Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.

Survival outcomes for relapsed/refractory pediatric acute myeloid leukemia (R/R AML) remain dismal. Epigenetic changes can result in gene expression alterations which are thought to contribute to both leukemogenesis and chemotherapy resistance. We report results from a phase I trial with a dose expansion cohort investigating decitabine and vorinostat in combination with fludarabine, cytarabine, and G-CSF (FLAG) in pediatric patients with R/R AML [NCT02412475]. Thirty-seven patients enrolled with a median age at enrollment of 8.4 (range, 1-20) years. There were no dose limiting toxicities among the enrolled patients, including two patients with Down syndrome. The recommended phase 2 dose of decitabine in combination with vorinostat and FLAG was 10 mg/m2 . The expanded cohort design allowed for an efficacy evaluation and the overall response rate among 35 evaluable patients was 54% (16 complete response (CR) and 3 complete response with incomplete hematologic recovery (CRi)). Ninety percent of responders achieved minimal residual disease (MRD) negativity (<0.1%) by centralized flow cytometry and 84% (n = 16) successfully proceeded to hematopoietic stem cell transplant. Two-year overall survival was 75.6% [95%CI: 47.3%, 90.1%] for MRD-negative patients vs. 17.9% [95%CI: 4.4%, 38.8%] for those with residual disease (p < .001). Twelve subjects (34%) had known epigenetic alterations with 8 (67%) achieving a CR, 7 (88%) of whom were MRD negative. Correlative pharmacodynamics demonstrated the biologic activity of decitabine and vorinostat and identified specific gene enrichment signatures in nonresponding patients. Overall, this therapy was well-tolerated, biologically active, and effective in pediatric patients with R/R AML, particularly those with epigenetic alterations.

Pediatric HCT in Florida (2014 -2016): A report from the FPBCC.

FPBCC was formed in 2018 by five pediatric transplant programs in Florida. One of the key objectives of the consortium is to provide outcome analyses by combining HCT data from all the participating centers in order to identify areas for improvement. In this first FPBCC landscape report we describe the patient and transplant characteristics of pediatric patients undergoing first allo and auto HCT between 2014 and 2016 in Florida. The source of data was eDBtC of the CIBMTR. Over the span of 3 years, a total of 230 pediatric patients underwent allo-HCT and 104 underwent auto-HCT at the participating centers. The most significant predictor of survival in allo-HCT recipients with malignant disorders was the degree of HLA- match, while in the recipients of allo-HCT with non-malignant disorders the predictors of survival included age, donor relationship and degree of HLA match. Our analyses identified the need to improve reporting of primary cause of death and improve on donor selection process given that the degree of HLA match remains the most important predictor of survival. This first FPBCC-wide review describes the trends in pediatric HCT activity between 2014 and 2016 among the participating centers in Florida and confirms feasibility of using eDBtC data platform and collaborative approach in order to identify areas for improvement in outcomes.

Instituting a New Central Line Policy to Decrease Central Line-associated Blood Stream Infection Rates During Induction Therapy in Pediatric Acute Lymphoblastic Leukemia Patients.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) require central lines to facilitate their care. Peripherally inserted central catheters (PICCs) may have lower rates of central line-associated bloodstream infections (CLABSIs) versus other central lines. OBJECTIVES: The objective of this study was to compare the CLABSI rate in the first month of therapy after initiating a policy to place PICCs in new patients with severe neutropenia (SN) and Mediports in those with moderate-to-no neutropenia. We also examined thrombosis rates. DESIGN/METHOD: We prospectively gathered data on new patients for 2.5 years following the policy change and retrospectively for the 2 years prior and compared rates of CLABSIs and thrombosis. RESULTS: CLABSIs decreased in SN patients from 7.52/1000 to 3.11/1000 line days (P=0.33). The CLABSI rate for all patients with SN who had a Mediport was 13.39/1000 versus 4.08/1000 line days for those that received PICCs (P=0.15). The thrombosis rate for Mediport patients was 3.13 clots/1000 versus 7.65/1000 line days for PICC patients, but the difference was not significant (P= 0.11). CONCLUSION: The differences observed suggest that placing PICCs versus Mediports in new ALL patients with SN may result in a lower incidence of CLABSIs in the first month of therapy without a significant increase in thrombosis.

Quantifying the psychosocial impact of a weekend retreat on adolescent and young adult (AYA) oncology patients.

