Pediatric Cancer Therapy Research Articles

An Analysis of Vertebral Body Growth after Proton Beam Therapy for Pediatric Cancer.

Simple SummaryRadiotherapy has a key role in treatment of pediatric cancer and has greatly improved survival in recent years. However, vertebrae are often included in the irradiated area, and this may affect growth after treatment. In this study, we examined the relationship of the dose of proton beam therapy with subsequent growth of 353 vertebral bodies in 23 children (10 boys, 13 girls) with a median age at treatment of 4 years old and a median observation period of 13.9 months. Most importantly, we found that the growth rate of vertebral bodies decreased even at a low proton beam therapy dose, which indicates the need for careful planning of the irradiation area in this patient population. Growth inhibition was clearly dose-dependent, and proton beam therapy had the same growth inhibitory effect as photon radiotherapy, at least within the irradiated field.Impairment of bone growth after radiotherapy for pediatric bone cancer is a well-known adverse event. However, there is limited understanding of the relationship between bone growth and irradiation dose. In this study, we retrospectively analyzed bone growth impairment after proton beam therapy for pediatric cancer. A total of 353 vertebral bodies in 23 patients under 12 years old who received proton beam therapy were evaluated. Compared to the non-irradiated vertebral body growth rate, the irradiated vertebral body rate (%/year) was significantly lower: 77.2%, 57.6%, 40.8%, 26.4%, and 14.1% at 10, 20, 30, 40, and 50 Gy (RBE) irradiation, respectively. In multivariate analysis, radiation dose was the only factor correlated with vertebral body growth. Age, gender, and vertebral body site were not significant factors. These results suggest that the growth rate of the vertebral body is dose-dependent and decreases even at a low irradiated dose. This is the first report to show that proton beam therapy has the same growth inhibitory effect as photon radiotherapy within the irradiated field.

Diagnosis, Prevention, Treatment and Surveillance of Anthracycline-Induced Cardiovascular Toxicity in Pediatric Cancer Survivors

Advances in pediatric cancer therapies have dramatically improved the likelihood of survival. As survivors are aging, however, we are now understanding that treatment carries a significant risk of cardiovascular toxicity, which can develop immediately, or even many years after completing therapy. Anthracycline derivates are some of the most commonly used agents in pediatric oncology treatment protocols, which have a dose-dependent correlation with the development of cardiac toxicity. As we learn more about the mechanisms of toxicity, we are developing prevention strategies, including improvements in surveillance, to improve early diagnosis of heart disease. Current survivorship surveillance protocols often include screening echocardiograms to evaluate systolic function by measuring the ejection fraction or fractional shortening. However, these measurements alone are not enough to capture early myocardial changes. The use of additional imaging biomarkers, serum biomarkers, electrocardiograms, as well as cholesterol and blood pressure screening, are key to the early detection of cardiomyopathy and cardiovascular disease. Medical treatment strategies are the same as those used for heart failure from other causes, but earlier recognition and implementation can lead to improved long term outcomes.

Personalized Drug Screens Could Guide Therapy for Pediatric Brain Cancer

Personalized Drug Screens Could Guide Therapy for Pediatric Brain Cancer

Immunotherapy approaches targeting neuroblastoma.

In the era of immune-oncology, a breakthrough in the field of pediatric solid tumor research has been the demonstration that immunotherapy for patients with high-risk neuroblastoma improves the event-free and overall survival. Immunotherapeutic approaches including a monoclonal antibody targeting the cell surface glycosphingolipid disialoganglioside and cytokines successfully eliminate minimal residual disease. Since this seminal discovery, clinical trials evaluating immunotherapy in combination with chemotherapy and cellular therapies have begun to demonstrate effectiveness in treatment of bulky disease. Broader knowledge has also been gained regarding immunotherapy-limiting side-effects. Furthermore, biologic studies in actively treated patients have contributed to our growing understanding of the underlying immunologic processes and mechanisms of tumor response and immune evasion. The example of neuroblastoma is beginning to demonstrate that various immunotherapies combined with more conventional anticancer treatments can be synergistic. These advancements pose new challenges to both clinical researchers and medical provider and herald a new era in pediatric cancer therapy.

