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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.
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BACKGROUND: Clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. The accumulated evidence of tumor agnostic agent has been made since PD-1 inhibitor was approved and used in clinical practice. Therefore, we have revised the guideline "Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition". METHODS: Clinical questions regarding medical care were formulated for patients with dMMR advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO and the public comments among all societies' members were done. RESULTS: The current guideline describes two clinical questions and eight recommendations for whom, when, and how MMR status should be tested. CONCLUSION: In this guideline, the committee proposed eight recommendations for performing MMR testing properly to select patients who are likely to benefit from immunotherapy.
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Neoplasias Colorrectales , Hematología , Neoplasias , Humanos , Neoplasias Colorrectales/patología , Reparación de la Incompatibilidad de ADN/genética , Inmunoterapia , Japón , Oncología Médica , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapiaRESUMEN
The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we developed recommendations for tumor-agnostic treatments in patients with solid tumors with DNA mismatch repair deficient or neurotrophic receptor tyrosine kinase fusions. Recently, immune checkpoint inhibitors have shown efficacy in patient with tumor mutation burden-high (TMB-H) solid tumors and have been established as a third tumor-agnostic agent, making it necessary to develop the guideline prioritized for these patients. Clinical questions regarding medical care were formulated for patients with TMB-H advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. The current guideline describes three clinical questions and seven recommendations for whom, when, and how TMB should be tested, and what is recommended for patients with TMB-H advanced solid tumors. In this guideline, the committee proposed seven recommendations for performing TMB testing properly to select patients who are likely to benefit from immunotherapy.
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Neoplasias Encefálicas , Hematología , Niño , Humanos , Antígeno B7-H1 , Biomarcadores de Tumor/genética , Pueblos del Este de Asia , Inmunoterapia , Japón , Oncología Médica , MutaciónRESUMEN
BACKGROUND: Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the 'Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)'. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.
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Neoplasias , Proteínas Tirosina Quinasas Receptoras , Tropomiosina , Adulto , Niño , Humanos , Pueblos del Este de Asia , Fusión Génica , Japón , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/genética , Tropomiosina/uso terapéuticoRESUMEN
Purpose: Recently, direct communication with children about cancer seems to have shifted, but little is known about communication regarding discussions of future infertility risk due to cancer therapy. This study conducted cross-cultural comparisons between Japan and the United States to clarify communication patterns about cancer notification and develop appropriate information about fertility issues. Methods: An online survey was distributed to members of the Japanese Society of Pediatric Hematology/Oncology in July 2019 and the American Society of Pediatric Hematology/Oncology in July 2020. Based on the results from the survey, we developed three types of educational videos: a prepubertal version A, B, and a pubertal version. Next, we conducted a survey to assess whether these were appropriate for clinical practice. Results: We analyzed 325 physicians in Japan and 46 in the United States. In Japan, 80.5%, 91.7%, and 92.1% of the physicians notified patients aged 7-9, 10-14, and 15-17 years of their cancer diagnosis directly, respectively, compared within the United States, where the rate was 100%, regardless of age. Further, 9% and 45% of physicians in Japan and the United States, respectively, discuss fertility issues directly with patients aged 7-9 years. In the survey to assess the educational videos, 85% of the physicians preferred to use the educational videos in clinical practice. Conclusion: This is the first step in bringing concordance to communication patters for emerging cancer care around the globe and that this study and its intervention arm provide guidance in ways that ensure global equity in care.
