT1208 administration. Two additional patients with gastric or esophageal cancer achieved stable disease lasting at least 3 months., Conclusions: IT1208 monotherapy successfully depleted CD4 + T cells with a manageable safety profile and encouraging preliminary efficacy signals, which warrants further investigations, especially in combination with immune checkpoint inhibitors.

Introduction: Pediatric schwannomas are rare, and most of them are associated with neurofibromatosis type 2 (NF2) and usually located in the vestibular nerve. Herein, we present the first pediatric case of intracranial schwannoma derived from the IX/X nerve complex unrelated to NF2., Case Report: The patient was a 9-year-old boy who presented with a 3-month history of headache and nausea. There was no family history of NF2. Imaging studies revealed a cystic lesion with enhanced wall in the left cerebellomedullary fissure. During the operation, the IX/X nerve complex was strongly adhered to the tumor at the jugular foramen. The tumor was totally excised, and the postoperative MRI demonstrated no residual tumor. Histopathological diagnosis was schwannoma. Genetic analysis revealed no mutation associated with NF2 and schwannomatosis., Conclusion: We reported the first case of pediatric lower cranial nerve schwannoma which was not associated with NF2. The schwannoma should be included as differential diagnosis of pediatric posterior fossa tumors.

ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species. The vulnerability of ARID1A-deficient cancer cells results from low basal levels of GSH due to impaired expression of SLC7A11. The SLC7A11-encoded cystine transporter supplies cells with cysteine, a key source of GSH, and its expression is enhanced by ARID1A-mediated chromatin remodeling. Thus, ARID1A-deficient cancers are susceptible to synthetic lethal targeting of GCLC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Transient depletion of CD4 + T cells results in tumor suppression and survival benefit in murine models; however, the tumor progression and recurrence still occur over more long-term monitoring of mice. Thus, we explored an additional strategy to enhance endogenous immune responses by an alarmin, high mobility group nucleosome binding protein 1 (HMGN1)., Methods: The anti-tumor effects of HMGN1, anti-CD4 depleting antibody, and their combined treatment were monitored in the Colon26 or the B16F10 subcutaneous murine models. The tumor-infiltrating CD8 + T cell proliferation, differentiation, exhaustion, and its gene expression were determined by flow cytometry, transcriptome analysis, and quantitative real-time PCR., Results: Our results show that a systemic administration of low doses of HMGN1 with an anti-CD4 depleting antibody (HMGN1/αCD4) promoted expansion of CD8 + T cell populations (e.g. CD137 + PD-1 + and CD44 hi PD-1 + ), recruited CCR7 + migratory dendritic cells to the tumor, and reduced co-inhibitory molecules (e.g. PD-1, LAG-3, and TIM-3) to counteract CD8 + T cell exhaustion., Conclusion: The HMGN1/αCD4 treatment expanded effector CD8 + T cells and prolonged their anti-tumor activities by rescuing them from exhaustion, thus resulting in tumor regression and even rejection in long-term monitored mice.

Depletion of CD4 + cells using an anti-CD4 monoclonal antibody (anti-CD4 mAb) induces the expansion of tumor-reactive CD8 + T cells and strong antitumor effects in several murine tumor models. However, it is not known whether the anti-CD4 mAb treatment activates a particular or a broad spectrum of tumor-reactive CD8 + T cell clones. To investigate the changes in the TCR repertoire induced by the anti-CD4 mAb treatment, we performed unbiased high-throughput TCR sequencing in a B16F10 mouse subcutaneous melanoma model. By Inter-Organ Clone Tracking analysis, we demonstrated that anti-CD4 mAb treatment increased the diversity and combined frequency of CD8 + T cell clones that overlapped among the tumor, draining lymph node (dLN), and peripheral blood repertoires. Interestingly, the anti-CD4 mAb treatment-induced expansion of overlapping clones occurred mainly in the dLN rather than in the tumor. Overall, the Inter-Organ Clone Tracking analysis revealed that anti-CD4 mAb treatment enhances the mobilization of a wide variety of tumor-reactive CD8 + T cell clones into the Cancer-Immunity Cycle and thus induces a robust antitumor immune response in mice.

Introduction: Sinus pericranii (SP) involves transosseous vessels that connect the intra- and extracranial venous systems. Accessory-type SP can be cured by surgical or endovascular treatment. Reports of recurrence are, however, rare., Case: A boy presented with a soft-tissue mass on the left parietal region of the head. Computed tomography and magnetic resonance imaging revealed the congenital SP with several small transosseous vessels surrounded by an area of thin bone. At the initial surgery, the vascular mass was completely excised by coagulating and cutting the -transosseous vessels. The skull defect was filled with bone wax. Two years later, SP recurred at the same site. At the second surgery, the skull defect and surrounding area were sealed with acrylic resin. The boy has been followed up for 6 years without recurrence., Discussion: Potential risk factors for recurrence proposed in the existing literature include an unusually large number of emissary veins, rich circulation between intra- and extracranial venous systems, large bone defects, raised intracranial pressure, and association of other developmental venous anomalies. Our case demonstrates that thin skull bone around the original lesion can be another risk factor for recurrence., Conclusion: Removing all abnormal vessels and sealing the skull defect as well as the surrounding thin bone area are important to prevent recurrence of congenital SP., (© 2019 S. Karger AG, Basel.)

