Comment on: Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib1Paige Vicenzi, OMS-IV, 2Anish Ray, MD1Texas College of Osteopathic Medicine, University of North Texas Health Science Center2Department of Pediatric Hematology/Oncology, Cook Children’s Health Care SystemCorresponding Author:Anish Ray, MD1500 Cooper St., 5th floor,Fort Worth, TX 76104Phone: [email protected] Count: 513Number of Tables: 0Number of Figures: 0Running Title: Langerhans cell histiocytosis treated by trametinibKeywords: Langerhans cell histiocytosis, MAP2K1, trametinib, pediatricThe authors have no financial support or conflicts of interest.Langerhans cell histiocytosis (LCH) is a rare but heterogenous myeloid malignancy. The discovery of mitogen-activated protein kinase (MAPK) pathway activating mutations as key oncogenic drivers offered only equivocal implications at best; the promise of targeted therapy was often eclipsed by a more severe clinical course, risk organ involvement, poorer response to standard therapy, and higher risk of relapse.1 There is, however, mounting evidence in support of MAPK pathway inhibition for patients with BRAF V600E mutations. A recent report outlines rapid and durable response of relapsed, multisystemic LCH with either BRAF p.N486_P490 or MAP2K1 p.K57_G61 deletion to MEK inhibitor trametinib.2 Two of the three patients achieved nonactive disease, including a 2-year-old male with MAP2K1 deletion who, despite reports attributing trametinib resistance to MAP2K1 mutations3, continues to thrive. We take this opportunity to describe an analogous experience treating a relapsed LCH patient with trametinib at Cook Children’s Medical Center from early 2020 to present.Our patient is a 4-year-old male who presented in March 2017 with new onset central diabetes insipidus (DI) and skin rash; skin biopsy provided diagnosis of LCH, but skeletal survey was negative for bone involvement. He was treated with twelve cycles of cytarabine (100 milligram (mg)/m2 intravenous daily for five days, every four weeks) and DDAVP for DI. At the completion of cytarabine, a second skin biopsy revealed recurrence of LCH, which warranted treatment with hydroxyurea (20 mg/kilogram (Kg) daily) and methotrexate (2.5 mg at 0.12 mg/Kg twice a week). This was continued for 52 weeks despite a brief interruption of methotrexate due to dermatitis. Three months following completion of this therapy, brain MRI revealed a 7 mm lesion of the skull. Curettage by neurosurgery confirmed relapse of LCH in January 2020. Genetic testing of this sample was negative forBRAF mutation, but positive for a mutation in the MAP2K1 gene, specifically a point mutation resulting in a substitution of Q56P. Shortly after his biopsy, the patient developed a soft tissue swelling on his skull. Due to these results and his multiple relapses, the patient was started on trametinib (2.5 mg daily) in February 2020 with rapid resolution of skull swelling and transient but dramatic reduction of his desmopressin dose from 3.2 mg twice a day to 0.2 mg twice a day. He has not experienced toxicity and continues to tolerate the drug well.Though trametinib presents a promising treatment for high-risk, relapsed LCH, it is not without limitations. In 2020, we also treated a 15-year-old male with relapsed LCH and BRAF V600E with trametinib monotherapy. Due to skin rash (Grade II), the patient became noncompliant. Despite stopping altogether after a month of treatment, he has yet to experience disease recurrence. But as stated in the aforementioned report, sufficient dose and treatment length to attain MAPK pathway suppression merits further investigation. In our similar experience treating a young child with multisystemic LCH and MAP2K1 mutation, we remain encouraged that MEK inhibition via trametinib monotherapy is a viable treatment option. In the context of genomic landscaping, we hope to incite further exploration of targeted therapy, and consequently, greater consensus on LCH management.

