Calcineurin inhibitors (CNI), cyclosporine and tacrolimus, are commonly used for pharmacotherapeutic prophylaxis of Graft-vs.-Host disease after hematopoietic cell transplantation (HCT). Unfortunately, their use is associated with significant toxicities. While intolerance to CNI is well defined, there is very little data on how they impact outcomes after HCT in children. Our retrospective study in a cohort of 82 children, shows a high intolerance rate of 39% in this population associated with lower event free survival and a higher transplant-related mortality.

Comment on: Secondary impacts of constipation in acute lymphoblastic leukemia in U.S. children’s hospitalsRameez Naqvi1, Saif Abbas Chatoo2, Zayn Ahmad31 UCL Medical School2 Cardiff School of Medicine3 Barts and The London School of Medicine and Dentistry* Correspondence to:Rameez Naqvi, UCL Medical School, 74 Huntley St, London WC1E 6DE, Tel.: 07851081725, Email: [email protected] word count 493;Abstract word count: N/A;Brief running title: Letter to the EditorKey words: Chemotherapy, ALL, Pediatric oncologyTables: 0Figures: 0We read, with great interest, the article by Belsky et al. on the effects of constipation in pediatric oncology patients, particularly looking at children who had undergone induction therapy for Acute Lymphoblastic Leukemia (ALL)1. As medical students who have recently had pediatric and oncology placements, we would like to share our thoughts on what we found to be a fascinating topic.The process of diagnosing and treating a child with cancer is an extremely distressing period for the patient and parent/carer of the patient. The majority of parents of pediatric oncology patients are said to be either mildly or severely distressed2. There is also the challenge that lies with the side effects of chemotherapy along with the struggle in communicating with some young children. Due to side effects, patients can present distressed and require hospital admission, under the guise that it is due to their original condition rather than the treatment. We applaud Belsky et al. for including patients who were readmitted in order to seek psychological support for the side effects of their treatment, as this is a factor often overlooked when looking at readmission data.On our placements, the diagnosis of constipation secondary to chemotherapy was difficult to navigate. We found that the side effects of the medication, such as constipation or fatigue, can cause some patient families to feel an incongruency with their agenda and the healthcare providers, as some find it difficult to perceive that the treatment can also cause the child pain. This can cause strain on an already difficult relationship to manage3. Although it was beyond the stated scope of this study, this would be an interesting secondary impact of chemotherapy side effects that can be explored in the same demographic of patients.As mentioned by Belsky et al., it can be difficult to attribute the constipation solely to the medication being used. There are a variety of confounding factors that can arise during induction therapy that can also cause constipation – dietary changes due to hospital admission, lack of water intake due to fatigue and lack of energy to exercise, to name a few. To further expand the study, looking into these factors and their magnitude of effect would provide a clearer understanding of the secondary effects of constipation.The study defined constipation by the presence of a diagnosis code or a patient who is receiving two constipation medications. The author recognizes that patients can receive these medications prophylactically, so ideally there should be a method of investigating the indication in these patients. It must also be said that diagnosis coding means that there is an element of human error which can cause inaccuracies in the data collected. This can be seen in some international studies4.Future retrospective studies should consider investigating the confounding factors and authenticating diagnoses in order to provide a more robust causality. Research into the true effects of chemotherapy in Pediatrics is crucial and we hope to see more research within this field.References:Belsky, J., Batra, S., Stanek, J. and O’Brien, S., 2021. Secondary impacts of constipation in acute lymphoblastic leukemia in U.S. children’s hospitals. Pediatric Blood & Cancer ,.Boyden, J., Hill, D., Nye, R., Bona, K., Johnston, E., Hinds, P., Friebert, S., Kang, T., Hays, R., Hall, M., Wolfe, J. and Feudtner, C., 2021. Pediatric palliative care parents’ distress, financial difficulty, and child symptoms. Journal of Pain and Symptom Management ,.Zarkowski, P. and Aksu, M., 2021. Legal and Ethical Issues in Treating Adolescent Patients. Dental Clinics of North America , 65(4), pp.815-826.Farhan, J., Al-Jummaa, S., Al-Rajhi, A., Al-Rayes, H. and Al-Nasser, A., 2005. Documentation and coding of medical records in a tertiary care center: a pilot study. Annals of Saudi Medicine , 25(1), pp.46-49.