OBJECTIVEThe goal of this study was to clarify the long-term outcome of endoscopic third ventriculostomy (ETV) in pediatric hydrocephalus in light of the ETV Success Score (ETVSS), shunt dependency, and intellectual development.METHODSThe authors retrospectively analyzed pediatric patients with hydrocephalus who underwent ETV between 2002 and 2012 and who were followed for longer than 5 years as a single-center cohort. The data of the patients' pre- and postoperative status were collected. The relationships between ETVSS and the full-scale IQ as well as shunt dependency were analyzed. The usefulness of ETVSS for repeat ETV and the change of radiological parameters of ventricle size before and after ETV were also analyzed. The success of ETV was defined as no requirement for further CSF diversion procedures.RESULTSFifty ETVs were performed in 40 patients. The average ETVSS was 61 and the success rate at 6 months was 64%. The mean follow-up was 9.9 years (5.2-15.3 years), and the long-term success rate of ETV was 50%. The Kaplan-Meier survival curve continued to show a statistically significant difference among patients with a low, moderate, and high ETVSS, even after 6 months (p = 0.002). After 15 months from the initial ETV, no patients required additional CSF diversion surgery. There was no statistical significance between ETVSS and the long-term full-scale IQ or shunt dependency (p = 0.34 and 0.12, respectively). The radiological improvement in ventricle size was not associated with better future educational outcome.CONCLUSIONSThe ETVSS was correlated with the long-term success rate. After 15 months from the initial ETV, no patients required an additional CSF diversion procedure. The ETVSS was not considered to be correlated with long-term intellectual status.

OBJECTIVEShunt surgery is the most common treatment for hydrocephalus, but it is associated with several long-term complications. Endoscopic choroid plexus coagulation (CPC) and endoscopic third ventriculostomy (ETV) are alternative surgeries that may avoid the need for shunt surgery. Although the short-term efficacy and safety of CPC have been reported in previous studies, long-term outcome, including not only avoiding shunt placement but also intellectual development, remains to be elucidated. The purpose of the present study was to investigate the long-term outcome of CPC.METHODSThe study population comprised patients who had infantile hydrocephalus treated by endoscopic CPC before the age of 24 months and who were followed until at least 5 years of age. Retrospective review was performed using the medical charts. The authors assessed educational status and the full-scale intelligence quotient (FSIQ) using the Wechsler Intelligence Scale for Children (WISC) IV as the means to evaluate the intellectual development.RESULTSFourteen patients with infantile hydrocephalus underwent CPC with or without ETV as a primary surgery. There were no intraoperative complications. In 7 patients (50%), hydrocephalus was successfully controlled without shunt placement. Six patients (43%) eventually required shunt placement. In one patient hydrocephalus was controlled by additional ETV. In the shunt-independent group, 4 patients went to age-appropriate school or achieved age-appropriate development according to intelligence quotient (IQ), 1 patient went to specialized school, and 2 patients had disabilities. In the shunt-dependent group, 4 patients went to an age-appropriate school or achieved age-appropriate development by IQ, 1 patient went to specialized school, and 1 patient had disabilities. The mean FSIQ score in 3 patients without shunts was 90 (range 89-91) and the mean FSIQ score in 4 patients with shunts was 80 (range 48-107). There was no significant difference in the rate of normal development between the shunt-independent group and the shunt-dependent group (p = 0.72).CONCLUSIONSThe CPC with or without ETV can be a safe and effective treatment in children with infantile hydrocephalus. Long-term control of hydrocephalus and normal intellectual development can be achieved in successful cases. Further prospective studies should be required to elucidate appropriate indications.

A surprising terminal-group effect on the structural and physical properties of an amorphous polymer is reported. We recently demonstrated that triptycene derivatives with substituents at the 1,8,13-positions show specific self-assembly behavior, enabling the formation of a well-defined "2D + 1D" structure based on nested hexagonal packing of the triptycenes. Upon terminal functionalization with a 1,8-substituted triptycene (1,8-Trip), a liquid polymer, polydimethylsiloxane (PDMS, M n = 18-24 kDa), turned into a highly viscous solid that exhibits birefringence at 25 °C. Small-angle and wide-angle X-ray scattering measurements revealed that the resulting telechelic PDMS assembles into a 2D + 1D structure, where layers of PDMS domains, formed between 2D assemblies of the triptycene termini, stack into a 1D multilayer structure with a layer spacing of 18-20 nm. Because of this structuring, the complex viscosity of the telechelic PDMS was dramatically enhanced, providing a value 4 orders of magnitude greater than that of the original PDMS. Remarkably, the structural and physical properties of PDMS were hardly changed upon terminal functionalization with another regioisomer of triptycene (1,4-Trip), which differs only in the substitution pattern.

High-temperature stress during the ripening stage leads to quality deterioration due to an increase in chalky grains in brown rice ( Oryza sativa L.). In a previous study, we identified a QTL for Appearance quality of brown rice 1 ( Apq1 ) using chromosome segment substitution lines of the indica cultivar 'Habataki' in the japonica cultivar 'Koshihikari' background and narrowed down the locus to a 48-kb region on chromosome 7. To verify the function and mechanisms of this QTL in grain appearance, in this study, we fine-mapped the gene and conducted high-temperature tolerance tests. As a result of the genetic mapping, we narrowed down the candidate region of Apq1 to a 19.4-kb region including three predicted genes. Among these, the temporal expression pattern of sucrose synthase 3 ( Sus3 ) corresponded well with the high temperature-sensitive period during ripening, and expression of the 'Habataki' allele of Sus3 was increased under high-temperature condition. In addition, we transformed the 'Habataki' Sus3 gene into 'Nipponbare', and the transformants obtained high-temperature tolerance. Therefore, we conclude that the causal gene underlying the QTL Apq1 is the thermo-responsive Sus3 allele, and the increase in Sus3 expression under high-temperature condition during ripening leads to high-temperature tolerance in rice.