Background: Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a progressive autosomal recessive disorder characterized by cachexia, gastrointestinal (GI) dysmotility, ptosis, peripheral neuropathy and brain MRI white matter changes. Bi-allelic TYMP mutations lead to deficient thymidine phosphorylase (TP) activity, toxic accumulation of plasma nucleosides (thymidine and deoxyuridine), nucleotide pool imbalances and mtDNA instability. Death is mainly due to GI complications: intestinal perforation, peritonitis, and/or liver failure. Based on our previous observations in 3 patients with MNGIE, that platelet infusions resulted in a transient 40% reduction of plasma nucleoside levels, in 2005 we performed the first HSCT worldwide as a life-long source of TP in a patient with MNGIE. Procedure: HSCT was performed in a total of six patients with MNGIE. The multiple factors involved in the prognosis of this cohort were analyzed and compared to the literature experience. Results: Cell source was bone marrow in five patients and peripheral stem cells in one, all from fully HLA-matched related donors, including four who were TYMP mutation carriers. Four of six (66%) survived compared to the 37% survival rate in the literature. Reduced intensity conditioning regimen contributed to secondary graft failure in 2 patients. 15 years post-HSCT the first transplanted patient is seemingly cured. Severe GI symptoms pre-transplantation were mostly irreversible and a poor prognostic factor. Conclusions: Allogenic HSCT could constitute a curative therapeutic option for carefully selected, young, pre-symptomatic or mildly affected patients. Timing, donor selection and optimal conditioning protocol are major determinants of outcome. HSCT is inadvisable in patients with advanced MNGIE disease.

Objective: Cytokine storms are central to the development of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Previous studies showed that single nucleotide polymorphisms (SNPs) of cytokine genes may be associated with the development of EBV-HLH in children. We investigated the associations between SNPs and haplotypes of interleukin-2 receptor subunit alpha (IL2RA), interleukin-10 (IL-10), interferon gamma (IFN-γ), IFN regulatory factor 5 (IRF5), and C-C chemokine receptor 2 (CCR2) and susceptibility to EBV-HLH in children. Methods: 66 children with EBV-HLH and 58 healthy EBV-seropositive controls were enrolled in the study. SNPs of IL2RA rs2104286, rs12722489, and rs11594656, IL-10 rs1800896, rs1800871, and rs1800872, IFN-γ rs2430561, IRF5 rs2004640, and CCR2 rs1799864 were assayed and genotyped using the SNaPshot technique. Results: The frequencies of the AA genotype and A allele of IL2RA rs2104286 and IL-10 rs1800896, and the CC genotype and C allele of IL-10 rs1800872 were significantly higher in the EBV-HLH group compared with those in the control group, respectively. The frequencies of genotypes and alleles of IL2RA rs2104286, IL-10 rs1800871, IFN-γ rs2430561, IRF5 rs2004640, and CCR2 rs1799864 were similar in both groups. In addition, the IL2RA AGT (rs2104286-rs12722489-rs11594656) and IL-10 ACC (rs1800896-rs1800871-rs1800872) haplotypes were also significantly more frequent in the EBV-HLH group. Conclusions: The SNPs of IL2RA rs2104286, IL-10 rs1800896 and rs1800872 and the haplotypes of IL2RA AGT and IL-10 ACC are highly associated with susceptibility to EBV-HLH in children.

Abstract: Background. Doxorubicin chemotherapy drug , use is limited by it’s potential to cause cardiotoxicity. In resource poor settings, like Malawi, monitoring of doxorubicin cardiotoxicity is not routinely conducted in cancer patients and the incidence of doxorubicin cardiotoxicity is not known. Methods. Children aged 3 months to 18 years with cancer were prospectively enrolled from the paediatric oncology ward and followed up from January 2016 to June 2019. Transthoracic echocardiographic monitoring of left ventricular ejection fraction (LVEF) was done at baseline, one month, six months and a year after completion of therapy. Cardiotoxicity was defined as a decline in LVEF of ≥10% to a final value of <50%, and an overall incidence risk of developing cardiotoxicity was estimated. A one-way analysis of variance was conducted to compare baseline LVEF with that measured during follow up intervals. Findings. A total of 91 children were enrolled into the study, 74% (68/91) were male, and 67% (62/91) were aged 5 months to 14 years. Burkitt lymphoma was diagnosed in 41% (38/91) of the children. No one experienced cardiotoxicity during the study period. However, of 77 children who had at least one follow up, five children 6·54% (95% CI: 2.1-14.5) experienced a reduction in LVEF of >10%, though not to a final value of <50%. No deterioration of systolic function was found among 20 children who had completed follow up. (F= 2·43, p-value=0·07). Interpretation. In this cohort, there were no observed cardiotoxic events associated with doxorubicin administration as per pre-defined criterion

