Publications by authors named "Clement Ma"

84 Publications

Early parental knowledge of late effect risks in children with cancer.

Pediatr Blood Cancer 2021 Nov 29:e29473. Epub 2021 Nov 29.

Harvard Medical School, Boston, Massachusetts, USA.

Background/objectives: Despite the pervasiveness of late effects in childhood cancer survivors, many parents feel inadequately informed about their child's risks. We assessed early parental knowledge of risks of late effects and predictors of increased knowledge.

Design/methods: Parents of children receiving cancer treatment at Dana-Farber/Boston Children's Cancer and Blood Disorders Center were surveyed about their knowledge of their child's likelihood of eight late effects. Individual risk for each late effect (yes/no) was assessed using the Children's Oncology Group's Long-Term Follow-Up Guidelines v5 as a reference. Descriptive statistics were used to summarize knowledge scores; ordinal logistic regression was used to identify predictors of higher knowledge.

Results: Of 96 parent participants, 11 (11.46%) correctly identified all of their child's risks for the eight late effects. Five of eight was the median number of correctly identified late effect risks. Among 21 parents whose children were at risk for ototoxicity, 95% correctly identified this risk. Conversely, parents of at-risk children were less knowledgeable about risks of secondary malignancy (63% correct identification, of N = 94 at risk), cardiac toxicity (61%; N = 71), neurocognitive impairment (56%; N = 63), and infertility (28%; N = 61). Ordinal logistic regression analysis identified no significant differences in parental knowledge of late effect risks by any factors evaluated.

Conclusions: Gaps in parental knowledge of potential late effects of childhood cancer treatment emerge early in a child's care, and parents are more knowledgeable about some late effects, such as ototoxicity, than others, such as infertility. As no child- or parent-specific factors were associated with increased knowledge of late effect risks, interventions must be applied broadly.
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http://dx.doi.org/10.1002/pbc.29473DOI Listing
November 2021

Stimulated Insulin Secretion Predicts Changes in Body Composition Following Weight Loss in Adults with High BMI.

J Nutr 2021 Sep 29. Epub 2021 Sep 29.

New Balance Foundation Obesity Prevention Center, Boston Children's Hospital, Boston, MA, USA.

Background: The aim of obesity treatment is to promote loss of fat relative to lean mass. However, body composition changes with calorie restriction differ among individuals.

Objectives: The goal of this study was to test the hypothesis that insulin secretion predicts body composition changes among young and middle-age adults with high BMI (in kg/m2) following major weight loss.

Methods: Exploratory analyses were conducted with pre-randomization data from 2 large feeding trials: the Framingham, Boston, Bloomington, Birmingham, and Baylor study (FB4; n = 82, 43.9% women, BMI ≥27) and the Framingham State Food Study [(FS)2; n = 161, 69.6% women, BMI ≥25]. Participants in the 2 trials consumed calorie-restricted moderate-carbohydrate or very-low-carbohydrate diets to produce 12-18% weight loss in ∼14 wk or 10-14% in ∼10 wk, respectively. We determined insulin concentration 30 min after a 75-g oral glucose load (insulin-30) as a measure of insulin secretion and HOMA-IR as a measure of insulin resistance at baseline. Body composition was determined by DXA at baseline and post-weight loss. Associations were analyzed using general linear models with adjustment for covariates.

Results: In FB4, higher insulin-30 was associated with a smaller decrease in fat mass (0.441 kg per 100 μIU/mL increment in baseline insulin-30; P = 0.005; -1.20-kg mean difference between the first compared with the fifth group of insulin-30) and a larger decrease in lean mass (-0.465 kg per 100 μIU/mL; P = 0.004; 1.27-kg difference). Participants with higher insulin-30 lost a smaller proportion of weight loss as fat (-3.37% per 100 μIU/mL; P = 0.003; 9.20% difference). Greater HOMA-IR was also significantly associated with adverse body composition changes. Results from (FS)2 were qualitatively similar but of a smaller magnitude.

Conclusions: Baseline insulin dynamics predict substantial individual differences in body composition following weight loss. These findings may inform understanding of the pathophysiological basis for weight regain and the design of more effective obesity treatment. Registered at clinicaltrials.gov as NCT03394664 and NCT02068885.
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http://dx.doi.org/10.1093/jn/nxab315DOI Listing
September 2021

Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial.

Am J Clin Nutr 2021 Sep 28. Epub 2021 Sep 28.

New Balance Foundation Obesity Prevention Center, Boston Children's Hospital, Boston, MA, USA.

Background: Carbohydrate restriction shows promise for diabetes, but concerns regarding high saturated fat content of low-carbohydrate diets limit widespread adoption.

Objectives: This preplanned ancillary study aimed to determine how diets varying widely in carbohydrate and saturated fat affect cardiovascular disease (CVD) risk factors during weight-loss maintenance.

Methods: After 10-14% weight loss on a run-in diet, 164 participants (70% female; BMI = 32.4 ± 4.8 kg/m2) were randomly assigned to 3 weight-loss maintenance diets for 20 wk. The prepared diets contained 20% protein and differed 3-fold in carbohydrate (Carb) and saturated fat as a proportion of energy (Low-Carb: 20% carbohydrate, 21% saturated fat; Moderate-Carb: 40%, 14%; High-Carb: 60%, 7%). Fasting plasma samples were collected prerandomization and at 20 wk. Lipoprotein insulin resistance (LPIR) score was calculated from triglyceride-rich, high-density, and low-density lipoprotein particle (TRL-P, HDL-P, LDL-P) sizes and subfraction concentrations (large/very large TRL-P, large HDL-P, small LDL-P). Other outcomes included lipoprotein(a), triglycerides, HDL cholesterol, LDL cholesterol, adiponectin, and inflammatory markers. Repeated measures ANOVA was used for intention-to-treat analysis.

Results: Retention was 90%. Mean change in LPIR (scale 0-100) differed by diet in a dose-dependent fashion: Low-Carb (-5.3; 95% CI: -9.2, -1.5), Moderate-Carb (-0.02; 95% CI: -4.1, 4.1), High-Carb (3.6; 95% CI: -0.6, 7.7), P = 0.009. Low-Carb also favorably affected lipoprotein(a) [-14.7% (95% CI: -19.5, -9.5), -2.1 (95% CI: -8.2, 4.3), and 0.2 (95% CI: -6.0, 6.8), respectively; P = 0.0005], triglycerides, HDL cholesterol, large/very large TRL-P, large HDL-P, and adiponectin. LDL cholesterol, LDL-P, and inflammatory markers did not differ by diet.

