The treatment and care of children with cancer in Japan during the past 70 years are reviewed from the standpoint of a doctor who worked for SLIH as physician-in-chief.

Although the heterogeneity of tissues in cancer has been classically reported since the 1970s, the developments in various techniques, including next-generation sequencing, have revealed the heterogeneity of tissues and cell populations in more detail. Single-cell RNA sequencing, a method of analyzing gene expression at the single-cell level, is a powerful tool to accurately capture heterogeneity. The main methods of single-cell RNA sequencing analysis are dimensionality reduction and differentiation trajectory analysis including pseudotime analysis. The dimensionality reduction method allows us to classify different clones of cancer and accurately capture not only the differences between clones at the initial onset and at recurrence but also the changes in immune cells during different treatment phases. This is also important for elucidating the characteristics of cancer stem cells. Identification of clonal populations that directly affect the outcome of patients has also been reported. Differentiation trajectory analysis can also provide insight into the clonal origin of each heterogeneous cell population. In the future, the integration of single-cell RNA sequencing and recently developed methods for analyzing chromatin dynamics in single cells has the potential to accurately elucidate the pathogenesis of cancers with heterogeneity of tissues and cell populations and realize tailor-made therapies for patients.

【Introduction】Proton radiation therapy is a promising treatment to reduce irradiation-induced adverse effects. Increasing numbers of pediatric patients are being administered proton radiation therapy, and insurance coverage for this treatment was approved in Japan in April 2016. We report the clinical characteristics of patients treated with proton radiation therapy at our hospital and propose further improvements in patient recruitment from the viewpoint of referrals.

【Methods and Results】We investigated the cases of 17 patients who received proton radiation therapy at Saitama Children’s Medical Center between April 2016 and March 2021. This therapy was administered for the following primary diseases: brain tumors (seven patients), rhabdomyosarcomas (five patients), Ewing sarcoma family of tumors (ESFT) (four patients), and neuroblastoma (one patient). The interval between tumor diagnosis and irradiation as primary treatment was a median of four months (0–8 months). The prognoses were as follows: two patients died of the disease, two patients were alive with the disease, and 13 patients were alive without evidence of the disease. No patient showed grade 3/4 adverse events (based on the Common Terminology Criteria for Adverse Events) associated with proton radiation therapy except for one patient who showed grade 3 esophagitis.

【Discussion/Conclusion】Although patients showed tolerable adverse effects of proton radiation therapy during short-term follow-up, long-term follow-up with close monitoring is warranted. Close coordination between hospitals that administer proton radiation therapy is important because increasing numbers of children are being treated by this approach and additionally require chemotherapy or sedation during irradiation.

Progress in multimodal therapy has contributed to a marked improvement in the clinical outcome of Ewing’s sarcoma family of tumors (ESFT) and osteosarcoma, which are the most common malignant bone tumors in children, adolescents, and young adults. However, the prognosis of patients whose bone tumors recurred during therapy or relapsed after treatment remains poor. The objective response rate of recently developed salvage chemotherapies for recurrent or refractory ESFT is approximately 50%, whereas that of molecular target therapy ranges from 10 to 20%, with a transient therapeutic effect. Local treatment (surgery and radiotherapy) for primary site or metastatic lesions may contribute to the increase in the survival rate. By contrast, the efficacy of hematopoietic cell transplantation (HCT) remains controversial. Because the objective response rate of salvage chemotherapy or molecular target therapy for recurrent or refractory osteosarcoma is low, aggressive local treatment of recurrent or refractory lesions is essential to obtain long-term survival. There is no consensus on the efficacy of HCT. There are very few patients with both diseases who achieved long-term survival by molecular target drug monotherapy because of the evolution of drug resistance. Furthermore, the prognosis of patients who experience relapse or progression during therapy was quite dismal. Further studies will be required to verify the optimal use of molecular target drugs and to develop cellular immunotherapy, such as chimeric antigen receptor T-cell therapy, for the improvement of the clinical outcome of recurrent or refractory malignant bone tumors.

