Results of the JRS-I LRA0401 and LRB0402 Japan Rhabdomyosarcoma Study Group trials for low-risk embryonal rhabdomyosarcoma.

BACKGROUND: Failure-free survival (FFS) rates of low-risk patients with rhabdomyosarcoma improved in Intergroup Rhabdomyosarcoma Study IV after the escalation of cyclophosphamide total dose to 26.4 g/m2. However, this dose may increase the risk of adverse events, including infertility, in some patients. The JRS-I LRA0401 and LRB0402 protocols aimed to reduce the cyclophosphamide dose to 9.6 g/m2 and 17.6 g/m2, respectively, without decreasing the FFS rates. METHODS: Subgroup-A patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 1.2 g/m2/cycle cyclophosphamide. Subgroup-B patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 2.2 g/m2/cycle cyclophosphamide, followed by six cycles (24 weeks) of vincristine and actinomycin D. Group II/III patients in both subgroups received radiotherapy. RESULTS: In subgroup A (n = 12), the 3-year FFS rate was 83% (95% confidence interval [CI], 48-96), and the 3-year overall survival (OS) rate was 100%. Only one isolated local recurrence was observed (8.3%). There were no unexpected grade-4 toxicities and no deaths. In subgroup B (n = 16), the 3-year FFS and OS rates were 88% (95% CI, 59-97) and 94% (95% CI, 63-99), respectively. There were no unexpected grade 4 toxicities and no deaths. CONCLUSIONS: Shorter duration therapy using vincristine, actinomycin D, and lower dose cyclophosphamide with or without radiotherapy for patients with low-risk subgroup A rhabdomyosarcoma (JRS-I LRA0401 protocol) and moderate reduction of cyclophosphamide dose for patients with low-risk subgroup B rhabdomyosarcoma (JRS-I LRB0402 protocol) did not compromise FFS.

Intraoperative Placement of an Absorbable Spacer Prior to Radiation Therapy for a Malignant Peripheral Nerve Sheath Tumor.

A 7-year-6-month-old female was diagnosed with a pelvic malignant peripheral nerve sheath tumor and lymph node metastases. Tumorectomy was performed after four cycles of chemotherapy. A 33-mm cystic lesion was observed around the left iliac muscle after three cycles of postoperative chemotherapy, and proton beam therapy (PBT) was recommended. She was referred for absorbable spacer (AS) placement. The left ovarian appendage (OA) was resected due to the direct tumor infiltration. The right OA was fixed to the uterosacral ligament. The AS was fixed to the lateral pelvis. The PBT (70.3 Gy relative biological effectiveness) was performed successfully with the AS, and she also had the reproducing possibility due to prevention of severe irradiation damage of the right OA. AS eliminated the surgical removal of spacers and enabled us high-dose PBT for residual tumor without severe irradiation damage including infertility.

Construction of a Humanized Artificial VHH Library Reproducing Structural Features of Camelid VHHs for Therapeutics.

A variable domain of heavy chain antibody (VHH) has different binding properties than conventional antibodies. Conventional antibodies prefer binding to the convex portion of the antigen, whereas VHHs prefer epitopes, such as crevices and clefts on the antigen. Therefore, developing candidates with the binding characteristics of camelid VHHs is important. Thus, To this end, a synthetic VHH library that reproduces the structural properties of camelid VHHs was constructed. First, the characteristics of VHHs were classified according to the paratope formation based on crystal structure analyses of the complex structures of VHHs and antigens. Then, we classified 330 complementarity-determining region 3 (CDR3) structures of VHHs from the Protein Data Bank (PDB) into three loop structures: Upright, Half-Roll, and Roll. Moreover, these structures depended on the number of amino acid residues within CDR3. Furthermore, in the Upright loops, several amino acid residues in the FR2 are involved in the paratope formation, along with CDR3, suggesting that the FR2 design in the synthetic library is important. A humanized synthetic VHH library, comprising two sub-libraries, Upright and Roll, was constructed and named PharmaLogical. A validation study confirmed that our PharmaLogical library reproduces VHHs with the characteristics of the paratope formation of the camelid VHHs, and shows good performance in VHH screening.