The event-free survival of pediatric low-grade gliomas is poor, and patients often require multiple treatment strategies. While MEK and RAF inhibitors are efficacious in early-phase trials, not all patients respond and many experience progression following completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. We report our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system tumors. Two of four patients using this combination therapy experienced severe thromboembolic events necessitating discontinuation of therapy. This combination requires further investigation, and we urge caution if used.

TITLE PAGETitle: Retiring as a Physician during the 2020 Coronavirus PandemicAuthor: Philippa G. Sprinz, MD, MScHasbro Children’s HospitalDivision of Pediatric Hematology/Oncology593 Eddy StProvidence, RI. [email protected] Author: Philippa G. Sprinz, MD, MScHasbro Children’s HospitalDivision of Pediatric Hematology/Oncology593 Eddy StProvidence, RI. [email protected]: (401) 444-5171fax: (401) 444 -8845Main Text Word Count: 1194 wordsNo Tables, Figures or other materialKeywords: Retiring, Pandemic, COVID 19,Congratulations! Well done! Bravo! Our compliments and best wishes! I sat outside, looking up at the night sky trying to make sense of everything. I could not. I had hoped, in the silence of night, that I might be able to find some peace and understanding, something positive to hold on to, some equipoise with where I was at in my life, in the midst of a global pandemic. Unfortunately, the cloud ceiling was too low; there were no stars to be seen, to add perspective to my life. I could not grasp my retirement from clinical practice, at this globally distressing time.My retirement was planned before Covid-19 was a name in the medical lexicon.I thought I had planned appropriately. Our son-in-law matched for his clinical fellowship some 2600 miles away. I was 65 years old, and had had a wonderful career as a pediatric hematologist/oncologist, training in the UK but moving to and practicing in the US for almost 40 years. My new job was going to be to help with grandchildren, so our children could pursue their own medical careers. As I clearly could not work and commute 2600 miles on a regular basis, I reasoned that I should retire from clinical practice.Practicing as a physician has been incredibly satisfying. It has been my identity. It is how I presented myself to my family, colleagues and friends. I have given so much of my life to my work. At the same time, unfortunately, I had not taken the time to develop other skills that were anywhere near as rewarding. I acquired some hobbies: diversions from the responsibilities of helping and supporting ‘my’ patients and colleagues, but not skills to keep my mind or body active when I stopped working. As I contemplated no longer working clinically, I developed an anxiety for ‘my’ patients. I knew I had excellent colleagues to hand my patients on to, but I could not escape the thought that I would be letting my patients down by not continuing to care for them, myself. I argued that I knew their health care needs ‘best’. Only, surely I was doing right by our kids and grandkids by helping them at this time.I found myself thinking over my years in practice. During that time, I saw the five-year survival rate of children with a cancer diagnosis increase from 58% to 86% (1); Hodgkin Lymphoma essentially became straightforwardly curable (5 year survival rate of 99.5% by 2016) (1). Even brain tumors experienced a twenty percent increase in their overall cure rate, (57.2% to 76.3%)(1). For individuals with sickle cell disease (SCD) (my particular area of expertise) the survival gain has been more modest: in the 1970s (ten years before the start of my fellowship) 80% of individuals with SCD died by age 30 years (2). In the 1990s females with sickle cell anemia had an average life expectancy of 48 years and males 42 years (3). Despite these improvements, the care of individuals with SCD still needs new drugs and better curative approaches. Life expectancy, for patients with SCD, is currently 54 years for both sexes (4). This is still signifiantly less than the non-SCD population of 76 years in the US(4). I do, nevertheless, look to the future in my field with optimism. Immunotherapy is in the forefront of cancer care, and sensitive molecular tests are allowing earlier