A document by Atish Bakane. Click on the document to view its contents.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors in childhood. Cancer predisposition syndromes (CPS) are increasingly recognized as the underlying cause for a number of pediatric malignancies and up to 40% of PPGL are currently thought to be associated with a hereditary predisposition1,2. With the increasingly widespread availability of functional molecular imaging techniques, nuclear medicine imaging modalities such as 18F-FDG-PET/CT, 123I-MIBG SPECT/CT, and 68Ga-DOTATATE PET/CT now play an essential role in the staging, response assessment and determination of suitability for targeted radiotherapy in patients with PPGL. Each of these imaging modalities targets a different cellular characteristic, such as glucose metabolism (FDG), norepinephrine transporter expression (MIBG), or somatostatin receptor expression (DOTATATE), and therefore can be complementary to anatomic imaging and to each other. Given the recent FDA approval3 and increasing use of 68Ga-DOTATATE for imaging in children4, the purpose of this article is to use a case-based approach to highlight both the advantages and limitations of DOTATATE imaging as it compares to current radiologic imaging techniques in the staging and response assessment of pediatric PPGL, and to offer a decision algorithm for the use of functional imaging that can be applied to PPGL, as well as other neuroendocrine malignancies.

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Objective: To evaluate group differences in social adjustment in survivors of pediatric ALL compared to survivor siblings, and controls; identify disease-related predictors of social adjustment in survivors; and explore whether executive functioning explained differences in social adjustment across groups and between disease-related predictors. Methods: Survivors of pediatric ALL (n=38, average age at diagnosis=4.27 years [SD=1.97]; average time off treatment=4.83 years [SD=1.52]), one sibling (if available, n=20), and one parent from each family were recruited from a long-term survivor clinic. Healthy age- and sex-matched controls (n=38) and one parent from each family were recruited from the community. Parents completed the Behavioral Assessment System for Children, Parent Rating Scale (BASC-3) Social Withdrawal subscale as a measure of social adjustment and the Behavior Rating Inventory of Executive Functions (BRIEF-2) as a measure of executive function for each of their children. Results: Parents reported that survivors had significantly worse social adjustment compared to controls (b=6.34, p=.004), but not survivor siblings. Among survivors, greater time off treatment (b=2.06, p=.058) and poorer executive functioning (b=0.42, p=.006) were associated with worse social adjustment. Executive function did not mediate differences in social withdrawal between survivors and controls or the relationship between time off treatment and social withdrawal among survivors. Conclusions: Survivors of pediatric ALL presenting to follow-up programs should be screened for difficulties with social adjustment. Future research should examine treatment- and non-treatment-related factors contributing to poorer social outcomes.

Background Consultation of specialty palliative care remains uncommon in pediatric stem cell transplant (SCT) despite growing evidence that early integration of palliative care improves outcomes in patients with advanced cancers or undergoing SCT. Little is known about how multidisciplinary pediatric SCT teams perceive palliative care and its role in SCT. Procedure We conducted semi-structured interviews of members of a multi-disciplinary SCT team to understand their perceptions of palliative care, how specialty palliative care is integrated into SCT, and to identify barriers to increased integration. Eligible participants included physicians, nurses, nurse practitioners, social workers, and child life specialists. Data was analyzed using thematic analysis. Results Four major themes were identified. First, SCT team members held a favorable perception of the palliative care team. Second, participants desired increased palliative care integration in SCT. Third, participants believed that the palliative care team had insufficient resources to care for the large number of SCT patients which led to the SCT team limiting palliative care consultation. And, finally, the lack of a standardized palliative care consultation process prevented greater integration of palliative care in SCT. Conclusions SCT team members held a favorable perception of palliative care and saw a role for greater palliative care integration throughout the SCT course. We identified modifiable barriers to greater palliative care integration. SCT teams who desire greater palliative care integration may adapt and implement an existing model of palliative care integration in order to improve standardization and increase integration of specialty palliative care in SCT.

A document by Bilawal Nadeem. Click on the document to view its contents.

