Magnesium supplementation therapy to prevent cisplatin-induced acute nephrotoxicity in pediatric cancer: a randomized phase-2 trial.

BACKGROUND: The present study aimed to examine the effect of magnesium (Mg) supplementation on cisplatin-induced nephrotoxicity (CIN) in pediatric cancer patients. METHODS: The present phase-2, open-label, multicenter, randomized controlled trial enrolled patients aged less than 20 years who were scheduled to receive cisplatin-containing chemotherapy and randomly allocated them at a ratio of 1:1 to a Mg supplementation arm with even-numbered chemotherapy courses (arm AB) or another arm with odd-numbered courses (arm BA). Analysis objects were reconstructed into two groups depending on whether the chemotherapy course had Mg supplementation (group B) or not (group A). The primary outcome was the proportion of chemotherapy courses resulting in elevated serum creatinine per chemotherapy course. The secondary outcomes included efficacies evaluated using other biomarkers and the safety of the Mg supplementation. RESULTS: Twenty-eight patients were randomly allocated to either group (16 to arm AB and 12 to arm BA). The baseline characteristics of the groups were similar. There was no significant difference in the proportion of courses with increased serum creatinine between the groups (group A: 10% vs. group B: 6%; P = 0.465) nor was any significant difference observed in other biomarkers during any chemotherapy course. The Mg value during chemotherapy was significantly higher in group B than that in group A. No adverse events related to magnesium administration were observed. CONCLUSIONS: The study design, which treated a single chemotherapy course as a study object, failed to detect a statistically significant benefit of Mg supplementation for preventing CIN in pediatric cancer patients. TRIAL REGISTRATION: JRCT ( https://jrct.niph.go.jp/ ) Identifier UMIN000029215 jRCTs031180251. UMIN-CTR ( http://www.umin.ac.jp/icdr/index.html ) Identifier UMIN000029215.

False-Positive Asymmetrical Tongue Muscle 18F-FDG Uptake in Hypoglossal Nerve Paralysis Following Lymph Node Dissection in a Pediatric Patient with Malignant Rhabdoid Tumor of the Neck.

BACKGROUND: Although positron emission tomography combined with computed tomography (PET-CT) plays an important role in detecting various types of childhood malignancy, it has low positive predictive value, owing to the nonspecific uptake of 18F-fluorodeoxyglucose (FDG) by normal tissue in various benign conditions. CASE SUMMARY: A 5-year-old male patient with a malignant rhabdoid tumor originating in the left neck underwent primary tumor resection concurrently with ipsilateral lymph node dissection after receiving neoadjuvant chemotherapy consisting of cyclophosphamide, carboplatin, etoposide, vincristine, and doxorubicin. He later received the same adjuvant chemotherapy as well as proton therapy for the primary tumor. Sixteen months after completing the initial therapy, follow-up PET-CT revealed a novel area of glucose hypermetabolism in the right side of the tongue, which was suspected of being a recurrence. However, a physical examination and magnetic resonance imaging (MRI) demonstrated no evidence of tumor recurrence. The patient had a significant leftward deviation of the tongue, suggesting left hypoglossal nerve paralysis. Denervation of the ipsilateral intrinsic tongue muscles secondary to the treatment had caused atrophy in the ipsilateral muscles and compensatory hypertrophy in the contralateral muscles, which increased FDG uptake. Physicians should carefully confirm any diagnosis of a locally recurrent tumor because PET-CT often produces ambiguous findings.

Treatment of Pediatric Acute Lymphoblastic Leukemia: A Historical Perspective.

Acute lymphoblastic leukemia (ALL) is the most common disease in pediatric oncology. The history of developmental therapeutics for ALL began in the 1960s with the repetition of "unreliable" medical interventions against this lethal disease. By the 1990s, the development of multi-agent chemotherapy and various types of supportive care rendered ALL treatable. Highly sophisticated, molecular, diagnostic techniques have enabled highly accurate prediction of the relapse risk, and the application of risk-adapted treatments has increased the survival rate in the standard-risk group to nearly 100% in most European nations and North America. Incorporation of state-of-the-art, molecularly targeted agents and novel treatments, including cell and immunotherapy, is further improving outcomes even in the high-risk group. On the other hand, the financial burden of treating children with ALL has increased, imperiling the availability of these diagnostic and treatment strategies to patients in low- and middle-income countries (LMICs). The fundamental treatment strategy, consisting of corticosteroid and classical cytotoxic therapy, has achieved fairly good outcomes and should be feasible in LMICs as well. The present review will discuss the history of developmental therapeutics for childhood ALL in various countries through an extensive literature review with the aim of proposing a model for a treatment backbone for pediatric ALL. The discussion will hopefully benefit LMICs and be useful as a base for future clinical trials of novel treatments.

Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects.

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

A Fatal Case of Neuroblastoma Complicated by Posterior Reversible Encephalopathy with Rapidly Evolving Transplantation-Associated Thrombotic Microangiopathy.

BACKGROUND: Transplantation-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation and is sometimes fatal. OBSERVATIONS: A 4-year-old, male patient with stage M neuroblastoma (NBL) who had received an allogeneic bone marrow transplantation (BMT) from his sibling five months previously presented with rapidly progressive posterior reversible encephalopathy (PRES) complicated with TA-TMA. Although the patient was transferred to the pediatric intensive care unit, he died within one week after the onset of the latest symptoms. CONCLUSIONS: This is the first description of a fatal case of NBL complicated by PRES with rapidly evolving TA-TMA after an allogenic BMT.

Role of Peer Support in Posttraumatic Growth Among Adolescent and Young Adult Cancer Patients and Survivors.

Purpose: Adolescents and young adults (AYA) who undergo cancer treatment sometimes report posttraumatic growth (PTG). Although the importance of peer support has been suggested, its association with PTG, especially its five distinct domains, needs to be investigated further in AYA cancer survivors. The present study examined the role of demographics and peer support in PTG among AYA cancer patients and survivors. Methods: The present, multicenter, cross-sectional, web-based study enrolled AYA cancer patients and survivors (median age: 28 years). Of 549 AYA patients recruited, 212 from 11 cancer centers and 12 cancer patient communities agreed to participate by completing a self-reported measure of PTG (Extended Version of the Posttraumatic Growth Inventory-Japanese) and providing information about their diagnosis, treatment, peer support (affiliation with an AYA patient community or friendship with other AYA patients), and social status. Multiple regression analysis was used to identify significant correlations overall and in the five PTG domains. Results: PTG was positively associated with male sex, having a confidant, and friendship with other AYA patients, and negatively associated with cranial radiation. Friendship with other AYA patients was positively associated with four of the five PTG subscales. For the five subscale scores, "cranial radiation" was negatively associated with "relating to others"; "belonging to a religion" was positively associated with "spiritual change"; and "having a confidant" was positively associated with "relating to others" and "new possibility." Conclusion: "Having a confidant" and "friendship with other AYA patients" were positively associated with PTG. Psychosocial interventions mobilizing peer support may contribute to promoting PTG in AYA patients. UMIN000035439.

Optimizing Rhabdomyosarcoma Treatment in Adolescents and Young Adults.

Rhabdomyosarcoma (RMS) is the most common form of soft tissue sarcoma in children, but can also develop in adolescents and young adults (AYA). The mainstay of treatment is multi-agent chemotherapy, ideally with concomitant local treatment, including surgical resection and/or radiation therapy. Although most treatment decisions for RMS in AYA are based on scientific evidence accumulated through clinical studies of pediatric RMS, treatment outcomes are significantly inferior in AYA patients than in children. Factors responsible for the significantly poor outcomes in AYA are tumor biology, the physiology specific to the age group concerned, refractoriness to multimodal treatments, and various psychosocial and medical care issues. The present review aims to examine the various issues involved in the treatment and care of AYA patients with RMS, discuss possible solutions, and provide an overview of the literature on the topic with several observations from the author's own experience. Clinical trials for RMS in AYA are the best way to develop an optimal treatment. However, a well-designed clinical trial requires a great deal of time and resources, especially when targeting such a rare population. Until clinical trials are designed and implemented, and their findings duly analyzed, we must provide the best possible practice for RMS treatment in AYA patients based on our own expertise in manipulating the dosage schedules of various chemotherapeutic agents and administering local treatments in a manner appropriate for each patient. Precision medicine based on state-of-the-art cancer genomics will also form an integral part of this personalized approach. In the current situation, the only way to realize such a holistic treatment approach is to integrate new developments and findings, such as gene-based diagnostics and treatments, with older, fundamental evidence that can be selectively applied to individual cases.

Predictive factors of acute respiratory events during initial induction chemotherapy in patients with advanced neuroblastoma.