The treatment landscape for cancer therapy has changed drastically over the past decade. Tisagenlecleucel, the first genetically engineered adoptive cellular therapy approved by the United States Food and Drug Administration, has revolutionized this field by demonstrating impressive clinical success in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL). Now three years since its approval, we have gained a deeper understanding on the basic immunobiology and clinical efficacy of this drug. This review will provide an updated summary of the clinical efficacy of tisagenlecleucel in childhood and young adults with r/r B-ALL, common side effects and their associated management strategies, as well as barriers that remain to be addressed in order to realize the maximum potential of this drug.

The incidence of bone marrow metastasis (BMM) in newly diagnosed Ewing sarcoma (ES) is variable across studies. An optimal staging strategy for detecting BMM is not defined. While BM biopsy and/or aspirate (BMBA) have been the gold standard, [F-18]fluorodeoxyglucose positron emission tomography (FDG-PET) to detect BM metastasis may decrease reliance on BMBA. We conducted a systematic review to assess incidence of BMM and the role of FDG-PET. We observed a pooled incidence by BMBA of BMM of 4.8% in all newly diagnosed ES patients and 17.5% among patients with metastatic disease. Only 1.2% of patients had BMM as their sole metastatic site. FDG-PET detection of BMM compared to BMBA demonstrated pooled 100% sensitivity and 96% specificity, positive predictive value of 75% and negative predictive value of 100%. In the era of FDG-PET imaging, omission of BMBA may be considered in patients with otherwise localized disease after initial staging studies.

Background Pediatric anticancer drug development has numerous challenges. The PREA and the BPCA were passed to address the deficiency in pediatric drug development in general. Until recently, the requirement for pediatric evaluation of most oncology products has been waived, because children typically do not have the same type of cancers which occur commonly in adults or the indication or drug had been granted orphan designation. PREA therefore had no impact. Pediatric studies for labeling updates are largely done through BPCA by a Written Request, issued by FDA. Because pediatric and adult populations do not share the same biology, natural history, or disease progression, there are limited opportunities to extrapolate adult efficacy and safety to the pediatric population. The requirements for the pediatric studies have varied greatly over time. Procedure In this study, we searched WRs that were issued by the FDA since 2001. We found 40 such requests issued for oncology drugs and biologics which had been accepted by sponsors. Results Clinical trials included in 23 of the WRs have been concluded, 19 have resulted in exclusivity, and 3 drugs that were studied have been approved for use in pediatric populations. Herein we present the spectrum of WRs from a regulatory, study design, dosing, formulation, analysis plan, evidential standard of efficacy and safety perspective. Conclusions This provides information on requests in the past nearly 20 years and studies completed. As WRs are the anchor of pediatric cancer development for the time being, this can potentially provide insight on how pediatric cancer drug development may change in the future.