OBJECTIVE: This study aimed to determine if AYA oncology patients experienced a quantifiable improvement in psychosocial outcomes after attending a weekend retreat with their peers. METHODS: AYA oncology patients attended a weekend retreat. They completed the Functional Assessment of Cancer Therapy - General (FACT-G) before, 1 month after, and 6 months after the weekend retreat. Controls were age-matched oncology patients who did not attend the retreat. FINDINGS: Retreat participants' scores did not significantly change over time; however, retreat participants' scores at 1-month follow-up were significantly higher than control group scores. CONCLUSIONS: AYA oncology patients may experience transient improvement in psychological well-being after attending a retreat, but benefits may not be durable. Work remains needed to examine the impact of retreat attendance on specific aspects of psychosocial well-being. Implications for psychosocial oncology: Work is needed to decrease perceived attendance barriers for AYA oncology patients who have a low quality of life. Future retreat planners may consider modifying retreat activities and consider alternative retreat locations that appeal to campers with limited mobility, chronic pain, and/or other quality of life limitations. Additional study is needed to determine whether brief overnight or weekend retreats can be as effective as week-long camps in enhancing oncology patients' quality of life. Future researchers should compare changes in weekend retreat attendees' quality of life to changes in quality of life for a control group (e.g., via a waitlist control study design).

No improvement in clinical trial enrollment for adolescents and young adults with cancer at a children's hospital.

BACKGROUND: We have previously published data from 2001 to 2006 showing that adolescent and young adult (AYA) oncology patients have significantly lower therapeutic clinical trial enrollment rates than younger patients. Our objective was to determine if the enrollment of AYA patients on therapeutic studies at the same institution has improved in recent years with the greater focus on this population locally and nationally. METHODS: We retrospectively analyzed cancer registry data at the Children's Hospital of Pittsburgh (CHP) for all new oncologic diagnoses between January 2010 and December 2014. These data included age, gender, diagnosis, race and whether the patient was enrolled on an open treatment study. Univariate analyses were carried out to compare demographic data between AYA patients (aged 15-22) who enrolled on study and those who did not. RESULTS: Eight hundred sixty-five new oncology patients were seen at CHP during this time, 23% of whom were 15 years or older; 33% of all patients were treated on a clinical trial, including 34% of younger patients and 24% of older patients (P = 0.0017). The differences between these rates and those from prior years in both age groups (38% and 27%, respectively) were not statistically significant (P = 0.15, 0.53). The most common reason for the low enrollment rates was again the lack of an open therapeutic trial. CONCLUSION: Despite initiatives at CHP and on the national level to enroll more AYA patients on clinical trials, our most recent data show no improvement. This is a potentially remediable factor that needs to continue to be prioritized nationally.

Adolescent and Young Adult (AYA) Oncology in the United States: A Specialty in Its Late Adolescence.

Over the last 30 years, it has become apparent that oncology patients ages 15 to 39 have not reaped the same rewards of improved survival that we have seen in younger and older patients. As a result, in 2006 the Adolescent and Young Adult (AYA) Oncology Progress Review Group convened and examined the factors that impact the care of the 70,000 new cases per year (approximately 7% of all new cases) in the United States and published their findings. The reasons for inferior survival gains are of course multiple and include the settings in which patients are cared for, clinical trial enrollment, insurance coverage, varied treatment of sarcomas, varied treatment of acute lymphoblastic leukemia, the psychosocial impact of cancer and cancer survivorship. A new area of a yet-to-be completely defined subspecialty was born out of this meeting: AYA oncology. As a medical community we realized that these patients do not fit neatly into the pediatric nor adult world and, therefore, require a unique approach which many individuals, oncology centers, advocacy groups, and cooperative trial groups have started to address. This group of dedicated providers and advocates has made strides but there is still much work to be done on the local, national, and international level to make up for shortcomings in the medical system and improve outcomes. We review key components of AYA cancer care in 2015 that all providers should be aware of, how far we have come, where this movement is headed, and the obstacles that continue to stand in the way of better cure rates and quality of life after cure for this unique group of patients. Like an adolescent maturing into adulthood, this movement has learned from the past and is focused on moving into the future to achieve its goals.

Piloting a Patient-Driven Online Survey to Better Understand Cancer in Adolescents and Young Adults (AYA) in the United States.

Adolescents and young adults (AYAs) with cancer are a unique patient population in oncology. An opt-in, secure online survey was conducted among a general population of AYA patients and survivors to better understand the current landscape of AYA cancer. A 28-item online survey was designed for cancer patients and survivors diagnosed between the ages of 18 and 39 years. It comprised questions about demographics, treatment site, clinical trial involvement, support services available, and impact on employment, schooling, and finances. A total of 590 patients registered and 447 (76%) completed the survey. This online exercise was found to be feasible and can serve as an effective method to survey the AYA cancer population.