diagnoses and hopefully, more successful treatments. There are a number of new, albeit expensive, drugs now being marketed for SCD. Stem cell transplantation is accepted as a ‘curative’ option for the disease, and gene therapy is not too far in the future.Then February 2020: SARS-CoV-2 arrived in the US. This virus has impacted so many lives in so many ways, in circumstances much, much worse than mine. For me, however, it reformatted my retirement. I could not travel to help our children: borders were closed and international travel all but halted. I would stop work with ‘nothing to do’. I suddenly needed to understand ‘Retirement from being a full time MD’, without a ‘plan B’. I recognised that not having to share life-threatening diagnoses with families, would take a weight off my shoulders. Instead, nonetheless, I would cease to be one of a team working painstakingly to help children and their families understand life-impacting illnesses: to hopefully feel better, for at least some periods of time. Despite sadnesses, ‘pedi heme-onc’ definitely has many rewards. Retirement from it includes the loss of deep family relationships and also daily interactions and stimulating meetings with friends and colleagues.I then wondered: why does one retire when one has a secure job (and no new occupation to move on to), with rewarding work, and a sense of serving ‘the greater good’. This, particularly if one is without ‘burn-out’ that over the years I have watched some of my colleagues experience? Does one really have to retire? A critical aspect of retirement may be to afford practices the opportunity to replenish the workforce with younger, more adaptable workers. Individuals trained recently on newer, clinical approaches and disease management present new skills and may improve efficiency. Does the fact that junior doctors have lesser salaries than those who have been in practice for many years make a difference? Recognising my predicament, I suggested I could help part-time during the pandemic. The coronavirus was not causing so many childhood illnesses, however, to need more pediatric staff and I am no expert in adult medicine.Notwithstanding concerns over my retirement, I did have an excitement to think that my leaving would afford a younger physician the opportunity to take a leading role in patients’ care and eventually have as rewarding a career in pediatric hematology/oncology as I had. So, I took stock: maybe I could volunteer in the community? I reached out to a number of organisations, all of which were very happy to have my help, ‘just not now’, in the middle of a pandemic. I listened in to as many medical and non-medical on-line lectures as I could. I ‘attended’ virtual conferences, easily, regionally and nationally, without any travel, and contributed to ‘Zoom’ teaching at my own institution. I worked for an online publishing company and reviewed manuscripts. I was in touch with ‘everyone’ and tried to support all the vulnerable people I knew.Ten months into the pandemic, nevertheless, I am still struggling to come to terms with not being a clinician. Did I devote too much time to my patients – that could not be? Should I have paid more attention to hobbies and have developed a ‘Plan B’? Probably ‘yes’. Will there be a time, after the pandemic has passed, when again I can contribute to ‘the greater good’ and do more clinical work? Perhaps it is true: ‘once a doctor, always a doctor’. But it is more than that: having spent all of my working days caring for others, with responsibilities of making accurate diagnoses, recommending potentially curative management and providing compassionate care when the cure did not come, I now have to learn a new life: a life of giving back without the rewards of clinical practice.References:SEER (Surveillance, Epidemiology and End Results program,) 2017Platt O et al Mortality in sickle cell disease. Life expectancy and risk factors for early death: N Eng J Med. 1994, Jun 9; 330(23):1639-443) Lanzkron S, Carroll CP, Haywood C Jr. Mortality rates and age at death from sickle cell disease: US, 1979 – 2005. Public Health Rep. 2013; 128: 110-116 4) Lubek et al Estimated Life Expectancy and Income of Patients With Sickle Cell Disease Compared With Those Without Sickle Cell Disease: JAMA Network Open. 2019;2(11):e1915374. doi:10.1001/jamanetworkopen.2019.15374, accessed 12/26/2020

