Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

While advances in the treatment of pediatric cancers have improved survival to>80%across all tumor types,drug resistance continues to limit survival for a considerable number of patients.We review the known mechanisms of resistance in pediatric cancers,including processes that impair conventional chemotherapies,newer classes of targeted small molecule antineoplastic drugs,and monoclonal antibodies.We highlight similarities and differences in treatment approach and resistance between pediatric and adult cancers.We also discuss newer areas of research into drug resistance,including extracellular and immune factors.

Spectrum of Pediatric Malignancies: An Observational Single Center Study from Western India

Cancer is a leading cause of death for children and adolescent worldwide.The cure rates in low middle-income countries are dismal(20%)in comparison to high income countries(80%).The first move is to assemble precise data on epidemiology of pediatric cancer across the country and its region wide variation.This study attempts to provide spectrum of pediatric malignancies from a tertiary care hospital in the state of Rajasthan,India.A total of 140 cases were studied retrospectively over a period of two years(April 2018-March 2020).Patients,0-18 years of age that are diagnosed as a case of malignancy were included in this study.The records of these patients were retrieved and analyzed.Patients were stratified in 4 groups;0-4 years,5-9 years,10-14 years and 15-18 years.Most of the patients fell in 15-18 year group(35.7%),followed by 5-9 year group(28.5%).Majority of cases,67.8%were male.The male to female ratio is 2.1:1.Leukemia(40%)was the most common malignancy followed by lymphoma,retinoblastoma and malignant bone tumors.Acute lymphoblastic leukemia comprises majority(35/56)of leukemia.Retinoblastoma was predominant malignancy among<5-year children.In all other groups,leukemia was predominant.This study gauges the trend of pediatric malignancies at one of the largest tertiary care hospitals in Rajasthan,which is important in the planning and evaluation of health strategies.As we lack a dedicated pediatric cancer registry,such epidemiological studies play a significant part for this small but distinguished group of patients.

Increasing BMI Z-Scores 3 Years after Diagnosis among a Multiethnic Cohort of Childhood Cancer Survivors Treated in South Los Angeles

Background: Due to successful treatment modalities, the majority of pediatric cancer patients will survive. Increased body mass index (BMI) is a complication among pediatric cancer survivors. Methods: This retrospective single-center study examined BMI changes among a cohort of predominantly Hispanic patients who were treated in South Los Angeles. Data were collected at diagnosis, 1, 2 and 3 years after. Analyses included z-scores derived from calculated BMIs compared over 3 years per gender, diagnosis, and treatment modality. The unhealthy BMI z-score was defined as >1.04. Results: Thirty-four percent of the predominantly Hispanic sample had unhealthy BMI z-scores of >1.04 correlating to at or greater than the 85th percentile for age and gender. The study cohort’s BMI z-scores significantly increased from 0.15 to 1.29 at year 3 (P < 0.0001), putting 55% of this population in the unhealthy category. Median BMI z-score significantly increased to the unhealthy category at 3 years. Conclusions: Due to the predominance of Hispanic patients in this group, culturally sensitive interventions beginning at diagnosis should be considered.

Assessment of Psychological Distress among Parents of Children with Cancer

Background and Aims: The diagnosis of pediatric cancer is a potentially traumatic event and a major source of psychological distress for parents. The aim of our study was to determine the prevalence and the risk factors of psychological distress among parents of children diagnosed with cancer. Methods: This is a descriptive study carried out on parents of children diagnosed with cancer and treated in the department of medical oncology at the Habib Bourguiba Hospital in Tunisia. Over a period of four months, from the beginning of December 2020 until the end of March 2021, forty-three parents (34 mothers and 9 fathers) were assessed, using psychometric scales of anxiety, depression and post-traumatic stress according to respectively to the Hamilton anxiety rating scale (HAM), the Beck Depression Inventory (BDI) and the Impact of Event Scale (IES-R). Results: Sixteen percent of the parents had scores indicating acute stress and 21% had scores indicating post-traumatic stress. Eighty six percent of the parents had mild to severe depression and 95% had minor to major anxiety. Post-traumatic stress and anxiety are significantly correlated with the female sex of parents. Significant correlations are also found between post-traumatic stress scores and symptoms of depression and anxiety. However, our study did not show a significant correlation between the others factors studied and the parents’ psychological distress. Conclusion: The prevalence of anxiety and depressive disorders was high among parents of children diagnosed with cancer and a significant correlation was found between stress and anxiety with the female sex of parents. Our results were similar to several studies although other risk factors for psychological distress in parents of children with cancer were described in the literature.

