Symptom management care pathway adaptation process and specific adaptation decisions.

BACKGROUND: There is substantial heterogeneity in symptom management provided to pediatric patients with cancer. The primary objective was to describe the adaptation process and specific adaptation decisions related to symptom management care pathways based on clinical practice guidelines. The secondary objective evaluated if institutional factors were associated with adaptation decisions. METHODS: Fourteen previously developed symptom management care pathway templates were reviewed by an institutional adaptation team composed of two clinicians at each of 10 institutions. They worked through each statement for all care pathway templates sequentially. The institutional adaptation team made the decision to adopt, adapt or reject each statement, resulting in institution-specific symptom management care pathway drafts. Institutional adaption teams distributed the 14 care pathway drafts to their respective teams; their feedback led to care pathway modifications. RESULTS: Initial care pathway adaptation decision making was completed over a median of 4.2 (interquartile range 2.0-5.3) weeks per institution. Across all institutions and among 1350 statements, 551 (40.8%) were adopted, 657 (48.7%) were adapted, 86 (6.4%) were rejected and 56 (4.1%) were no longer applicable because of a previous decision. Most commonly, the reason for rejection was not agreeing with the statement (70/86, 81.4%). Institutional-level factors were not significantly associated with statement rejection. CONCLUSIONS: Acceptability of the 14 care pathways was evident by most statements being adopted or adapted. The adaptation process was accomplished over a relatively short timeframe. Future work should focus on evaluation of care pathway compliance and determination of the impact of care pathway-consistent care on patient outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT04614662. Registered 04/11/2020, https://clinicaltrials.gov/ct2/show/NCT04614662?term=NCT04614662&draw=2&rank=1 .

45 GyRBE for group III orbital embryonal rhabdomyosarcoma.

Purpose: Despite widespread concerns of radiotherapy toxicity in children with head and neck tumors, recent Children's Oncology Group (COG) findings suggest that the use of 45 Gy results in an unacceptably high rate of local recurrences in patients with low-risk orbital rhabdomyosarcoma. We therefore evaluated outcomes in our pediatric patients who received 45 GyRBE using proton therapy. Material and methods: To assess disease control and toxicity, we reviewed the medical records of 30 children (≤21 years old) with COG stage 1, group III embryonal orbital rhabdomyosarcoma enrolled on a prospective outcome study and treated with proton therapy between 2007 and 2018. Results: Median age at the time of radiation was 4.8 years old. Twenty-one and nine patients received ifosfamide- and cyclophosphamide-based chemotherapy according to their respective cooperative group regimens. Median duration between the start of induction chemotherapy and radiation was 12 weeks. Two patients had a complete response to induction chemotherapy and two had stable disease. Twenty-six patients had a partial response to induction chemotherapy, with a median volume reduction of 66%. With a median follow-up of 4.0 years (range, 0.5-9.5 years), we observed 1 local failure 6 months following treatment in a patient who had a partial response to cyclosphophomide-based induction chemotherapy. The 5-year local control, progression-free survival, and overall survival rates were 97%, 97%, and 100%, respectively. Serious late toxicities included 18 patients with cataracts, 4 with exposure keratoconjunctivitis resulting in permanently reduced visual acuity, and 1 with chronic sinusitis. Conclusion: 45 GyRBE offers effective local control for most patients with group III orbital rhabdomyosarcoma. The delivery of proton therapy to the postinduction tumor volume plus a small margin can mitigate early- and intermediate-term toxicity, but side effects still occur and long-term data are needed to demonstrate the dosimetric advantage of proton therapy.

Esophagitis associated with multimodality management of pediatric Ewing sarcoma of thorax.

BACKGROUND: Ewing sarcoma of the thoracic spine and chest wall is frequently treated with concurrent chemotherapy and radiation therapy (RT). Treatment-related acute esophagitis can lead to hospitalization and treatment delays. The aim of this study was to analyze the incidence, risk factors, and management of esophagitis in pediatric patients with Ewing sarcoma of the thoracic region. METHODS: We conducted a single-institution retrospective review of patients treated over a 10-year period. Medical records were reviewed for patient and treatment characteristics associated with Common Terminology Criteria for Adverse Events grade 2 or higher esophagitis. RT plans were also reviewed and various esophageal dose metrics were analyzed. RESULTS: Twelve of 37 patients (32%) developed acute esophagitis. Neutropenia was associated with an increased risk of esophagitis (60% vs. 14%; P < 0.01). RT significantly contributed to its incidence when maximum esophageal dose was >47 Gy (69% vs. 5%; P < 0.0001) and esophageal D5cm3 was >15 Gy (67% vs. 9%; P < 0.001). All 12 patients with esophagitis were managed with oral opioid analgesics. Nine patients with persistent symptoms received subsequent fluconazole for empiric fungal treatment and each had a decreased need for opioid analgesics within 2-5 days. CONCLUSION: Approximately one-third of patients with Ewing sarcoma of the thoracic region will develop acute esophagitis. An esophageal D5cm3 dose < 15 Gy and maximal esophageal dose < 47 Gy may keep the rate of acute esophagitis under 5%. However, the association with neutropenia and consistent response to antifungal therapy suggest chemotherapy-associated toxicity and an infectious component as part of the process.

