WHEN BONE PAIN AND BLEEDING MEAN MORE THAN LEUKEMIA:

Background: An effective chemotherapy calendar system between the clinician and the patient/caregiver can improve patient centered outcomes. There is lack of research on how chemotherapy calendars are created and what aspects are important to pediatric oncology providers. Procedure: In an online survey of pediatric oncology providers, we evaluated institutional practices, perceptions of chemotherapy calendar creation, and desires for future tools. 220 survey participants provided data, with a 10.4% response rate. Results: Participants indicated that 72% always or most of the time their institution provides a chemotherapy calendar, most commonly at the start of a new cycle (90%) or with a dosing change (68%). Factors such as the health literacy of the family, prior non-adherence, type of cancer, and desire of the family affected the creation decision. Advanced practice providers (45%) or nurse coordinator/navigators (43%) were most likely to create the calendar. No significant difference was found between the likelihood of creating a calendar and institutional size (p=0.09) or provider years in practice (p=0.26). About 95% of participants indicated chemotherapy calendar creation software that improved ease and efficiency would be moderately to extremely useful. Conclusion: Future efforts should focus on patient and caregiver perspectives of chemotherapy calendar elements and utilization.

Background: Outcomes for children with high-risk renal (HRR) and INI-1-deficient (INI-) tumors are unacceptably poor. Concerns about excessive toxicity – as many are infants and/or undergo nephrectomy – have resulted in decreased chemotherapy dosing and omission of the nephrotoxic drug ifosfamide in collaborative group studies. As cause of death for children with these cancers remains overwhelmingly more from progressive disease rather than treatment toxicity, we examined the tolerability of an intensive ifosfamide-containing-regimen. Procedure: Retrospective review of children with HRR/INI- tumors treated at a single institution with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, carboplatin, etoposide (VDC-ICE) from 2006-2016. The primary outcome was regimen tolerability including kidney injury and grade 3-5 non-hematologic toxicities. Results: Fourteen patients with a median age of 1.7 years (range 0.1-10.5) treated with VDC-ICE were identified. Diagnosis included malignant rhabdoid tumor (n=9) [primary renal (n=2)]; diffuse anaplastic Wilms tumor (n=3); clear cell sarcoma of the kidney (n=1); and anaplastic chordoma (n=1). All children with primary renal tumors (43%) underwent complete (n=5) or partial nephrectomy (n=1) before chemotherapy. Nine (64%) completed all intended cycles of chemotherapy; n=5 (36%) did not due to disease progression. Unplanned hospitalizations occurred in 13 (93%) patients, most commonly for febrile neutropenia. No patient experienced severe organ toxicity, diminished renal function, treatment discontinuation due to toxicities, or treatment-related death. Conclusions: In children with HRR/INI- tumors, VDC-ICE chemotherapy was well-tolerated without excessive toxicities, even amongst young patients with solitary kidneys. Concerns about toxicity should not preclude an intensive ifosfamide-containing regimen from use in future trials in this population.

Introduction Pathophysiologic pathways of sickle cell disease (SCD) and air pollution involve inflammation, oxidative stress, and endothelial damage. It is therefore plausible that children with SCD are especially prone to air pollution’s harmful effects. Methods Patient data were collected from a single center, urban/peri-urban cohort of children with confirmed SCD. Daily ambient concentrations of particulate matter (PM 2.5) were collected via satellite-derived remote-sensing technology, and carbon monoxide (CO), nitrogen dioxide (NO 2), and ozone from local monitoring stations. We used multivariable regression to quantify associations of pollutant levels and daily counts of emergency department (ED) visits, accounting for weather and time trends. For comparison, we quantified the associations of pollutant levels with daily all-patient (non-SCD) ED visits to our center. Results From 2010-2018, there were 17 731 ED visits by 1740 children with SCD (64.8% HbSS/HbSβ 0). Vaso-occlusive events (57.8%), respiratory illness (17.1%), and fever (16.1%) were the most common visit diagnoses. Three-day (lags 0-2) rolling mean PM 2.5 and CO levels were associated with daily ED visits among those with SCD (PM 2.5 incident rate ratio (IRR) 1.051 (95% CI 1.010-1.094) per 9.4 µg/m 3 increase; CO 1.088 (1.045-1.132) per 0.5 ppm). NO 2 showed positive associations in secondary analyses; ozone levels were not associated with ED visits. The comparison, all-patient ED visit analyses showed lower IRR for all pollutants. Conclusions Our results suggest short-term air pollution levels as triggers for SCD events and that children with SCD may be more vulnerable to air pollution than those without SCD. Targeted pollution-avoidance strategies could have significant clinical benefits in this population.