There is no question that developing new medications in children is fraught with challenges, particularly for rare conditions including pediatric venous thromboembolism (VTE). This is due to both logistical and ethical considerations which are nicely described in a document on the Food & Drug Administration (FDA) website.[1] Furthermore, gaining an approval from the FDA for pediatric use requires a functional partnership between pharmaceutical companies (Pharma), academia, and the regulators/officers at the FDA. When this relationship works well, novel agents can be made available to children that have the assurance of efficacy and safety which is in the best interest of all involved parties, especially patients. The licensure of emicizumab for the prevention of bleeding in hemophilia A patients is one excellent example in which a serious unmet need for a rare disease was addressed in a timely manner (~18 months from the start of a phase 3 trial to approval), and where the labelled indication even includes the word “newborn” with respect to the included age groups. [2,3]Unfortunately, this is not the case with respect to anticoagulants in children, and there is plenty of blame to go around including Pharma, academia (myself included), but also the FDA. I know this all too well as I have had a front seat view having served as an advisor to the FDA on this very topic in 2011 as well as on several other occasions involving specific discussions regarding fondaparinux and rivaroxaban. Although the authors and investigators of this report [4] are to be commended for the significant effort it took to achieve an FDA-approved indication, one can’t help but feel that with respect at least to injectable anticoagulants that “the ship has sailed.” What do I mean by this? Enoxaparin is the most commonly used low molecular weight heparin (LMWH) and anticoagulant in children with fondaparinux also gaining more use with the prime advantage being that it is a once-a-day option. Despite dalteparin (a less commonly used LMWH) now being licensed for children [5], I doubt it will ever supersede enoxaparin in prescriptions nor does it have the advantages of fondaparinux, particularly once daily dosing.How did we arrive at such an unenviable situation? Certainly, it is nobody’s fault that enoxaparin does not have a pediatric indication—the author’s clearly explained the fact that enoxaparin came to the market prior to the Pediatric Research Equity Act (PREA), and at this point, despite the sheer volume of data on the pediatric use of enoxaparin, it will likely never be licensed for children. This is not the case, however, for fondaparinux which has been in regulatory limbo with respect to pediatric use for nearly 15 years. This, despite the fact that there is more published data on fondaparinux than dalteparin including a similarly (to dalteparin) designed, prospective, dose-finding, pharmacokinetic, efficacy and safety study [6-8], and the fact that the Pharma companies (the compound has changed hands a few times) have been in discussions with the FDA repeatedly. Unlike with dalteparin, the FDA has placed numerous and pointless hurdles upon the responsible Pharma for capricious reasons succeeding only in potentially putting children at increased risk of harm by, for example, requiring a dose-finding study when the dose of fondaparinux is already well-established. This is the antithesis of what the FDA should be doing. This unending process of which I have played a significant part as an academician has been nothing short of befuddling. While the FDA clearly went to great lengths to work with the sponsor to have dalteparin approved for children, they owe the pediatric hematology community an explanation on what has gone so wrong with fondaparinux.So, where does this leave us currently and what would I recommend pediatric hematologists do with the data from this report [4] and the licensure of dalteparin for children? Importantly, off-label use in the pediatric setting is quite common typically ranging around 50% depending on the setting [9] so there is no need for any pediatric treater to fret over prescribing anticoagulants as such. Thus, if you are comfortable using enoxaparin or fondaparinux based on the available data, the collective pediatric experience and your personal experience, then I would advocate that you continue to do so until there are better options (more on that later). If, however, you prefer to prescribe medications per the prescribing information (to the extent possible) and you find the data from this study compelling, then certainly you may choose dalteparin as your anticoagulant of choice for your pediatric patients with VTE.Above I discussed the current situation, however on a strongly positive note, there has been outstanding cooperation between Pharma, academicians and the FDA when it comes to the development of the direct oral anticoagulants (DOACs) which without a doubt will dramatically change the management of pediatric VTE. While I have been privy to discussions with the FDA regarding rivaroxaban and have served on the steering committee for the rivaroxaban and edoxaban studies, I am also aware of the productive discussions with respect to dabigatran and apixaban. This trilateral collaboration is the epitome of what PREA is for, and in the coming year or two, it is highly likely that several DOACs will be licensed for use in children and will also lead to the availability of pediatric-friendly formulations.In conclusion, the approval of dalteparin is on the one hand far too little and too late to be of any meaningful clinical use, yet it does set an example of what fruitful pediatric drug development can look like in hematology/oncology (and other specialties as well) particularly for rare diseases. It is incumbent upon the academic community not to request, but in fact to demand that Pharma fund proper studies (not just ones that “check the box”), and that the FDA review data in a fair and reasonable manner such that the future will be filled with more examples like dalteparin and fewer debacles like fondaparinux.Referenceshttps://www.fda.gov/drugs/drug-information-consumers/drug-research-and-children [Accessed September 9, 2020]Young G, Liesner R, Chang , Sidonio R, Oldenburg J, Jimenez-Yuste V, Mahlangu J, Kruse-Jarres R, Wang M, Uguen M, Doral MY, Wright LY, Schmitt C, Levy GG, Shima M, Mancuso ME. A multicenter, open-label, phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019; 134: 2127-2138.https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf [Accessed September 9, 2020]Merino M, Richardson N, Reaman G, Ande A, Zvada S, Liu C, Hariharan S, De Claro A, Farrell A, Pazdur R. FDA approval summary: Dalteparin for the treatment of venous thromboembolism in pediatric patients. Pediatr Blood Cancer 2020 (in press).https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020287s072lbl.pdf [Accessed September 9, 2020]Young G, Yee DL, O’Brien SH, Khanna R, Barbour A, Nugent DJ. FondaKIDS: A prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age. Pediatr Blood Cancer 2011; 57: 1049-1054.Ko RH, Michieli C, Lira JL, Young G. FondaKIDS II: Long-term follow-up data of children receiving fondaparinux for treatment of venous thromboembolic events. Thromb Res 2014; 134: 643-647.Shen X, Wile R, Young G. FondaKIDS III: A long-term retrospective cohort study of fondaparinux for treatment of venous thromboembolism in children. Pediatr Blood Cancer 2020; 67:e28295.Yackey K, Stukus K, Cohen D, Kline D, Zhao S, Stanley R. Off-label prescribing practices in pediatrics: An update. Hosp Pediatr 2019; 9:186-193.