Microbiologically documented fungal infections in pediatric patients with acute myeloid leukemia: 12.5-year experience at a single institution.

The primary objective of this study was to determine the incidence and types of microbiologically documented fungal infections in 56 children with acute myeloid leukemia admitted to Wolfson Children's Hospital. The secondary objective was to determine the factors that may affect the treatment and outcome of these infections, such as antifungal prophylaxis, absolute neutrophil count, age, and phase of therapy. Medical records were reviewed from January 1, 2000 to July 31, 2012. Over the 12.5-year study period, there were 11 patients with 25 episodes of fungal infections. Adolescents with acute myeloid leukemia (13 to 18 y old) represented 48% of the population. Children less than 3 years of age and between 3 and 12 years of age represented one quarter each. None of the patients less than 3 years of age developed fungal infections, whereas 64% of the adolescents did (P=0.01). Blood-borne infections were the most common site of infection (44%). Eighty-four percent of infections occurred in neutropenic patients. The mortality rate in the overall cohort was 28%. Patients with fungal infections had increased mortality rate of 55%. Overall candidiasis and aspergillosis were the major pathogens (28% each), although there have been no occurrences of Aspergillus sp. since 2005. On the basis of the results of our study, it would be prudent to provide antifungal coverage for both these pathogens, such as with voriconazole or echinocandins over fluconazole.

Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma.

Retinoblastoma is a childhood cancer of the retina involving germline or somatic alterations of the RB Transcriptional Corepressor 1 gene, RB1. Rare cases of sellar-suprasellar region retinoblastoma without evidence of ocular or pineal tumors have been described. A nine-month-old male presented with a sellar-suprasellar region mass. Histopathology showed an embryonal tumor with focal Flexner-Wintersteiner-like rosettes and loss of retinoblastoma protein (RB1) expression by immunohistochemistry. DNA array-based methylation profiling confidently classified the tumor as pineoblastoma group A/intracranial retinoblastoma. The patient was subsequently enrolled on an institutional translational cancer research protocol and underwent comprehensive molecular profiling, including paired tumor/normal exome and genome sequencing and RNA-sequencing of the tumor. Additionally, Pacific Biosciences (PacBio) Single Molecule Real Time (SMRT) sequencing was performed from comparator normal and disease-involved tissue to resolve complex structural variations. RNA-sequencing revealed multiple fusions clustered within 13q14.1-q21.3, including a novel in-frame fusion of RB1-SIAH3 predicted to prematurely truncate the RB1 protein. SMRT sequencing revealed a complex structural rearrangement spanning 13q14.11-q31.3, including two somatic structural variants within intron 17 of RB1. These events corresponded to the RB1-SIAH3 fusion and a novel RB1 rearrangement expected to correlate with the complete absence of RB1 protein expression. Comprehensive molecular analysis, including DNA array-based methylation profiling and sequencing-based methodologies, were critical for classification and understanding the complex mechanism of RB1 inactivation in this diagnostically challenging tumor.

YAP1-FAM118B Fusion Defines a Rare Subset of Childhood and Young Adulthood Meningiomas.

Meningiomas are a central nervous system tumor primarily afflicting adults, with <1% of cases diagnosed during childhood or adolescence. Somatic variation in NF2 may be found in ∼50% of meningiomas, with other genetic drivers (eg, SMO, AKT1, TRAF7) contributing to NF2 wild-type tumors. NF2 is an upstream negative regulator of YAP signaling and loss of the NF2 protein product, Merlin, results in YAP overexpression and target gene transcription. This mechanism of dysregulation is described in NF2-driven meningiomas, but further work is necessary to understand the NF2-independent mechanism of tumorigenesis. Amid our institutional patient-centric comprehensive molecular profiling study, we identified an individual with meningioma harboring a YAP1-FAM118B fusion, previously reported only in supratentorial ependymoma. The tumor histopathology was remarkable, characterized by prominent islands of calcifying fibrous nodules within an overall collagen-rich matrix. To gain insight into this finding, we subsequently evaluated the genetic landscape of 11 additional pediatric and adolescent/young adulthood meningioma patients within the Children's Brain Tumor Tissue Consortium. A second individual harboring a YAP1-FAM118B gene fusion was identified within this database. Transcriptomic profiling suggested that YAP1-fusion meningiomas are biologically distinct from NF2-driven meningiomas. Similar to other meningiomas, however, YAP1-fusion meningiomas demonstrated overexpression of EGFR and MET. DNA methylation profiling further distinguished YAP1-fusion meningiomas from those observed in ependymomas. In summary, we expand the genetic spectrum of somatic alteration associated with NF2 wild-type meningioma to include the YAP1-FAM118B fusion and provide support for aberrant signaling pathways potentially targetable by therapeutic intervention.