Tristan Boam1, Bethan G Rogoyski2, Melissa Gabriel3, Paul D Losty4Department of Paediatric Surgery, Leicester Royal Infirmary, Leicester, UKLeicester School of Allied Health Sciences, De Montfort University, Leicester, UKDepartment of Urology, Norfolk and Norwich Hospital, Norwich, UKAlder Hey Children’s Hospital NHS Foundation Trust, School of Health and Life Science, University of Liverpool, UK

Severe autoimmune lymphoproliferative syndrome phenotype in a pediatric patient with a germline FAS gene variant Authors: Alexandra Dreyzin MD MS1; Jinjun Cheng MD PhD2, David Leitenberg MD PhD3, and Yaser Diab MBBS1Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DCDivision of Pathology and Laboratory Medicine, Children’s National Hospital, Washington, DCDepartment of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.

Objective: To compare outcomes data of obese and non-obese pediatric patients with acute promyelocytic leukemia from the Cancer and Leukemia Group B trial C9710 and the Children’s Oncology Group trial AAML0631. Methods: Data including demographics, adverse events, overall survival and event free survival was analyzed, with a focus on mortality in obese patients. Results: The incidence of obesity was 34% on C9710 and 35% on AAML0631. There was significantly lower overall survival in the obese population on AAML0631. Thirteen patients died during therapy or in follow up; seven of these occurred during induction. Conclusion: The incidence of obesity is higher in patients with APL compared to the general population. The presence and degree of obesity can influence OS on the most current treatment regimen. This implies the need for close management of obese patients at diagnosis as well as reinforces the need for further research on obesity driven APL

Pyruvate kinase (PK) deficiency is an important cause of hereditary non-spherocytic hemolytic anemia caused by a defect in the glycolytic pathway in red blood cells. PK deficient erythrocytes have impaired ATP production and resultant difficulty maintaining normal cell integrity and function, leading to mild to severe anemia due to increased extravascular hemolysis and splenic destruction. Sequelae of chronic hemolysis can result in severe and occasionally life-threatening complications such as hepatobiliary disease, iron overload, bone and cardiopulmonary disease, as well as often markedly impaired quality of life. While the mainstay of management of PK deficiency involves supportive care, comprehensive screening recommendations and disease modifying therapies in development are likely to significantly improve the management of patients. Here, we provide a case-based comprehensive review of the diagnostic evaluation, complications, monitoring recommendations and management of PK deficiency in children.

A document by Seema Biswas. Click on the document to view its contents.

Concurrence of a Kinase-dead BRAF and an OncogenicKRAS Gain-of-function Mutation in Juvenile Xanthogranuloma

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.

Background: Vitamin D deficiency and insufficiency have been associated with poorer health outcomes. Children with cancer are at high risk for Vitamin D deficiency and insufficiency. At our institution, we identified high variability in Vitamin D testing and supplementation in this population. Of those tested, 65% were Vitamin D deficient/insufficient. We conducted a quality improvement (QI) initiative with aim to improve Vitamin D testing and supplementation among children aged 2-18 years old with newly-diagnosed cancer to ≥ 80% over 6 months. Methods: An inter-professional team reviewed baseline data, then developed and implemented interventions using Plan-Do-Study-Act (PDSA) cycles. Barriers were identified using QI tools, including lack of automated triggers for testing and inconsistent supplementation criteria and follow-up testing post-supplementation. Interventions included an institutional Vitamin D guideline, clinical decision-making tree for Vitamin D deficiency, insufficiency and sufficiency, electronic medical record triggers, and automated testing options. Results: Pre-intervention: N=26 patients, four (15%) had baseline Vitamin D testing; two (8%) received appropriate supplementation. Post-intervention: N=33 patients; 32 (97%) had baseline Vitamin D testing; 33 (100%) received appropriate supplementation and completed follow-up testing timely (6-8 weeks post-supplementation). Change was sustained over 24 months. Conclusions: We achieved and sustained our aim for Vitamin D testing and supplementation in children with newly-diagnosed cancer through inter-professional collaboration of hematology/oncology, endocrinology, hospital medicine, pharmacy, nursing, and information technology. Future PDSA cycles will address patient compliance with Vitamin D supplementation and impact on patients’ Vitamin D levels.