Laparoscopic assisted extracorporeal ovarian harvest: A novel technique to optimize ovarian tissue for cryopreservation in young females with cancer

BackgroundAdvances in pediatric cancer therapy have improved the long-term survival for many children with cancer. The awareness of quality of life aspects, specifically fertility preservation, has become a reality for many of these families and children. Ovarian tissue cryopreservation has emerged as an available fertility option for young females with cancer. Safe and effective removal of ovarian tissue in these girls is paramount. We report a laparoscopic assisted extracorporeal ovarian harvest technique that achieves this goal. Operative techniqueWe place a 5 mm port at the umbilicus and in the right lower quadrant. Under laparoscopic guidance we place a 12 mm port in the left suprapubic area. Utilizing the 12 mm port site a monofilament traction suture is placed through the left ovary. The traction suture is used to translocate the ovary to an extracorporeal position via the 12 mm port site. Ovarian tissue is then excised utilizing standard surgical technique with the scalpel. Hemostasis is obtained and the capsule is closed with a running absorbable suture. The ovary is placed back in its native position laparoscopically. ConclusionsThe use of this extracorporeal ovarian harvesting technique is a safe and effective method to optimize removal and minimize tissue injury. Utilization of this technique, may have potential benefit to the young female with cancer.

Age-Related Considerations in Cardio-Oncology.

Cardio-Oncology has blossomed as a new field in cardiovascular medicine, in large part due to new therapies, which may have cardiovascular sequelae. Despite this, anthracyclines still serve as cornerstone therapy for most pediatric cancers, several solid tumors and hematological malignancies. Cardiotoxicity is the main limiting concern with anthracyclines, and this is particularly an issue in patients in extremes of age (both young and old patients). Pediatric hearts are susceptible for cardiotoxicity, while in older patients, concomitant risk factors may contribute to lower threshold for cardiotoxic effects. With increasing patient survival, a significant increase in elderly cancer patients and long-term cardiotoxicity effects of anthracyclines, a better mechanistic understanding of age-dependent processes-that define cardiotoxicity-is needed. This review sheds light on how age affects underlying molecular pathways of anthracycline-associated cardiotoxicity and aims to provide preventive strategies that can be used in clinical practice.

Commonly Reported Adverse Events Associated With Pediatric Immunotherapy: A Systematic Review From the Children's Oncology Group

Immunotherapy is a new and promising approach to treating pediatric cancers. These types of therapies have unique mechanisms of action for identifying and fighting cancer, as compared with traditional chemotherapy, and therefore are associated with different therapy-related adverse events (AEs). The purpose of this systematic review was to review available evidence to: (a) identify commonly reported AEs associated with immunotherapy agents frequently used in pediatric oncology and (b) generate recommendations for nursing practice. A clinical question was developed and used to guide the systematic literature review. Five immunotherapy agents (dinutuximab, blinatumomab, rituximab, inotuzumab ozogamicin, brentuximab vedotin) were selected for inclusion secondary to their high relevance to pediatric oncology. A literature search was conducted to locate articles published between January 1, 2003 and October 31, 2018. Seventeen articles met eligibility criteria for inclusion and were evaluated using the Grading of Recommendations Assessment, Development, and Evaluation criteria. The most commonly reported AEs for the selected immunotherapy agents were identified and summarized. Strong recommendations are made for nurses to become familiar with the unique AE profiles associated with individual immunotherapy agents. Agent-specific recommendations for nursing practice regarding AEs associated with dinutuximab and rituximab were generated. Immunotherapy is rapidly emerging as an effective therapy for pediatric cancers. Nurses need to be aware of the breadth of agent-specific, immunotherapy-related AEs to appropriately monitor and manage patients receiving these therapies. Additional work is needed to confidently profile immunotherapy-related AEs in pediatric oncology and to develop agent-specific educational materials for patients/families.

Safety considerations for nanoparticle gene delivery in pediatric brain tumors.

Current standard of care for many CNS tumors involves surgical resection followed by chemotherapy and/or radiation. Some pediatric brain tumor types are infiltrative and diffuse in nature, which reduces the role for surgery. Furthermore, children are extremely vulnerable to neurological sequelae from surgery and radiation therapy, thus alternative approaches are in critical need. As molecular targets underlying various cancers become more clearly defined, there is an increasing push for targeted gene therapies. Viral vectors and nonviral nanoparticles have been thoroughly investigated for gene delivery and show promise as vectors for gene therapy for pediatric brain cancer. Here, we review inorganic and organic materials in development for nanoparticle gene delivery to the brain with a particular focus on safety.

Clinical and genetic risk factors for radiation-associated ototoxicity: A report from the childhood cancer survivor study and the St. Jude Lifetime Cohort.