Nasal delivery of single-domain antibody improves symptoms of SARS-CoV-2 infection in an animal model.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the disease COVID-19 can lead to serious symptoms, such as severe pneumonia, in the elderly and those with underlying medical conditions. While vaccines are now available, they do not work for everyone and therapeutic drugs are still needed, particularly for treating life-threatening conditions. Here, we showed nasal delivery of a new, unmodified camelid single-domain antibody (VHH), termed K-874A, effectively inhibited SARS-CoV-2 titers in infected lungs of Syrian hamsters without causing weight loss and cytokine induction. In vitro studies demonstrated that K-874A neutralized SARS-CoV-2 in both VeroE6/TMPRSS2 and human lung-derived alveolar organoid cells. Unlike other drug candidates, K-874A blocks viral membrane fusion rather than viral attachment. Cryo-electron microscopy revealed K-874A bound between the receptor binding domain and N-terminal domain of the virus S protein. Further, infected cells treated with K-874A produced fewer virus progeny that were less infective. We propose that direct administration of K-874A to the lung could be a new treatment for preventing the reinfection of amplified virus in COVID-19 patients.

Proton beam therapy for children and adolescents and young adults (AYAs): JASTRO and JSPHO Guidelines.

Children and adolescents and young adults (AYAs) with cancer are often treated with a multidisciplinary approach. This includes use of radiotherapy, which is important for local control, but may also cause adverse events in the long term, including second cancer. The risks for limited growth and development, endocrine dysfunction, reduced fertility and second cancer in children and AYAs are reduced by proton beam therapy (PBT), which has a dose distribution that decreases irradiation of normal organs while still targeting the tumor. To define the outcomes and characteristics of PBT in cancer treatment in pediatric and AYA patients, this document was developed by the Japanese Society for Radiation Oncology (JASTRO) and the Japanese Society of Pediatric Hematology/Oncology (JSPHO).

Anal Canal Carcinoma in a Child With Disorders of Sex Development.

Squamous cell carcinoma of the anal canal in children is rare. To date, the etiology and outcome of this condition have been not fully understood. Here, we report an 11-year-old child with anal canal cancer who had concomitant disorders of sex development. Radiotherapy followed by salvage surgery achieved disease-free survival of 3 years. Since overexpression of cell cycle regulatory protein p16 was immunohistochemically evident in tumor tissue, human papillomavirus infection was considered as a causative factor in the carcinogenesis.

Japanese consensus guidelines for pediatric nuclear medicine. Part 1: Pediatric radiopharmaceutical administered doses (JSNM pediatric dosage card). Part 2: Technical considerations for pediatric nuclear medicine imaging procedures.

The Japanese Society of Nuclear Medicine has recently published the consensus guidelines for pediatric nuclear medicine. This article is the English version of the guidelines. Part 1 proposes the dose optimization in pediatric nuclear medicine studies. Part 2 comprehensively discusses imaging techniques for the appropriate conduct of pediatric nuclear medicine procedures, considering the characteristics of imaging in children.

The value of radiographic findings for the progression of pandemic 2009 influenza A/H1N1 virus infection.