Background: V enetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more robust data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population. Procedure: We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco (UCSF) Benioff Children’s Hospitals from 2016 to 2022. Results: We identified 13 patients (AML , n= 8, B-ALL, n= 3, MDS, n= 2) aged 4 months to 27 years. A median of 3 prior lines of therapy were given (range 0 to 5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved a complete remission (CR); 2 (15%) achieved a partial remission (PR); 3 (23%) had stable disease (SD), and 5 (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5 to 52 months), and 3 months (range 2 weeks to 7.5 months), respectively. Five patients (38%) developed life-threatening infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, encephalitis with bacterial brain abscesses. Conclusions: Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but was frequently associated with severe atypical infections, particularly in combination with cytotoxic chemotherapy.

Background It is important to ensure access to hydroxyurea (HU) for patients with sickle cell anemia (SCA) living in rural areas without easy access to experts in sickle cell management. The UAB Pediatric Sickle Cell program’s satellite clinics reduce the barrier of transportation to the university-based clinic. However, as compared to the university clinic, these satellite clinics do not offer immediate access to HU dosing laboratory results. Therefore, a nurse clinician calls families with HU dose adjustments after the completion of the clinic visit. This study evaluated the impact of telehealth dosing adjustments on HU laboratory and clinical response as compared to university-based patients. Methods A one year retrospective chart reviewed was performed to evaluate HU laboratory and clinical response based on clinic location and socioeconomic status for patients with SCA. We identified the number of clinic and acute care visits for one year and calculated the mean CBC and HbF values for each patient. Results We identified 107 academic center participants with SCA prescribed HU and 65 satellite clinic participants. We identified no difference in HbF, Hb, MCV, or ANC by clinic location. We also identified no difference in hospital admissions based on clinic location. Finally, mean socioeconomic indicators by zip code were lower in satellite clinic patients but not associated with a difference in HbF response. Conclusions The use of telehealth did not negatively impact laboratory response to HU. Future studies should identify novel approaches to improve access to HU among patients with SCA living in rural areas.

Purpose/Objectives: To evaluate dosimetric differences between auto-planned Volumetric Modulated Arc Therapy (VMAT) Total Body Irradiation (TBI) technique and 2D AP/PA TBI technique. Methods: Ten pediatric patients treated with VMAT-TBI on Varian c-arm linac were included in this study. VMAT-TBI plans were generated using our in-house developed and publicly shared auto-planning scripts. For each VMAT-TBI plan, a 2D AP/PA plan was created replicating the institution’s clinical setup with the patient positioned at extended SSD with a compensator to account for differences in patient thickness, 50%-transmission daily lung blocks and electron chest-wall boosts prescribed to 50% of the photon prescription. Clinically relevant metrics were analyzed and compared between the VMAT and 2D plans. Results: All VMAT-TBI plans achieved PTV D90%≥100% of prescription. VMAT-TBI PTV D90% significantly increased (6.2%±2.4%, p<0.001) compared to the 2D technique, whereas no differences were observed in global Dmax (p<0.2) and PTV V110% (p<0.4). Compared to the 2D plans, significant decreases in the Dmean to the lungs (-25.6%±11.5%, p<0.001) and lungs-1cm (-34.1%±10.1%, p<0.001) were observed with the VMAT plans. The VMAT technique also provided additional sparing to other organs: for 12Gy prescription, kidneys Dmean of 64.7%±3.3%; for 2Gy prescription, testes/ovaries (Dmean of 31.6%±10.7%), brain (Dmean of 74.8%±1.6%) and thyroid (Dmean of 72.5±3.5%). Conclusions: Superior lung sparing with improved target coverage and similar global Dmax were observed with the VMAT plans as compared to 2D plans. In addition, VMAT-TBI plans provided greater dose reductions in gonads, kidneys, brain, and thyroid.