10550 Background: Cranial radiation therapy (CRT) for pediatric cancer often results in ototoxicity in the form of hearing loss and tinnitus. We sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with cranial radiation. Methods: Relationships between age at last observation, sex, cumulative CRT dose and self-reported ototoxicity were evaluated for hearing loss and tinnitus among 1,991 (tinnitus) and 2,198 (hearing loss) survivors in the Childhood Cancer Survivor Study who received CRT. Logistic regression evaluated associations with non-genetic risk factors and comorbidities as well as SNP dosages in GWAS of CRT-related tinnitus (cases: 146; controls: 1,845) and hearing loss (cases: 270; controls: 1,928). Results: Males were more likely to report CRT-related tinnitus (9.4% vs. 5.4%; p = 5.81x10−4) and hearing loss (14.0% vs. 10.7%; p = 0.02) than females after adjusting for dose and age at last observation. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: p < 2.00x10−16; hearing loss: p = 6.35x10−9), take antidepressants (tinnitus: p = 0.02; hearing loss: p = 0.01) and report poorer overall health (tinnitus: p = 9.40x10−7; hearing loss: p = 1.30x10−6) compared to survivors without tinnitus or hearing loss after age-adjustment. GWAS of CRT-related tinnitus revealed a prominent signal in chromosome 1 led by rs203248 (p = 1.50x10−9), while GWAS of CRT-related hearing loss identified rs332013 (p = 5.79x10−7) in chromosome 8 and rs67522722 (p = 7.78x10−7) in chromosome 6 as approaching genome-wide significance. Replication analysis in an independent cohort of pediatric cancer survivors (SJLIFE) indicated that rs67522722, intronic to ATXN1, a gene associated with the neurodegenerative disorder spinocerebellar ataxia type 1, was significantly associated with CRT-related hearing loss (p = 0.03). Enrichment analysis and LD score regression with previous GWAS results of cisplatin-related hearing loss and tinnitus in testicular cancer survivors showed no detectable enrichment in genetic architecture with CRT-related hearing loss and tinnitus, respectively. Conclusions: Radiation-associated ototoxicity was associated with sex, several neuro-otological symptoms, increased antidepressant use and poorer self-reported health. GWAS of CRT-related hearing loss identified rs67522722 that was replicated in an independent cohort of pediatric cancer survivors.

First person profile: Leslie L. Robison, PhD: A world-renowned epidemiologist, Dr. Robison played key roles in developing both the national Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort Study.

First person profile: Leslie L. Robison, PhD: A world-renowned epidemiologist, Dr. Robison played key roles in developing both the national Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort Study.

Oral and dental considerations in pediatric cancers.

Oral health care is an integral component of interprofessional collaborative care for children and adolescents diagnosed with cancer. The current review highlights the phases of cancer therapy when dental interventions and palliative care are necessary for children diagnosed with cancer. Contemporary research and review articles pertinent to the oral and dental complications during pediatric cancer therapy and late effects in pediatric cancer survivors were identified by PubMed/MEDLINE search. Best practice guidelines set forth by specialty organizations were also included. The literature search was limited to articles published in the English language. Baseline oral and dental health assessment should occur before initiation of cancer therapy to prevent debilitating complications during the immunosuppressed phase. Counseling on preventive oral health practices is imperative during cancer treatment. Ideally, all dental treatment should be completed before initiation of immunosuppressive therapy. Palliative care and treatment for mucositis, opportunistic oral infections, pain, and other oral complications associated with cancer therapy should be provided as necessary. Survivors of childhood cancers present with unique craniofacial and dental anomalies, dependent on the type of cancer treatment and age at the time of treatment. Pediatric dentists and pediatric oncology teams work collaboratively to screen for and treat dental and oral diseases. As the survival rates of childhood cancers improve, it is essentialfor the dental profession to provide the individualized care necessary for this vulnerable population. The oral health profession also reinforces health practices congruent with cancer prevention and cancer screening.

Biofabrication of zinc oxide nanoparticles, characterization and cytotoxicity against pediatric leukemia cell lines

AbstractIn this work, we showed the synthesis of zinc oxide nanoparticles (ZnO NPs) using leaf extract of Punica granatum. Characterization results showed the synthesis of stable ZnO NPs with average size of 7 nm. Fourier transform infrared (FT-IR) and zeta potential results confirmed the capping of ZnO NPs with plant extract polyphenols. X-ray diffraction (XRD) and selected area electron diffraction (SAED) examinations showed the crystalline nature of prepared ZnO NPs. Further, the cytotoxic properties of the green synthesized ZnO NPs are examined against pediatric leukemia cells and the morphology of cells was studies under microscope. The results of cytotoxicity and microscopic images revealed the dose dependent cytotoxicity, indicating their prospects for the development of novel techniques and materials for pediatric leukemia cancer therapy.