BACKGROUND: Most illnesses caused by pandemic influenza A (H1N1) pdm09 virus (A/H1N1) infection are acute and self-limiting among children. However, in some children, disease progression is rapid and may require hospitalization and transfer to a pediatric intensive care unit (PICU). We investigated factors associated with rapid disease progression among children admitted to hospital for A/H1N1 infection, particularly findings on initial chest radiographs. METHODS: In this retrospective study, we investigated the records of children who had received a laboratory or clinical diagnosis of A/H1N1 infection and were admitted to the largest children's hospital in Japan between May 2009 and March 2010. The medical records were reviewed for age, underlying diseases, vital signs on admission, initial chest radiographic findings, and clinical outcomes. According to chest radiographic findings, patients were classified into 4 groups, as follows: [1] normal (n = 46), [2] hilar and/or peribronchial markings alone (n = 64), [3] consolidation (n = 64), and [4] other findings (n = 29). Factors associated with clinical outcomes were analyzed using logistic regression. RESULTS: Two hundreds and three patients (median 6.8 years) were enrolled in this study. Fifteen percent (31/203) of patients were admitted to PICU. Among 31 patients, 39% (12/31) of patients required mechanical ventilation (MV). When the initial chest radiographic findings were compared between patients with consolidation (n = 64) and those without consolidation (n = 139), a higher percentage of patients with consolidation were admitted to PICU (29.7% vs.8.6%, P < 0.001) and required MV (17.2% vs. 0.7%, P < 0.001). These findings remain significant when the data were analyzed with the logistic regression (P < 0.001, P < 0.001, respectively). CONCLUSIONS: Consolidation on initial chest radiographs was the most significant factor to predict clinical course of hospitalized children with the 2009 A/H1N1 infection.

Recanalization of post-transplant late-onset long segmental portal vein thrombosis with bidirectional transhepatic and transmesenteric approach.

PV complications are the most frequent vascular complications in pediatric LT. We have experienced a case with chronic postoperative PVT that necessitates combined transhepatic and transmesenteric approach and have confirmed mid-term patency. An eight-yr-old boy had successful LDLT with a left lateral segment graft at the age of two months for HBV-related acute liver failure. Seven years after transplantation, the patient suddenly showed a melena with hypovolemic shock. Doppler ultrasound and CT revealed intrahepatic bile duct dilatation and main PVT with collateral formation at hepatic hilus and mesenterium of the Roux-en-Y jejunal loop. Urgent splenic artery embolization was performed to control the bleeding and was temporarily effective. Therefore, recanalization of PVO was attempted. Because of long segmental PVO and steep angle between the intrahepatic PV and the portal trunk, bidirectional transhepatic and transmesenteric approach was selected and resulted in deploying three metallic stents necessitating additional infusion thrombolytic therapy. The patient is now followed as an outpatient with patent stents for two yr since the procedure. For the rescue of these patients, recanalization of obstructed PV trunk with bidirectional approach would be feasible with better graft survival and less invasiveness than conventional surgical interventions.

Syndromes associated with vascular tumors and malformations: a pictorial review.

Use of the International Society for the Study of Vascular Anomalies (ISSVA) classification system has been strongly recommended in recent years because of the need for separate therapeutic measures for patients with vascular tumors and malformations. In the ISSVA classification system, vascular tumors, which are neoplastic, are distinguished from vascular malformations, which are caused by vascular structural anomalies and are not neoplastic, on the basis of the presence or absence of neoplastic proliferation of vascular endothelial cells. It is important that radiologists be familiar with the development, diagnosis, and treatment of vascular tumors and malformations, especially the imaging features of low- and high-flow vascular malformations. Some vascular tumors and malformations develop in isolation, whereas others develop within the phenotype of a syndrome. Syndromes that are associated with vascular tumors include PHACE syndrome. Syndromes that are associated with vascular malformations include Sturge-Weber, Klippel-Trénaunay, Proteus, blue rubber bleb nevus, Maffucci, and Gorham-Stout syndromes, all of which demonstrate low flow, and Rendu-Osler-Weber, Cobb, Wyburn-Mason, and Parkes Weber syndromes, all of which demonstrate high flow. Because imaging findings may help identify such syndromes as systemic, it is important that radiologists familiarize themselves with these conditions.

Vein of Galen aneurysmal malformation associated with an endoglin gene mutation.

A child with vein of Galen aneurysmal malformation (VGAM) presented with cardiac failure in the neonatal period. The family history revealed his mother to have hereditary hemorrhagic telangiectasia. The child underwent an endoglin genetic analysis after the newborn period, which eventually demonstrated an endoglin mutation. The pathogenesis of VGAM is currently unknown. The findings of this case suggest that an endoglin mutation might be linked with VGAM.

Pediatric high-flow, cervical spinal, macro-arteriovenous fistula, treated with the endovascular cotton candy glue injection technique.