Background: At least 5-10% of malignancies occur secondary to an underlying cancer predisposition syndrome (CPS). For patients with a CPS, cancer surveillance is recommended with the goal of identifying malignancy earlier, in a presumably more curable form. Surveillance protocols, including imaging studies, lab work, and procedures, can be complex, differing based on age, gender, and syndrome, which may adversely affect adherence. Mobile health (mHealth) applications have been utilized in the oncology field and could help to facilitate adherence to cancer surveillance protocols. Methods: Applying a user-centered mobile app design approach, patients with a CPS and/or primary caregivers were interviewed to identify current methods for care management and barriers to compliance with recommended surveillance protocols. Broad themes from these interviews informed the design of the mobile app, HomeTown, subsequently evaluated by usability experts. The design was then converted into software code in phases, evaluated by patients and caregivers in an iterative fashion. User population growth and app usage data were assessed. Results: Common themes identified include general distress surrounding surveillance protocol scheduling and results, difficulty remembering medical history, assembling a care team, and seeking resources for self-education. These themes were translated into specific functional app features including push reminders, syndrome-specific surveillance recommendations, ability to annotate visits and results, storage of medical histories, and links to reliable educational resources. Conclusions: Families with CPS demonstrate a desire for mHealth tools to facilitate adherence to cancer surveillance protocols, reduce related distress, relay medical information, and provide educational resources. HomeTown may be a useful tool for engaging this patient population.

Title: Sweet syndrome masquerading as a disseminated and pulmonary fungal disease in a child with acute myeloid leukemia: case report and review of the literature

Title : Comment on: [Lost at Sea in Search of a Diagnosis: A Case of Unexplained Bleeding]Subtitle : Scurvy from chemotherapy-induced adverse effects in an adolescent oncology patientAuthors : Michelle Toker, BS and Benedict Wu, DO, PhDAffiliation : Division of Dermatology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USACorresponding author :Michelle TokerAlbert Einstein College of Medicine, Montefiore Medical CenterEmail: [email protected]: 516-946-4726Funding and support : NoneConflicts of Interest : NoneManuscript word count : 452Reference count : 6Figure count : 1Table count : 0Key words : chemotherapy, oncology, pediatrics, nutritional deficiency, vitamin C deficiency, scurvyDear Editor,The brief report published by Amos et al in 2016 shed light on the occurrence of scurvy in pediatric and adolescent patients with dietary restrictions.1 Indeed, patients with neurodevelopmental conditions are most commonly associated with the risk of developing scurvy; other at-risk patients include those with gastrointestinal disorders, alcoholism, and psychiatric conditions.2, 3 We aim to expand upon the situations when scurvy should be considered by presenting a case of an adolescent male diagnosed with scurvy secondary to the adverse effects of his chemotherapy.A 19-year-old male with a 10-month history of high-risk pre-B-cell acute lymphoblastic leukemia was consulted by the dermatology service for a new diffuse rash present for four days. He was recently enrolled in a phase 3 randomized trial of inotuzumab ozogamicin and was receiving methotrexate and vincristine. The chemotherapy regimen induced severe dizziness, nausea, and vomiting refractory to anti-emetic medications. His aversion to chemotherapy was so strong that it caused him to feel nauseated between treatment sessions. He also endorsed painful oral and pharyngeal sores that made it difficult to tolerate a regular diet. In addition to oropharyngeal pain, he experienced marked arthralgia and fatigue, which he also attributed to the chemotherapy. Additionally, the patient reported that vincristine reduced his taste sensation, which led to a poor appetite. These adverse symptoms culminated in a loss of 6.7 kg (9.1%) in less than one month.Physical examination revealed peri-follicular purpura on the back (Fig 1A), face, and bilateral upper and lower extremities. Upon closer inspection, we noted prominent corkscrew (spiral and curly appearance) hairs (Fig 1B). The lower mucosal lip had superficial erosions with scalloped-borders and fine petechiae (Fig 1C). Laboratory evaluation revealed pancytopenia with a platelet count of 42 k/UL and low serum levels of vitamin C (<0.1 mg/dL), potassium (3.4 mEq/L), magnesium (1.1 mg/dL), and albumin (2.8 g/dL). Serum vitamin A (35 mcg/dL) levels were within normal limits. The patient was diagnosed with scurvy due to poor food intake from his chemotherapy-induced nausea, emesis, and mucositis. It was thought that acidic foods, such as citrus, exacerbated the mucosal erosions, which caused him to avoid vitamin C-rich foods.Scurvy, caused by a prolonged L-ascorbic acid (vitamin C) deficiency, may manifest as pathognomonic corkscrew hairs with petechiae, gingival pain and bleeding, vascular fragility, arthralgias, fatigue, and numerous gastrointestinal symptoms.4,5, 6 Although vitamin C deficiency was an indirect result of his chemotherapy, scurvy, by itself, may have aggravated his symptoms, thereby creating a vicious cycle of poor oral intake. Our case highlights the complex relationship between chemotherapy-induced mucocutaneous adverse effects, a limited diet, and vitamin C deficiency. We recommend clinicians to consider scurvy in oncology patients, with or without thrombocytopenia, presenting with peri-follicular purpura and corkscrew hairs.Ethics Statement: Informed patient consent was obtained for publication of the case details and photographs.