Conclusions: A low-carbohydrate diet, high in saturated fat, improved insulin-resistant dyslipoproteinemia and lipoprotein(a), without adverse effect on LDL cholesterol. Carbohydrate restriction might lower CVD risk independently of body weight, a possibility that warrants study in major multicentered trials powered on hard outcomes.
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http://dx.doi.org/10.1093/ajcn/nqab287DOI Listing
September 2021

Thinking ahead: Parents' worries about late effects of childhood cancer treatment.

Pediatr Blood Cancer 2021 Dec 14;68(12):e29335. Epub 2021 Sep 14.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Many childhood cancersurvivors experience at least one late effect of treatment, and both late effects and persistent cancer-related worry can negatively impact quality of life in survivorship. Little is known about the prevalence or impact of parental worry about late effects early in treatment. This study evaluated parental perceived likelihood, impact, and worry about late effects of childhood cancer.

Procedure: We surveyed 96 parents of pediatric cancer patients at Dana-Farber/Boston Children's Cancer and Blood Disorders Center within a year of diagnosis. Parents were asked about their experiences with late effects communication, general worry about late effects, and specific late effect worries.

Results: Most (96%) parents valued information about late effects, and 93% considered late effects in their treatment decision-making. Yet, 24% could not recall receiving any information about late effects, and only 51% felt well prepared for potential late effects. Though only 20% of parents considered their child at high risk of experiencing late effects, 61% were extremely/very worried about late effects. Those who felt their child was at high risk of experiencing late effects were more likely to worry (OR = 4.7, P = 0.02).

Conclusions: Many parents feel inadequately informed about late effects of cancer treatment, and only one-fifth of parents consider late effects to be likely for their child. However, a majority of parents worry about late effects, including ones they think their child is unlikely to experience. Although some worry is anticipated, disproportionate worry may be mitigated by addressing both educational shortfalls and emotional concerns.
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http://dx.doi.org/10.1002/pbc.29335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541904PMC
December 2021

Disparities in pediatric psychosocial oncology utilization.

Pediatr Blood Cancer 2021 Nov 14;68(11):e29342. Epub 2021 Sep 14.

Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.

Background: Integratedbehavioral health models have been proposed as care delivery approaches to mitigate mental health disparities in primary care settings. However, these models have not yet been widely adopted or evaluated in pediatric oncology medical homes.

Methods: We conducted a retrospective cohort study of 394 children with newly diagnosed cancer at Dana-Farber/Boston Children's Cancer and Blood Disorders Center (DF/BCH) from April 2013 to January 2017. Baseline sociodemographic characteristics and psychiatry utilization outcomes at 12 months following diagnosis were abstracted from the medical record. The severity of household material hardship (HMH), a concrete poverty exposure, at diagnosis and race/ethnicity were characterized by parent report using the Psychosocial Assessment Tool 2.0 (PAT). Associations between sociodemographic characteristics and receipt of psychiatry consultation were assessed with multivariable logistic regression models.

Results: Among 394 children, 29% received a psychiatric consultation within 12 months postdiagnosis. Of these, 88% received a new psychiatric diagnosis, 76% received a psychopharmacologic recommendation, and 62% received a new behavioral intervention recommendation. In multivariable logistic regression adjusting for age, cancer diagnosis, and PAT total score, there was no statistically significant association between HMH severity or household income and psychiatry utilization. Children who identified as racial/ethnic minorities were significantly less likely to receive a psychiatry consultation (OR = 0.48, 95% CI = 0.27-0.84).

Conclusions: In a pediatric oncology medical home with an integrated behavioral health model, socioeconomic status was not associated with disparate psychiatry utilization. However, there remained a profound racial/ethnic disparity in psychiatry utilization, highlighting the need for additional research and care delivery intervention.
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http://dx.doi.org/10.1002/pbc.29342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463506PMC
November 2021

Phase 3 randomised trial of eltrombopag versus standard first-line pharmacological management for newly diagnosed immune thrombocytopaenia (ITP) in children: study protocol.

BMJ Open 2021 08 27;11(8):e044885. Epub 2021 Aug 27.

Pediatrics, Columbia University Medical School, New York, New York, USA.

Introduction: Immune thrombocytopaenia (ITP) is an acquired disorder of low platelets and risk of bleeding. Although many children can be observed until spontaneous remission, others require treatment due to bleeding or impact on health-related quality of life. Standard first-line therapies for those who need intervention include corticosteroids, intravenous immunoglobulin and anti-D globulin, though response to these agents may be only transient. Eltrombopag is an oral thrombopoietin receptor agonist approved for children with chronic ITP who have had an insufficient response to corticosteroids, intravenous immunoglobulin or splenectomy. This protocol paper describes an ongoing open-label, randomised trial comparing eltrombopag to standard first-line management in children with newly diagnosed ITP.

Methods And Analysis: Randomised treatment assignment is 2:1 for eltrombopag versus standard first-line management and is stratified by age and by prior treatment. The primary endpoint of the study is platelet response, defined as ≥3 of 4 weeks with platelets >50×10/L during weeks 6-12 of therapy. Secondary outcomes include number of rescue therapies needed during the first 12 weeks, proportion of patients who do not need ongoing treatment at 12 weeks and 6 months, proportion of patients with a treatment response at 1 year, and number of second-line therapies used in weeks 13-52, as well as changes in regulatory T cells, iron studies, bleeding, health-related quality of life and fatigue. A planned sample size of up to 162 randomised paediatric patients will be enrolled over 2 years at 20 sites.

Ethics And Dissemination: The study has been approved by the centralised Baylor University Institutional Review Board. The results are expected to be published in 2023.

Trial Registration Number: NCT03939637.
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http://dx.doi.org/10.1136/bmjopen-2020-044885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404450PMC
August 2021

Symptoms and Suffering at End of Life for Children With Complex Chronic Conditions.

J Pain Symptom Manage 2021 Jul 24. Epub 2021 Jul 24.

Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.

Context: Children with cancer and cardiac disease suffer with high symptom burden at end of life (EOL). Little is known about the EOL experience for children with other complex chronic conditions (CCCs).