Congenital Mastocytosis: Case Report and Review of the Literature.

Mastocytosis is a rare infiltrative disorder characterized by mast cell proliferation within the skin and various extra-cutaneous organ systems. We report the case of a full-term neonate admitted to the neonatal intensive care unit for evaluation of diffuse skin lesions on her face, trunk and extremities. Initially, the lesions appeared to be consistent with a blueberry muffin rash. However, over a period of days the lesions became vesicular and changed in shape and number. The neonate underwent evaluation for infective etiologies, skin biopsy of the lesions, and flow cytometry analysis of the peripheral blood. The surgical pathology examination of the skin biopsy demonstrated mast cells consistent with a diagnosis of cutaneous mastocytosis. A review of relevant literature is also provided.

Outcomes Following Proton Therapy for Group III Pelvic Rhabdomyosarcoma.

PURPOSE: This study aimed to report on the institutional outcomes after proton therapy for pelvic rhabdomyosarcoma (RMS). METHODS AND MATERIALS: Thirty-one children (≤21 years old) with group III pelvic RMS were enrolled on a prospective outcome study and treated between 2007 and 2018. Patients with vaginal/cervical RMS were excluded. The median age was 2.6 years. Twenty-four patients had embryonal RMS. At diagnosis, the median tumor volume was 185 cm3 and the median maximum diameter was 9.4 cm. Seven patients had N1 disease. Nineteen and 12 patients received European Pediatric Soft Tissue Sarcoma Study Group- and Children's Oncology Group-based chemotherapy, respectively. Fourteen patients underwent resection of the primary tumor after induction chemotherapy, including 6 patients who had a total cystectomy. The median radiation dose was 50.4 Gy relative biological effectiveness. RESULTS: With a median follow-up of 4.2 years, the 5-year local control, progression-free survival, and overall survival rates were 83%, 80%, and 84%, respectively. Patients <3 years old had better local control (100% vs 68%; P = .02), and patients with embryonal histology had better survival (96% vs 54%; P = .02). No other factors were significantly associated with disease control or survival. Specifically, no statistically significant difference was observed in local control, progression-free survival, or overall survival when comparing patients who underwent biopsy versus gross total resection (75% vs 93%, 68% vs 93%, 75% vs 93%, respectively). Excluding patients who underwent cystectomy, urinary toxicity was limited to 2 patients with nocturnal enuresis. Exploratory surgery to address a persistent mass or thickened bladder wall after radiation was the most common source of serious toxicity. CONCLUSIONS: This cohort of young children with large pelvic tumors treated with proton therapy demonstrates similar local control with less toxicity than historic reports. Functional bladder preservation is possible in most patients. Exploratory biopsy in the 18 months after radiation should be approached with caution.

Surgical Revascularization for Pediatric Patients with Sickle Cell Disease and Moyamoya Disease in the Prevention of Ischemic Strokes: A Single-Center Case Series and a Systematic Review.

BACKGROUND: This systematic review aims to identify and analyze the available evidence on the safety and efficacy of surgical revascularization for pediatric patients with sickle cell disease (SCD) and moyamoya disease (MMD). METHODS: A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The following databases were searched: PubMed, Ovid MEDLINE, and Scopus. Studies included in the review were original research articles in peer-reviewed journals in which individual participant data were available. The articles were thoroughly examined and compared on study design, outcomes, and results. The authors reviewed their institution's database to identify pediatric patients with SCD and MMD who underwent surgical revascularization and were included in the analysis. RESULTS: A total of 53 patients were included and 82 hemispheres were intervened with direct or indirect surgical revascularization. Encephaloduroarteriosynangiosis (EDAS) was the most common procedure performed (42/82; 51.2%) followed by pial synangiosis (31/82; 37.8%). There was 1 intraprocedural complication. The median clinical follow-up was 37 months (interquartile range, 24.1-73.5 months) and during this period, 3 of 52 patients (5.8%) had ischemic strokes. All ischemic strokes occurred within the first 30 days after the surgery and the rate of ischemic stroke-free survival was 94.3% (95% confidence interval, 83.3-98.1). The estimated incidence rate of ischemic stroke was 1.42 events/100 patient-years (95% confidence interval, 0.46-4.4). CONCLUSIONS: Our study suggests that surgical revascularization in pediatric patients with SCD and MMD is safe to perform and results in a low rate of future ischemic insults.