Standard management of pediatric Non-Hodgkin’s Lymphoma (NHL) patients have included an initial assessment of the disease at presentation to establish it’s extent. This “staging” process has historically assigned patients using traditional classifications which were established decades ago when, like other pediatric malignancies, the more extensive involvement of the cancer for a patient directly correlated with the patient’s long term survival[[1]](#ref-0001). Advances in radiologic technology have evolved in the way the disease extent was evaluated, moving from conventional radiographs, to computerized tomography (CT) to magnetic resonance imaging (MRI) to most recently positron emission tomography (PET)[[2]](#ref-0002). Despite the development and use of PET scans for decades for various cancer diagnoses, the role of PET scans for NHL remains unclear[[3]](#ref-0003). Indeed, its value for many conditions is its ability to assess the response to initial therapy and establish the patient’s risk stratification guiding the remaining treatment plan[[4]](#ref-0004). Such efforts have not occurred in clinical trials of NHL and thus we are left to examine case series and try to discern its value for this disease.

Background: Clinical informatics tools to integrate data from multiple sources have the potential to catalyze population health management of childhood cancer survivors at high risk for late heart failure through the implementation of previously validated risk calculators. Methods: The Oklahoma cohort (n=365) harnessed data elements from Passport for Care (PFC) and the Duke cohort (n=274) integrated cancer registry and electronic health record data, using standard query language, to automatically extract chemotherapy exposures for survivors <18 years old at diagnosis. The Childhood Cancer Survivor Study (CCSS) late cardiovascular risk calculator was implemented and risk groups for heart failure were compared to the Children’s Oncology Group (COG) Long-Term Follow-up Guidelines. Results: The Oklahoma and Duke cohorts both observed good overall concordance between the CCSS and COG risk groups for late heart failure with weighted Kappa statistics of 0.70 and 0.75, respectively. Low-risk groups showed excellent concordance (Kappa >0.9). Moderate and high-risk groups showed moderate concordance (Kappa 0.44-0.60 across both cohorts). In the Oklahoma cohort, adolescents at diagnosis were significantly less likely to receive guideline-adherent care for echocardiogram surveillance compared with survivors <13 years old at diagnosis (OR 0.22; 95% CI 0.10-0.49). Conclusions: Clinical informatics tools represent a feasible approach to leverage discrete data elements regarding key treatment exposures from PFC or the EHR to successfully implement previously validated late cardiovascular risk prediction models on a population health level. Real-world evidence on the concordance of CCSS, COG, and IGHG risk groups promises to refine current guidelines and identify inequities in guideline-adherent care.

Treatment for childhood solid tumors may lead to an increased risk for gonadal dysfunction/infertility. Discussion of risk should occur at diagnosis, any changes in therapy, and during survivorship. Gonadotoxic therapies were abstracted from 32 Children’s Oncology Group (COG) phase III, frontline solid tumor protocols, in use from 2000-2022. Risk for gonadal dysfunction/infertility was assessed based on gonadotoxic therapies, sex, and pubertal status and assigned as minimal, significant, and high following the Oncofertility Consortium Pediatric Initiative Network (PIN) risk stratification. Most protocols (65.6%, 21/32) contained at least one therapeutic arm with a high level of increased risk. Solid tumor therapies present challenges in risk stratification due to response-adjusted therapy and the need to account for radiation field in the risk assessment. This guide hopes to serve as a tool to assist in standardizing gonadotoxic risk assessments across disciplines and improve referral for fertility services and reproductive health counseling for patients receiving COG based solid tumor therapy.

OBJECTIVES In the etiology of childhood cancers, many genetic and environmental factors play a role. One of these factors is cigarette smoking and the main source of tobacco smoke exposure of children is parental smoking. However, establishing a causal relationship between parental smoking and childhood cancers has proven challenging due to difficulties in accurately detecting tobacco smoke exposure METHODS To address this issue, we used hair cotinine analysis and a questionnaire to get information about tobacco smoke exposures of pediatric cancer patients and healthy children. 104 pediatric cancer patients and 99 healthy children participated in our study. Parental smoking behaviours (pre-conceptional, during pregnancy and current smoking) and environmental tobacco smoke (ETS) exposures of children are compared. RESULTS We have found no differences between two groups by means of maternal smoking behaviours. However, the rates of paternal pre-conceptional smoking and smoking during pregnancy were significantly low in cancer patients (p<0,05). These data suggests that social desirability bias among fathers of cancer patients may have contributed to this discrepancy. According to questionnaire cancer patients had significantly lower ETS exposures than healthy children (p<0,05). However, ETS exposure assessment through cotinine analysis demonstrated that cancer patients had higher exposure to ETS compared to healthy children (p<0.001). CONCLUSION Our findings provide evidence supporting the potential role of smoking as a risk factor for childhood cancers. This study also revealed that questionnaires could cause biases. We suggest that cotinine analysis along with validated questionnaires can be used to prevent biases in studies of tobacco smoke in the etiology of childhood cancers.