BACKGROUND: Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end of induction (EOI) Curie Scores (CS) was previously described in patients undergoing a single autologous hematopoietic cell transplant (AHCT) as consolidation therapy. OBJECTIVE: We now examine the prognostic significance of CS in patients randomized to tandem AHCT on the Children’s Oncology Group (COG) trial ANBL0532. STUDY DESIGN: A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received a tandem AHCT (n=80). Optimal CS cut points maximized the outcome difference (≤ vs >CS cut-off) according to the Youden index. RESULTS: For recipients of tandem AHCT, the optimal cut point at diagnosis was CS=12, with superior EFS from study enrollment for patients with CS<12 (3-year EFS 74.2±7.9%) vs CS>12 (59.2±7.1%) (p=0.002). At EOI, the optimal cut point was CS=0, with superior end-induction EFS for patients with CS=0 (72.9±6.4%) vs CS>0 (46.5±9.1%) (p=0.002). CONCLUSION: In the setting of tandem transplantation for children with high-risk neuroblastoma, Curie scores at diagnosis and end-induction may identify a more favorable patient group. Patients treated with tandem AHCT who exhibited a CS<12 at diagnosis or CS=0 at EOI had superior EFS compared to those with CS above these cut points.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT). Aim:In this retrospective study, we evaluated HSCT that was performed using a reduced toxicicity myeloablative conditioning regimen in patients with MNGIE at our center. Results: A total of 6 allogeneic transplant procedures were performed in 4 patients. Three patients’ donors had fully matched donors, and one patients’ donor was haploidentical. Treosulfan-based myeloablative conditioning regimen was applied in 5 of 6 transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without Graft versus host disease (GVHD). One patient died of acute stage IV GIS GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant. Conclusions: Treosulfan-based regimen is well tolerated. Engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.

Cytomegalovirus retinitis (CMVR) following hematopoietic stem cell transplantation (HCT) for a primary immunodeficiency is a rare but highly morbid condition with potential irreversible consequences despite optimal antiviral pharmacotherapy. Viral-specific T cells (VSTs) pose a promising and safe approach eradicating intractable viral disease. We describe the case of a 21-month-old male with Wiskott-Aldrich syndrome (WAS) and CMVR post-HCT with sustained long-term virologic and clinical response after CMV-specific T cell therapy. This case highlights the need to consider VSTs as an adjunct upfront strategy in refractory CMVR and for routine ophthalmologic screening and surveillance in high-risk patients post-HCT.

Background: Pain is the clinical hallmark of sickle cell disease (SCD) leading to hospitalization, psychological sequelae and a decreased health-related quality of life. The aim of this systematic literature review is to evaluate the efficacy of non-pharmacological interventions in reducing sickle cell-related pain in children with SCD. Methods: A comprehensive literature search up until October 2022 was performed to identify studies that investigated the efficacy of non-pharmacological interventions on (1) pain frequency and/or intensity, and (2) analgesic and health service use in children with SCD. Randomized controlled (RCTs) trials and quasi-experimental designed (QED) studies that investigated non-pharmacological interventions for pediatric patients with SCD until the age of 21 years were considered for inclusion. Results: Ten articles (5 RCTs and 5 QED studies) with 422 participants were included. They investigated cognitive behavioral therapy (CBT) (n =5), biofeedback (n=2), massage (n=1), virtual reality (n=1) and yoga (n=1). CBT, biofeedback, massage, virtual reality and yoga significantly reduced frequency and/or intensity of SCD-related pain. Biofeedback also significantly reduced analgesic use. Conclusion: Non-pharmacological interventions may be effective in reducing pain in pediatric SCD patients. However, due to the heterogeneity of the included studies a quantitative analysis could not be performed. Awaiting further supporting evidence, healthcare providers should consider implementing these interventions as valuable part of a comprehensive pain management strategy plan to improve the outcome of sickle cell-related pain.