CASE REPORT: A 3-year-old boy presented to our hospital with progressive neurological deficits. Spinal magnetic resonance imaging (MRI) revealed a perimedullary macro-arteriovenous fistula (PMAVF) resulting in a large venous pouch within the parenchyma of the lower cervical spinal cord. Transarterial varix embolization of the fistula from the venous side was performed using N-butyl cyanoacrylate with tantalum powder. Postembolization angiography confirmed obliteration of the fistula, and MRI revealed thrombosis and reduction in size of the venous component. The patient's clinical symptoms were reduced dramatically following the intervention, and no neurological complications occurred due to the treatment. The prognosis of spinal PMAVF depends primarily on the presence of medullar signs and symptoms and on time to treatment. The volume of the venous pouch after the intervention was markedly reduced, and complete clinical recovery was obtained. Urgent endovascular intervention, as seen in this case, is considered first-line therapy and aims to decrease the risk of neurological sequela.

CT and MR imaging for pediatric cochlear implantation: emphasis on the relationship between the cochlear nerve canal and the cochlear nerve.

BACKGROUND: Cochlear implantation has become an accepted treatment for deafness. As the frequency of cochlear implantation has increased, requests for images have also increased in the work-up for candidates. An absent cochlear nerve (CN) is a contraindication to cochlear implantation. Therefore, MRI is performed to evaluate the CN in patients with sensorineural hearing loss. Recently, some authors have reported the relationship between cochlear nerve canal (CNC) stenosis and CN hypoplasia. OBJECTIVE: To review the relationship between CNC and CN. MATERIALS AND METHODS: During a period of 78 months, 21 children (42 ears) with unilateral or bilateral sensorineural hearing loss underwent both HRCT and MRI of the cochlear nerve. We retrospectively reviewed two factors: the evaluation of inner ear malformations and the relationship between CNC stenosis and CN hypoplasia. RESULTS: Inner ear malformations were recognized in ten ears. The mean CNC diameter was approximately 2 mm (ranging from 0.6 to 2.7 mm). CN hypoplasia was seen in eight of the 42 ears; all eight were associated with CNC stenosis (1.5 mm in diameter and the remaining two ears, with incomplete partition type I, had CNC stenosis. CONCLUSION: Children with CNC stenosis had a high incidence of CN hypoplasia. CNC stenosis (1.5 mm. Therefore, we conclude that children with CNC stenosis or malformations on HRCT should receive MR imaging of the CN.

National structure of radiation oncology in Japan with special reference to designated cancer care hospitals.

BACKGROUND: The structure of radiation oncology in designated cancer care hospitals in Japan was investigated in terms of equipment, personnel, patient load, and geographic distribution, and compared with the structure in other radiotherapy facilities. METHODS: The Japanese Society of Therapeutic Radiology and Oncology (JASTRO) conducted a questionnaire survey about the national structure of radiation oncology in 2005. In the current study, the structures of 326 designated cancer care hospitals and the other 386 radiotherapy facilities in Japan were compared. RESULTS: Designated cancer care hospitals accounted for 45.3% of all radiotherapy facilities. The patterns of equipment and personnel in designated cancer care hospitals and the other radiotherapy facilities were as follows: linear accelerators/facility, 1.2 and 1.0; dual-energy function, 73.1% and 56.3%; three-dimensional conformal radiotherapy function, 67.5% and 52.7%; intensity-modulated radiotherapy function, 30.0% and 13.9%; annual number of patients/linear accelerator, 289.7 and 175.1; (192)Ir remote-controlled afterloading systems, 27.6% and 8.6%; and average number of full-time equivalent radiation oncologists/facility, 1.4 and 0.9 (P < 0.0001). There were significant differences in equipment and personnel between the two types of facilities. Annual patient loads/full-time equivalent radiation oncologist in the designated cancer care hospitals and the other radiotherapy facilities were 252 and 240. Geographically, the number of designated cancer care hospitals was associated with the population, and the number of JASTRO-certified physicians was associated with the number of patients undergoing radiotherapy. CONCLUSION: The Japanese structure of radiation oncology in designated cancer care hospitals was more mature than that in the other radiotherapy facilities in terms of equipment, although a shortage of personnel still exists. The serious understaffing problem in radiation oncology should be corrected in the future.