A document by Laila Alkhouli. Click on the document to view its contents.

Title: Vaccine Preventable Illness After Blinatumomab Therapy: A Case ReportAuthors: Katie Voelz MD1,2, Anthony Salvatore DO1, Sudarshawn Damodharan DO1,2 & Cathy Lee-Miller MD1,21Department of Pediatrics, University of Wisconsin School of Medicine & Public Health, Madison, WI, USA2Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, University of Wisconsin School of Medicine & Public Health, Madison, WI, USACorrespondence:Cathy Lee-MillerUniversity of Wisconsin School of Medicine & Public Health1111 Highland Ave, WIMR 4105Madison, WI 53705Email: [email protected] Count: Main Text: 848Manuscript contains 1 TableShort running Title: Vaccine-preventable, ALL, immunotherapyKeywords: Blinatumomab, ALL, vaccination, pediatrics

Background Progressive transformation of germinal centers (PTGC) is a rare diagnosis characterized by asymptomatic lymph node enlargement. It has previously been associated with lymphoma, autoimmune conditions, and lymphoproliferative diseases in small pediatric case series. Procedures We conducted a single-center retrospective review of pediatric cases of PTGC diagnosed at our institution by hematopathologists from 2000 - 2020. Results We identified 57 primary cases and 3 recurrent cases of PTGC. There was a male predominance in cases (32/57), with median age at diagnosis of 11 years. Head and neck lymph nodes were the most commonly involved and biopsied sites. Laboratory and imaging evaluations were obtained inconsistently. Only 16% of patients saw a pediatric hematology/oncology (PHO) specialist prior to diagnosis and 37% had follow-up with PHO after diagnosis. Six patients (10%) had a preceding or concurrent diagnosis of lymphoma and 5% of patients returned with recurrent PTGC. Conclusions Patients with PTGC had similar characteristics to those from previous case series. Fewer patients underwent recurrent lymph node biopsy than previously described. PTGC has been linked to certain types of lymphoma, although never definitively associated with lymphoma. Follow-up with a PHO provider is indicated to ensure that close surveillance is performed.

A document by Denise Adams. Click on the document to view its contents.

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.

Background: Anaplastic large cell lymphoma (ALCL) is an uncommon form of Non-Hodgkin Lymphoma (NHL) in younger patients, accounting for less than 15% of cases. The median age at presentation is 12 years and is exceedingly rare in infants. Various prognostic factors, risk stratification and novel treatment strategies have been studied in pediatric ALCL. There is no separate data available on the disease biology, treatment regimens and prognostic factors among infantile ALCL. Outcomes for infants with ALCL have been reported to be inferior to that of older children. The long-term Event Free Survival (EFS) in general among pediatric patients is approximately 70% regardless of the treatment approach. We report a case of an 8month old infant diagnosed with ALK positive ALCL with visceral organ involvement stratified as high risk and treated according to ALCL 99 protocol with excellent clinical response, on regular follow up and is disease free since 2years.