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Preservación de la Fertilidad , Infertilidad , Neoplasias , Humanos , Niño , Estados Unidos , Preservación de la Fertilidad/métodos , Neoplasias/terapia , Consejo , Oncología Médica , Infertilidad/etiología , Infertilidad/prevención & controlRESUMEN
Rhabdomyosarcoma (RMS) is the most common highly malignant pediatric soft tissue sarcoma. While recent multidisciplinary treatments have improved the 5year survival rate of low/intermediaterisk patients to 7090%, there are various complications that arise due to treatmentrelated toxicities. Immunodeficient micederived xenograft models have been widely used in cancer drug research; however, these models have some limitations, including i) they are timeconsuming and expensive, ii) their use needs to be approved by animal experimental ethics committees, and iii) the inability to visualize where tumor cells or tissues were engrafted. The present study performed a chorioallantoic membrane (CAM) assay in fertilized chicken eggs, which is timesaving, simple, and easy to standardize and handle because of the high vascularization and the immature immune system of the fertilized eggs. The present study aimed to examine the usability of the CAM assay as a novel therapeutic model for the development of precision medicine for pediatric cancer. A protocol was developed for constructing cell linederived xenograft (CDX) models using a CAM assay by transplanting RMS cells on the CAM. It was then examined as to whether these CDX models could be used as therapeutic drug evaluation models using vincristine (VCR) and human RMS cell lines. After grafting and culturing the RMS cell suspension on the CAM, threedimensional proliferation over time was observed visually and by comparing volumes. VCR reduced the size of the RMS tumor on the CAM in a dosedependent manner. Currently, treatment strategies based on patientspecific oncogenic backgrounds have not been adequately developed in the field of pediatric cancer. The establishment of a CDX model with the CAM assay may lead to the advancement of precision medicine and help formulate novel therapeutic strategies for intractable pediatric cancer.
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Rabdomiosarcoma , Sarcoma , Animales , Ratones , Humanos , Niño , Membrana Corioalantoides , Xenoinjertos , Rabdomiosarcoma/tratamiento farmacológico , Medicina de Precisión , Vincristina , Modelos Animales de Enfermedad , Ratones Desnudos , Ratones SCIDRESUMEN
Erythroid sarcoma is a very rare subtype of myeloid sarcoma with undetermined biological features. Here, we present an infant with a multifocal erythroid sarcoma, diagnosed because the tumor cells were positive for glycophorin A. After acute myeloid leukemia-oriented chemotherapy and surgical resection followed by cord blood transplantation, he has successfully maintained complete remission without any late effects. Total transcriptome analysis of the tumor identified a novel fusion gene, RCC1-LCK, and high LCK expression levels, suggesting that LCK overexpression was involved in leukemogenesis in this case.
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Leucemia Mieloide Aguda , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/genética , Sarcoma Mieloide , Sarcoma , Proteínas de Ciclo Celular , Factores de Intercambio de Guanina Nucleótido , Humanos , Lactante , Leucemia Mieloide Aguda/genética , Masculino , Proteínas Nucleares , Sarcoma Mieloide/genéticaRESUMEN
BACKGROUND: Patients with high-risk neuroblastoma have a poor prognosis; new therapeutic agents are therefore required. We investigated the antitumor effects of OBP-801, a novel histone deacetylase inhibitor, its underlying mechanism, and its potential as a therapeutic agent for patients with neuroblastoma. METHODS: The study included five human neuroblastoma cell lines: IMR32, GOTO, KP-N-RTBM, SK-N-AS, and SH-SY5Y. We investigated cell proliferation, cell cycle status, protein expression patterns, and apoptosis in neuroblastoma cells after OBP-801 treatment in vitro. Cell survival rate and cell cycle were analyzed using the WST-8 assay and flow cytometry, respectively. Apoptosis was detected using annexin V staining, and the expression of apoptosis-related proteins was investigated by western blotting. The antitumor activity of OBP-801 was examined in an in vivo xenograft mouse model. RESULTS: Dose-effect curve analysis showed that the mean half-maximal inhibitory concentration value was 5.5 ± 5.9 nM for the MYCN-amplified cell lines (IMR32, GOTO, and KP-N-RTBM) and 3.1 ± 0.7 nM for the MYCN-nonamplified cell lines (SK-N-AS and SH-SY5Y). OBP-801 inhibited cell proliferation and growth in all the cell lines. It induced G2/M phase arrest through the p21 (CDKN1A) pathway, increasing histone H3 levels and, subsequently, apoptosis in human neuroblastoma cells. OBP-801 suppressed the growth of neuroblastoma cells in the mouse xenograft model. CONCLUSIONS: Overall, OBP-801 induces M-phase arrest and apoptosis in neuroblastoma cells via mitotic catastrophe. Our results indicate that OBP-801 is a promising therapeutic agent with fewer adverse effects for patients with neuroblastoma.