Blood transfusion is an important supportive therapy for children with cancer. However, no clear blood transfusion adaptation criteria have been established in Japan. According to the blood transfusion indication criteria for children with cancer in the pediatric blood transfusion guidelines in other countries, the hemoglobin level should be 7–8 g/dL for red blood cell transfusion, and the platelet count should be 10,000–20,000/μL for platelet transfusion to prevent bleeding. Although these are not based on sufficient scientific evidence, many facilities in Japan refer to these values. In contrast, a judgment based on the medical condition of children is necessary in some cases, while also considering the safety of blood transfusion products, without being overly caught up in these indicators. In particular, much debate about blood transfusion still exists for terminal pediatric cancer patients who are judged difficult to cure. For patients with hematologic cancers such as leukemia, blood transfusion is essential for maintaining the quality of end-of-life (EOL) care, although it is a barrier to staying at home for children desiring home care. Although blood transfusion in any situation should be performed safely, there are no reports on the indications for home blood transfusions and safe implementation systems for childhood cancer patients during EOL care in Japan. Herein, we summarize the current status and adverse effects of pediatric blood transfusion and indications for blood transfusion in pediatric cancer patients, and we consider the indications and issues of home blood transfusion for terminal children with cancers.

Pediatric cancer radiotherapy has a unique background, compared with that of adult radiotherapy. The management of pediatric cancer developed through single-arm prospective studies. Optimized pediatric cancer management includes a multidisciplinary approach, multidrug treatment, and radiotherapy. Organ preservation is most desirable for children with cancer. Since pediatric cancer is responsive to both chemotherapy and radiotherapy, low-dose irradiation for a large target volume, such as the area surrounding the tumor or the space where tumor cells may disseminate, is preferred over margin-free resection. The dose constraint of pediatric patients, which is defined as the threshold dose administered to avoid specific adverse events, is lower than that of adults. Adverse events avoided by dose constraints include deterioration endocrinological function and cognitive function. Although these effects are not fatal or present acutely, these may affect the patient’s quality of life. Optimum radiotherapy management may be delivered if one has adequate knowledge of the unique features of pediatric cancer. Treatment approaches undergoing investigation may be applied outside of trials for pediatric cancer patients. Updating information of the trial outcomes is crucial to avoiding suboptimal treatment.

Recent advances in genome analysis technology have led to a better understanding of the pathophysiology of cancer, and cancer genome profiling tests have become clinically available. However, the results obtained by next-generation sequencers are often huge and complex, and literacy is required to interpret the results of genomic analysis. Thus, basic knowledge of genome analysis and understanding of terminologies are essential. As an example, variant allele frequencies are affected by tumor content and copy number variations in cancer cells. It is also important to note that among a number of mutations, there are driver and passenger mutations, the pathological significance of which is classified on the basis of expert knowledge. However, many mutations cannot be clearly distinguished and criteria for classification may even change according to new findings. Knowing the characteristics of genomic analysis will also help us understand the limitations of genomic tests so that we can maximize the potentials of cancer genomic medicine.

[Background] Although high school students with cancer require educational support encompassing studying and returning to school, currently, this support has been inadequately provided. One factor preventing the provision of this educational support is that its outcomes’ effectiveness is unclear. Thus, we surveyed patients who received such educational support to determine its outcomes and effects.

[Materials and Methods] On the basis of medical records, we retrospectively targeted 14 high school students requiring long-term hospitalization due to blood cancer between April 2005 and April 2021 concerning their return to school, further education, and employment.

[Results] Among them, 10 received educational support (the educational support group), and four did not (the noneducational support group). Aside from study assistance, patients under the educational support group received assistance for returning to school. This took the form of an agreement before being transferred to a special needs school, where they could only return to their original high schools upon being discharged from the hospital. Whereas three of the four students in the noneducational support group stayed back a year after returning to school, those in the other group graduated as scheduled. Compared with the noneducational support group wherein none of the students were able to enroll in a four-year university course, approximately 55% of students in the educational support group were able to do so.