BACKGROUND: Acute respiratory events (ARE) occasionally occur during induction chemotherapy as a complication in patients with advanced neuroblastoma. AIMS: The present study aimed to identify the predictive factors of ARE, defined as severe hypoxia, during initial induction chemotherapy in patients with newly diagnosed advanced neuroblastoma. METHODS AND RESULTS: The medical records of 75 consecutive patients in whom stage III or IV neuroblastoma was newly diagnosed between January 2003 and December 2018 at two medical institutions were retrospectively reviewed. The outcome was ARE, which were assessed by measuring oxygen saturation between days 1 and 14 of initial induction chemotherapy. Severe hypoxia was defined as grade 3 or higher according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.0) or decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mmHg). Possible predictive factors on admission were first screened for using univariate analyses with P = .05, then models of the predictive power of the outcome were evaluated by generating receiver operating characteristic (ROC) curves. Eleven patients (14.7%) had the outcome, including three (4.0%) who required respiratory support in the intensive care unit. The area under the curve of the ROC for the predictive factors screened by univariate analyses was 0.84 (95% confidence interval [CI]: 0.73-0.95) for lactate dehydrogenase (LDH) and 0.90 (95% CI: 0.82-0.98) for the disseminated intravascular coagulation (DIC) score. CONCLUSION: The LDH value and DIC score on admission may be clinically useful predictors of ARE during initial induction chemotherapy in patients with advanced neuroblastoma.

Development of a Selective Tumor-Targeted Drug Delivery System: Hydroxypropyl-Acrylamide Polymer-Conjugated Pirarubicin (P-THP) for Pediatric Solid Tumors.

Most pediatric cancers are highly chemo-sensitive, and cytotoxic chemotherapy has always been the mainstay of treatment. Anthracyclines are highly effective against most types of childhood cancer, such as neuroblastoma, hepatoblastoma, nephroblastoma, rhabdomyosarcoma, Ewing sarcoma, and so forth. However, acute and chronic cardiotoxicity, one of the major disadvantages of anthracycline use, limits their utility and effectiveness. Hydroxypropyl acrylamide polymer-conjugated pirarubicin (P-THP), which targets tumor tissue highly selectively via the enhanced permeability and retention (EPR) effect, and secondarily releases active pirarubicin molecules quickly into the acidic environment surrounding the tumor. Although, the latter rarely occurs in the non-acidic environment surrounding normal tissue. This mechanism has the potential to minimize acute and chronic toxicities, including cardiotoxicity, as well as maximize the efficacy of chemotherapy through synergy with tumor-targeting accumulation of the active molecules and possible dose-escalation. Simply replacing doxorubicin with P-THP in a given regimen can improve outcomes in anthracycline-sensitive pediatric cancers with little risk of adverse effects, such as cardiotoxicity. As cancer is a dynamic disease showing intra-tumoral heterogeneity during its course, continued parallel development of cytotoxic agents and molecular targeting agents is necessary to find potentially more effective treatments.

Tumor-Treating Fields Therapy for Pediatric Brain Tumors.

Tumor-treating fields (TTFields) are alternating electric fields applied continuously to the brain by attaching two-pair arrays on the scalp. Although TTFields therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. Despite differences in the genetic etiology of the adult and pediatric forms of GBM, both have certain clinical behaviors in common, allowing us to test TTFields therapy in pediatric GBM. Recently, several, pediatric case-series using TTFields therapy have been published, and a few, prospective, pediatric studies are ongoing. Because GBMs are extremely rare in pediatric patients, where they comprise a wide variety of genetic subtypes, these pediatric studies are feasibility studies targeting various types of malignant brain tumor. Although they are important for confirming the safety and feasibility of TTFields therapy in the pediatric population, confirming its efficacy against each type of pediatric brain tumor, including the GBM, is difficult. Our clinical research team, therefore, planned an investigator-initiated clinical trial targeting pediatric supratentorial GBMs (as in adults) with the aim of expanding regulatory approval of TTFields therapy for pediatric GBM treatment based on safety and exploratory efficacy data in combination with the accumulated evidence on adult GBMs.

Magnesium supplementation therapy to prevent cisplatin-induced acute nephrotoxicity in pediatric cancer: A protocol for a randomized phase 2 trial.

Although cisplatin is one of the most effective agents against various pediatric cancers, it is sometimes difficult to manage due to its dose-limiting nephrotoxicity. Magnesium sulfate (Mg) showed a kidney-protective effect against cisplatin-induced nephrotoxicity (CIN) by regulating renal platinum accumulation both in vitro and in vivo, and the body of clinical data demonstrating the efficacy of this drug in adult cancer patients is increasing.In this open, multicenter, phase-2, randomized trial, patients under age 18 years who are scheduled to receive cisplatin-containing chemotherapy will be enrolled and randomly allocated either to an Mg supplementation arm in even-numbered chemotherapy courses (arm AB) or to another arm in odd-numbered courses (arm BA), with a 1:1 allocation. Analysis objects will be reconstructed into two groups depending on whether the chemotherapy course has Mg supplementation (group B) or not (group A). The primary endpoint is the proportion of chemotherapy courses resulting in elevated serum creatinine equal to or greater than 50% of the prechemotherapy value. For the secondary endpoints, various parameters for measuring kidney function, such as serum cystatin-C, B2M, L-FABP, NGAL, and urinary NAG in the two groups will be compared. A sample size based on alpha = 5% and 80% power requires at least 40 samples per group (ideally, 60 samples per group).If Mg demonstrates efficacy, a phase-3 study to confirm the prophylactic effect of Mg supplementation in both acute and chronic CIN will be developed using novel and better biomarkers. TRIAL REGISTRATION: UMIN-CTR (http://www.umin.ac.jp/icdr/index.html) Identifier UMIN000029215.