Spontaneous perforation of choledochal cyst: a case with unusual distribution of fluid in the retroperitoneal space.

Images of perforated choledochal cysts typically show an intraperitoneal fluid collection. We report a case with, in addition to free intraperitoneal fluid, fluid collection in the right-side anterior pararenal and perirenal spaces. Surgery confirmed the presence of a perforation at the junction of the cystic duct and the common bile duct. This perforation may explain the biliary leakage extending into the free peritoneal space as well as into the anterior pararenal space and the hepatoduodenal ligament. Anterior pararenal and perirenal spaces communicate with the infrarenal space, and this may result in extension of the fluid into the perirenal space from the anterior pararenal space.

Induction of systemic bone changes by preconditioning total body irradiation for bone marrow transplantation.

BACKGROUND: Preconditioning total body irradiation (TBI) prior to bone marrow transplantation (BMT) has been believed to be a safe procedure that does not cause late morbidity; yet, a recent report raises the suspicion that TBI-induced chondroosseous abnormalities do occur. OBJECTIVE: To evaluate the radiological manifestations of TBI-induced skeletal alterations and their orthopaedic morbidity. MATERIALS AND METHODS: Subjects included 11 children with TBI-induced skeletal changes, including 9 in our hospital and 2 in other hospitals. The former were selected from 53 children who had undergone TBI with BMT. Radiographic examinations (n=11), MRI (n=3), CT (n=2), and medical records in the 11 children were retrospectively reviewed. RESULTS: The skeletal alterations included abnormal epiphyseal ossification and metaphyseal fraying (8/11), longitudinal metaphyseal striations (8/11), irregular metaphyseal sclerosis (6/11), osteochondromas (4/11), slipped capital femoral epiphysis (2/10), genu valgum (3/10), and platyspondyly (2/3). MRI demonstrated immature primary spongiosa in the metaphysis. Of the 11 children, 9 had clinical symptoms. CONCLUSION: TBI can induce polyostotic and/or generalized bone changes, mainly affecting the epiphyseal/metaphyseal regions and occasionally the spine. The epi-/metaphyseal abnormalities represent impaired chondrogenesis in the epiphysis and growth plate and abnormal remodelling in the metaphysis. Generalized spine changes may lead to misdiagnosis of a skeletal dysplasia.

Prognostic significance of circulating tumor cells and bone marrow micrometastasis in advanced neuroblastoma.

PURPOSE: The aim of this study was to study the prognostic significance of circulating tumor cells (CTC) and the appropriate indications for aggressive surgery in advanced neuroblastoma. MATERIALS AND METHODS: Micrometastasis was sequentially explored using our reverse transcriptase-polymerase chain reaction method in 29 neuroblastoma patients (International Neuroblastoma Staging System stage 4, n = 24; stage 3, n = 5) who treated at our department with the united chemotherapeutic regimen since 1991. Their medical records and detection of CTC and/or the bone marrow micrometastasis were retrospectively reviewed then analyzed statistically. RESULTS: The overall survival rate was 58.6% (17/29). Circulating tumor cells were detected in 55.6% of the stage 4 patients, and all deaths were related to systemic metastases in the CTC-positive patients. The detection of CTC scarcely associated with MYCN amplification. In the patients showing MYCN amplification but no CTC, all deaths were related to local relapse or chemotherapy-associated complications. The survival rate was not significantly different between the patients with and without MYCN amplification (56.8% vs 52.7%). However, it was significantly lower in the patients with CTC and/or persistent bone marrow micrometastasis compared to those without detectable micrometastasis (33.8% vs 87.5%; P < .05). CONCLUSIONS: The presence of CTC and/or persistent micrometastasis may indicate a significantly high risk, regardless of MYCN amplification. Patients with MYCN amplification but no micrometastasis would be most benefited by highly intensive surgery.