Objectives: To evaluate symptoms and suffering at EOL for children with noncancer, noncardiac CCCs as well as parental distress related to child suffering.

Methods: This study is a secondary data analysis of a cross-sectional, single-center survey of bereaved parents of children with CCCs who died between 2006 to 2015. The primary outcome was parent-reported child suffering in the final two days of life.

Results: Among 211 eligible parents contacted for participation, 114 completed the survey, and 99 had complete primary outcome data (participation rate 47%). Most children had congenital/chromosomal (42%) or progressive central nervous system (22%) conditions. Twenty-eight percent of parents reported high child suffering in the final two days of life. Parents reported that pain and difficulty breathing caused the greatest suffering for children and distress among themselves. Some parents also reported distress related to uncertainty about child suffering. Parents were less likely to report high child suffering if they were confident in knowing what to expect when their child was dying (AOR 0.20; 95% CI 0.07-0.60) or felt prepared for medical problems at EOL (AOR 0.12; 95% CI 0.04-0.42).

Conclusion: Nearly one-third of parents of children with CCCs report high suffering in their child's final days of life. Parent preparedness was associated with lower perceived child suffering. Future research should target symptoms contributing to parent and child distress and assess whether enhancing parent preparedness reduces perceived child suffering.
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http://dx.doi.org/10.1016/j.jpainsymman.2021.07.010DOI Listing
July 2021

Race, ethnicity, and goal-concordance of end-of-life palliative care in pediatric oncology.

Cancer 2021 Oct 13;127(20):3893-3900. Epub 2021 Jul 13.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Racial and ethnic minority children with cancer disproportionately receive intensive care at the end of life (EOL). It is not known whether these differences are goal-concordant or disparities. The authors sought to explore patterns of pediatric palliative care (PPC) and health care utilization in pediatric oncology patients receiving subspecialty palliative care at the end-of-life (last 6 months) and to examine goal-concordance of location of death in a subset of these patients.

Methods: This was a retrospective cohort study of pediatric oncology patients receiving subspecialty palliative care at a single large tertiary care center who died between January 2013 and March 2017.

Results: A total of 115 patients including 71 White, non-Hispanic patients and 44 non-White patients (including 12 Black patients and 21 Hispanic patients) were included in the analytic cohort. There were no significant differences in oncologic diagnosis, cause of death, or health care utilization in the last 6 months of life. White and non-White patients had similar PPC utilization including time from initial consult to death and median number of PPC encounters. Non-White patients were significantly more likely to die in the hospital compared to White patients (68% vs 46%, P = .03). Analysis of a subcohort with documented preferences (n = 45) revealed that 91% of White patients and 93% of non-White patients died in their preferred location of death.

Conclusions: Although non-White children with cancer were more likely to die in the hospital, this difference was goal-concordant in our cohort. Subspecialty PPC access may contribute to the achievement of goal-concordant EOL care.
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http://dx.doi.org/10.1002/cncr.33768DOI Listing
October 2021

Gene Fusions Create Partner and Collateral Dependencies Essential to Cancer Cell Survival.

Cancer Res 2021 Aug 7;81(15):3971-3984. Epub 2021 Jun 7.

Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene fusions play an important role in oncogenesis; in other instances, they are thought to be passenger events. Although regulatory element rearrangements and copy number alterations resulting from these structural variants are known to lead to transcriptional dysregulation across cancers, the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. Here we used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines from the Cancer Dependency Map. We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency on a gene within the same topologically associating domain as a fusion partner. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types. SIGNIFICANCE: This study provides insights into how fusions contribute to fitness in different cancer contexts beyond partner-gene activation events, identifying partner and collateral dependencies that may have direct implications for clinical care.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338889PMC
August 2021

Socioeconomic disparities in survival after high-risk neuroblastoma treatment with modern therapy.

Pediatr Blood Cancer 2021 Oct 22;68(10):e29127. Epub 2021 May 22.

Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.

Background: Modern therapeutic advances in high-risk neuroblastoma have improved overall survival (OS), but it is unclear whether these survival gains have been equitable. This study examined the relationship between socioeconomic status (SES) and overall survival (OS) in children with high-risk neuroblastoma and whether SES-associated disparities have changed over time.

Procedure: In this population-based cohort study, children <18 years diagnosed with high-risk neuroblastoma (diagnosis at age ≥12 months with metastatic disease) from 1991 to 2015 were identified through the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Associations of county-level SES variables and OS were tested with univariate Cox proportional hazards regression. For a subcohort diagnosed after 2007, insurance status was examined as an individual-level SES variable. Multivariable regression analyses with treatment era and interaction terms were performed when SES variables reached near-significance (p ≤ .1) in univariate and bivariate modeling with treatment era.

Results: Among 1217 children, 2-year OS improved from 53.0 ± 3.4% in 1991-1998 to 76.9 ± 2.9% in 2011-2015 (p < .001). In univariate analyses, children in high-poverty counties (hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.17-2.60, p = .007), and those with Medicaid (HR = 1.40, 95% CI = 1.05-1.86, p = .02) experienced an increased hazard of death. No interactions between treatment era and SES variables were statistically significant in multivariable analyses, indicating that differences in the OS between SES groups did not change over time.

Conclusions: Survival disparities among children with high-risk neuroblastoma have not widened over time, suggesting equitable access to and benefit from therapeutic advances. However, children of low SES experience persistently inferior survival. Interventions to narrow this disparity are paramount.
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http://dx.doi.org/10.1002/pbc.29127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384664PMC
October 2021

Retrospective evaluation of single patient investigational new drug (IND) requests in pediatric oncology.

Cancer Med 2021 Mar 9. Epub 2021 Mar 9.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Background: Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology.

Methods: We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017-2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity.

Results: Over the 2-year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12-year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0-12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4-1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three-year overall survival was 50% (95% CI, 35-64).

Conclusions: Single patient INDs in pediatric oncology were universally approved in our national and single-center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial.
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http://dx.doi.org/10.1002/cam4.3791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982629PMC
March 2021

Building a Harmonized Datamart by Integrating Cross-Institutional Systems of Clinical, Outcome, and Genomic Data: The Pediatric Patient Informatics Platform ().

JCO Clin Cancer Inform 2021 02;5:202-215

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.