Overall survival,late mortality,and cancer-directed surgery among children and adolescents with ultra-rare pediatric pancreatoblastoma in the United States,1975-2018

Background:Pediatric pancreatoblastoma is an extremely rare malignant tumor,posing diagnostic and treatment difficulties for pediatric surgeons.Using the Surveillance,Epidemiology,and End Results(SEER)database,we present an up-to-date report of the epidemiology,clinicopathological features,survival rates,and prognosis of pancreatoblastoma in pediatric patients.Methods:All pediatric patients diagnosed with pancreatoblastoma between 1975 and 2018 were identified in the SEER regis-tries(SEER 8 registries and SEER 17 registries).We conducted a survival analysis to assess overall survival and 1-and 5-year late mortality rates.Descriptive statistics and log-rank test were performed.Results:A total of 22 children and adolescents with pancreatoblastoma were identified.In this cohort,12 of 22 were male(54.55%),14 were White(63.64%),and 11 were diagnosed between the ages of 1 and 4 years(50.0%).Among the 22 patients,11(50.0%)had distant metastases,whereas 7(31.82%)had localized,and 4(18.18%)had a regional disease.A total of 5 children and adolescents died during the study period,with cumulative survival rates of 14 of 17(82.35%)and 10 of 11(90.95%)among 1-and 5-year survivors,respectively.Cancer-directed surgery was significantly associated with an increased life expectancy(log-rank test,P=.018).Conclusion:Pediatric pancreatoblastoma is a rare entity.Cases that underwent surgery had a greater likelihood of overall survival and reduced late mortality.

Correlation between TERT C228T and clinic-pathological features in pediatric papillary thyroid carcinoma

The aims of the present study were to reveal the prevalence of the TERT C228 T mutation in pediatric papillary thyroid carcinoma(PPTC) and to further investigate the role of the TERT C228 T mutation in PPTC. We also tested another TERT mutation, TERT C250 T, although this was not detected in PPTC patients. In this study, 48 patients with PPTC(41 with classic PPTC) were enrolled. DNA was extracted from PPTC tissues and TERT C228 T mutation analysis was performed. Chi-squared analysis,Fisher’s exact test, and a t-test were applied to test the significance of differences. The TERT C228 T mutation presented in 13(27.1%) of the 48 PPTC patients and 10(24.4%) of the 41 classical PPTC patients. There were significant differences between PPTC patients with the TERT C228 T mutation and those without in terms of modified radical neck dissection, multifocality,capsular invasion, extrathyroidal invasion, and American Joint Committee on Cancer(AJCC) tumor stage(P<0.05). In classical PPTC, there were additional significant differences in other clinic-pathological features, such as AJCC nodal stage(P=0.009)and American Thyroid Association(ATA) PPTC stage(P=0.021) between patients with and without the TERT C228 T mutation.These findings indicate that the TERT C228 T mutation is significantly correlated with certain aggressive clinic-pathological features of PPTC.

Therapeutic modulation of the CD47-SIRPαaxis in the pediatric tumor microenvironment:working up an appetite

Evasion of immune surveillance is one of the hallmarks of cancer.Although the adaptive immune system has been targeted via checkpoint inhibition,many patients do not sustain durable remissions due to the heterogeneity of the tumor microenvironment,so additional strategies are needed.The innate immune system has its own set of checkpoints,and tumors have co-opted this system by expressing surface receptors that inhibit phagocytosis.One of these receptors,CD47,also known as the“don’t eat me”signal,has been found to be overexpressed by most cancer histologies and has been successfully targeted by antibodies blocking the receptor or its ligand,signal regulatory proteinα(SIRPα).By enabling phagocytosis via antigen-presenting cells,interruption of CD47-SIRPαbinding leads to earlier downstream activation of the adaptive immune system.Recent and ongoing clinical trials are demonstrating the safety and efficacy of CD47 blockade in combination with monoclonal antibodies,chemotherapy,or checkpoint inhibitors for adult cancer histologies.The aim of this review is to highlight the current literature and research on CD47,provide an impetus for investigation of its blockade in pediatric cancer histologies,and provide a rationale for new combination therapies in these patients.

Complementary and alternative medicine practices,traditional healing practices,and cultural competency in pediatric oncology in Hawai'i

OBJECTIVE： Hawai＇i is an ethnically diverse island state with a high rate of both traditional healing （TH） and complementary and alternative medicine （CAM） use. The aim of this project was to assess TH and CAM use within the pediatric oncology population in Honolulu and improve the delivery of culturally competent care. METHODS： A 9-item survey was distributed to all pediatric oncology patients at Kapi＇olani Medical Center for Women and Children for 3 months. The survey inquired about patient ethnicity, TH practices CAM practices and perception of cultural competence of the care received. Descriptive statistics were calculated for the survey items. Qualitative analysis was done with participant comments to identify themes. RESULTS： Sixty-two surveys were completed. TH was used by 39% of the respondents in the home, and 10% in the hospital （top method was traditional foods）. CAM was used by 27% of the respondents in the home, and 68% in the hospital （top method was healing touch）. Ninety-seven percent of the respondents reported receiving culturally competent care. Areas for improvement included language services and dietary choices. CONCLUSION： CAM and TH are used frequently by pediatric oncology patients in Hawai＇i, and the vast majority of patients and families felt that the care they received was culturally competent.