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Neuroblastoma , Animales , Línea Celular Tumoral , Proliferación Celular , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Ratones , Proteína Proto-Oncogénica N-Myc/uso terapéutico , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéuticoRESUMEN
Purpose: In 2017, the first guidelines for fertility preservation in cancer patients were published in Japan. However, the impact of the guidelines remains unknown. Therefore, the authors conducted a nationwide survey on cryopreservation procedures in the period from shortly before to after publication of the guidelines (2016-2019) and compared the results with our previous survey (2011-2015). The authors also surveyed reproductive specialists' awareness of the guidelines and implementation problems. Methods: The authors sent a questionnaire to 618 assisted reproductive technology facilities certified by the Japanese Society of Obstetrics and Gynecology. Results: The authors received responses from 395 institutions (63.8%). Among them, 144 institutions conducted cryopreservation for cancer patients (vs. 126 in 2011-2015) and performed 2537 embryo or oocyte and 178 ovarian tissue cryopreservation procedures (vs. 1085 and 122, respectively). Compared with the previous period, indications were more varied and protocols for controlled ovarian stimulation were more standardized. Reproductive specialists' interest in oncofertility was high, but many reported three main difficulties: selecting a treatment method, storing samples in the long term, and securing the necessary human resources. Conclusions: The practice of fertility preservation in cancer patients in Japan has been considerably affected by the first Japanese guidelines.
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BACKGROUND: These clinical practice guidelines are intended to provide recommendations based on the best evidence obtained to date on key issues in clinical practice to improve the prognosis, diagnostic and therapeutic processes for patients with soft tissue tumors. METHODS: The Guidelines Development Committee and Systematic Review Committee were composed of a multidisciplinary team of specialists who play an important role in soft tissue tumor care. Clinical questions (CQs) were determined by choosing key decision-making points based on Algorithms for the diagnosis and treatment of soft tissue tumors. The guidelines were developed according to the "Medical Information Network Distribution Service (Minds) Handbook for Clinical Practice Guideline Development 2014" and "Minds Manual for Clinical Practice Guideline Development 2017." Recommendation strength was rated on two levels and the strength of evidence was rated on four levels. The recommendations were decided based on agreement by 70% or more voters. RESULTS: Twenty-two CQs were chosen by the Guidelines Development Committee. The Systematic Review Committee reviewed the evidence concerning each CQ, a clinical value judgment was added by experts, and the text of each recommendation was determined. CONCLUSION: We established 22 CQs and recommendations for key decision-making points in the diagnosis and treatment of soft tissue tumors according to the Minds Clinical Practice Guideline development methods. We hope that these guidelines will assist the decision-making of all medical staff engaged in the treatment and diagnosis of soft tissue tumors, and eventually lead to improved soft tissue tumor care in the country.
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Ortopedia , Neoplasias de los Tejidos Blandos , Algoritmos , Humanos , Japón , Pronóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/terapiaRESUMEN
Most cases of rhabdomyosarcoma (RMS) are sporadic and not associated with the Lynch syndrome (LS) spectrum. We report a young adult patient with RMS and a family history of colorectal cancer. Comprehensive cancer genomic profiling (CGP) of his tumor revealed a likely pathogenic variant of MSH2, NM_000251.3:c.1741delA (p.I581Lfs*9), which was also present in his blood sample. The widespread use of CGP may reveal that RMS can be a rare manifestation of LS.
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The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.
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Preservación de la Fertilidad , Neoplasias , Oncólogos , Adolescente , Niño , Humanos , Japón , Oncología Médica , Neoplasias/terapia , Adulto JovenRESUMEN
In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).
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Preservación de la Fertilidad , Neoplasias , Oncólogos , Adolescente , Niño , Femenino , Humanos , Japón , Oncología Médica , Neoplasias/terapia , Adulto JovenRESUMEN
In recent years, local governments in Japan have established a public financial support system for fertility preservation in pediatric, adolescent, and young adult cancer patients. Fertility preservation has become popular for patients with cancers included in the gonadal toxicity risk classification of the 2017 edition of the Guideline for Fertility Preservation in Children, Adolescents and Young Adult Cancer Patients from the Japan Society of Clinical Oncology. However, patients with cancer and non-cancer diseases that are not included in the Guideline's gonadal toxicity risk classification also often receive treatment that may affect fertility, but they are often denied the opportunity of fertility preservation because no public financial support is available for diseases not listed in the Guideline. The national research project proposes including these diseases in the indications and treatment for fertility preservation. Therefore, we cooperated with the Japan Society for Fertility Preservation and the Ministry of Health, Labour and Welfare research group to solicit opinions from experts in each therapeutic area and reviewed the literature and overseas guidelines. This paper summarizes the findings of the project. We believe that it will be an important source of information for clinicians treating patients who need fertility preservation but note that the appropriateness of fertility preservation for the disorders listed in this report needs to be continuously reviewed as medical care advances.