Purpose: Siloed electronic medical data limits utility and accessibility. At the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, cross-institutional data were inconsistent and difficult to access. To unify data for clinical operations, administration, and research, we developed the Pediatric Patient Informatics Platform (), an integrated datamart harmonizing multiple source systems across two institutions into a common technology.

Patients And Methods: Starting in 2009, user requirements were gathered and data sources were prioritized. Project teams, including biostatisticians, database developers, and an external contractor, were formed. Read-access to source systems was established. The 3-layer architecture was developed: STAGING, a near-exact copy of source data; INTEGRATION, where data were reorganized into domains; and, CONSUMPTION, where data were optimized for rapid retrieval. The diverse systems were integrated into a common IBM Netezza technology. Data filters were defined to accurately capture the Center's patients, and derived data items were created for harmonization across sources. An interactive online query tool, , was developed using Microstrategy Analytics.

Results: Driven by scientific objectives, the datamart was created, including 33,674 patients, 2,983 protocols, and 3.6 million patient visits from 14 source databases, 164 source tables, and 2,622 source data items. The has 605 data items and 33 metrics across 11 reports and dashboards. Dana-Farber and Boston Children's established a legal data-sharing agreement. The has supported hundreds of faculty, staff, and projects, including planning clinical trials and informing strategic planning.

Conclusion: The has successfully harmonized and integrated diagnostic, demographic, laboratory, treatment, clinical outcome, pathology, transplant, meta-protocol, and -omics data, for efficient, daily operational and research activities at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and future external sharing.
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http://dx.doi.org/10.1200/CCI.20.00083DOI Listing
February 2021

Bile-duct ligation renders the brain susceptible to hypotension-induced neuronal degeneration: Implications of ammonia.

J Neurochem 2021 05 13;157(3):561-573. Epub 2021 Feb 13.

Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada.

Hepatic encephalopathy (HE) is a debilitating neurological complication of cirrhosis. By definition, HE is considered a reversible disorder, and therefore HE should resolve following liver transplantation (LT). However, persisting neurological complications are observed in as many as 47% of LT recipients. LT is an invasive surgical procedure accompanied by various perioperative factors such as blood loss and hypotension which could influence outcomes post-LT. We hypothesize that minimal HE (MHE) renders the brain frail and susceptible to hypotension-induced neuronal cell death. Six-week bile duct-ligated (BDL) rats with MHE and respective SHAM-controls were used. Several degrees of hypotension (mean arterial pressure of 30, 60 and 90 mm Hg) were induced via blood withdrawal from the femoral artery and maintained for 120 min. Brains were collected for neuronal cell count and apoptotic analysis. In a separate group, BDL rats were treated for MHE with the ammonia-lowering strategy ornithine phenylacetate (OP; MNK-6105), administered orally (1 g/kg) for 3 weeks before induction of hypotension. Hypotension 30 and 60 mm Hg (not 90 mm Hg) significantly decreased neuronal marker expression (NeuN) and cresyl violet staining in the frontal cortex compared to respective hypotensive SHAM-operated controls as well as non-hypotensive BDL rats. Neuronal degeneration was associated with an increase in cleaved caspase-3, suggesting the mechanism of cell death was apoptotic. OP treatment attenuated hyperammonaemia, improved anxiety and activity, and protected the brain against hypotension-induced neuronal cell death. Our findings demonstrate that rats with chronic liver disease and MHE are more susceptible to hypotension-induced neuronal cell degeneration. This highlights MHE at the time of LT is a risk factor for poor neurological outcome post-transplant and that treating for MHE pre-LT might reduce this risk.
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http://dx.doi.org/10.1111/jnc.15290DOI Listing
May 2021

Feasibility and acceptability of the "Day 100 Talk": An interdisciplinary communication intervention during the first six months of childhood cancer treatment.

Cancer 2021 04 15;127(7):1134-1145. Epub 2020 Dec 15.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Communication gaps arise early in the childhood cancer trajectory and may persist. The authors conducted a pilot study of the feasibility and acceptability of a communication intervention, the Day 100 Talk (D100). D100 involves an interprofessional family conference during initial months of treatment between oncologists, psychosocial clinicians, and parents, facilitated by a 3-part conversation tool.

Methods: The authors enrolled English-speaking parents of children with nonrelapsed, nonprogressive cancer who were receiving continuity care from enrolled pediatric oncologists and psychosocial clinicians at a single site. The a priori feasibility threshold was 60% parent completion of the D100 intervention. Surveys from parents and professionals and debrief interviews with professionals assessed D100 acceptability.

Results: Thirty-seven parents (77%) and 38 oncology professionals (67%) enrolled. Twenty of 33 evaluable parents (61%) participated in a D100 family conference. Most commonly, parents did not complete the D100 intervention because of scheduling difficulties related to clinical team constraints. All 17 parents who completed a post-D100 survey agreed or strongly agreed that D100 participation was helpful. In debrief interviews, professionals identified D100 benefits, namely, stepping back to the big picture and getting on the same page, and barriers related to logistical challenges and professionals' anticipatory dread.

Conclusions: The D100 intervention pilot demonstrates high acceptability among parents of children with cancer. Despite meeting the prespecified feasibility threshold, findings highlight important barriers to D100 dissemination, namely, perceived burdens on professionals. Potential strategies to reduce burden may include using virtual visit platforms, incorporating D100 elements across multiple visits, or prioritizing intervention delivery to parents with the greatest need for enhanced communication.
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http://dx.doi.org/10.1002/cncr.33362DOI Listing
April 2021

Derivation and validation of risk groups in patients with osteosarcoma utilizing regression tree analysis.

Pediatr Blood Cancer 2021 03 30;68(3):e28834. Epub 2020 Nov 30.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Background: For patients with osteosarcoma, apart from stage and primary site, we lack reliable prognostic factors for risk stratification at diagnosis. There is a need for further defined, discrete prognostic groups using presenting clinical features.

Methods: We analyzed a cohort of 3069 patients less than 50 years of age, diagnosed with primary osteosarcoma of the bone between 1986 and 2013 from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly split into test and validation cohorts. Optimal cut points for age, tumor size, and grade were identified using classification and regression tree analysis. Manual recursive partitioning was used to identify discrete prognostic groups within the test cohort. These groups were applied to the validation cohort, and overall survival was analyzed using Cox models, Kaplan Meier methods, and log-rank tests.