Expanding the clinical history associated with syndromic Klippel-Feil: A unique case of comorbidity with medulloblastoma.

Klippel-Feil syndrome (KFS) is an exceedingly rare constitutional disorder in which a paucity of knowledge exists about the disease and its associated morbidity and mortality. We present a 4-year-old male with KFS, who notably was also diagnosed with large-cell anaplastic medulloblastoma. We evaluated the genetic basis of co-occurring KFS and medulloblastoma and the role of MYO18B as related to medulloblastoma. Constitutional and somatic variant and copy number analyses were performed from DNA-based exome studies, along with RNA-sequencing of tumor tissue, to elucidate the genetic etiology of the co-existing disease states. We identified novel constitutional compound heterozygous frameshift variants (NM_032608.5: p.Leu2257SerfsTer16 and p.Arg2220SerfsTer74) each encoding a premature stop of translation in MYO18B, consistent with a diagnosis of KFS. We did not identify any somatic variants of known relevance or disease-relevant therapeutic targets in the tumor. The somatic copy number profile was suggestive of Group 3γ medulloblastoma. Relative to pediatric brain tumors, medulloblastoma, particularly, Group 3, had increased gene expression of MYO18B. In summary, coexisting constitutional and somatic diagnoses in this patient enabled the elucidation of the genetic etiology of KFS and provided support for the role of MYO18B in tumor suppression.

Association of Lipid Profile and Uric Acid with Pre-eclampsia of Third Trimester in Nullipara Women.

BACKGROUND: Pre-eclampsia (PE) affects approximately 3% of all pregnancies worldwide, with onset of symptoms in the late second or third trimester, commonly after 32(nd) week. It is common in nulliparous women. To avoid complications it is necessary to diagnose it in advance, but the available tools are unable to clinch the diagnosis of preeclampsia effectively in majority. AIM: To find out an association of lipid profile and uric acid with PE in nullipara pregnant women in third trimester. MATERIALS AND METHODS: One hundred nulliparous pregnant women in their third trimester of 18-35 years were divided into; 50 pre-eclamptics of study group and 50 non pre-eclamptic in control group; further subdivided according to age, 18-26 and 27-35 yrs. Diagnosis was confirmed as per the standard criteria. Lipid profile and uric acid levels were estimated by Vitros 250 dry chemistry analyser. Data was analysed statistically by student t-test at p<0.01 level of significance. RESULTS: TC, LDL-c and VLDL-c levels in the study group as a whole and in the patients between 18-26 years were significant; HDL-c levels in the patients between 27-35 years were significant while TG and uric acid levels in all the three study groups were significant. CONCLUSION: Total cholesterol, LDL-c, VLDL-c, triglycerides (TGs) and uric acid levels were raised in preeclampsia and statistically significant; while HDL-c levels were raised in these patients but statistically non-significant, it can be concluded that there exists an association in lipid profile and uric acid with PE therefore dyslipidemia and raised uric acid levels are the features of PE in nullipara pregnant women in their third trimester.

Relationship of Lipid Profile and Serum Ferritin levels with Acute Myocardial Infarction.

INTRODUCTION: National Health and Nutrition Examination Survey (NHANES III), 1988-1994, first time reported a significant, positive association in iron storage and heart disease risk. Thereafter several researchers have found an association between iron overload, serum ferritin (SF) and MI. No such Indian study was available in the literature and so we decided to find out the relation of lipid profile and Serum Ferritin with myocardial infarction (MI). MATERIALS AND METHODS: Fifty indian patients of AMI (study group) and fifty indian healthy volunteers (control group) were included for the present study. Lipid profile including TC, HDL-c, LDL-c, VLDL-c & TG and SF levels were estimated in all subjects. OBSERVATIONS AND RESULTS: Mean ± SD of TC level was 250.64 ± 25.61, of HDL-c was 36.52 ± 2.86, of LDL-c was 165.69 ± 26.80, of VLDL-c was 42.35 ± 8.53 and of TG was 211.83 ± 42.65 in study group while these values were 174.46±47.68, 43.2±12.52, 98.37±41.13, 32.88±21.45 and 164.42±107.29 respectively in control group. All the parameters were found not only raised in patients of acute myocardial infarction (AMI) but were also statistically significant when compared with control group (p=<0.01). Mean ± SD of SF levels was 268.43±30.17 ng/ml in study group and 110.96±56.5 ng/ml in control group; this level was found not only raised in patients of AMI but were also statistically significant when compared with control group (p=<0.01). CONCLUSION: TC, LDL-c, VLDL-c, TG and SF levels were raised in patients of AMI and found to be statistically significant; while HDL-c levels were reduced in such patients and is also statistically significant. It can be concluded that there exists an association in lipid profile and SF with AMI therefore dyslipidemia and raised SF levels are the features of AMI.