[Discussion] The provision of educational support showed positive outcomes. It was considered that it is important for medical professionals, educators, and even the government to understand the effectiveness of educational support that comprises both learning support and support for returning to school.

Background: Recent improvements in the overall survival rate of childhood cancer survivors (CCSs) has brought increased attention to its late effects. We conducted a questionnaire survey to determine the attitudes of CCSs towards comprehensive medical checkups, which can be effective to screen for late effects. Methods: Questionnaires were sent to CCSs who were aged ≤ 15 years at diagnosis, received cancer treatment at the University of Tsukuba Hospital from 1976 to March 2018, were ≥ 16 years at the time of the survey, and for whom five years had passed since diagnosis. Results: We sent questionnaires to 249 CCSs and 61 responded. Among the 61, 54 had valid responses, which we analyzed. The median age at diagnosis was 8.5 years, the median age at survey was 21.5 years, and the median number of years since diagnosis was 13.3 years. Forty (74%) CCSs answered that they did not know much about late effects. However, 49 (90%) answered that they would like to undergo a comprehensive medical checkup, 25 (46%) answered they would take it if it were free of charge, and 27 (50%) said they would take it even if they had to pay themselves. Discussion: Although CCSs had limited knowledge of late effects, most favored undergoing comprehensive medical checkups for their own health management. However, half of those who favored to receive medical checkups felt that the financial burden was a barrier, which may prevent some from taking such checkups.”

Background: There is only limited information currently available on the types of central venous catheter (CVC) used and how they are managed nationwide during the long-term treatment of childhood leukemia/lymphoma. Therefore, we investigated the selection and management of CVCs at institutions participating in the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG).

Method: Between February 2016 and July 2016, the JPLSG Supportive Care Committee conducted a web questionnaire survey using SurveyMonkey^® on the use and management of CVCs at 155 institutions participating in JPLSG.

Results: Responses were received from 98 institutions (63%). In the following, “%” refers to the response ratio based on the number of facilities that responded. Regarding children with leukemia/lymphoma, 97% of institutions answered that they used CVCs for all cases. Regarding the type of CVC, 86% of institutions used long-term indwelling types, 16% short-term indwelling types, 7% ports, and 44% peripherally inserted types. Differences were observed in the management of skin puncture sites and the infusion line, including the access port, and suspected catheter-related bloodstream infections among institutions.

Discussion: Owing to differences in the scale of institutions and the medical care system, the management of CVCs markedly differed among institutions. On the basis of the results of this survey, we plan to develop a guide for the management of CVCs.

Blinatumomab is a bispecific T-cell-engaging antibody construct, which is highly effective for patients with relapsed/refractory CD19+ B-cell acute lymphoblastic leukemia. Owing to its distinct toxic profiles compared with conventional chemotherapies, especially its very low rate of hematological toxicities, blinatumomab can offer a higher quality of life (QOL) to patients undergoing this treatment. However, blinatumomab requires continuous infusion for 28 days per cycle owing to its short half-life; therefore, the drug is usually given in an inpatient setting in Japan. To further improve patients’ QOL, we have worked on introducing blinatumomab administration with an ambulatory infusion pump to treat patients in an outpatient setting. We have successfully applied this to two cases so far. A medication cassette reservoir filled with blinatumomab was replaced twice a week on the same day of the week by preparing three-day and four-day medications, alternately. Materials such as the medication cassette reservoir, infusion route, and filter are required, but note that products using materials unsuitable for blinatumomab should be avoided. We once experienced a liquid leakage from the filter in the beginning, but the issue was solved by replacing the filter with another type of external filter. Blinatumomab infusion was possible while the patient is showering without discontinuation by placing the infusion pump in a waterproof bag and by covering the external filter with a waterproof film. From our experiences, blinatumomab can be safely administered in an outpatient setting using an ambulatory infusion pump, which is expected to contribute to an improvement of the patient’s QOL during therapy.