Results: After applying recursive partitioning to the test cohort, our initial model included six groups. Application of these groups to the validation cohort resulted in four final groups. Key risk factors included presence of metastases, tumor site, tumor grade, age, and tumor size. Patients with localized axial tumors were identified as having similar outcomes to patients with metastases. Age and tumor size were only prognostically important in patients with extremity tumors when assessed in the validation cohort.

Conclusions: This analysis supports prior reports that patients with axial tumors are a high-risk group, and demonstrates the importance of age and tumor size in patients with appendicular tumors. Biologic and genetic markers are needed to further define subgroups in osteosarcoma.
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http://dx.doi.org/10.1002/pbc.28834DOI Listing
March 2021

Induction of a proliferative response in the zebrafish retina by injection of extracellular vesicles.

Exp Eye Res 2020 11 19;200:108254. Epub 2020 Sep 19.

Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA. Electronic address:

Ongoing research using cell transplantation and viral-mediated gene therapy has been making progress to restore vision by retinal repair, but targeted delivery and complete cellular integration remain challenging. An alternative approach is to induce endogenous Müller glia (MG) to regenerate lost neurons and photoreceptors, as occurs spontaneously in teleost fish and amphibians. Extracellular vesicles (EVs) can transfer protein and RNA cargo between cells serving as a novel means of cell-cell communication. We conducted an in vivo screen in zebrafish to identify sources of EVs that could induce MG to dedifferentiate and generate proliferating progenitor cells after intravitreal injection into otherwise undamaged zebrafish eyes. Small EVs (sEVs) from C6 glioma cells were the most consistent at inducing MG-derived proliferating cells. Ascl1a expression increased after intravitreal injection of C6 sEVs and knockdown of ascl1a inhibited the induction of proliferation. Proteomic and RNAseq analyses of EV cargo content were performed to begin to identify key factors that might target EVs to MG and initiate retina regeneration.
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http://dx.doi.org/10.1016/j.exer.2020.108254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655690PMC
November 2020

Engaging Parents of Children Who Died From Cancer in Research on the Early Grief Experience.

J Pain Symptom Manage 2021 04 16;61(4):781-788. Epub 2020 Sep 16.

Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.

Context: Bereaved parents provide an important perspective for improving care for patients and families throughout the illness and after a child's death. However, involvement of bereaved parents in research studies is fraught with concerns over inflicting psychological distress and issues with study recruitment. Data on research strategies to engage parents early in their bereavement are limited.

Objectives: To describe involvement of bereaved parents in the development of a comprehensive survey, examine the response rates with varying recruitment strategies and describe participation experiences of parent participants.

Methods: Parents of children who endured the death of their child from cancer six to 24 months prior were invited to complete a 195-item survey examining their early grief experience.

Results: Forty-nine of the 137 eligible parents from 36 different households completed the survey (response rate 36%). The respondents were predominantly white (N = 43; 88%), female (N = 32; 65%), and non-Hispanic (N = 43; 88%). The median length of time from child's death to survey completion was 11 months (range 7-26). Thirty parents (61%) indicated they were comfortable/very comfortable answering the survey, 40 (82%) answered that they experienced at least a little benefit from involvement, and 36 (73%) indicated they experienced at least some distress.

Conclusion: Some parents of children who died of cancer are willing to participate in research early in their bereavement, and although most experience some distress, they are comfortable answering questions about their experience and benefit from participation. Recruitment strategies including personal outreach may result in better response rates.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.09.014DOI Listing
April 2021

Landscape of phase 1 clinical trials for minors with cancer in the United States.

Pediatr Blood Cancer 2020 11 4;67(11):e28694. Epub 2020 Sep 4.

Harvard Medical School, Boston, Massachusetts.

Objectives: Understanding trends in characteristics of early phase trials that allow minors with cancer to participate may inform additional efforts to improve cancer drug development for young people.

Methods: We accessed data for oncology phase 1 or phase 1/2 trials in the United States from ClinicalTrials.gov with lower age bound for eligibility <18 years. Descriptive statistics were calculated and trends over time evaluated using logistic and multinomial logistic regression.

Results: Six hundred twelve trials met inclusion criteria. Sixty-five percent of trials were for older adults that also allowed minors, while 9% were exclusively for patients ≤18 years of age. Eighty-three percent of trials included at least one novel agent, while 17% studied only conventional therapies. Fifty-eight percent of trials studied treatments not yet Food and Drug Administration (FDA) approved (48% if exclusively for patients ≤18 years). Fifteen percent of trials for which dose-escalation method could be determined, utilized a model-based design. Eighteen percent of all trials were industry sponsored (48% if exclusively for patients ≤18 years). Forty-nine percent of all trials were multicenter (69% if exclusively for patients ≤18 years). There was an increase in trials exclusively focused on patients with central nervous system (CNS) tumors over the study period (P ≤ .02). No other temporal trends were seen. The median times from first-in-adult to first-in-pediatric for monotherapy and combination trials were 5.7 and 3.3 years, respectively.

Conclusion: The paucity of clear temporal trends highlights the need for innovation in early drug development for young people. Our analysis serves as a benchmark against which to evaluate initiatives to improve pediatric cancer drug development.
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http://dx.doi.org/10.1002/pbc.28694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896417PMC
November 2020

Off-label prescribing of targeted anticancer therapy at a large pediatric cancer center.

Cancer Med 2020 09 4;9(18):6658-6666. Epub 2020 Aug 4.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Background: Off-label drug prescribing is common in pediatric clinical medicine, though the extent and impact of this practice in pediatric oncology has not yet been characterized.

Methods: We completed a retrospective single-institution cohort study evaluating prevalence, characteristics, and clinical outcomes of off-label prescribing of 108 FDA-approved targeted anticancer drugs in patients < 30 years old treated for cancer from 2007 to 2017. Dosing strategies were adjusted for body size and compared to FDA-approved adult dosing regimen. A composite toxicity endpoint was defined as a patient having unplanned clinic visits, emergency department visits, or unplanned hospital admissions that were at least possibly related to the off-label treatment.