We studied the psychosocial impact of the start of the COVID-19 pandemic on Dutch children with cancer in outpatient care and their caregivers (n=799) using regular monitoring and screening outcomes. No differences were observed between the pre-COVID-19 and COVID-19 era in health-related quality of life and fatigue of children. Fewer caregivers were distressed during the COVID-19 era than pre-COVID-19. In conclusion, the additional stress of COVID-19 did not deteriorate psychosocial functioning of children with cancer and their caregivers. Results may be explained by alleviating daily life changes, experience in coping with medical traumatic stress and appropriate care and support.

Background: The quantitative assessment of neuroblastoma cell content in bone marrow aspirates for response evaluation has been introduced recently. Data on the concordance of interobserver reports are lacking so far. Methods: Investigators of seven European countries representing national reference or large oncological centres convened in 2016. They agreed to quantitatively assess routine bone marrow smears of the participating institutions and to discuss the discrepant results in joint meetings. Results From 2017 through 2019, three cytology rounds with 24, 28, and 28 bone marrow samples were run evaluating the representativity of the smears (yes/(restricted)/no) and the presence of tumors cells (yes/no and %). The comparison of the reports using κ (Fleiss) and α (Krippendorff) statistics demonstrated no robust reliabilities. The agreement on the representativity was moderate to poor, on the presence of tumor cells moderate to good and on the percentage of tumor cells slight to moderate. Though the unquestioned value of cytology to detect even tiny metastatic cells in bone marrow, the investigators unanimously agreed that a reliable quantification of the tumor cell content in bone marrow smears is unrealistic. For the key issue of representativity, a new practical definition was developed. Conclusion For any work with bone marrow aspirates the representativity of the material is of paramount importance. A practical definition is proposed. A reliable quantitative cytological assessment of tumor cell content in bone marrow aspirates is not feasible in metastatic neuroblastoma. Therefore its use as response criterion should be re-considered.

Bone marrow necrosis (BMN) is a rare pathologic finding, but when encountered is most often associated with malignancy. In adults its presence correlates with an inferior prognosis, however in children the prognostic implication is unclear. We performed a retrospective review of 3,760 bone marrow specimens in patients ≤ 18 years over a ten-year period. BMN was identified in less than 1% of specimens and only in patients with leukemia, lymphoma or neuroblastoma. BMN contributed to a delay in diagnosis; however, advanced medical imaging may serve as a tool to localize non-necrotic areas for bone marrow sampling, facilitating an expedited diagnosis.