Trends in Pediatric Cancer Care in Florida From 1981-2020: Changing Patterns in a Growing and Increasingly Diverse Population.

Background The Florida Association of Pediatric Tumor Programs (FAPTP) has used the Statewide Patient Information Reporting System (SPIRS) since 1981 to track all new cases of pediatric cancer. We reviewed the last 40 years of data to see how pediatric cancer care has evolved. Methods We retrospectively analyzed SPIRS data from 1981 through 2020 in five-year increments, looking at numbers of new diagnoses, care delivery sites, and trial enrollment in Children's Oncology Group (COG) studies. Results From 1981-2020 Florida's population increased almost 88% while the pediatric population only grew 61%. New pediatric cancer diagnoses increased 326% to over 1,000 new cases/year. The percentage of patients treated at FAPTP centers grew from 30% to 57% with an annual percentage change (APC) of 10.3% (95% Confidence Interval [CI] of 0.6 to 20.9%). The rate of COG clinical trial enrollment decreased from 32% in 1981-1985 to 20% in 2016-2020, for an APC of 8.91% (95% CI of -13.3 to -4.3%). Conclusions The striking increase in pediatric cancer cases in Florida over the last 40 years was out of proportion to the population growth. More patients received care at FAPTP centers, but a lower percentage were enrolled on COG trials.

Improved clinical trial enrollment in adolescent and young adult (AYA) oncology patients after the establishment of an AYA oncology program uniting pediatric and medical oncology divisions.

BACKGROUND: Since 1975, there has been a dramatic increase in the survival rates of pediatric and older cancer patients, but adolescent and young adult (AYA) patients ages 15 to 40 years have not had a similar improvement. Data indicate a direct correlation between increased cure rates and clinical trial enrollment. METHODS: The authors previously published data indicating inferior clinical trial enrollment when AYA patients were treated at an adult oncology center versus a pediatric oncology center. To address this deficit, a joint pediatric and adult AYA Oncology Program was established in July 2006 with the primary objective of improving outcomes by increasing therapeutic clinical trial enrollment in this population. Patients who were referred to that program from July 2006 through June 2010 were examined retrospectively to establish whether clinical trial enrollment increased compared with historic controls. RESULTS: Fifty-seven patients were referred to the program from 2006 to 2010 (range, 12-16 new patients per year). Eight patients were referred for consultation only and were not treated at the University of Pittsburgh Cancer Institute or Children's Hospital of Pittsburgh. Five of 22 patients (23%) who received treatment at the pediatric cancer center were enrolled onto a clinical trial, whereas 9 of 27 patients (33%) patients who received treatment at the adult cancer center were enrolled. There was superior trial participation compared with the previous 3 years for those shared AYA patients who were treated at the adult center (P < .001). CONCLUSIONS: Data from this study demonstrated that establishing a unified AYA oncology program can lead to improved clinical trial enrollment for patients who are treated at medical oncology centers.

Predictors of von Willebrand disease in children.

BACKGROUND: Bleeding and bruising are common symptoms for which children are referred to a pediatric hematologist. Although bleeding scores have been validated to quantify bleeding risk in adults, there are no similar definitive data in children. The aim was to describe presenting bleeding symptoms in children and evaluate if these bleeding symptoms were predictive of von Willebrand disease (VWD) or low von Willebrand factor (VWF). PROCEDURE: We performed a retrospective chart review of consecutive pediatric patients referred for perceived bleeding symptoms to the coagulation clinic at The Children's Hospital of Pittsburgh of UPMC. All underwent a uniform bleeding symptom inventory and hemostatic testing. Single and multiple variable logistic regression models were created to predict either VWD, low VWF, or nonspecific defective platelet aggregation, using the predictor variables of family bleeding history, mucocutaneous bleeding, cutaneous bleeding, and surgical bleeding, based on The International Society on Thrombosis and Hemostasis (ISTH) bleeding definitions. RESULTS: Of 298 pediatric patients evaluated, 8% had VWD (VWF:RCo and VWF:Ag ≤ 30 IU/dl) and 34% had low VWF (VWF:RCo and VWF:Ag 30-50 IU/dl). Further, 16% had a nonspecific platelet aggregation disorder, 41% had normal hemostatic testing, and 1% had factor VIII or IX deficiency. In single and multiple variable logistic regression analysis, neither a personal or family bleeding history at presentation, nor the presence of two or more bleeding symptoms were predictive of VWD, low VWF, or nonspecific defective platelet aggregation. CONCLUSIONS: These findings suggest that qualitative assessment of bleeding symptoms alone is not useful in children.