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Preservación de la Fertilidad , Neoplasias , Adolescente , Niño , Fertilidad , Humanos , Japón , Oncología Médica , Neoplasias/tratamiento farmacológico , Adulto JovenRESUMEN
Purpose: We conducted a questionnaire survey in 15 pediatric oncology hospitals in Japan to better understand the current status of fertility preservation in childhood and adolescents. Methods: The survey period was from September 2020 to December 2020. We mailed questionnaires to 64 departments involved in pediatric cancer treatments at the 15 hospitals. The primary outcomes were the timing of providing explanations on fertility preservation, presence of health care provider while providing explanations, cooperation between medical staff, and cooperation between hospitals. Results: The response rate was 100% (64/64). Regarding the time at which this information was provided, 79.6% of patients (43/54) received it before cancer treatment; 5.6% (3/54), after remission; and 14.8% (8/54), both time points. Nurses were mostly in attendance (70%) when oncologists provided information to patients. Nine (60%) hospitals did not have a reproductive department. Among these, 28.6% of the respondents referred patients to a reproductive facility that performed fertility preservation. Providing information about fertility preservation was challenging owing to the shortage of specific explanatory materials (35.1%) and the lack of cooperation between pediatric oncologists and reproductive endocrinologists (24.6%). Conclusion: Based on this survey, educational activities regarding fertility preservation centered on pediatric oncologists and nurses are needed. Furthermore, a system for providing explanatory materials for fertility preservation and encouraging cooperation at the physician and hospital levels is also needed (IRB No. H2020-111).
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Preservación de la Fertilidad , Neoplasias , Adolescente , Niño , Hospitales Pediátricos , Humanos , Japón , Oncología Médica , Neoplasias/terapiaRESUMEN
B7-H3 (also known as CD276) is associated with aggressive characteristics in various cancers. Meanwhile, in alveolar rhabdomyosarcoma (ARMS), PAX3-FOXO1 fusion protein is associated with increased aggressiveness and poor prognosis. In the present study, we explored the relationship between PAX3-FOXO1 and B7-H3 and the biological roles of B7-H3 in ARMS. Quantitative real time PCR and flow cytometry revealed that PAX3-FOXO1 knockdown downregulated B7-H3 expression in all the selected cell lines (Rh-30, Rh-41, and Rh-28), suggesting that PAX3-FOXO1 positively regulates B7-H3 expression. Gene expression analysis revealed that various genes and pathways involved in chemotaxis, INF-γ production, and myogenic differentiation were commonly affected by the knockdown of PAX3-FOXO1 and B7-H3. Wound healing and transwell migration assays revealed that both PAX3-FOXO1 and B7-H3 were associated with cell migration. Furthermore, knockdown of PAX3-FOXO1 or B7-H3 induced myogenin expression in all cell lines, although myosin heavy chain induction varied depending on the cellular context. Our results indicate that PAX3-FOXO1 regulates B7-H3 expression and that PAX3-FOXO1 and B7-H3 are commonly associated with multiple pathways related to an aggressive phenotype in ARMS, such as cell migration and myogenic differentiation block.
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Antígenos B7/metabolismo , Diferenciación Celular , Movimiento Celular , Proteína Forkhead Box O1/metabolismo , Desarrollo de Músculos , Factor de Transcripción PAX3/metabolismo , Rabdomiosarcoma Alveolar/metabolismo , Western Blotting , Línea Celular Tumoral , Regulación hacia Abajo , Citometría de Flujo , Técnicas de Silenciamiento del Gen , Humanos , Miogenina/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Rabdomiosarcoma Alveolar/patología , TranscriptomaRESUMEN
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).