To the Editor,We read the letter entitled “Acute lymphoblastic leukemia onset in a 3-year-old child with COVID-19 ” by Marcia et al . with great interest and we hereby suggest to start chemotherapy within the same timeline as for non-COVID-19 acute lymphoblastic leukemia (ALL) patients, following our experience managing a 3-year-old boy with concomitant diagnoses of precursor B-ALL and COVID-19. The patient was a previously healthy boy who presented to our hospital with a two-month history of intermittent fevers, night sweats, fatigue and cervical lymphadenopathies. His mother had been tested positive for COVID-19 three months earlier. He had been seen by his family physician by teleconference at the onset of his symptoms, at which point a COVID-19 infection was suspected but not confirmed. The persistence of symptoms and new onset of bone pain led his parents to reconsult at our hospital. At presentation, he had no respiratory symptoms. Physical examination was remarkable for fever, tachycardia and cervical lymphadenopathies. Bloodwork revealed pancytopenia and circulating peripheral blasts. Inflammatory markers were elevated (fibrinogen 7.08 g/L; C-reactive protein 255 mg/L; sedimentation rate 63 mm/h; ferritin 185 ug/L; D-dimers 0.51 ug/ml). Capillary gas, renal function, hepatic function, coagulation studies (INR/aPTT) and cardiac biomarkers (troponin and pro-BNP) were normal. Chest radiograph (CXR) was normal. COVID-19 testing by nasopharyngeal swab was positive. Bone marrow aspiration revealed 80% precursor B lymphoblasts of hyperdiploid subtype.Patient was admitted to a dedicated COVID-19 ward. Given the absence of SARS-CoV-2 infection’s severity criteria, no COVID-19-specific treatment was initiated. Chemotherapy was started promptly once the diagnostic work-up was completed, 6 days following the patient’s confirmed COVID-19 diagnosis. The patient was treated with a three-drug chemotherapy induction based on National Cancer Institute standard-risk criteria consisting of methylprednisolone, vincristine and asparaginase. Supportive treatment consisted of intravenous hydration and allopurinol for tumor lysis prevention, empirical antibiotics, blood transfusions and prophylactic low molecular weight heparin for COVID-19-associated thromboembolic complications. The patient’s clinical course was favorable; fevers, bone pains, peripheral blasts and inflammatory markers resolved quickly following the steroid prophase. Persistent and unexplained tachycardia led to extensive investigations given concerns for COVID-19-related thromboembolic complications. Troponins, pro-BNP, electrocardiogram, echocardiography, CXR and chest CT scan were unremarkable, and the tachycardia improved with packed red blood cell transfusion. The first negative COVID-19 test was obtained on day 4 of induction therapy but came back positive 48 hours later. The patient was discharged on day 13 of induction therapy. Three consecutive nasopharyngeal swabs were negative on days 21, 23 and 38 following COVID-19 diagnosis (Fig.1). End-induction bone marrow aspiration was consistent with morphologic remission and end-induction minimal residual disease by flow cytometry was positive at 0.025%.This case demonstrates the feasibility of treating children with newly diagnosed ALL who tested positive for COVID-19, without chemotherapy delay or modification, nor specific COVID-19 treatments, as done by Marcia et al . The province of Quebec constitutes the COVID-19 epicenter in Canada with half of all Canadian cases; the prevalence of COVID-19-positive cases was 3.3% among children under the age of 10, 5.3% between the age of 10-20 years and 49.2% for people aged 50 years and above.1 Importantly, no death has been reported among children in the province of Quebec, while 97.6% of COVID-related deaths were among individuals over the age of 60 years.1 Children appear to be less affected from COVID-19 infection and exhibit a milder disease course compared to adults, although the impact of COVID-19 infection among pediatric oncology patients remains unknown.2-4 Current published recommendations in the management of pediatric oncology patients during the COVID-19 pandemic emphasize on the importance of pursuing protocol-prescribed chemotherapy regimens based on the curable nature of most pediatric malignancies and the milder COVID-19 disease course observed in the pediatric population.4 However, case reports of severe COVID-19 disease in pediatric oncology patients start to emerge,5 and management of concomitant COVID-19 infection and newly diagnosed ALL can be challenging. First, our patient presented with a multisystem inflammatory syndrome which made it difficult to discern whether he was symptomatic from the COVID-19 infection versus the leukemia itself. Furthermore, we questioned whether the positive COVID-19 test by polymerase chain reaction (PCR) amplification in our patient truly reflects active infection since there was a nearly 3-month period between the first positive test in his family and when our patient was first tested positive. The positive PCR test could result from prolonged viral shedding in an immunocompromised patient affected by his leukemia onset. Alternatively, a positive test does not necessarily indicate the presence of viable virus as Wolfel and colleagues demonstrated that virus could not be grown from samples obtained from hospitalized patients beyond the eighth day of illness.6 Therefore, the general approach to await a negative result prior to begin chemotherapy might cause significant therapy delay and adversely impact outcomes in newly diagnosed ALL patients during the COVID-19 pandemic. Indeed, our patient took over 23 days to have 2 consecutive negative PCR tests 48 hours apart. Furthermore, the use of COVID-19-specific antiviral treatment in non-critically ill children is controversial given the lack of efficacy in this population.7Antiviral treatment may have significant drug interactions with chemotherapy and contribute to additive gastrointestinal and myelosuppressive toxicities. Nevertheless, the benefit of dexamethasone in COVID-19-positive patients requiring respiratory support in reducing early mortality8 and the exquisite sensitivity of lymphoblasts to corticosteroids could be an effective early strategy to safely initiate therapy in newly diagnosed ALL patients affected with COVID-19, particularly for those presenting with oncologic emergencies such as hyperleukocytosis or mediastinal mass. As the COVID-19 pandemic continues to evolve, pediatric oncologists will be confronted with the ongoing challenge to manage newly diagnosed cancer patients with concomitant COVID-19 infection. International COVID-19 registries in pediatric oncology are actively collecting clinical data to comprehensively assess the impact of COVID-19 within this patient population and to develop standardized management guidelines.9 As for now, an assessment of risks and benefits to initiate or delay cancer therapy will need to be carefully balanced on a case-by-case basis according to the patient’s clinical symptoms, type of malignancy, evidence-based treatment options, and emerging knowledge of COVID-19’s impact in our young cancer patients.CONFLICT OF INTEREST: The authors declare no conflict of interest.REFERENCES1. INSPQ. Données COVID-190 au Québec. 2020.2. Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663-1665.3. Cruz AT, Zeichner SL. COVID-19 in Children: Initial Characterization of the Pediatric Disease. Pediatrics. 2020;145(6).4. Bouffet E, Challinor J, Sullivan M, Biondi A, Rodriguez-Galindo C, Pritchard-Jones K. Early advice on managing children with cancer during the COVID-19 pandemic and a call for sharing experiences. Pediatr Blood Cancer. 2020;67(7):e28327.5. Stokes CL, Patel PA, Sabnis HS, Mitchell SG, Yildirim IB, Pauly MG. Severe COVID-19 disease in two pediatric oncology patients.Pediatr Blood Cancer. 2020;67(9):e28432.6. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature.2020;581(7809):465-469.7. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc. 2020.8. Group RC, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020.9. Sullivan M, Bouffet E, Rodriguez-Galindo C, et al. The COVID-19 pandemic: A rapid global response for children with cancer from SIOP, COG, SIOP-E, SIOP-PODC, IPSO, PROS, CCI, and St Jude Global.Pediatr Blood Cancer. 2020;67(7):e28409.Figure 1. Variation of C-reactive protein (CRP) throughout the hospitalization course (blue line). COVID-19 test results are identified in green when positive and red when negative. The day of ALL diagnosis, the day of chemotherapy start (black arrows), the duration of hospitalization (red box) and the duration of symptoms (green box) are indicated. Induction chemotherapy includes: Methylprednisone/prednisone (Day 1-32), Vincristine (Day 4, 11, 18, 25), PEG-Asparaginase (Day 7) and intrathecal cytarabine (Day 1 & 18).