A comparison of clinical trial enrollment between adolescent and young adult (AYA) oncology patients treated at affiliated adult and pediatric oncology centers.

PURPOSE: Over the past 30 years, there has been a dramatic increase in the survival rates of younger pediatric cancer patients in contrast to adolescent and young adult (AYA) oncology patients. The reasons for this discrepancy are multifactorial, but it is clear that clinical trial enrollment correlates with better outcomes. PATIENTS AND METHODS: We examined the rate of clinical trial accrual of AYA oncology patients (aged 15 to 22 y) treated at affiliated pediatric and adult cancer centers, the Children's Hospital of Pittsburgh and the University of Pittsburgh Cancer Institute. We retrospectively analyzed all new cancer diagnoses and clinical trial enrollment status between 2003 and 2006 for AYA patients at both institutions. RESULTS: There were 91 new AYA cancer diagnoses at Children's Hospital of Pittsburgh, of which 24 (26%) were enrolled on a clinical trial. During the same time period, only 5 of 121 new AYA cancer patients (4%) at University of Pittsburgh Cancer Institute were enrolled on a clinical trial, which was significantly lower (P<0.001). CONCLUSIONS: Our data demonstrate that clinical trial enrollment was superior when AYA patients were treated at a pediatric cancer center. As most AYA patients are not treated at pediatric centers, this may partly explain why their cure rates have not improved as significantly as younger pediatric oncology patients.

A Comparison of Extremity Thrombosis Rates in Adolescent and Young Adult Versus Younger Pediatric Oncology Patients at a Children's Hospital.

PURPOSE: To examine whether the rates of thrombosis in children (≤14 years of age) and adolescent/young adult (AYA) patients (15-22 years of age) with cancer is different. METHODS: We retrospectively studied the rates of thrombosis in children and AYA patients at the Children's Hospital of Pittsburgh during the years 2002-2010, using the tumor registry database. This list was then divided into two groups based on age at diagnosis. A review of ICD-9 codes from hospital billing records was then performed to identify patients who carried diagnoses of cancer (140.x-239.x) and venous thrombosis of the extremities/vena cavae (453.x) simultaneously. This list was confirmed by electronic medical record review. Proportions, comparisons, and descriptive statistics were then performed. RESULTS: One thousand three hundred nine total patients were identified; 274 patients fit into the AYA age category (mean age 17.3 years) and 1036 patients were in the child group (mean age 6.5 years). Overall, 30 patients (2.29%) had thrombosis: 4.76% of the AYA patients (13/273) and 1.64% of the child group (17/1036). The difference in these proportions had a p-value = 0.004. CONCLUSIONS: This study suggests that the risk of extremity deep vein thrombosis is higher in the AYA subset of oncology patients than in the patients who are 14 years or younger. Prospective studies to elucidate the true rate of thrombosis, as well as to study the benefit of prophylactic anticoagulation in the AYA population, should be undertaken.

A case of myelodysplastic syndrome with acquired monosomy 7 in a child with a constitutional t(1;19) and a mosaicism for trisomy 21.

A 3-year-old patient presented with anemia, thrombocytopenia, and blasts in the peripheral blood. A bone marrow aspirate revealed a myelodysplastic syndrome (MDS). A mosaic abnormal female karyotype 46,XX, t(1;19)(q42; p13.1)c[12]/ 47,idem,+21c[3]/ 47,idem,-7,+21c,+mar[7] was obtained on G-banded metaphases from unstimulated bone marrow aspirate cell culture. To rule out constitutional abnormalities, we performed a cytogenetic analysis on the patient's phytohemagglutinin-stimulated peripheral blood and cultured skin fibroblasts. A karyotype of 46,XX,t(1;19) (q42;p13.1)c was found in all 20 peripheral lymphocytes analyzed, confirming the constitutional origin of the translocation. In addition, 5 out of 50 cells from two separate cultures of the skin fibroblasts contained an extra chromosome 21. The presence of two cell lines in multiple cultures indicates that the patient is a true low-level mosaic for trisomy 21. Because of the finding of monosomy 7 and a marker chromosome only in the trisomy 21 clone, we conclude that the leukemic clone arose from a hematopoietic precursor with constitutional trisomy 21. It is also possible that the t(1;19) played some role in the development of the MDS. Because acute myelogenous leukemia (AML) and MDS with Down syndrome (DS) have distinct biologic and clinical features, the identification of DS patients with a mild or normal phenotype in the AML/MDS population is of fundamental importance for clinical diagnosis and management.