Registration-directed phase 1/2 trial of irinotecan for pediatric solid tumors.

BACKGROUND: Although irinotecan hydrochloride (IRI) is a promising chemotherapeutic agent for pediatric solid tumors, its indications had been off-label in the USA, EU and Japan. Therefore, we conducted a phase 1/2 trial of IRI monotherapy in a registration-directed setting. METHODS: Children aged 2-18 years with solid tumors who were either refractory to or relapsed after standard chemotherapy were enrolled. Phase 1 was a conventional dose escalation study to determine the dose-limiting toxicity (DLT) and the recommended dose. IRI was given i.v. on days 1, 2, 3 and 8, 9, 10 in up to eight, 21 day cycles. RESULTS: The starting dose (40 mg/m2 /day) was determined to be the recommended dose because the next higher dose level (45 mg/m2 /day) resulted in two cases of DLT. Seventeen children (11 in phase 1 and six in phase 2) with a refractory solid tumor received IRI. Of the 12 patients treated with 40 mg/m2 /day, seven (58.3%) achieved a stable disease condition for >8 weeks. CONCLUSIONS: The RD of IRI in this treatment schedule was 40 mg/m2 /day. IRI did not cause tumor shrinkage but might help to stabilize refractory pediatric solid tumors. Based on the accumulating evidence from international studies of the efficacy of IRI against refractory pediatric solid tumors, the Japanese regulatory authority approved its use for this indication in 2011.

Kidney-protective Effect of Magnesium Supplementation in Cisplatin-containing Chemotherapy for Pediatric Cancer: A Retrospective Study.

In total, 158 chemotherapy courses containing cisplatin for 37 pediatric cases of newly diagnosed cancer were divided into 2 groups depending on whether magnesium (Mg) supplementation was administered (Mg+: 92 courses) or not (Mg-: 66 courses). Renal impairment was defined as grade 2 or higher creatinine elevation (CE) after each chemotherapy course. The incidence of CE in the Mg+ was significantly lower than in the Mg- (9.8% vs. 22.7%; P=0.025). Multivariate analysis revealed that Mg supplementation significantly reduced the incidence of CE (odds ratio, 0.36; confidence interval, 0.13-0.99). In pediatric patients, Mg supplementation during cisplatin-containing chemotherapy was associated with less cisplatin-induced nephrotoxicity to prevent cisplatin-induced nephrotoxicity.

Treatment outcome of children with acute lymphoblastic leukemia: the Tokyo Children's Cancer Study Group (TCCSG) Study L04-16.

The survival rate of children with acute lymphoblastic leukemia (ALL) has increased to approximately 90% after substantial progress in risk-oriented treatment strategies. Between 2005 and 2013, the Tokyo Children's Cancer Study Group (TCCSG) conducted a risk-oriented, non-randomized study, L04-16. The principal aim of this study was to assemble background characteristics and treatment outcomes, and gather genetic information on leukemic cells under central diagnosis. This report outlines the background characteristics and treatment outcomes of 1033 children with ALL treated according to a TCCSG platform. The 5-year event-free and overall survival (OS) rates for all children were 78.1 ± 1.3 and 89.6 ± 1.0%, respectively. The OS rate was significantly higher in children with B-cell precursor (BCP)-ALL (91.9 ± 1.0%, n = 916) than in those with T-ALL (71.9 ± 4.3%, n = 117, p < 0.001). In univariate analysis for BCP-ALL, children aged 1-6 years (5y-OS: 94.2 ± 1.0%), with an initial white blood cell count of < 20,000/µL (94.0 ± 1.0%), high hyperdiploidy (95.4 ± 1.6%), ETV6-RUNX1 (97.4 ± 1.2%) or TCF3-PBX1 (96.9 ± 2.1%), and "Day8NoBlasts" (96.4 ± 1.1%) had the best outcomes. Genetic investigation revealed two novel fusion genes within this cohort: ETV6-ZNF385A and ZNF362-TCF4. Our study highlighted the clinical aspects of genomic features of ALL in Japanese children. We provide fundamental information for the further molecular investigation of this disease.