Jones et al. have given us an excellent guide for the management of symptomatic osteonecrosis in children and young adults with ALL. (1) I would like to present our 10 year retrospective concurrent control evaluation of pamidronate for reducing the incidence of symptomatic osteonecrosis which may be of interest.Patients aged 10-28 years at time of ALL diagnosis were given intravenous pamidronate (1 mg/kg IV over 2 hours) monthly for one year at the discretion of the primary oncologist, starting as early as possible after diagnosis.Concurrent controls age 10-28 did not receive pamidronate. All were treated according to the concurrent COG protocols with intermittent dexamethasone during delayed intensification.(2) Imaging was performed if osteonecrosis was suspected based on symptoms. Patients with BCR-ABL ALL were excluded, as dasatinib may increase the risk of osteonecrosis. (3,4)Patients were diagnosed between January 2010 and March 2018. They were censored at relapse (n=4; 2 controls) bone marrow transplant (n=4; 3 controls) or at last follow up. Data was analyzed 6/1/2020. The median follow up is 3.3 years from diagnosis to event or censoring. This retrospective study was approved by Children’s Minnesota IRB. Data was entered into excel and transferred to SPSS version 23 for analysis.There were 65 patients, 38 males, 27 females, of which 49 had B-lineage and 16 T-lineage ALL. Pamidronate was started during induction in 63% of patients, and before delayed intensification in 85%. The mean, median and interquartile range for the number of pamidronate doses was 11.6, 12, 10.8 to 12. Pamidronate was used in 26 patients, with four subsequently developing symptomatic osteonecrosis. There were 39 concurrent controls who did not receive pamidronate with 14 developing osteonecrosis. Five from this group have since received joint replacements. There were no short or long term side-effects from pamidronate infusions including osteonecrosis of the jaw or hypocalcemia.The incidence of symptomatic osteonecrosis by Kaplan-Meier analysis with was 16% with pamidronate vs. 39% in controls (figure 1). P-value is significant at 0.043 (Breslow Generalized Wilcoxan). There was no significant difference in the leukemia lineage, gender distribution or Body Mass Index (BMI) at diagnosis between groups. For all patients the mean, median, and interquartile range for BMI was 25.8; 22.0; 14.2 to 28.8 Kg/m2.The age at diagnosis was significantly greater in the pamidronate group with a mean, median and Interquartile range 18.4; 18.6; 13.8 to 23.4 years for pamidronate patients vs. 15.6; 15.7; 11.5 to 19.9 in concurrent controls (independent means t-test p = 0.01). Age was not significant for osteonecrosis in Cox Proportional Hazard analysis (p=0.10).Study limitations include small numbers of patients from a single institution and lack of a randomized control group. Strengths of the study are the long duration of followup, as most of the patients are beyond the peak risk time for osteonecrosis. We hope these results even with its limitations would spark interest in a randomized trial of pamidronate in patients at high risk of symptomatic osteonecrosis.Author Contributions and Disclosures: Bruce Bostrom was the sole contributor to this submission and has no conflict-of-interest to disclose. Jack Knutson assisted with data collection as part of a high school senior mentor connection project. Char Bostrom provided invaluable editorial assistance.Figure 1 legend : Incidence of symptomatic osteonecrosis from time of ALL diagnosis in patients who received prophylactic pamidronate and concurrent controls.