Children’s Oncology Group’s 2023 Blueprint For ResearchDouglas S. Hawkins,1 Lia Gore2Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WADepartment of Pediatrics, University of Colorado School of Medicine and Center for Cancer and Blood Disorders, Children’s Hospital Colorado,, Aurora, CO

Purpose : To determine whether extent of surgical resection of the primary tumour correlates with survival in patients with International Neuroblastoma Staging System (INSS) stage 4, high-risk neuroblastoma. Methods : Data were extracted for patients with newly diagnosed INSS stage 4, high-risk neuroblastoma between 2001-2019 from the national Cancer in Young People in Canada (CYPC) database. Complete resection was defined as gross total resection of primary tumour based on operative reports. Primary endpoints were 3 and 5-year event-free (EFS) and overall survival (OS). Survival analyses were completed using log-rank test and Cox proportional hazards regression including covariates of age, sex, decade of treatment (2001-2009 vs. 2010-2019), immunotherapy, and tandem stem-cell transplant (SCT). Results : One-hundred and forty patients with complete surgical data were included. On univariate analysis, 3-year EFS and OS for patients that had complete vs. incomplete resection was 71% (95% CI 57-80%) vs. 48% (36-60%) and 86% (75-93%) vs. 64% (51-74%), p=0.008 and p=0.002, respectively. 5-year EFS and OS for patients with complete resection also demonstrated significantly improved survival. On Cox Proportional Hazards models adjusted for age, immunotherapy, tandem SCT and surgical resection, only complete resection was associated with statistically significant improved 3 yr EFS and OS, HR=0.48 (0.29-0.81; p=0.006) and HR=0.42 (0.24-0.73; p=0.002). Conclusions : In a large Canadian INSS stage 4 high-risk neuroblastoma cohort, complete surgical resection was associated with increased EFS and OS. Within the constraints of a retrospective study, these results suggest that the ability to achieve primary tumor complete resection in patients with metastatic high-risk disease is associated with improved survival.

Title: Symptomatic Hyperammonemia Secondary to Recombinant Erwinia AsparaginaseCatherine E. Martin, Pharm.D., Department of Pharmacy – Ambulatory Service, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAMira A. Kohorst, M.D., Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAAsmaa Ferdjallah, M.D., M.P.H, Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAJessica L. Kalmes, APRN, C.N.P., M.S.N, Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAHeather M. Johnson, APRN, C.N.P., M.S.N, Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAPaul J. Galardy, M.D., Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAShakila P. Khan, M.D., Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAAlexis K. Kuhn, Pharm.D., Department of Pharmacy – Ambulatory Service, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USACorresponding author: Catherine E. Martin; address: 200 First Street SW, Rochester, MN 55905; phone: 507-284-2695; fax: 507-266-4912; email: [email protected] text word count: 967Number of tables, figures, and supporting information: NoneShort running title: Hyperammonemia after recombinant Erwinia asparaginaseKeywords: Asparaginase, hyperammonemia, pediatrics, Erwinia, leukemiaAbbreviations

Background: While intravenous fluid (IVF) therapy in patients with sickle cell disease (SCD) admitted for a vaso-occlusive episodes (VOE) can help reduce red blood cell sickling, clinical practice varies across institutions. We examined the relationship between IVF therapy and hospital length of stay (HLOS), as well as adverse events, such as acute chest syndrome (ACS), pediatric intensive care unit (PICU) transfer and 28-day readmission. Methods: This is a single-center retrospective analysis of SCD VOE hospitalizations between January 2015 and April 2020. Patients with SCD, age 0-30, with consecutive hospitalizations for VOE were included. For the first 3 days of each admission, an “IVF ratio” was calculated by dividing actual IVF rate administered by weight-based maintenance IVF (mIVF) rate. Results: A total of 617 hospitalizations for 161 patients were included. Mean HLOS was 5.7 days, (SD 3.9), and mean IVF volume over the first 3 days of admission was 139.6 ml/kg/day (SD 57.8). Multivariate analysis showed that for each additional 0.5 times the mIVF rate, HLOS increased by 0.53 days (P<0.001; 95% CI: 0.609–0.989), but there was no significant association between IVF therapy and adverse events. History of chronic pain was associated with increased odds of readmission (OR, 6.4; 95% CI: 3.93 – 10.52). Conclusions: Despite the theoretical potential for IVF therapy to slow down the sickling process, our findings suggest that increased IVF therapy was associated with prolonged HLOS, which places a burden on patients, families, and the health system.