Results: The overall prevalence of off-label use of targeted therapies was 9.2% (n = 374 patients). The prevalence increased significantly over the study period (P < .0001). Patients treated off-label were more likely to have neuro-oncology diagnoses compared to patients not treated off-label (46% vs 29%; P < .0001). Of the 108 potential agents, 38 (35%) were used by at least one patient. The median starting dose was below the FDA-approved normalized dose for 44.4% of agents. Fifteen percent of patients had a complete response while receiving off-label therapy, 38% experienced toxicity as defined, and 13% discontinued off-label therapy due to toxicity.

Conclusions: In this real-world evaluation of prescribing at a large pediatric cancer center, off-label prescribing of FDA-approved targeted therapies was common, increasing in prevalence, encompassed a broad sample of targeted agents, and was tolerable. Clinicians commonly start dosing below the equivalent FDA-approved dose.
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http://dx.doi.org/10.1002/cam4.3349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520353PMC
September 2020

Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort.

Blood Adv 2020 06;4(11):2536-2547

Pediatric Hematopoietic Cellular Therapy, Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a well-recognized complication of hematopoietic cell transplantation (HCT). Diagnosis is challenging and in the absence of a tissue biopsy, TA-TMA is provisionally diagnosed by meeting clinical criteria. In this study, we describe the prevalence, outcomes, and risk factors for meeting 2 different diagnostic criteria for TA-TMA and for increased transplant-related mortality (TRM). In this retrospective study of 307 pediatric HCT patients, records were reviewed for the first 100 days after HCT. Patients who were diagnosed with TA-TMA by a provider during this time were included. In addition, the Cho et al criteria (2010) and Jodele et al (2014) TA-TMA criteria were applied retrospectively. Eight patients (2.6%) were diagnosed with TA-TMA by their provider. However, on retrospective review, 20% and 36% met the Cho and Jodele criteria for TA-TMA, respectively. Overall survival was significantly worse (P < .0001) and TRM was significantly higher in patients who met criteria for TA-TMA (MC-TA-TMA) (P < .0001). After controlling for comorbid conditions, MC-TA-TMA (hazard ratio [HR], 10.9; P = .0001) and grade 3/4 acute graft-versus-host-disease (aGVHD) (HR 3.5; P = .01) remained independently associated with increased TRM. Among allogeneic HCT recipients, features associated with an increased risk for MC-TA-TMA included ≥2 HCT, concurrent grade 3/4 aGVHD and concurrent infections. Among patients who MC-TA-TMA, LDH ≥2 times the upper limit of normal (P = .001), the need for ≥2 antihypertensive medications (P < .0001), and acute kidney injury (P = .003) were associated with significantly increased TRM.
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http://dx.doi.org/10.1182/bloodadvances.2019001242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284101PMC
June 2020

Parent Perceptions of Team-Delivered Care for Children With Advanced Cancer: A Report From the PediQUEST Study.

J Pain Symptom Manage 2020 10 22;60(4):811-817. Epub 2020 May 22.

Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Context: Childhood cancer care is delivered by interprofessional health care teams; however, little is known about how parents perceive overall team-delivered care (TDC).

Objectives: We sought to describe parent perceptions of TDC and associated factors, including care rendered by individual clinicians, teamwork, information consistency, and patient and parent characteristics.

Methods: Cross-sectional surveys were distributed to parents of 104 children with recurrent/refractory cancer enrolled in a multisite symptom management trial. The primary outcome, TDC, was parent report of care quality delivered by the child's care team during the preceding three months. Likert-scaled items (excellent/very good/good/fair/poor) queried care quality delivered by individual clinicians, perceived teamwork, and other factors. Factors associated with parent perceptions of excellent TDC were identified using Fisher's exact test.

Results: Eighty-six parents (83%) responded. During the preceding three months, 63% (n = 54) of parents reported excellent TDC. However, only 47% (n = 40) described their care team's teamwork as excellent. Approximately one-quarter (24%) described care rendered by their child's oncologist as less-than-excellent. Among parents who reported psychosocial clinician involvement (71%; n = 60), only 43% described this care as excellent. Individually, excellent care from each clinician type (oncologist, psychosocial clinician, and primary nurse) was associated with excellent TDC (all P ≤ 0.001; no correction for multiple comparisons).

Conclusion: Among parents of children with advanced cancer, more than one-third report less-than-excellent TDC. In addition, less than half report excellent teamwork, and ratings of care rendered by individual clinicians are highly variable. Findings suggest that interventions are needed to enhance interprofessional teamwork in the care of children with advanced cancer.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508972PMC
October 2020

Testing the carbohydrate-insulin model of obesity in a 5-month feeding study: the perils of post-hoc participant exclusions.

Eur J Clin Nutr 2020 07 20;74(7):1109-1112. Epub 2020 May 20.

New Balance Foundation Obesity Prevention Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

A large feeding study reported that total energy expenditure (TEE) was greater on a low- versus high-carbohydrate diet, supporting the carbohydrate-insulin model of obesity. Recently, the validity of this finding was challenged in a post-hoc analysis excluding participants with putative non-adherence to the study diets. Here, we show why that analysis, based on a post-randomization variable linked to the outcome, introduced severe confounding bias. With control for confounding, the diet effect on TEE remained strong in a reanalysis. Together with sensitivity analyses demonstrating robustness to plausible levels of non-adherence, these data provide experimental support for a potentially novel metabolic effect of macronutrients that might inform the design of more effective obesity treatment.
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http://dx.doi.org/10.1038/s41430-020-0658-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340622PMC
July 2020

Sponsorship of oncology clinical trials in the United States according to age of eligibility.

Cancer Med 2020 07 29;9(13):4495-4500. Epub 2020 Apr 29.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Background: The sponsorship mix of trials relevant to young people with cancer has not been reported. Understanding this sponsorship mix may have implications for policies and regulations related to pediatric cancer drug development.

Methods: We analyzed sponsorship of interventional trials first opened in the United States from 2007 to 2018 using the ClinicalTrials.gov registry. A total of 51 781 trials across non-oncology disciplines and 18 431 oncology trials were classified according to lower age of eligibility (≥18 years vs < 18 years). Studies were stratified according to sponsorship (industry vs non-industry). Trial characteristics were compared by sponsorship category. Trends in sponsorship were tracked over time.