Introduction. Mutations of the APC (adenomatous polyposis coli) gene correlate mainly with familial adenomatous polyposis (FAP), but can occasionally be pathogenic for medulloblastoma (MBL) WNT subtype as well, the course of which has only recently been described. Methods. We retrospectively retrieved all patients with documented germline APC mutations and a centrally-reviewed diagnosis of MBL to examine the outcome of their MBL, late effects of its treatment, and further oncological events. Results. Between 2007-2016 we diagnosed and treated 6 patients, all with a pathogenic APC variant mutation, who all had MBL, classic histotype. None had metastatic disease. All patients were in complete remission a median 65 months after treatment with craniospinal irradiation at 23.4 Gy, plus a boost on the posterior fossa/tumor bed up to 54 Gy, followed by cisplatin/carboplatin, lomustine and vincristine for a maximum of 8 courses. Five of 6 diagnostic revised MRI were suggestive of the WNT molecular subgroup typical aspects. Four of 6 patients had a positive family history of FAP, while gastrointestinal symptoms prompted its identification in the other 2 cases. Four patients had developed other tumors (desmoid, MELTUMP, melanoma, pancreatoblastoma, thyroid Tir3) from 5 to 7 years after MBL. Discussion. Our data confirm a good prognosis for patients with MBL associated with FAP. Patients’ secondary tumors may or may not be related to their syndrome or treatment, but warrant adequate attention when planning shared guidelines for these patients.

Pediatric oncology is justifiably proud of its long tradition of multi-institutional collaboration in clinical research. Perhaps no other field of medicine has more effectively shown what can be achieved by pooling talent and resources to study challenging diseases. Historically, most collaborative projects were limited to a single country or continent. However, more progress comes from even broader international cooperation. With rare cancers, this may be the only way to gather sufficient patient numbers to address key questions. Sharing national experiences can also lead to a deeper understanding of the advantages and risks associated with different therapeutic approaches. The first steps to increased global cooperation, however, is agreeing on a common language to describe patient cohorts and consensus standards to guide diagnosis, evaluation, and treatment. Applying these lofting goals to pediatric soft tissue sarcomas, the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) was born.From its initial formative meeting in May 2017, INSTRuCT has patterned its structure and purpose on the successful model of the International Neuroblastoma Risk Group (INRG).1,2 The membership of INSTRuCT is composed of three large cooperative clinical trials organizations: Children’s Oncology Group (COG), Cooperative Weichteilsarkom Studiengruppe (CWS), and European paediatric Soft tissue sarcoma Study Group (EpSSG). The first goal for INSTRuCT is to develop an international risk stratification system for rhabdomyosarcoma (RMS) to replace competing systems used in Europe and North America. A common RMS risk stratification system would facilitate the comparison of clinical trial results across cooperative groups. Before generating a RMS risk stratification system, INSTRuCT agreed upon a standard RMS data dictionary, leveraging the University of Chicago’s Pediatric Cancer Data Commons expertise in data standardization.3 The compilation of COG, CWS, and EpSSG data (and data from their legacy groups) from finished studies into a single INSTRuCT dataset is nearly complete, and will include more than 7000 patients enrolled on previous RMS clinical trials. Once the RMS risk stratification project is finished, INSTRuCT will mine its dataset for answers to questions that can only be addressed with large, well-annotated clinical data. Future work will also include expanding the RMS data dictionary and adding a non-RMS soft tissue sarcoma dataset, also drawn from COG, CWS, and EpSSG clinical trials.As the multi-disciplinary members of INSTRuCT were defining their RMS data dictionary, they realized they had the opportunity to develop international consensus statements on the diagnosis, evaluation, and management of pediatric soft tissue sarcomas. Clinical trial protocols include guidelines for pathologic diagnosis, imaging staging evaluation, and local control approaches with surgery and radiation therapy varied by primary anatomic site. INSTRuCT provided the forum for international discussion and consensus building, with the goal of publishing these expert opinions for broad dissemination and use by pediatric oncologists, surgeons, radiation oncologists, radiologists, and pathologists worldwide. In this issue of Pediatric Blood & Cancer, Morris et al. publish the one of first in a series of consensus statements from INSTRuCT, focusing on the surgical management in the diagnosis and local control of RMS arising in the extremity.4 Morris et al. outline recommended biopsy approaches, the rational for routine use of regional lymph node evaluation including the role of fluorodeoxyglucose positron emission tomography, and the decision-making behind up-front versus delayed primary excision. The recommendations are guided by the principles of maximizing oncologic outcome while maintaining extremity function. Given the rarity of extremity RMS and the absence of randomized trials comparing different management strategies, Morris et al. draw upon a combination of clinical data and expert opinion in their consensus guidelines, carefully documenting the level of evidence that supports each of their recommendations. Nonetheless, these guidelines represent the current state of the art for surgical management of extremity RMS and the basis for future clinical trial recommendations. A similar consensus statement on RMS of the female genital tract has also been published in Pediatric Blood & Cancer, by Lautz et al.5 With these two consensus statements, the INSTRuCTPediatric Blood & Cancer special series is off to an excellent start, with manuscripts on the surgical management for other primary sites and the pathologic evaluation of RMS to follow soon. As INSTRuCT co-chairs, we are pleased to introduce INSTRuCT to the global pediatric oncology community and look forward to many more contributions to come.