Novel therapy for pediatric and adolescent kidney cancer.

Pediatric and adolescent renal tumors account for approximately 7% of all new cancer diagnoses in the USA each year. The prognosis and treatment are varied based on factors including the underlying histology and tumor stage, with survival rates ranging from greater than 90% in favorable histology Wilms tumor to almost universally fatal in other disease types, including those patients with advanced stage malignant rhabdoid tumor and renal medullary carcinoma. In recent years, our understanding of the underlying genetic drivers of the different types of pediatric kidney cancer has dramatically increased, opening the door to utilization of new targeted biologic agents alone or in combination with conventional chemotherapy to improve outcomes. Several ongoing clinical trials are investigating the use of a variety of targeted agents in pediatric patients with underlying genetic aberrations. In this manuscript, the underlying biology and early phase clinical trials relevant to pediatric renal cancers are reviewed.

Complications of biologic therapy for pediatric cancer – What the surgeon needs to know

Biologic therapy for pediatric cancer has gained much enthusiasm over the past two decades.Recent advances in the clinical sequencing of tumors, have also allowed for the identification of targetable mutations. These findings have created a new avenue of biologic agent development and study. As experience with biologic agents builds, so too must the awareness of the surgeon to identify potential complications of these drugs. Complications can result from the direct effect of a biologic on the patient, such as gastrointestinal perforation or secondary spontaneous pneumothorax, or they can be related to the effect a biologic has on another aspect of a patient's care, such as wound complications following surgery. The morbidity caused by these complications must be weighed against any potential benefit of an agent, when determining the role for biologic therapy in the overall cancer treatment strategy.

Anti-CXCR4 Antibody Combined With Activated and Expanded Natural Killer Cells for Sarcoma Immunotherapy.

Sarcoma is one of the most severe forms of pediatric cancer and current therapies -chemotherapy and surgery- fail to eradicate the disease in half of patients. Preclinical studies combining new therapeutic approaches can be useful to design better therapies. On one hand, it is known that CXCR4 expression is implicated in rhabdomyosarcoma progression, so we analyzed relapses and chemotherapy-resistant rhabdomyosarcoma tumors from pediatric patients and found that they had particularly high levels of CXCR4 expression. Moreover, in assays in vitro, anti-CXCR4 blocking antibody (MDX1338) efficiently reduced migration and invasion of alveolar rhabdomyosarcoma RH30 cells. On the other hand, activated and expanded natural killer (NKAE) cell therapy showed high cytotoxicity against sarcoma cells in vitro and completely inhibited RH30 tumor implantation in vivo. Only the combination of MDX1338 and NKAE treatments completely suppressed metastasis in mice. In this study, we propose a novel therapeutic approach based on anti-CXCR4 blocking antibody in combination with NKAE cell therapy to prevent rhabdomyosarcoma tumor implantation and lung metastasis. These results provide the first evidence for the efficacy of this combined immunotherapy for preventing sarcoma disease dissemination.

Immune checkpoint inhibitor therapy for pediatric cancers: A mini review of endocrine adverse events.

.In recent years, immune checkpoint inhibitor therapy has attracted a great deal of attention in the field of cancer treatment. In the clinical setting, antibodies targeting programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been successfully used to treat adult patients with various types of intractable cancer. However, in a substantial number of patients, ICI therapy is associated with autoimmune toxicities known as immune-related adverse events (IRAEs). Endocrinopathies, such as hypophysitis or autoimmune thyroid disease, may occur and can present unique clinical features that have not been documented with traditional chemotherapies. A Japanese clinical trial evaluating the anti-PD-1 antibody nivolumab for the treatment of pediatric patients with refractory malignant solid tumors and Hodgkin lymphoma has been ongoing since 2017. Moreover, tumors associated with Lynch syndrome, a hereditary form of mismatch repair deficiency, are being focused and represent the next target for ICI therapy in Japan. For the safe management of pediatric cancer patients treated with ICIs, pediatric endocrinologists must be aware of the risk of autoimmune endocrinopathies and perform relevant screening tests at appropriate stages of growth and development.

Half a century of anesthesia for children: An interview with Dr. Nishan G. 'Nick' Goudsouzian.

The career of Dr Nishan Goudsouzian spanned half a century of pediatric anesthesia. His 50years saw seminal contributions to the use of neuromuscular blocking agents in children, the development of proton beam therapy and magnetic resonance imaging for pediatric cancer, the introduction of the laryngeal mask airway, an explosion in the volume and depth of knowledge about pediatric anesthesia, the expansion of formal training in pediatric anesthesia, and the widening of academic efforts to improve anesthetic care for children worldwide. Based on interviews with Dr Goudsouzian, this article reviews the contributions of this Robert M. Smith Award winner to the development of pediatric anesthesia.