An eight-year-old girl was diagnosed as having acute myeloid leukemia (FAB M4), and induction therapy with cytarabine, mitoxantrone, and etoposide was started. On Day 21 of induction therapy, sudden facial pallor and decreased oxygen saturation (SpO₂) were observed. Venous blood gas analysis showed that the methemoglobin (MetHb) level was critically elevated at 54.7%, but no symptoms such as cyanosis or disturbance of consciousness were evident. The MetHb level improved after oxygen administration and erythrocyte transfusion. The cause was identified as ethyl aminobenzoate (Gingicaine Gel 20%^®) used as a topical oral anesthetic in dental and oral surgery, with the presence of febrile neutropenia, which further contributed to the high MetHb level. Methemoglobinemia should be considered in the differential diagnosis for a decrease in SpO₂ of unknown origin.

Williams syndrome (WS) is a rare disorder caused by a microdeletion on chromosome 7q11.23, and it is characterized by a specific facial dysmorphism, visuospatial deficits, and cardiovascular disease. Our patient was a 13-year-old boy who had intussusception and was diagnosed as having Murphy stage II Burkitt lymphoma. He was administered a standard combination chemotherapy and has been in complete remission for more than three years. Recently, some cases of malignant lymphoma have been noted in patients with WS. Genes at chromosome 7q11.23 may play a role in the occurrence of malignant lymphoma.

We report a case of primary left-sided adrenal neuroblastoma treated with continuous intravenous infusions of morphine and ketamine combined with amitriptyline for managing cancer pain. Increased dosing of morphine (maximum dose: 42 μg/kg/h) failed to provide adequate pain control. Therefore, combined use of continuous intravenous ketamine (1–1.5 mg/kg/day) and amitriptyline infusions resulted in adequate pain control. Symptoms such as nausea/vomiting, somnolence, and delirium due to continuous infusions of ketamine and amitriptyline combined with morphine were not observed; no analgesia-related respiratory depression was observed. The combined use of continuous intravenous ketamine was effective for morphine-resistant pain. In cases in which there is difficulty in subjective evaluation, adequate pain management could be achieved while considering facial expressions or behaviors (increased nighttime pain) by continuous intravenous infusions of morphine and ketamine combined with antidepressants.

A two-year-old girl was diagnosed as having right retinoblastoma (international classification E) after her mother noticed right eye leukocoria for one month. Contrast-enhanced magnetic resonance imaging (MRI) demonstrated a left–right difference in the optic nerve diameter without any orbital or brain parenchymal lesion. The right eye was enucleated and the cut end of the optic nerve was positive for tumor cells on histopathology. Bone marrow and cerebrospinal fluid analyses showed no tumor invasion. Five courses of chemotherapy were administered, including intrathecal anticancer agents, proton therapy at 45 Gy (RBE)/25 Fr. to the right optic nerve, and high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Five months after treatment completion, there was no recurrence. We expect that the intensified treatment involving both local and systemic approaches is curative despite a tumor-cell-positive surgical margin of the optic nerve. All possible interventions, such as the choice of proton beams and long-term follow-up, could also reduce late complications.

Embryonal tumor with Multilayered Rosettes (ETMRs) has the worst prognosis among fetal brain tumors. There is no established standard of care, and multidisciplinary treatment that includes a combination of surgery, radiation therapy, and multidrug chemotherapy is often performed empirically. We encountered two cases of ETMR with different outcomes after multidisciplinary treatment, including surgery, radiation therapy, and chemotherapy for medulloblastoma. One patient developed local recurrence one month after treatment and underwent re-operation, re-irradiation, and bevacizumab (BEV) therapy and remained in remission for four years. The other patient developed three recurrences, including those during treatment, and underwent re-operation and additional radiotherapy with BEV but died 16 months after onset. Re-operation and re-irradiation for the recurrence of ETMR may be useful prolonging survival, and BEV therapy may be useful for preventing or suppressing the progression of radiation necrosis associated with an increased cumulative radiation dose.