Mechanism of cancer: Oncohistones in action

Oncohistones are histones with high-frequency point mutations that are associated with tumorigenesis. Although each histone variant is encoded by multiple genes, a single mutation in one allele of one gene seems to have a dominant effect over global histone H3 methylation level at the relevant amino acid residue. These oncohistones are highly tumor type specific. For example, H3K27M and H3G34V/R mutations occur only in pediatric brain cancers, whereas H3K36M and H3G34W/L have only been found in pediatric bone tumors. H1 mutations also seem to be exclusively linked to lymphomas. In this review, we discuss the occurrence, frequency and potential functional mechanisms of each oncohistone in tumorigenesis of its relevant cancer. We believe that further investigation into the mechanism regarding their tumor type specificity and cancer-related functions will shed new light on their application in cancer diagnosis and targeted therapy development.

Detection and quantifi cation of extracellular microRNAs in medulloblastoma

Aim:Medu lloblastoma(MB)is the most common malignant brain tumor in children.The crucial role of extracellular-microRNAs(ex-miRNAs)in cancer has been widely recognized;however,their role in MB remains unknown.This study aimed to investigate MB-driven ex-miRNAs.Methods:Microarray analysis was used to disclose the identity and quantity of key miRNAs excreted in culture-medium(CM)of 3 human MB cell lines and cere brospinal fl uid(CSF)of brain tumors(including MB)and leukemia patients.MiRNA expression was validated by quantitative reverse transcription polymerase chain reaction.Results:We have demonstrated that the 3 MB cell lines tested commonly expressed 1,083 miRNAs in their spent CM.Among them,57 miRNAs were specifi c to the CM of metastasis-related cell lines which represents the aggressive group 3 and group 4 MB subtypes.A signifi cant number(1,254)of ex-miRNAs were identifi ed in the CSF of a MB patient.Eighty-six of these miRNAs were found to be differentially expressed in this patient’s CSF compared with controls.Interestingly,3 metastasis-associated miRNAs over-represented in CM of metastasis-related MB cell lines were found to be significantly enriched in the CSF of the MB patient.Conclusion:Although more samples are required to fully verify these results,our work provides the first evidence for the presence of a signifi cant amount of miRNAs excreted extracellularly by MB cells and raises the possibility that,in the near future,miRNAs could be probed in CSF of MB patients and serve as novel biological markers.

Are demographics associated with mucoepidermoid or acinic cell carcinoma parotid malignancies in children?

Objective:To identify possible associations between patient demographics and parotid cancer histological type in pediatric patients.Methods:Pediatric patients(ages:birth-18.0 years)in the Surveillance,Epidemiology,and End Results(SEER)database were included from 1973 to 2014 based on a diagnosis of mucoepidermoid carcinoma or acinic cell carcinoma of the parotid gland using the ICD O-3 codes of C07.9 and 8430 or 8550.Patients were classified into the following cohorts:<14 and 14-18 years of age based on the mean age at diagnosis.Results:Three hundred and three pediatric patients were diagnosed with mucoepidermoid carcinoma or acinic cell carcinoma of the parotid gland within the SEER 18 registries.Female pediatric patients 14-18 years of age were 7.68 times more likely to have an acinic cell carcinoma(adjusted OR:7.68[95%Cl:2.01-29.44]).When stratified by histological type,58.9%of female pediatric patients≥14 years of age had an acinic cell carcinoma as compared to 37.3%of male pediatric patients≥14 years of age,36.5%of female pediatric patients<14 years of age,and 34.0%of male pediatric patients<14 years of age(P=0.01).Conclusions:Based on this study,pediatric female patients between the ages of 14 and 18 years are the most likely cohort to have acinic cell carcinoma.The results of this study may assist providers during the work up of a pediatric patient with a suspected parotid malignancy.

Fibrolamellar hepatocellular carcinoma:Exploring molecular mechanisms and differentiation pathways to better understand disease outcomes and prognosis

Fibrolamellar hepatocellular carcinoma(FLC)is a rare but aggressive liver cancer of children that occurs predominantly in teenagers without a history of liver disease.Surgical resection remains the only therapeutic option,and the recurrence rate is extremely high(>50%within 3 years).A newly discovered chromosomal deletion that occurs in the majority of FLCs generates a novel kinase fusion between DnaJ heat shock protein family member B1(DNAJB1)and protein kinase cAMP-activated catalytic subunit alpha(PRKACA)(DNAJB1-PRKACA).Despite its high penetrance and apparent specificity for FLC,the oncogenic role of this fusion event remains unclear.In this review article,we discuss the histology,presentation and diagnosis,current treatment,and roles of the DNAJB1-PRKACA as well as research models contributing to our understanding of this disease.