Evaluating the Use of Patient-Reported Non-Routine Events in Pediatric and Radiation Oncology: A Pilot Study

This prospective pilot study evaluated (1) the potential for collecting structured longitudinal data on patient-reported non-routine events (PNREs) (i.e., events that deviate from expected or optimal care) during pediatric and adult radiation cancer therapies and (2) the potential relationship between PNREs, Patient-Reported Outcomes Measures (PROMs), and unplanned treatment events (UTEs). Along with PNREs, data were collected on patient’s background, distress, quality of life, hospital system care experience rating, and treatment intensity, during a 3-month period; UTEs were retrospectively captured through review of patients’ records. Initial results suggest a relationship exists between both PNREs and safety-relevant PNREs with patient distress, quality of life, and care experience ratings. UTEs occurred more often in pediatric patients and were primarily related to patients’ underlying disease. This systems-safety approach to identifying at-risk points in treatment pathways has the potential to provide actionable information for the mitigation of shortcomings in cancer therapy.

2214 Nutritional outcomes in pediatric oncology patients less than 3 years of age

OBJECTIVES/SPECIFIC AIMS: Brain tumors are the most common solid tumor diagnosed in children and their location predisposes patients to oromotor dysfunction leading to feeding difficulties. Brain tumor patients experience feeding difficulties more frequently than other pediatric malignancies, largely due to central nervous system directed chemotherapy, radiation, and surgery. Treatment increases the risk of malnutrition and increases risk for infection, ICU admissions, and death. Infants and children (less than 3 years of age) are at higher risk for malnutrition due to rapidly changing nutritional requirements and the underdevelopment of motor skills. Incidence and prevalence of malnutrition in pediatric cancer patients is not well known. METHODS/STUDY POPULATION: This is an observational, retrospective study of our center’s pediatric cancer patients. Patients are classified by diagnosis, treatment intensity (ITR-2), vital status, and heights and weights (with standardized Z-scores) will be recorded with through 2 years after diagnosis. Adaptation of Intensity of Treatment Rating ITR-2. Nutrition consultation, ICU admissions, and use of parenteral or enteral nutrition will be recorded. Weight loss greater than a 5-percentile point change or Z-score decrease greater than 0.5 will be treated as a binary outcome and considered significant weight loss. RESULTS/ANTICIPATED RESULTS: Preliminary analysis has identified 465 eligible subjects as described above: brain tumor (n=45) and nonbrain tumor patients (n=420). Patient Schema. This study is still in progress and aims to better identify incidence of malnutrition during pediatric cancer therapy. It is expected that a greater number of nonbrain tumor patients compared with brain tumor patients will be malnourished as defined by decrease in Z-score greater than 0.5 at any point in therapy or falling below the 5th percentile of weight for age. Weight loss will be associated with higher number of ICU admissions and higher treatment intensity score. Finally, we expect to find that patients with a larger decrease in Z-score for age will be more likely to die during therapy. DISCUSSION/SIGNIFICANCE OF IMPACT: In addition to this study being valuable in better defining incidence of malnutrition, this data will serve as preliminary data in defining target populations for focused nutritional intervention during cancer therapy. Using this established and published intensity rating scale, we may be able to identify better methods of identifying and preventing malnutrition during cancer therapy.

Development of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy.

Preclinical and clinical development of agents that inhibit cell-cycle progression have brought an understanding of the feasibility of targeting various cell-cycle regulators in patients with cancer. Small molecule inhibitors targeting key proteins that participate in cell-cycle progression including the cyclin-dependent kinases and checkpoint kinases induce cell-cycle arrest and apoptosis in neoplastic cells. Early phase I studies demonstrate targeted inhibitors can be administered safely in adult and pediatric cancer patients, but these agents generally show limited clinical benefits as single agents. In this review, we discuss biological mechanisms that support dual combination strategies of cell-cycle inhibition with chemotherapeutic agents that are anticipated to achieve rationally targeted therapies for cancer patients. The rationale for evaluating these combination strategies is that DNA damage renders tumors highly responsive to irreversible cell-cycle arrest therapy. This approach is predicted to generate less intensive therapies and to maximize the efficacy of individual agents against solid tumors and hematologic malignancies. Cancer Res; 78(2); 320-5. ©2018 AACR.