Identification of Unique, Heterozygous Germline Mutation, STK11 (p.F354L), in a Child with an Encapsulated Follicular Variant of Papillary Thyroid Carcinoma within Six Months of Completing Treatment for Neuroblastoma.

Papillary thyroid carcinoma (PTC) is rare in children, although it is a known secondary malignancy after treatment for neuroblastoma (NB). The interval between NB treatment completion and PTC is usually more than 5 years. A 4-year-old, female patient with a high risk adrenal NB was found to have a 2.9-cm, right thyroid nodule on surveillance chest computed tomography (CT) 6 months after completion of her NB treatment (induction chemotherapy, tumor resection, autologous stem cell transplantation, external beam radiation to the abdominal tumor site, immunotherapy, and retinoic acid). Posttreatment surveillance included iodine-123-metaiodobenzylguanidine scans and CT scans. Fine-needle aspiration of the thyroid nodule diagnosed a follicular neoplasm, which was negative for BRAF, NRAS, KRAS, HRAS, PAX8/PPARg, and RET/PTC mutations, without evidence of metastatic NB. Nodule histology demonstrated an encapsulated follicular variant of PTC (FVPTC). Next-generation sequence analysis for a 46 cancer-gene profile was performed on both tumors with subsequent peripheral blood DNA testing. A heterozygous missense mutation in STK11 (F354L) was identified in both the NB and FVPTC. This mutation was also detected in peripheral blood mononuclear cells. Two additional heterozygous somatic missense mutations of uncertain significance were identified: KDR/VEGF receptor 2 (Q472H) on chromosome 4 and MET (N375S) on chromosome 7. To our knowledge, this is the shortest reported duration from completion of NB treatment to detection of thyroid cancer. The association of the STK11 gene with Peutz-Jeghers syndrome, lung adenocarcinomas, and medullary thyroid cancer leads to a possible association between this genetic variant and our patient's tumors.

Improving enrollment in clinical trials for adolescents with cancer.

Overall cancer cure rates have risen over the last 30 years. Adolescent and young adult (AYA) oncology patients aged 15 to 39 have not shared in these successes as an age group, including those who fall into the younger age group of 15 to 19 years. The reasons for this deficit in survival improvement are manifold, but research has shown that an important factor is decreased enrollment in therapeutic clinical trials in this population versus younger patients. The paucity of adolescents treated in clinical trials is itself the result of several elements of the health care landscape in the United States. On the local level, these factors include referral patterns and facilities available; on the national level, related factors include the number of clinical trials available for this age group and health care provider education in the care of these patients. We examine the data available that have contributed to this deficit in the United States and offer broad strategies to address these shortcomings with the goal of improving outcomes in this underserved population.

Analysis of national and single-center incidence and survival after liver transplantation for hepatoblastoma: new trends and future opportunities.

BACKGROUND: Liver transplantation (LTx) for hepatoblastoma appears to be increasing. Favorable tumor histology is increasingly linked to survival after surgical resection and could also determine posttransplantation outcomes. METHODS: To evaluate national trends in tumor and LTx incidence as the basis for observations at some LTx centers, and determinants of survival after LTx for hepatoblastoma, we queried the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) registry representing 9.451% of the U.S. population (1975-2007), the United Network for Organ Sharing (UNOS, 1988-2010, n = 332), and Children's Hospital of Pittsburgh database (CHP, 1987-2011, n = 35). RESULTS: In the United States, hepatoblastoma cases increased 4-fold, LTx for hepatoblastoma increased 20-fold, and hepatoblastoma surpassed other unresectable liver malignancies requiring LTx by nearly 3-fold. Actuarial 5-year patient survival exceeded 75%. Recurrences in 16% were greater after segmental LTx in the total U.S. experience (P = .049). At CHP, 5 children died from recurrences (n = 4) and sepsis (n = 1). Tumors were epithelial (57%) or mixed epithelial-stromal (42%), Children's Oncology Group stage III (77%) or IV (23%). Recurrences were related to previous pulmonary metastases (P = .016), and tumor necrosis <50% (P = .013), but not to small cell undifferentiated tumor histology (P = NS). Hepatic artery thrombosis was more common after LTx for hepatoblastoma compared with nonmalignant indications (P = .0089). Thirty-three children received pre-LTx chemotherapy, 88.6% with cisplatin, and 85.7% received post-LTx chemotherapy. CONCLUSION: Outcomes after LTx for hepatoblastoma may benefit from improved detection and treatment of pretransplantation metastases, adequate tumor lysis after chemotherapy, and perioperative antithrombotic agents but are unaffected by undifferentiated tumor histology.