Ketamine is a dissociative anesthetic agent, with excellent analgesic properties and a favorable safety profile. Although it acts predominantly through NMDA receptor antagonism, numerous other molecular targets have been characterized, rendering anti-inflammatory, anti-depressant, and thus expanding its scope for new clinical applications. The noticeable safety of ketamine in children enables its widespread use in pediatric oncology, chiefly for procedural sedation. Its value for chronic pain management in children with cancer is being increasingly recognized but requires more evidence. The topical use of ketamine is largely in investigational stages.. Rational medical use of ketamine is largely free from significant long-term neurological side effects but may have some troublesome short-term effects such as vomiting, palpitations, urinary retention, and hallucinations. This review will provide a brief account of the pharmacology of ketamine and primarily focus on the relevant aspects of ketamine in pediatric oncology.

BACKGROUND Despite improvements in overall survival for pediatric cancers, treatment disparities remain for racial/ethnic minorities compared to non-Hispanic white; however, the impact of race on treatment outcomes for pediatric brain and central nervous system (CNS) tumors in the United States is not well known. METHODS We included 8713 children aged 0 – 19 years with newly diagnosed primary brain and CNS tumors between 2000 – 2015 from the Census Tract-level SES and Rurality Database developed by Surveillance, Epidemiology and End Results Program. We used Chi-square tests to assess differences in sociodemographic, cancer, and treatment characteristics by race/ethnicity and Kaplan–Meier curves and Cox proportional hazards models to examine differences in 10-year survival, adjusting for these characteristics. RESULTS Among 8,713 patients, 56.75% were non-Hispanic white, 9.59% non-Hispanic black, 25.46% Hispanic, and 8.19% from “other” racial/ethnic groups. Median unadjusted survival for all pediatric brain tumors was 53 months but varied significantly by race/ethnicity with a median survival of 62 months for Non-Hispanic whites, 41 months for Non-Hispanic blacks, and 40 months for Hispanic and Other. Multivariable analyses demonstrated minority racial groups still had significantly higher hazard of death than non-Hispanic whites; Hispanic [aHR 1.25 (1.18 - 1.31)]; non-Hispanic black [aHR 1.12(1.04 - 1.21)]; Other [aHR 1.22(1.12 - 1.32)]. Results were consistent when stratified by tumor histology. CONCLUSION We identified disparities in survival among racial/ethnic minorities with pediatric brain and CNS tumors, with Hispanic patients having the highest risk of mortality. Eliminating these disparities requires commitment towards promoting heath equity and personalized cancer treatment.

A document by Denis Cozzi. Click on the document to view its contents.

Background. Adolescents/young adults (AYAs) with acute lymphoblastic leukemia (ALL) are more likely to have chemotherapy-related complications than children. In addition, several reports have shown that infections account for most of the therapy-related mortality during cancer treatment in AYAs. Thus, we hypothesized that chemotherapy-induced myelosuppression is more severe in AYAs than in children, and the state of neutropenia was compared between children and AYAs using the D-index, a numerical value calculated from the duration and depth of neutropenia. Procedure. This study retrospectively analyzed 95 patients newly diagnosed with ALL at our institution between 2007 and 2019. Of these, 81 were children (< 15 years old) and 14 were AYAs (≥ 15 years old). The D-index and duration of neutropenia during induction chemotherapy for ALL were compared between children and AYAs. Results. The median D-index of children was significantly higher than that of AYAs (8,187 vs. 6,446, respectively, P = 0.017). Moreover, the median duration of neutropenia was also significantly longer in children than in AYAs (24.0 days vs. 11.5 days, respectively, P = 0.007). Conclusion. Contrary to our expectations, myelosuppressive toxicity during induction chemotherapy for ALL was more severe in children than in AYAs.