We present the cases of two patients with recurrent or refractory (R/R) osteosarcoma, who received the multikinase inhibitor regorafenib. [Case 1] A 15-year-old male with right humerus osteosarcoma experienced disease progression during post-operative chemotherapy and started regorafenib treatment. He obtained partial response after one cycle of regorafenib treatment; however, his disease exacerbated again following nine cycles of the treatment. [Case 2] A 9-year-old male with right tibia osteosarcoma experienced frequent (pulmonary) relapses after initial treatment consisting of surgical resection of the primary tumor and preoperative and postoperative chemotherapy. He started regorafenib treatment after the fifth relapse. Although he had stable disease after two cycles of regorafenib, regorafenib treatment was terminated after four cycles owing to rapid progression of the disease. Both patients did not experience any severe adverse effects. Since the antitumor effect varies in different patients, data on genetic abnormalities to predict the efficacy of regorafenib for R/R osteosarcoma should be accumulated.

A five-year-old girl presented with pallor that had persisted for three weeks. A blood test showed low titers of both hemoglobin and haptoglobin, and high titers of reticulocytes, total bilirubin, and LDH with a positive result of the direct Coombs’ test; accordingly, autoimmune hemolytic anemia (AIHA) was diagnosed. A palpable mass was detected in the lower abdomen. CT revealed a presacral cystic lesion. Her anemia improved upon prednisolone (PSL) administration, and we performed tumorectomy without transfusion to establish a definitive diagnosis and eliminate the cause of AIHA. Pathological findings identified mature cystic teratoma, the cystic fluid of which showed positive results of the indirect Coombs’ test. Postoperatively, the Coombs’ test result was negative and the PSL dose was gradually decreased. She was then in remission without relapse. These suggest that pediatric patients with AIHA might also have teratoma in areas other than the ovaries and that transfusion during surgery can be avoided if steroids are administered prior to tumor resection.

Invasive pulmonary aspergillosis (IPA) is a life-threatening infectious complication in neutropenic patients with hematologic diseases. Although there is no widely accepted standard treatment strategy, lobectomy is required when antifungal prophylaxis fails to control a pulmonary fungal ball in an existing pulmonary cavity. We report the successful lobectomy for IPA in a patient on combined immunosuppressive therapy (IST) as an integral part of induction of cord blood transplantation (CBT). A 12-year-old girl with aplastic anemia showed persistent fever and cough of lung origin with classical roentgenographic signs of aspergilloma following the finding of left upper pulmonary lobe infiltration. Left upper lobectomy for treatment was selected considering the uncontrollable fungal infection despite antifungal agent therapy. Dense pleural adhesions adjacent to the fungal ball settling within a cavity were observed. Her postoperative course was uneventful, and the patient received CBT induction 33 days after surgery.

A review was conducted regarding novel coronavirus disease (COVID-19) in pediatric cancer patients since December 2021. In the United Kingdom, there was a decrease (−17%) in the number of cancer diagnoses since the declaration of the COVID-19 pandemic with particularly significant decreases for brain tumors (−38%) and lymphomas (−28%). The total incidence of hemophagocytic syndrome also decreased to 73.7% in Japan. Mortality rates for childhood cancer with COVID-19 varied from 3% in high-income countries, 12% in upper-middle-income countries, and 13% in low-income countries, with a meta-analysis of 3,354 cases showing a mortality rate of 4%. In the large US COVID-19 registry of pediatric cancer, 1,950 cases were accumulated, with hematologic tumors accounting for 45% and relapsed cases for 59% among the 73 deaths (3.7%). In Japan, 61 cases were reported as of July 1, 2022, and most were mild or asymptomatic with no deaths. Five-year survivors (n=12,410) of childhood, adolescent, and young adult in Canada were compared with 124,100 controls. Although cancer survivors had a higher number and frequency of PCR tests, they were equally likely to be SARS-CoV-2-positive (3.1% vs. 3.2%) and no one died with no increased clinical risk. Cancer survivors had significantly higher vaccination rates and did not have an increased risk of COVID-19 infection or severe disease. The COVID-19 pandemic has had a major impact on the global pediatric oncology work environment, resulting in difficult changes in staffing and the use of telemedicine and other methods in long-term follow-up.