Survival from pediatric cancers in low-middle-income countries is often very low compared to that of high-income countries due to multifactorial etiologies, including late presentation, delayed diagnosis, difficulty with accessing health care, drug unavailability and treatment abandonment. The St. Jude Pediatric Oncology Facility Integrated Local Evaluation Tool (PrOFILE) was developed to identify the strengths and weaknesses of individual institutions, as well as whole countries. Following the completion of data analysis from Kenyan institutions, the first PrOFILE hybrid in-person and virtual workshop was held. Multi-disciplinary stakeholders prioritized recommendations for improving care and developed smart objectives to accomplish identified goals over the following 2 years. Strengths and weaknesses of conducting a hybrid global workshop were identified.

Xeroderma pigmentosum (XP) is a rare genodermatosis characterized by defective DNA repair, leading to hypersensitivity to ultraviolet (UV) sunlight and predisposes to various cutaneous and non-cutaneous malignancies. Platinum compounds are used against cutaneous cancers as concurrent chemoradiotherapy. But the XP gene polymorphism has a potential role in metabolism of these agents and their susceptibility. Here, we report a case of cutaneous squamous cell carcinoma in a patient with XP who had severe toxicity to chemotherapy. We also discuss other similar cases reported in literature of this entity, to highlight this potentially lethal pharmacogenomic association.

A document by Charles S. Hemenway. Click on the document to view its contents.

Background: Childhood cancer survivors need regular, long-term survivor care. The Children’s Oncology Group (COG) recommends that pediatric cancer patients receive ongoing, evidence-based surveillance for late-effects beginning two years after cancer therapy completion. A third of survivors are not engaging in long-term survivorship care. This study assessed barriers and facilitators to follow-up survivorship care through the perspectives of pediatric cancer clinic representatives. Methods: As part of a hybrid implementation-effectiveness trial, a representative from 12 participating pediatric cancer survivor clinics completed a survey about site characteristics, and a semi-structured interview on barriers and facilitators to survivor care delivery at their institution. Interviews were grounded in the socio-ecological model (SEM) framework and utilized a Fishbone diagram to identify the root causes of a problem. We ran descriptive statistics and conducted thematic analyses of the interview transcripts to create two meta-Fishbone diagrams. Results: Participating clinics (n=12) have existed for at least five years (mean=30, range= 5-97), and half (50%) report seeing 100-200 survivors annually. In the Fishbone diagram, top facilitators were in the SEM domain of Organization, specifically with familiar staff (100%), resource utilization (92%), survivorship-exclusive staff (83%), and clinic processes (83%). Common barriers were in the domains of Organization, Community, and Policy which included technology limits (92%), scheduling issues (92%), insufficient funding/insurance (92%), and distance/transportation (100%). Conclusion: Using the Fishbone diagram was instrumental in understanding multilevel contextual issues related to survivor care delivery for pediatric cancer clinics. Future efforts can develop education, processes, and services to promote cancer follow-up care.

CD19-directed chimeric antigen receptor T lymphocytes (CAR-T) have led to durable remissions in children with refractory and/or multiply relapsed B-lymphoblastic leukemia. For those who relapse or lose B-cell aplasia post-CAR-T, the role of CAR-T reinfusion is unclear. We report a case of durable remission with tisagenlecleucel reinfusion despite failure to achieve B-cell aplasia and compare this case to seven additional children who received multiple tisagenlecleucel infusions at our institution. Our experience suggests that reinfusion is safe and may be a definitive therapy for a small subset of patients. Reinfusion can also reintroduce remission and/or B-cell aplasia, allowing for subsequent therapies.

A document by Muhammad Rafay Shahzad Cheema. Click on the document to view its contents.

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon immunologic disorder associated with high rates of morbidity and mortality characterized by systemic inflammation and multiorgan dysfunction. The standard of care for primary treatment of HLH is chemotherapy (i.e. etoposide), but consideration of alternative therapies is warranted to support treatment goals for critically ill pediatric patients. We present the case of a 7-year-old male with trisomy 21, acute multiorgan failure secondary to infection, and subsequent HLH who was successfully treated with ruxolitinib. This represents the first use of ruxolitinib as a first-line agent for secondary HLH in a critically ill child with trisomy 21.