Results: Within oncology trials for patients ≥ 18 years, sponsorship was 33% industry and 67% non-industry. Among oncology trials that included patients < 18 years, sponsorship was 16.6% industry and 83.4% non-industry (P < .001). 15.5% of industry-sponsored trials in non-oncology disciplines included patients < 18 years, whereas only 5.2% of industry-sponsored oncology trials were open to patients < 18 years (P < .001). Relative to trials with non-industry sponsors, there was a statistically significant increase in industry sponsorship of oncology trials that included patients < 18 years over time (P < .001). Trial characteristics differed significantly according to sponsor type regardless of age of eligibility.

Conclusions: Interventional oncology trials that include patients < 18 years are less likely to be industry-sponsored compared to oncology trials exclusively in patients ≥ 18 years. Compared to other medical disciplines, a smaller proportion of industry-sponsored oncology trials included patients < 18 years. Trial sponsorship is associated with differential trial characteristics, such as trial duration and number of patients enrolled, regardless of age.
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http://dx.doi.org/10.1002/cam4.3083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333829PMC
July 2020

An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients.

JNCI Cancer Spectr 2020 Apr 6;4(2):pkz094. Epub 2019 Nov 6.

Harvard Medical School, Boston, MA.

Background: NUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis.

Methods: Clinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT midline carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS).

Results: For 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the fusion (78%), followed by (15%) and (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors.

Conclusions: We identify three risk groups defined by anatomic site and fusion type. Nonthoracic primary with non- fusion confers the best prognosis, followed by nonthoracic primary with . Thoracic NC patients, regardless of the fusion, have the worst survival.
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http://dx.doi.org/10.1093/jncics/pkz094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165803PMC
April 2020

Parental Considerations Regarding Cure and Late Effects for Children With Cancer.

Pediatrics 2020 05 13;145(5). Epub 2020 Apr 13.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: More than 80% of children with cancer become long-term survivors, yet most survivors experience late effects of treatment. Little is known about how parents and physicians consider late-effects risks against a potential survival benefit when making treatment decisions.

Methods: We used a discrete choice experiment to assess the importance of late effects on treatment decision-making and acceptable trade-offs between late-effects risks and survival benefit. We surveyed 95 parents of children with cancer and 41 physicians at Dana-Farber/Boston Children's Cancer and Blood Disorders Center to assess preferences for 5 late effects of treatment: neurocognitive impairment, infertility, cardiac toxicity, second malignancies, and impaired growth and development.

Results: Each late effect had a statistically significant association with treatment choice, as did survival benefit ( < .001). Avoidance of severe cognitive impairment was the most important treatment consideration to parents and physicians. Parents also valued cure and decreased risk of second malignancies; physician decision-making was driven by avoidance of second malignancies and infertility. Both parents and physicians accepted a high risk of infertility (parents, a 137% increased risk; physicians, an 80% increased risk) in exchange for a 10% greater chance of cure.

Conclusions: Avoidance of severe neurocognitive impairment was the predominant driver of parent and physician treatment preferences, even over an increased chance of cure. This highlights the importance of exploring parental late-effects priorities when discussing treatment options.
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http://dx.doi.org/10.1542/peds.2019-3552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193979PMC
May 2020

New approaches to therapeutic drug development for childhood cancers.

Curr Opin Pediatr 2020 02;32(1):35-40

Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA.

Purpose Of Review: We provide an overview of the current landscape of drug development relevant to childhood cancers. We present recent and ongoing efforts to identify therapeutic targets in pediatric cancers. We describe efforts to improve the approach to clinical trials and highlight the role regulatory changes and multistakeholder platforms play in advancing pediatric cancer drug development.

Recent Findings: Expanding knowledge of the genetic landscape of pediatric malignancies through clinical genomics studies has yielded an increasing number of potential targets for intervention. In parallel, new therapies for children with cancer have shifted from cytotoxic agents to targeted therapy, with examples of striking activity in patients with tumors driven by oncogenic kinase fusions. Innovative trial designs and recent governmental policies provide opportunities for accelerating development of targeted therapies in pediatric oncology.

Summary: Novel treatment strategies in pediatric oncology increasingly utilize molecularly targeted agents either as monotherapy or in combination with conventional cytotoxic agents. The interplay between new target identification, efforts to improve clinical trial design and new government regulations relevant to pediatric cancer drug development has the potential to advance novel agents into frontline care of children with cancer.
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http://dx.doi.org/10.1097/MOP.0000000000000850DOI Listing
February 2020

Rate of Progression through a Continuum of Transit-Amplifying Progenitor Cell States Regulates Blood Cell Production.

Dev Cell 2019 04 28;49(1):118-129.e7. Epub 2019 Feb 28.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address:

The nature of cell-state transitions during the transit-amplifying phases of many developmental processes-hematopoiesis in particular-is unclear. Here, we use single-cell RNA sequencing to demonstrate a continuum of transcriptomic states in committed transit-amplifying erythropoietic progenitors, which correlates with a continuum of proliferative potentials in these cells. We show that glucocorticoids enhance erythrocyte production by slowing the rate of progression through this developmental continuum of transit-amplifying progenitors, permitting more cell divisions prior to terminal erythroid differentiation. Mechanistically, glucocorticoids prolong expression of genes that antagonize and slow induction of genes that drive terminal erythroid differentiation. Erythroid progenitor daughter cell pairs have similar transcriptomes with or without glucocorticoid stimulation, indicating largely symmetric cell division. Thus, the rate of progression along a developmental continuum dictates the absolute number of erythroid cells generated from each transit-amplifying progenitor, suggesting a paradigm for regulating the total output of differentiated cells in numerous other developmental processes.
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http://dx.doi.org/10.1016/j.devcel.2019.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456386PMC
April 2019

Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors.

Biol Blood Marrow Transplant 2019 05 11;25(5):e163-e168. Epub 2019 Jan 11.

Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, United States.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a known complication of autologous hematopoietic cell transplantation (aHCT), particularly in children with neuroblastoma. We describe a pediatric single-institution experience of TA-TMA after aHCT. Data were abstracted from the medical record of patients who underwent aHCT between January 1, 2008, and July 1, 2018, at Boston Children's Hospital. TA-TMA was diagnosed using either the International Working Group criteria or the "probable TA-TMA criteria" of Cho et al. Overall, 318 aHCTs were performed in 243 patients. Nine patients (3.7%) were diagnosed with TA-TMA. TA-TMA occurred most frequently in children with neuroblastoma (n = 7; 78%), all of whom were conditioned with carboplatin, etoposide, and melphalan. The median age at aHCT in children who developed TA-TMA was 3 years, 5 months (range, 18 months to 25 years). TMA was diagnosed at a median of 35 days (range, 8 to 106 days) after stem cell infusion. On a retrospective chart review using the same criteria used by the provider, patients met criteria a median of 5 days before the clinical diagnosis (range, 0 to 58 days). Eight patients had renal involvement at presentation, including nephrotic range proteinuria and severe hypertension, requiring from 2 to 6 antihypertensive medications. Two patients presented with multiorgan failure. Six patients were treated with eculizumab a median of 0 days after TA-TMA diagnosis (range, 0 to 11 days). On retrospective review, patients were treated a median of 18 days (range, 0 to 58 days) after meeting criteria for TA-TMA. Before initiation of therapy, 4 of 6 patients checked for serum complement levels had normal values, 1 had elevated CH50 and 1 had elevated sC59-b and CH50. All patients had CH50 levels within the target range (≤3 CAE) after induction therapy. Two patients (33%) had no response to eculizumab and died of multiorgan failure. The other 4 had both a hematologic response with transfusion independence (median, 6.5 weeks; range, 4 to 9 weeks) and renal response, defined as resolution of nephrotic range proteinuria (median, 21 weeks; range, 13 to 25 weeks). Among the eculizumab-treated survivors, 2 patients remained on prolonged eculizumab therapy, and one had recurrence of TA-TMA after discontinuation of eculizumab. All 4 eculizumab treated survivors have persistent organ dysfunction. Three children were treated with supportive care only; 2 died of relapsed cancer, and the third is alive with stage 2 chronic kidney disease. The median duration of follow-up after TA-TMA diagnosis was 2.5 years (range, 9 months to 4 years). The 1-year overall survival was 78% (SE = 14%). However, regardless of treatment, no survivors had complete normalization of function in all organs. Three children with normal serum CH50 and sc5b-9 levels responded to eculizumab. This report highlights the importance of maintaining a high suspicion for TA-TMA after aHCT. Further study is warranted to identify individual risk factors for TMA after aHCT, predict the response to eculizumab, and capture long-term sequelae in survivors.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822269PMC
May 2019

The relationship between household income and patient-reported symptom distress and quality of life in children with advanced cancer: A report from the PediQUEST study.

Cancer 2018 10 14;124(19):3934-3941. Epub 2018 Sep 14.

Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

Background: Children with advanced cancer experience high symptom distress, which negatively impacts their health-related quality of life (HRQOL). To the authors' knowledge, the relationship between income and symptom distress and HRQOL is not well described.

Methods: The Pediatric Quality of Life and Symptoms Technology (PediQUEST) multisite clinical trial evaluated an electronic patient-reported outcome system to describe symptom distress and HRQOL in children with advanced cancer via repeated surveys. The authors performed a secondary analysis of PediQUEST data for those children with available parent-reported household income (dichotomized at 200% of the Federal Poverty Level and categorized as low income [<$50,000/year] or high income [≥$50,000/year]). The prevalence of the 5 most commonly reported physical and psychological symptoms was compared between groups. Multivariable generalized estimating equation models were used to test the association between household income and symptom distress and HRQOL.

Results: A total of 78 children were included in the analyses: 56 (72%) in the high-income group and 22 (28%) in the low-income group. Low-income children were more likely to report pain than high-income children (64% vs 42%; P=.02). In multivariable models, children from low-income families demonstrated a uniform trend toward higher total (β =3.1; 95% confidence interval [95% CI], -0.08 to 6.2 [P=.06]), physical (β=3.8; 95% CI, -0.4 to 8.0 [P=.09]), and psychological (β=3.46; 95% CI, -1.91 to 8.84 [P=.21]) symptom distress compared with children from high-income families. Low income was associated with a uniform trend toward lower total (β=-7.9; 95% CI, -14.8, to -1.1 [P=.03]), physical (β=-11.2; 95% CI, -21.2 to -1.2 [P=.04]), emotional (β=-5.8; 95% CI, -13.6 to 2.0 [P=.15]), social (β=-2.52; 95% CI, -9.27 to 4.24 [P=.47]), and school (β=-9.8; 95% CI, -17.8 to -1.8 [P=.03]) HRQOL.

Conclusions: In this cohort of children with advanced cancer, children from low-income families were found to experience higher symptom burden and worse QOL.
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http://dx.doi.org/10.1002/cncr.31668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561342PMC
October 2018

The Impact of Intraoperative Electrocorticography on Seizure Outcome After Resection of Pediatric Brain Tumors: A Cohort Study.

Neurosurgery 2019 09;85(3):375-383

Harvard Medical School, Boston, Massachusetts.

Background: Intraoperative electrocorticography (ECoG) has been utilized in patients with tumor-associated seizures; however, its effectiveness for seizure control remains controversial.

Objective: To evaluate clinical outcomes in pediatric patients undergoing lesionectomy with or without ECoG.

Methods: Patients undergoing brain tumor resection at Boston Children's Hospital were examined retrospectively (2005-2014). Inclusion criteria involved diagnosis of a supratentorial tumor, ≥2 unequivocal seizures, and ≥6 mo follow-up. Patients with isolated cortical dysplasia or posterior fossa tumors were excluded. Logistic regression models evaluated predictors of ECoG use, and the impact of ECoG, gross total resection, and focal cortical dysplasia with tumors on seizure freedom by Engel Class and anti-epileptic drug use (AED).

Results: A total of 119 pediatric patients were included (n = 69 males, 58%; median age, 11.3 yr). Forty-one patients (34.5%) had ECoG-guided surgery. Preoperative seizure duration and number and duration of AED use were significant predictors for undergoing ECoG. There were no differences in seizure freedom (Engel Class I) or improved Engel Score (Class I-II vs III-IV) in patients who did or did not have ECoG at 30 d, 6 mo, and 1, 2, or 5 yr. Patients undergoing ECoG required a greater number of AEDs at 6 mo (P = .01), although this difference disappeared at subsequent time intervals. Gross total resection predicted seizure freedom at 30 d and 6 mo postsurgery (P = .045).

Conclusion: This retrospective study, one of the largest evaluating the use of ECoG during tumor resection, suggests that ECoG does not provide improved seizure freedom compared to lesionectomy alone for children.
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http://dx.doi.org/10.1093/neuros/nyy342DOI Listing
September 2019
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